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  Tricyclic 6-alkylidene-penems as beta-lactamase inhibitorsUSPTO Application #: 20060074064Title: Tricyclic 6-alkylidene-penems as beta-lactamase inhibitors Abstract: The present invention provides a compound of formula I, pharmaceutical compositions and the use thereof for the treatment of bacterial infection or disease in a patient in need thereof. (end of abstract)
Agent: Wilmer Cutler Pickering Hale And Dorr LLP / Wyeth - Boston, MA, US Inventors: Aranapakam Mudumbai Venkatesan, Tarek Suhayl Mansour, Takao Abe, Ado Mihira, Atul Agarwal, Hideki Ushirogochi, Yansong Gu, Satoshi Tamai, Fuk-Wah Sum USPTO Applicaton #: 20060074064 - Class: 514192000 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, 1-thia-4-aza-bicyclo (3.2.0) Heptane Ring Containing (including Dehydrogenated) (e.g., Penicillins, Etc.) The Patent Description & Claims data below is from USPTO Patent Application 20060074064. Brief Patent Description - Full Patent Description - Patent Application Claims
[0001] This application claims priority from copending provisional application Ser. No. 60/377,051, filed May 1, 2002, the entire disclosure of which is hereby incorporated by reference. FIELD OF INVENTION [0002] This invention relates to certain tricyclic 6-alkylidene penems which act as a broad spectrum .beta.-lactamase inhibitors. .beta.-Lactamases hydrolyze .beta.-lactam antibiotics, and as such serve as the primary cause of bacterial resistance. The compounds of the present invention when combined with .beta.-lactam antibiotics will provide an effective treatment against life threatening bacterial infections. BACKGROUND OF THE INVENTION [0003] Penicillins and cephalosporins are the most frequently and widely used .beta.-lactam antibiotics in the clinic. However, the development of resistance to .beta.-lactam antibiotics by different pathogens has had a damaging effect on maintaining the effective treatment of bacterial infections. (Coleman, K. Expert Opin. Invest. Drugs 1995, 4, 693; Sutherland, R. Infection 1995, 23 (4) 191; Bush, K, Cur. Pharm. Design 1999, 5, 839-845). The most significant known mechanism related to the development of bacterial resistance to the .beta.-lactam antibiotics is the production of class-A, class-B and class-C serine .beta.-lactamases. These enzymes degrade the .beta.-lactam antibiotics, resulting in the loss of antibacterial activity. Class-A enzymes preferentially hydrolyze penicillins where as Class-C lactamases have a substrate profile favoring cephalosporin hydrolysis. (Bush, K.; Jacoby, G. A.; Medeiros, A. A. Antimicrob. Agents Chemother. 1995, 39, 1211). To date over 250 different .beta.-lactamases have been reported (Payne, D. J,: Du, W and Bateson, J. H. Exp. Opin. Invest. Drugs 2000, 247) and there is a need for a new generation of broad spectrum .beta.-lactamase inhibitors. Bacterial resistance to these antibiotics could be greatly reduced by administering the .beta.-lactam antibiotic in combination with a compound which inhibits these enzymes. [0004] The commercially available .beta.-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam are all effective against class-A producing pathogens. Clavulanic acid is clinically used in combination with amoxicillin and ticarcillin; similarly sulbactam with ampicillin and tazobactam with piperacillin. However, these compounds are ineffective against class C producing organisms. The mechanism of inactivation of class-A .beta.-lactamases (such as PCI and TEM-1) has been elucidated. (Bush, K.; Antimicrob. Agents Chemother. 1993, 37, 851; Yang, Y.; Janota, K.; Tabei, K.; Huang, N.; Seigal, M. M.; Lin, Y. I.; Rasmussen, B. A. and Shlaes, D. M. J. Biol. Chem. 2000, 35, 26674-26682). [0005] In 1981, the Beecham group disclosed 6-alkylidine penems of general structure 1 as inhibitors of .beta.-lactamases. [N. F. Osborne, U.S. Pat. No. 4,485,110 (1984); N. F. Osborne, Eur. Pat. Appl. 81 301683.9.] [0006] R.sub.1 and R.sub.2 are independently hydrogen or a C.sub.1-10 hydrocarbon group or mono heterocyclic, and R.sub.3 represents a hydrogen or an organic group. Subsequently, the same group disclosed compounds of the general formula 1, wherein R.sub.1 comprises a 1,2,3-triazole moiety. [N. F. Osborne, Eur. Pat. Appl. 84301255.0]. The following year, the same group filed three patent applications of the structure 1, wherein R.sub.1 is an optionally substituted six membered or five membered mono aromatic ring system. [N. F. Osborne, Eur. Pat. Appl. 85100520.7; Eur. Pat. Appl. 85100521.5 and Eur. Pat. Appl. 85300456.2]. European patent application No. 86305585.1 discloses the synthesis and the utility of (Z)-6-(1-methyl-1,2,3-triazol-4-ylmethylene)-penem-3-carboxylate 2 as a class-A and class-C .beta.-lactamase inhibitor. [0007] Eur. Pat. Appl. 86305584.4 disclosed the preparation of compounds of general formula 1, wherein R.sub.1=non-aromatic heterocyclic group and a PCT application [N. J. Broom; P. D. Edwards, N. F. Osborne and S. Coulton PCT WO 87/00525] disclosing R.sub.1=fused bicyclic hetero-aromatic group was published. Similarly patent applications [N. J. Broom; G. Brooks; S. Coulton, Eur. Pat. Appl. 88311786.3; N. J. Broom; G. Brooks; B. P. Clarke, Eur. Pat. Appl. 88311787.1) disclosed the preparation and use of compounds of general structure 1, wherein R.sub.1 is a substituted five membered hetero-aromatic ring. A process for the preparation of compounds of general formula 1 has been disclosed by Coulton, et al. [S. Coulton; J. B. Harbridge; N. F. Osborne and G. Walker Eur. Pat. Appl. No 87300193.7] [0008] In the year 1993, Beecham disclosed [A. V. Stachulski and R. walker, PCT WO 93/03042] the preparation and the use of compounds of general formula 1, in which R.sub.1=(Cue) alkyl and R.sub.2.dbd.CH.sub.2X or COY wherein X=halogen or CONR.sub.2. [0009] During the last decade three patents have been filed by Beecham describing compounds of general formula 3. [N. J. Broom; F. P. Harrington, PCT WO 94/10178; K. Coleman; J. E. Neale PCT WO 95/28935; K. Coleman; J. E. Neale PCT WO 95/17184] wherein R.sub.a=hydrogen or an organic group, and R.sub.d and R.sub.e may be both hydrogen or one or more substituents replacing hydrogen atoms in the ring system shown below. BRIEF SUMMARY OF THE INVENTION [0010] The present invention relates to novel, low molecular weight broad spectrum .beta.-lactam compounds and in particular to a class of tricyclic heteroaryl substituted 6-alkylidene penems which have .beta.-lactamase inhibitory and antibacterial properties. The compounds are therefore useful in the treatment of antibacterial infections in humans or animals, either alone or in combination with other antibiotics. [0011] In accordance with the present invention there are provided compounds of general formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: wherein: [0012] One of A and B denotes hydrogen and the other an optionally substituted fused tricyclic heteroaryl group; [0013] X is S or O, preferably S; [0014] R.sub.5 is H, an in vivo hydrolyzable ester such as C1-C6 alkyl, C5-C6 cycloalkyl, CHR.sub.3OCOC1-C6 or salts such as Na, K, Ca; and [0015] R.sub.3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. DETAILED DESCRIPTION OF THE INVENTION [0016] In accordance with the present invention there are provided compounds of general formula I or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof: wherein: [0017] One of A and B denotes hydrogen and the other an optionally substituted fused tricyclic heteroaryl group; [0018] X is S or O, preferably S; [0019] R.sub.5 is H, an in vivo hydrolyzable ester such as C1-C6 alkyl, C5-C6 cycloalkyl, CHR.sub.3OCOC1-C6 or salts such as Na, K, Ca; preferable R.sub.5 groups are H or salts. [0020] The expression "Fused tricyclic heteroaryl group" is used in the specification and claims to mean: [0021] a group comprising three fused rings in which at least one ring has aromatic character (i.e meets Huckel's rule (4n+2)). The fused tricyclic heteroaryl group contains 1-6 heteroatoms selected from the group consisting of O, S, N and N--R.sub.1. The fused tricyclic heteroaryl must be bonded through a carbon preferably in one of the at least one aromatic rings to the remainder of the formula I molecule. The fused tricyclic heteroaryl group may contain 1-3 aromatic rings and 0-2 non-aromatic rings. Each aromatic ring(s) in the fused tricyclic heteroaryl group may contain 5 to 7 ring atoms (including the bridgehead atoms) selected from CR.sub.2, O, S, N, and N--R.sub.1. Each of the aromatic ring(s) of the fused tricyclic heteroaryl group may contain 0 to 3 heteroatoms selected from O, S, N or N--R.sub.1. The non-aromatic ring(s), if any, of the fused tricyclic heteroaryl group may contain 5-8 ring atoms (including bridgehead atoms) and contain 0-4 heteroatoms selected from N, N--R.sub.1, O or S(O).sub.n, wherein n is 0-2. In each non-aromatic ring of the fused tricyclic heteroaryl group, one or two of the non-bridgehead carbon atoms may each be optionally substituted with one or two R.sub.4, and each R.sub.4 may be independently the same or different. Examples of fused tricyclic heteroaryl are optionally substituted ring systems such as imidazo[2,1-b]1,3]benzothiazole optionally substituted e.g., by for example C1-C6alkyl, C1-C6alkoxy or halo (such as chlorine or fluorine); imidazo[1,2-a]quinoline; 6,7-dihydro-5H-cyclopenta[d]imidazo[2,1-b][1,3]thiazole; imidazo[1,2-a]quinoxaline; 5,6,7,8-tetrahydro-[1,2,4]triazolo[1,5-a]pyridine dibenzo[b,f][1,4]-oxazepin-11(10H)-one optionally substituted e.g., by arylalkyl such as benzyl; 7,8-dihydro-6H-3,4,8b-triaza-as-indacene optionally substituted by C1-C6 alkoxy; 4H,10H-pyrazolo[5,1-c][1,4]benzoxazepine optionally substituted e.g., by C1-C6 alkoxy; 5H-Imidazo[2,1-a]isoindole; 5,8-dihydro-6H-imidazo[2,1-b]pyrano[4,3-d][1,3]thiazole; imidazo[2,1-b]benzothiazole; [1,3]thiazolo[3,2-a]benzimidazole; 7,8-dihydro-6H-cyclopenta[3,4]pyrazolo[5,1-b][1,3]thiazole; 5,6,7,8-tetrahydroimidazo[2,1-b][1,3]-benzothiazole; 9H-imidazo[1,2-a]benzimidazole optionally substituted e.g., by C1-C6alkyl; 4H-thieno[2',3':4,5]thiopyrano[2,3-b]pyridine; 7,8-dihydro-6H-cyclopenta[e][1,2,4]-triazolo[1,5-a]pyrimidine optionally substituted e.g., by C1-C6alkyl; 6,7,8,9-tetrahydropyrido[3,4-e][1,2,4]triazolo[1,5-a]pyrimidine optionally substituted e.g., by C2-C7alkoxycarbonyl; 8',9'-dihydro-6'H-spiro[1,3-dioxolane-2,7'-[1,2,4]triazolo[1,5-a]-quinazo- line; 6,7,8,9-tetrahydro[1,2,4]triazolo[1,5-a]quinazoline optionally substituted e.g., by C1-C6alkyl; 7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidine optionally substituted e.g., by C1-C6alkoxy; 7,8-dihydro-6H-cyclopenta[e]imidazo[1,2-a]pyrimidinyl optionally substituted e.g., by arylalkyloxyalkyloxy; 3-dihydro[1,3]thiazolo[3,2-a]-benzimidazole; 2,3-dihydro[1,3]thiazolo[3,2-a]benzimidazole; 4-dihydro-2H-[1,3]thiazino[3,2-a]-benzimidazole; [1,3]thiazolo[3,2-a]benzimidazole; 7,8-dihydro-5H-pyrano[4,3-d]pyrazolo[5,1-b][1,3]-oxazole; 5,6,7,8-tetrahydropyrazolo[5,1-b][1,3]benzoxazole; and 5,6,7,8-tetrahydropyrazolo[5',1':2,3][1,3]oxazolo[5,4-c]pyridine optionally substituted e.g., by C2-C7alkoxycarbonyl. [0022] R.sub.1 is H, optionally substituted --C1-C6 alkyl, optionally substituted -aryl, optionally substituted -heteroaryl or mono or bicyclic saturated heterocycles, optionally substituted --C3-C7 cycloalkyl, optionally substituted --C3-C6 alkenyl, optionally substituted --C3-C6 alkynyl with the proviso that both the double bond and the triple bond should not be present at the carbon atom which is directly linked to N; optionally substituted --C1-C6 per fluoro alkyl, --S(O).sub.p optionally substituted alkyl or aryl where p is 2, optionally substituted --C.dbd.Oheteroaryl, optionally substituted --C.dbd.Oaryl, optionally substituted --C.dbd.O(C1-C6) alkyl, optionally substituted --C.dbd.O(C3-C6) cycloalkyl, optionally substituted --C.dbd.O mono or bicyclic saturated heterocycles, optionally substituted C1-C6 alkyl aryl, optionally substituted C1-C6 alkyl heteroaryl, optionally substituted aryl-C1-C6 alkyl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, --CONR.sub.6R.sub.7, --SO.sub.2NR.sub.6R.sub.7, optionally substituted arylalkyloxyalkyl, optionally substituted -alkyl-O-alkyl-aryl, optionally substituted -alkyl-O-alkyl-heteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkyl aryloxyheteroaryl, optionally substituted alkyl aryloxy alkylamines, optionally substituted alkoxy carbonyl, optionally substituted aryloxy carbonyl, optionally substituted heteroaryloxy carbonyl. Preferred R.sub.1 groups are H, optionally substituted alkyl, optionally substituted aryl, --C.dbd.O(C1-C6)alkyl, C3-C6alkenyl, C3-C6alkynyl, optionally substituted cycloalkyl, SO.sub.2alkyl, SO.sub.2aryl, optionally substituted heterocycles, --CONR.sub.6R.sub.7, and optionally substituted heteroaryl. [0023] R.sub.2 is hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl having 1 to 2 double bonds, optionally substituted C2-C6 alkynyl having 1 to 2 triple bonds, halogen, cyano, N--R.sub.6R.sub.7, optionally substituted C1-C6 alkoxy, hydroxy; optionally substituted aryl, optionally substituted heteroaryl, COOR.sub.6, optionally substituted alkyl aryloxy alkylamines, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted C3-C6 alkenyloxy, optionally substituted C3-C6 alkynyloxy, C1-C6 alkylamino-C1-C6 alkoxy, alkylene dioxy, optionally substituted aryloxy-C1-C6 alkyl amine, C1-C6 perfluoro alkyl, S(O).sub.q-- optionally substituted C1-C6 akyl, S(O).sub.q-- optionally substituted aryl where q is 0, 1 or 2, CONR.sub.6R.sub.7, guanidino or cyclic guanidino, optionally substituted C1-C6 alkylaryl, optionally substituted arylalkyl, optionally substituted C1-C6 alkylheteroaryl, optionally substituted heteroaryl-C1-C6 alkyl, optionally substituted C1-C6 alkyl mono or bicyclic saturated heterocycles, optionally substituted arylalkenyl of 8 to 16 carbon atoms, SO.sub.2NR.sub.6R.sub.7, optionally substituted arylalkyloxyalkyl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted aryloxyaryl, optionally substituted aryloxyheteroaryl, optionally substituted heteroaryloxyaryl, optionally substituted C1-C6alkyl aryloxyaryl, optionally substituted C1-C6 alkylaryloxyheteroaryl, optionally substituted aryloxyalkyl, optionally substituted heteroaryloxyalkyl, optionally substituted alkylaryloxyalkylamines, optionally substituted C3-C7 cycloalkyl, optionally substituted C3-C7 saturated or partially saturated heterocycle. Preferred R.sub.2 groups are H, optionally substituted alkyl, optionally substituted alkoxy, optionally substituted heteroaryl, halogen, CN, hydroxy, optionally substituted heterocycle, --CONR.sub.6R.sub.7, COOR.sub.6, optionally substituted aryl, S(O).sub.q-- alkyl, and S(O).sub.q-aryl. [0024] R.sub.3 is hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl. Preferred R.sub.3 groups are H or C1-C6 alkyl. [0025] R.sub.4 is H, optionally substituted C1-C6 alkyl, one of R.sub.4 is OH, C1-C6 alkoxy, --S--C1-C6 alkyl, COOR.sub.6, --NR.sub.6R.sub.7, --CONR.sub.6R.sub.7; or R.sub.4R.sub.4 may together be .dbd.O or R.sub.4R.sub.4 together with the carbon to which they are attached may form a spiro system of five to eight members with or without the presence of heteroatoms selected N, O, S.dbd.(O).sub.n (where n=0 to 2), N--R.sub.1; preferred R.sub.4 groups are H, C1-C6 alkyl, NR.sub.6R.sub.7, or R.sub.4R.sub.4 together with the carbon to which they are attached forming a spiro system of five to eight members. [0026] R.sub.6 and R.sub.7 are independently H, optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, optionally substituted C1-C6 alkyl heteroaryl, R.sub.6 and R.sub.7 can together with the nitrogen to which they are attached form a 3-7 membered saturated ring system optionally having one or two heteroatoms such as N--R.sub.1, O, S.dbd.(O).sub.n n=0-2. Preferred R.sub.6R.sub.7 groups are H, C1-C6 alkyl, arylalkyl, heteroarylalkyl, or R.sub.6R.sub.7 together with the nitrogen to which they are attached forming a 3-7 membered saturated ring system. Chemical Definitions Continue reading... 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