Title of Invention

1,8/7, 8, FUSED IMIDAZOQUINOLONE CARBOXAMIDES

Abstract The invention relates to the synthesis of new tricyclic quinolone carboxamide derivatives fused at 1,8 positions by imidazole ring as in general formula I are prepared and tested for antibacterial activity.
Full Text 1,8-IMIDAZOFUSED QUINOLONE CARBOXAMIDE Field of the invention:
The invention relates to the synthesis of new tricyclic quinolone carboxamide derivatives fused at 1,8 positions by imidazole ring as in general formula I are prepared and tested for antibacterial activity.
(FORMULA REMOVED)


Background of the invention:
Fluoroquinolone carboxylic acids are considered as potent antibacterials in vitro / in vivo and have good pharmacological applications for the last two decades with several molecules being commercially available as drugs. However, recent investigations have shown the occurrence of multidrug resistance to bacterial infections.(Chem.Ind.l7-2-1997, page 131). In order to overcome this problem, extensive research is in progress to synthesise polycyclic fluoroquinolones by novel and innovative methods.
US patent 4,847,375 (1989) discloses certain bridged quinolones as antibacterial agents of the formula
(FORMULA REMOVED)


where Y is COOH,CN or COOR7 or CONR8R9; X, is H, N02, 1-3 carbon alkyl, halogen or methyl; NR10R11 is a 5 or 6 member heterocyclic ring with optional substituents in the ring and on the ring; Z is oxygen or NR15.
European patent 6306764 (1989) describes bicyclic and tricyclic quinolones of the formula
(FORMULA REMOVED)


where R1 is H, lower alkyl; R2 is alkyl, substituted alkyl, -OCH3 or -NHCH3, etc.; R3 is H,halogen,CF3, NHR5, etc.; X is CH, CF, CBr, CNO2, CCl, CCF3, etc.; X and R2 when taken together may form a five or six membered ring which may contain two or more carbons, one O, one S, one N, etc.
U.S patent 5,318,915 (1994) discloses quinobenzoxazine tetracyclic system and their antineoplastic activity having the formula
(FORMULA REMOVED)


where R,R1 are different substituents and R2 may be an alkyl or H. U.S patents 5,605,910 (1997) and 5,457,104 (1995) disclose new quinolones and Naphthyridine carboxylic acid derivatives which are substituted in the 7-position by a tricyclic amine radical, their salts and hydrogen in the 6th position respectively and their antibacterial activity. Description
The novelty of the present invention includes the synthesis of new class of 1,8-fused imidazo quinolone-3-carboxamide tricyclic fluoroquinolones.
Main objective of the present invention is to provide 1,8-imidazofused quinolone carboxamides
Another objective of the present invention is to describe the preparation of various new class of 1,8-heteroring fused fluoroquinolones.
The other objective of the present invention is to study the antibacterial activity of these compounds.
Accordingly, the present "'invention provides a novel 1,8-fused imidazoquinolone carboxamides of the formula I in which R,R.2 are alkyl, R1 is H and R3 is aryl optionally substituted alkyl, alkoxy, halogen, N,N-dialkylamino and furyl functionality.
(FORMULA REMOVED)


Another important embodiment of the present invention is all the products are new compounds and tested for their antibacterial activity.
I. In an embodiment of the present invention wherein the representation compound of general formula is 2-Phenyl-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino-3,6-dihydroquinoline-5-N-methyl carboxamide. II. 2-(4'-Chlorophenyl) imidazo [4,5,l-i,j]-6-oxo-8-fluoro-9-N-methyl amino -3,6-dihydroquinoline-5-N-methyl carboxamide.
III. 2-(4'Fluorophenyl)-imidazo[4,5,l -i,j]-6-oxo-8-fluoro-9-N methylamino-
3,6- dihydroquinoline-5-N-methyl carboxamide.
IV. 2-(4'-Methylphenyl) - imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methyl amino
-3,6-dihydroquinoline-5-N-methyl carboxamide.
V. 2-(4'-Methoxyphenyl)-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methyl
amino -3,6-dihydroquinoline-5-N-methyl carboxamide. VI. 2-(4'-N,N-dimethylaminophenyl) - imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-
methylamino-3,6-dihydroquinoline-5-N-methyl carboxamide. VII. 2-(4'-Nitrophenyl) - imidazo [4,5„l-i,j]-6-oxo-8- fluoro-9-N-methyl
amino-3,6-dihydro quinoline-5-N-methyl carboxamide.
VIII. 2-[4'-HydroxyphenylJ-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N- methyl
amino-3,6-dihydroquinoline-5-N- methyl carboxamide.
IX. 2-Fuiyl-imidazo[4,5,l-ij]-6-oxo-8-fluoro-9-N methylamino -3,6-dihydro
quinoline-5-N-methyl carboxamide. X. In another embodiment of the present invention wherein antibacterial composition comprising an antibacterially effecting amount of compound as claimed in claim 1 is used. XI. In another important embodiment of the present invention wherein antibacterial composition as claimed in claim 3 wherein the MIC value for all the compounds is in the range of 6-25 µg/ml. XII. In another embodiment of the present invention wherein antibacterial composition as claimed in claim 3 wherein the compounds are active against gram positive and gram negative bacteria. We have disclosed and claimed the process of preparation of compound of formula in our copending patent application No. NF...318/05 . Details of invention
Various substituents on quinolone ring system are prepared and fusion of third ring between 1,2; 2,3; 6,7; 8,1 positions is the current interest worldwide as some of them showed promising antibacterial activity. The present invention relates to the synthesis of new class of 1,8-heteroring fused tricyclic quinolones of biological interest.
The present invention confines to the synthesis of 1,8 fused quinolones starting from 6-fluoro-7-methylamino-8-amino-4-hydroxy quinoline-3-N-methyl carboxamide of formula II and the final products are
2-aryl -imidazo[4,5,l-ij]-8-fluoro-9-N-methylamino-6-oxo-3,6-dihydroquinoline-5-N methyl carboxamide I and another compound a 7,8-fused quinoline III.
The aryl groups contemplated by the invention include substituted or unsubstituted phenyl. The substituents include halogen, nitro, alkyl, alkoxy. The term heteroaryl intended to include furan. The term halogen is intended to include fluorine and chlorine. The compounds of formula I are prepared as follows :
The diamino compound II reacted with aromatic aldehydes and gave a mixture of compounds 1,8-fused-imidazoquinolones I and 7,8-fused imidazoquinolines III as shown in scheme - 1 (Table - 1).
(SCHEME REMOVED)

EXPERIMENTAL
The following examples are given by way of illustration and therefore, should not be
construed to limit the scope of the present invention.
Example - 1
Imidazo [4,5,l-i,j] aryl substituted Quinolone (I).
A mixture of 6-fiuoro -7-methylamino -8-amino-4-hydroxyquinoline-3-N-methyl
carboxamide II (10 mmole) and benzaldehyde (10 mmole) were taken in acetic acid
(10ml) and refluxed for 4h.The reaction mixture was cooled and poured on to crushed
ice. The resulted solid was filtered, washed with water and dried. The separated solid
was purified by passing through a column of silicagel using chloroform to get the 1,8 -
fused compound la and 7,8-fused compound III.
2-Phenylimidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino-3,6-dihydroquinoline-5-N-
methyl carboxamide la
M.p : 289-290°c, Yield: 9.1%
I R(KBr) v : 3212,1680 cm"1. 'H-NMRCCDCb) 5: 3.0 (d,3H,-CH3); 3.4 (d,3H,-CH3); 7.6
(m,3H,phenyl); 7.7 (d,lH,Ar-H); 7.9 (m, 2H, phenyl); 8.9 (m,lH,-NH-); 9.4 (s,lH,Ar-H);
9.6 (m,lH,-NH-). Mass(EI m/z): 350 (M+). Analysis Calcd. for C19H15FN4O2: C.65.13;
H,4.31%; N.15.99. Found: C,65.20; H,4.30, N,15.94%.
Example - 2
Antibacterial Activity studies :
The minimum inhibitory concentration was done by broth dilution method (NCCLS1982). A set of sterilized test tubes with nutrient broth medium capped with cotton plugs (1-9). The test compound is dissolved in suitable solvent and concentration of 100µg/ml of the test compound is added in the first test tube, which is serially diluted from 1-9. A fixed volume of 0.5ml overnight culture is added in all the test tubes and are incubated at 37°C for 24h. After 24h, these tubes were measured for turbidity.
(TABLE REMOVED)






We claim
1. A novel 1,8-imidazo fused quinolone carboxamide of the formula I in which R,
R2 are alkyl, R1 is hydrogen and R3 is aryl optionally substituted with alkyl,
alkoxy, halogen, N.N-dialkylamino and furyl functionality.
(FORMULA REMOVED)

2. A novel 1,8-imidazo fused quinolone carboxamides of the formula I as claimed in
claim 1 wherein the representative compound of the general formula are given
below:
Formula -1
I. 2-Phenyl-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino-3,6-dihydro
quinoline-5-N-methyl carboxamide. II. 2-(4'-Chlorophenyl) imidazo [4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino -3,6-dihydroquinoline-5-N-methyl carboxamide.
III. 2-(4'Fluorophenyl)-imidazo[4,5,l -i,j]-6-oxo-8-fluoro-9-N-methylamino-
3,6- dihydroquinoline-5-N-methyl carboxamide.
IV. 2-(4'-Methylphenyl)-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino-3,6-
dihydroquinoline-5-N-methyl carboxamide.
V. 2-(4'-Methoxy phenyl)-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-methylamino-3,6-dihydroquinoline-5-N-methyl carboxamide. VI. 2-(4'-N,N-dimethyl amino phenyl)-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N-
methylamino-3,6-dihydroquinoline-5-N-methyl carboxamide. VII. 2-(4'-Nitrophenyl) imidazo [4,5„l-i,j]-6-oxo-8- fluoro-9-N-methylamino-
3,6-dihydroquinoline-5-N-methyl carboxamide. VIII. 2-(4'-Hydroxy phenyl)-imidazo[4,5,l-i,J]-6-oxo-8-fluoro-9-N- methylamino-3,6-dihydroquinoline-5-N- methyl carboxamide.
IX. 2-Furyl-imidazo[4,5,l-i,j]-6-oxo-8-fluoro-9-N methylamino - 3,6-dihydroquinoline-5-N-methyl carboxamide.
3. A novel compound as claimed in claim 1 wherein the compounds are useful as antibacterial agent.
4. An antibacterial composition comprising an antibacterially effecting amount of compound as claimed in claim 1 optionally along with the pharmaceutically acceptable additive and diluents.
5. An antibacterial composition as claimed in claim 3 wherein the MIC value for all the compounds is in the range of 6-25 ug/ml.
6. An antibacterial composition as claimed in claim 3 wherein the compounds are active against gram positive and gram negative bacteria.
7. 1,8-Imidazofused quinolpne carboxamide substantially as herein described with reference to the examples.

Documents:

2852-del-2005-abstract.pdf

2852-del-2005-claims.pdf

2852-del-2005-correspondence-others.pdf

2852-del-2005-description (complete).pdf

2852-del-2005-form-1.pdf

2852-del-2005-form-18.pdf

2852-del-2005-form-2.pdf

2852-del-2005-form-3.pdf

2852-del-2005-form-5.pdf

abstract.jpg


Patent Number 259318
Indian Patent Application Number 2852/DEL/2005
PG Journal Number 11/2014
Publication Date 14-Mar-2014
Grant Date 07-Mar-2014
Date of Filing 26-Oct-2005
Name of Patentee COUNCIL OF SCIENTIFIC & INDUSTRIAL RESEARCH
Applicant Address ANUSANDHAN BHAWAN, RAFI MARG, NEW DELHI-110 001, INDIA
Inventors:
# Inventor's Name Inventor's Address
1 PAMULAPARTHY SHANTHAN RAO INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
2 GHOJALA VENKAT REDDY INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
3 YADLA RAMBABU INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA`
4 SRIPATHI NARAYAN REDDY INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
5 DRAVIDUM MAIDRAIE INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
6 VEJJU VVNS RAMA RAO INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
7 SRIBHASHYAM RAVIKANTH INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
8 KANKIPATI HARAKISHORE INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
9 UPADHYAULA, SURYANARAYANA MURTHY INDIAN INSTITUTE OF CHEMICAL TECHNOLOGY, HYDERABAD, 500 007, INDIA
PCT International Classification Number C07C 229/34
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA