|HAI LAILA ATA A US009732081B2UN MAI MULT MAI MULT (12 ) United States Patent ( 10 ) Patent No. : US 9 ,732 ,081 B2 Patil et al. (45 ) Date of Patent: Aug . 15 , 2017 ( 54) 1 ,6 -DIAZABICYCLO [3 , 2 , 1 ] OCTAN - 7 -ONE (51 ) Int. CI. DERIVATIVES AND THEIR USE IN THE C07D 471 /08 ( 2006 .01 ) TREATMENT OF BACTERIAL INFECTIONS A61K 31/ 439 (2006 .01 ) A61K 31/ 4545 ( 2006 .01 ) A61K 31 / 496 ( 2006 . 01 ) ( 71 ) Applicant: WOCKHARDT LIMITED , A61K 31 / 55 ( 2006 .01 ) Aurangabad ( IN ) C07D 487 / 08 ( 2006 .01 ) A61K 31/ 407 (2006 . 01 ) ( 72 ) Inventors : Vijaykumar Jagdishwar Patil, Solapur A61K 31/ 546 ( 2006 .01 ) ( IN ) ; Ravikumar Tadiparthi, A61K 45 / 06 ( 2006 .01 ) Auranagabad ( IN ) ; Bharat Dond , C07C 211/ 63 ( 2006 . 01 ) Aurangabad ( IN ) ; Amol Kale , ( 52 ) U . S . CI. Aurangabad ( IN ) ; Loganathan CPC . .. .. C070 471 /08 (2013 .01 ) ; A61K 31/ 407 Velupillai , Aurangabad ( IN ) ; Deepak ( 2013 .01 ) ; A61K 31/ 439 ( 2013 . 01 ) ; A61K Dekhane , Maharashtra Pune ( IN ) ; 31/ 4545 (2013 . 01 ) ; A61K 31/ 496 ( 2013. 01 ) ; Satish Shrimant Birajdar , Pin - O Latur A61K 31/ 546 ( 2013 .01 ) ; A61K 31/ 55 ( IN ) ; Mohammad Usman Shaikh , ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; C07C Shrirampur ( IN ) ; Sushilkumar 211/ 63 ( 2013 .01 ) ; CO7D 487/ 08 ( 2013. 01 ) Maurya , Maharashtra Aurangabad ( IN ) ; (58 ) Field of Classification Search Piyush Ambalal Patel, Gujarat Anand CPC . .. .. .. C07D 471 /08 ( IN ) ; Prasad Dixit, Maharashtra See application file for complete search history . Aurangabad ( IN ) ; Mangesh Pawar , Maharashtra Aurangabad (IN ) ; Mahesh (56 ) References Cited Vithalbhai Patel , Aurangabad ( IN ) ; Sachin Bhagwat, M . S . Aurangabad U . S . PATENT DOCUMENTS ( IN ) 2013 /0225554 AL 8 /2013 Maiti et al. ( * ) Notice: Subject to any disclaimer, the term of this Primary Examiner — Bruck Kifle patent is extended or adjusted under 35 (74 ) Attorney , Agent, or Firm — Bio Intellectual Property U . S . C . 154 (b ) by 0 days. Services LLC (Bio IPS ) ; O . (Sam ) Zaghmout (21 ) Appl. No. : 15/ 062, 148 (57 ) ABSTRACT Compounds of Formula ( I ) , their preparation and use in ( 22 ) Filed : Mar. 6 , 2016 preventing or treating bacterial infections are disclosed . (65 ) Prior Publication Data US 2016 / 0213655 A1 Jul . 28 , 2016 Formula ( I) Related U . S . Application Data R3 -Z (63 ) Continuation of application No . 14 / 365 , 064 , filed as R2 application No . PCT / IB2013 /053092 on Apr. 19 , 2013 . N - R1 ( 30 ) Foreign Application Priority Data Aug. 25 , 2012 ( IN ) .. .. 2471 /MUM / 2012 36 Claims, No Drawings US 9 , 732 ,081 B2 1 , 6 -DIAZABICYCLO ( 3 , 2 , 1 ] OCTAN - 7 -ONE or a stereoisomer or a pharmaceutically acceptable salt DERIVATIVES AND THEIR USE IN THE thereof ; TREATMENT OF BACTERIAL INFECTIONS wherein : R , is : CROSS -REFERENCE TO RELATED ( a ) SO3M , APPLICATIONS ( b ) SO2NH2, ( C ) PO , M , This application is a Continuation of U . S . application Ser . ( d ) CH , COOM , No. 14 / 365 , 064, filed Jun . 12 , 2014 , now pending, which ( e ) CF , COOM , entered the National Phase of Serial No. PCT/ IB2013 / 10 ( f ) CHFCOOM , or 053092 , filed Apr. 19 , 2013 , which claims priority to Indian ( g ) CF3 ; Application No . IN2012MU2471A , filed Aug. 25 , 2012 . The M is hydrogen or a cation ; entire disclosure of these prior applications are hereby R2 is : incorporated by reference . ( a ) hydrogen , 15 ( b ) (CH ) n - R3, or FIELD OF THE INVENTION ( c ) COOR3, The invention relates to nitrogen containing compounds , n is 0 , 1 or 2 ; use of these compounds as antibacterial agents , composi Rz is : tions comprising them and processes for their preparation . ( a ) hydrogen , 20 ( b ) C . - C . alkyl optionally substituted with one or more BACKGROUND OF THE INVENTION substituents independently selected from halogen , OR , CN , COORS, CONRR7, NR R7, NR , COR , , Emergence of bacterial resistance to known antibacterial NR , CONRGR7, heterocyclyl , heteroaryl , cycloalkyl or agents is becoming a major challenge in treating bacterial aryl, infections. One way forward to treatat bacterial infectionsinfections , and 25 ( c ) CN , especially those caused by resistant bacteria , is to develop ( d ) NRGR7, newer antibacterial agents that can overcome the bacterial ( e ) CONRR , resistance . Coates et al. (Br . J . Pharmacol . 2007 ; 152 ( 8 ) , ( 1 ) NHCONRR , 1147 - 1154 ) have reviewed novel approaches to developing ( g ) aryl optionally substituted with one or more substitu new antibiotics . However , the development of new antibac - 30 ents independently selected from C . - C . alkyl, OR , terial agents is a challenging task . For example , Gwynn et al. NR R7, halogen , CN , CONRGR7, SO2- alkyl, SO2- aryl, ( Annals of the New York Academy of Sciences, 2010 , 1213 : OSO2- alkyl , OSO2- aryl, or NHCONRGR7, 5 - 19 ) have reviewed the challenges in the discovery of ( h ) heterocyclyl optionally substituted with one or more antibacterial agents . substituents independently selected from C - C . alkyl, Several antibacterial agents have been described in the 35 OR . , NR R7, halogen , CN , CONRGR7, SO2- alkyl, prior art ( for example , see PCT International Application SO2- aryl, OSO2- alkyl , OSO2- aryl, or NHCONRGR7, Nos. PCT /US2010 / 060923 , PCT / EP2010 / 067647 , PCT / ( i) heteroaryl optionally substituted with one or more US2010 /052109 , PCT/ US2010 /048109 , PCT/ GB2009 / substituents independently selected from C1- C6 alkyl, 050609 , PCT /EP2009 /056178 and PCT/ US2009 /041200 ) . OR5, NR R7, halogen , CN , CONRGR7, SO2 - alkyl, However , there remains a need for potent antibacterial 40 SO2- aryl , OSO2- alkyl, OSO2- aryl, or NHCONRR7, agents for preventing and / or treating bacterial infections, (j ) cycloalkyl optionally substituted with one or more including those caused by bacteria that are resistant to substituents independently selected from C , - C alkyl , known antibacterial agents . ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl , The inventors have surprisingly discovered nitrogen con SO2- aryl , OSO , - alkyl , OSO , - aryl, or NHCONRR , , taining compounds with antibacterial properties . 45 ( k ) cycloalkyl substituted with C1- C6 alkylwherein C , - C6 alkyl is further substituted with one or more substitu SUMMARY OF THE INVENTION ents independently selected from OR5 , NRR , , halo gen , CN , or CONRGR7 , or Accordingly there are provided nitrogen containing com ( 1) ORS; pounds, methods for preparation of these compounds, phar - 50 R4 18 : maceutical compositions comprising these compounds, and ( a ) hydrogen , method for preventing or treating bacterial infection in a ( b ) C . - C . alkyl optionally substituted with one or more subject using these compounds . substituents independently selected from halogen , OR5, In one general aspect , there are provided compounds of CN , COOR , CONRGR7, NR R7, NR , CORg, hetero Formula ( I ) : 55 cyclyl , heteroaryl, cycloalkyl or aryl, ( c ) aryl optionally substituted with one or more substitu ents independently selected from C . - C . alkyl, OR , Formula ( I) NR R7, halogen , CN , CONRR7, SO2- alkyl, SO2- aryl, OSO , - alkyl, OSO , - aryl, or NHCONRR , 60 ( d ) heterocyclyl optionally substituted with one or more R3 substituents independently selected from C , - C . alkyl, Z- ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl, R2 SOZ- aryl, OSO2 - alkyl, OSO2- aryl, or NHCONRGR7, ( e ) heteroaryl optionally substituted with one or more DARI 65 substituents independently selected from C . - C . alkyl, ORs, NR R7, halogen , CN , CONRGR7, SO2- alkyl , SO2- aryl , OSO2- alkyl , OSO2- aryl, or NHCONRGR7, or US 9 ,732 ,081 B2 ( f) cycloalkyl optionally substituted with one or more thereof, and ( b ) at least one beta - lactamase inhibitor selected substituents independently selected from C , - C6 alkyl, from sulbactam , tazobactam , clavulanic acid , or a pharma OR5, NR R7, halogen , CN , CONRR7, SO2- alkyl, ceutically acceptable derivative thereof. SO2- aryl, OSO2- alkyl, OSO2 - aryl, or NHCONR Rz; In another general aspect, there are provided pharmaceu R , and R , are each independently : 5 tical compositions comprising : ( a ) a compound of Formula ( a ) hydrogen , or ( I ) , or a stereoisomer or a pharmaceutically acceptable salt ( b ) C -C6 alkyl optionally substituted with one or more thereof, and ( b ) at least one antibacterial agent or a phar substituents independently selected from halogen , CN , maceutically acceptable derivative thereof. CONRR , NR R7, heterocyclyl, heteroaryl, In another general aspect , there are provided pharmaceu cycloalkyl or aryl; 10 tical compositions comprising : ( a ) a compound of Formula Ro and R , are each independently : ( I ) , or a stereoisomer or a pharmaceutically acceptable salt ( a ) hydrogen , thereof, ( b ) at least one beta - lactamase inhibitor selected (b ) C . - Cô alkyl optionally substituted with one or more from sulbactam , tazobactam , clavulanic acid , or a pharma substituents independently selected from halogen , OR , ceutically acceptable derivative thereof , and ( c ) at least one CN , COORS, CONR = R3, NR =Rs , NR ,CORg , hetero - 15 antibacterial agent or a pharmaceutically acceptable deriva cyclyl , heteroaryl , cycloalkyl or aryl, tive thereof. ( c ) aryl optionally substituted with one or more substitu - In another general aspect, there is provided a method for ents independently selected from C , - C , alkyl, OR5 , preventing or treating bacterial infection in a subject , said NR =Rg , halogen , CN , CONR Rg, SO2- alkyl, SO2- aryl, method comprising administering to