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Carbocyclic Nucleoside Analogs

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Carbocyclic Nucleoside Analogs Europaisches Patentamt J) European Patent Office 0 Publication number: 0 366 059 Office europeen des brevets A2 EUROPEAN PATENT APPLICATION © Application number: 89119703.0 © int. ci.5: C07D 473/00 C07D 487/04 C07D 471/04 A61K 31/52 , © Date of filing: 24.10.89 C07D 239/54 C07D 253/06 C07D 251/26 C07D 213/69 C07C 215/42 C07F 7/18 , C07C 275/26 ® Priority: 25.10.88 US 262547 245 Grassy Hill Road 03.03.89 US 319385 East Lyme Connecticut 06333(US) 17.10.89 US 420691 Inventor: Pariza, Richard J. 420 Russell Avenue © Date of publication of application: Winthrop Harbor Illinois 60096(US) 02.05.90 Bulletin 90/18 Inventor: Sowin, Thomas J. 17502 West Huntington Circle © States: Designated Contracting Grayslake Illinois 60030(US) AT BE CH DE ES FR GB GR IT LI LU NL SE Inventor: Garmaise, David L. 4910 79th Place © Applicant: ABBOTT LABORATORIES Kenosha Wisconsin One Abbott Park Road 53142(US) Inventor: Hannick, Steven M. Abbott Park, IL 60064-3500(US) 1403 Glencoe Avenue @ Inventor: Norbeck, Daniel W. Highland Park Illinois 60035(US) 307 Hazelwood Lindenhurst, IL 60046(US) Inventor: Plattner, Jacob J. © Representative: Modiano, Guido et al 1301 St. William Drive MODIANO, JOSIF, PISANTY & STAUB Libertyville, IL 60048(US) Modiano & Associati Via Meravigli, 16 Inventor: Rosen, Terry J. 1-20123 Milano(IT) © Carbocyclic nucleoside analogs. © A compound of the formula: < CO CO CO Q. wherein A is purin-9-yl isostere of a LU a group, a heterocyclic a purin-9-yl group, a pyrimidin-1-yl group or heterocyclic isostere of a pyrimidin-1-yl group; E is hydrogen, -CH2OH or -OH; and G and D are independently selected from hydrogen, C1 to C10 alkyl, -OH, -CH20H, -CH2OR20 wherein R20 is C1 to C6 Xerox Copy Centre EP 0 366 059 A2 alkyl, -CH2OC(0)R2i wherein R2i is Ci to Co alkyl, -CH2OC(0)CH(R22)(NHR23) wherein R22 is the side chain of any of the naturally occuring amino acids and R23 is hydrogen or -C(0)CH(R24.)(NH2) wherein R24. is the side chain of any of the naturally occuring amino acids, -CH2SH, -CH2CI, -CH2F, -CH2Br, -CH2I, -C- (O)H, -CH2CN, -CH2N3, -CH2NR1R2, -CO2R1, -CH2CH2OH, -CH2CH2OR20 wherein R20 is as defined above, -CH2CH2OC(0)R2i wherein R21 is as defined above -CH2CH20C(0)CH(R22)(NHR23) wherein R22 and R23 are as defined above -CH2CH2P03H2, -CH2OP03H2, -OCH2P03H2 and -CH2C02R3 wherein R1 and R2 are independently selected from hydrogen and Ci to C10 alkyl and R3 is hydrogen, C1 to C10 alkyl carboxyalkyi or aminoalkyl; or a pharmaceutical^ acceptable salt thereof. 2 EP 0 366 059 A2 CARBOCYCLIC NUCLEOSIDE ANALOGS This is a continuation-in-part of U.S. patent application Serial No. 319,385, filed March 3, 1989, which is a continuation-in-part of U.S. patent application Serial No.262,547, filed October 25, 1988. 5 Technical Field The present invention relates to novel compounds and compositions which have antiviral and antitumor activity, processes for making such compounds, synthetic intermediates employed in these processes and methods for treating a host in need of antiviral or antitumor treatment. 70 Background Art Viruses are implicated in a variety of animal and human diseases. Numerous approaches have been rs proposed to combat these pathogens which include, but are not limited to, herpesviruses 1 and 2 (HSV-1 and HSV-2), influenza viruses A, B and C (orthomyxoviruses), parainfluenza viruses 1-4, mumps virus (paramyxovirus), adenoviruses, respiratory syncytial virus, Epstein-Barr virus, rhinoviruses, human im- munodeficiency viruses (HIV), polioviruses, coxsackieviruses, echoviruses, rubella virus, varicella-zoster virus, neurodermotropic virus, variola virus, cytomegalovirus, hepatitis A, B and non-A, non-B viruses, 20 papoviruses and rabies virus. One approach in the development of antiviral compounds has been to identify compounds which interfere with the normal viral metabolism of nucleosides. Because the structures of these compounds are usually closely related to nucleosides which occur naturally in the mammalian host, few have good activity against the virus without untoward side effects. Some of the few compounds having activity are very 25 expensive to produce. Thus, there is a continuing need for new compounds which act to kill viruses, to inhibit viral replication or to block the pathogenic actions of viruses. The following references disclose various carbocyclic analogs of nucleosides: Ichikawa, et al., European Patent Application No. EP0330992, published September 9, 1989, discloses 2- hydroxy-3-hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; 30 Zahler, et al., European Patent Application No. EP0322854, published July 5, 1989, discloses 2-hydroxy-3- hydroxymethylcyclobutyl substituted purines and pyrimidines having antiviral activity; Slusarchyk, et al., European Patent Application No. EP0335355, published October 4, 1989, discloses 2,3- bis(hydroxymethyl)cyclobutyl substituted purines and pyrimidines having antiviral activity; Tolman, et al., U.S. Patent No. 4,782,062, issued November 1, 1988, discloses 9-((Z)-2-(hydroxymethyl)- 35 cyclobutylmethyl)guanine as a viral thymidine kinase inhibitor; Kjellin, et al., U.S. Patent No. 4,644,001, issued February 17, 1987, and U.S. Patent No. 4,548,818, issued October 22, 1985, disclose cyclopropyl-, cyclobutyl- and cyclopentyl-substituted purine analogs which are useful for treating obstructive airway disease or cardiac disease; Maccoss, et al., European Patent Application No. EP01 84473, published June 11, 1986, discloses 2-amino- 40 9-((2)-2-(benzoyloxymethyl)cyclobutylmethyl-6-benzoylpurine; Albrecht, et al., U.S. Patent No. 3,923,792, issued December 2, 1975, discloses cyclopropyl-, cyclopropylmethyl- and cyclopentyl-substituted cytosine analogs which are useful as antibacaterial agents; Albrecht, et al., U.S. Patent No. 4,016,267, issued April 5, 1977, discloses cyclopropyl-, cyclopropylmethyl- and cyclopentyl-substituted nucleoside analogs which are useful as antibacaterial agents; 45 Ashton, et al., U.S Patent No. 4,617,304, issued October 14, 1986, discloses ((hydroxymethylcyclopropyl)- methyl)-substituted purine and pyrimidine analogs as antiviral agents; Temple, et al., J. Med. Pharm. Chem. 5 866 (1962), discloses cyclopropyl-substituted purine analogs which are useful for treating human epidermal carcinoma; Masoliver, et al., C.A. 107:236375e, Spanish Patent No. ES519898, published March, 16, 1984, discloses 50 cyclopropylmethyl-substituted purine analogs; and Marquez, et al., Medicinal Research Reviews, 6 1-40 (1986) discloses substituted-cyclopentyl nucleoside analogs. Disclosure of the Invention 3 EP 0 366 059 A2 In accordance with the present invention there are antiviral compounds of the formula: A I wherein A is a purin-9-yl group or a heterocyclic isostere of a purin-9-yl group selected from the group consisting of 1) 2) 3) 4) EP 0 366 059 A2 5 I o 70 15 20 25 wherein J and L are independently selected from hydrogen, -OH, halogen, alkoxy, -SH, thioalkoxy, -N3, 30 wherein m is 1 to 5, -NR1R2 wherein R1 and R2 are independently selected from hydrogen and Ci to C10 alkyl, -NHC(0)R3 wherein R3 is hydrogen, Ci to C10 alkyl, carboxyalkyl or aminoalkyl, -N = CHNR+R5 wherein R+ and R5 are independently selected from Ci to C10 alkyl, -N(Rs)0R7 wherein Rs and R7 are independently selected from hydrogen and Ci to C10 alkyl, and -N(R8)NR9Ri0 wherein Rs, Ra and R10 are independently selected from hydrogen and Ci to C10 alkyl; and wherein M is hydrogen, Ci to C10 alkyl, halogen, wherein m is 1 to 5, or -NR1R2 wherein R1 and R2 are as defined above; and Z is hydrogen, halogen, formyl, carboxyi, alkoxycarbonyi, carboxamido or cyano; or A is a pyrimidin-1-yl group or a heterocyclic isostere of a pyrimidin-1-yl group selected from the group consisting of 5- EP 0 366 059 A2 and 11) i wherein V is 0 or S; Q is -OH, -SH, alkoxy, thioalkoxy, halogen, wherein m is 1 to 5, -NP>1 R2 wherein R1 and R2 are as defined above, or -NHC(0)R3 wherein R3 is as defined above; and T is hydrogen, Ci to C10 alkyl, 2-haloethyl, halomethyl, difluoromethyl, trifluoromethyl, halogen, cyano, nitro, vinyl, 2-halovinyl, alkynyl, hydroxmethyl, formyl, azidomethyl, 2-hydroxyethyl, -NR1 R2 wherein R1 and R2 are as defined above, -NHOH, -SH, propenyl, 3,3,3-trifluoropropenyl, 2-(alkoxycarbonyl)ethenyl, 2- cyanoethenyl, -</ wherein m is 1 to 5, or -CH2NR1R2 wherein R1 and R2 are as defined above; and wherein E is hydrogen, -CH2OH or -OH; and G and D are independently selected from hydrogen, Ci to C10 alkyl, -OH, -CH2OH, -CH2OR20 wherein 6 EP 0 366 059 A2 R20 is Ci to C6 alkyl, -CH2OC(0)R2i wherein R2, is Ci to Ciq alkyl, -CH2OC(0)CH(R22)(NHR23) wherein R22 is the side chain of any of the naturally occuring amino acids and R23 is hydrogen or -C(0)CH(R2*)- (NH2) wherein R24. is the side chain of any of the naturally occuring amino acids, -CH2SH, -CH2CI, -CH2F, -CH2Br, -CH2I, -C(0)H, -CH2CN, -CH2N3, -CH2NRiR2, -CO2R1, -CH2CH2OH, -CH2CH2OR20 wherein R20 is 5 as defined above, -CH2CH2OC(0)R2i wherein R21 is as defined above, -CH2CH2OC(0)CH(R22)(NHR23) wherein R22 and R2a are as defined above, -CH2CH2P03H2, -CH2OPO3H2, -OCH2P03H2 and -CH2CO2R3 wherein R1 , R2 and Rs are as defined above, with the proviso that when E is -OH then D is not -OH and with the proviso that when E is hydrogen and D is hydrogen or Ci to C10 alkyl then Q is not hydrogen or Ci to Ci 0 alkyl; or a pharmaceuticaily acceptable salt thereof. 10 The term "Ci to C10 alkyl" as used herein refers to straight or branched chain alkyl radicals containing from 1 to 10 carbon atoms including, but not limited to, methyl, ethyl, isopropyl, n-butyl, isobutyl, sec-butyl, n-pentyl, 1-methylbutyl, 2,3-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n-hexyl, n-heptyl, n-octyl, n- nonyl, n-decyl and the like.
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