Title of Invention	NOVEL SUBSTITUTED BENZOCYCLOALKYL AZOLE DERIVATIVES AS ANTILEISHMANIAL AGENTS
Abstract	The present invention relates to novel aryloxy benzocycloalkyl azoles of general formula 4 where R is selected from the group consisting of R =H, Me, Cl, F and Br etc.; R1 = CFs, COCHa, NOa etc.; X= H or N etc. ; n=l or 2. The present invention further relates to provide a process for the preparation of novel aryloxy benzocycloalkyl azoles of the general formula 4. More particularly the present invention relates to the novel aryloxy benzocycloalkyl azoles. These compounds are potentially useful in the treatment of leishmaniasis.

Title of Invention

NOVEL SUBSTITUTED BENZOCYCLOALKYL AZOLE DERIVATIVES AS ANTILEISHMANIAL AGENTS

Abstract

The present invention relates to novel aryloxy benzocycloalkyl azoles of general formula 4 where R is selected from the group consisting of R =H, Me, Cl, F and Br etc.; R1 = CFs, COCHa, NOa etc.; X= H or N etc. ; n=l or 2. The present invention further relates to provide a process for the preparation of novel aryloxy benzocycloalkyl azoles of the general formula 4. More particularly the present invention relates to the novel aryloxy benzocycloalkyl azoles. These compounds are potentially useful in the treatment of leishmaniasis.

Full Text	FIELD OF INVENTION The present invention relates to novel aryloxy benzocycloalkyl azoles. The presep.t invention · . I particularly relates to the synthesis of novel aryloxy benzocycloalkyl azole deri\atives as of formula 4 and their use _as potent antileishmanial. agents for the treatment 1of visceral leishmaniasis. R~~)n FI b N ,,N .:. 'x () 0 R'- h 4 BACKGROUND OF INVENTION R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 ·x=CH,N n =I, 2 Leishmaniases are parasitic diseases transmitted by the bite of the infect.~d female phlebotomine sand fly and manifest with visceral, cutaneous, and mucocutane~us forms. I They are a significant cause of morbidity and mortality in the developing coundies of the world, and they affect about 2 million people per annum (TOR-Leishmaniasis 2007 Update) mostly in tropical and subtropical regions, the geographical distribution being limited by the I . biotope of the insect vector (P.J. Guerin, P. Olliaro, S. Sundar, M. Boelaert, S.L.I Croft, P. I Desjeux, M.K.Wasunna, A.D. Bryceson, Lancet Infect. Dis. 2 (2002) 494-501). However, . ' ~ official data underestimate the reality of the human affliction. Of the various types, visceral leishmaniasis (VL), known as kala-azar (black fever) .)r Assam ',] fever is caused by Leishmania donovani and is transmitted by phlebotomine s1md flies i (Phlebtomus argentipes). VL is characterized by irregular bouts of fever, substanti~l weight loss, swelling of the spleen and liver, and anaemia (occasionally serious). If left untreated, I . • I the fatality rate in developing_ countries can be as high as I 00% within 2 years. It is _preval·ent mostly_ in eastern India and still remains problematic as early diagnosis is difftbult and treatment often results in drug resistance. Chemotherapy. for these parasitic diseases is generally ineffective. mainly duei 1 to the emergence of drug-resistant strains and toxicity of the therapeutic agents. The pentavalent 2 antimonials are widely used as pnmary therapy ·whereas alternative drtigs include I amphotericin B, pentamidine, paromomycin, and azoles. Azole antifungal drug3 have been used as antileishmanial agents since 1980s [J.A. Maertens, Clin. Microbiol. Infect. i 0 (2004) I 1-10]. However, resistance to antimonials is common and treatments with amrhotericin B and pentamidine are plagued by severe toxic side effects. Newly introduced first drally active drug miltefosine is quite effective but shows teratogenic effects and cannot be used in the pregnant women. Though th~re have been commendable research efforts towards ~lucidating the basic biology of Leishmania parasites, little progress has been made in the field of therapeutic interest (F. Chappuis, S. Sunder,· H. Ghalib. S.Rijai., R. W. Peeling, i Alavaran, I M. Boelaert, Nature Reviews Microbiology 5, Nov. 2007). Drug resistance, high t::>xicity and high treatment costs necessitate the need for novel therapeutics. In order to find new drugs with antileislunanial activity the aryloxy benzocycloa\kyl azoles I have been synthesized and screened in vitro (against promasdgote/ and intracellular amastigotes) and in vivo (against Leishmania donovani./Haemester model). OBJECTS OF THE INVENTION ' The main objective of the present invention IS to provide novel ',substituted benzocycloalkyl azoles. More particularly the present invention relates to the novel aryloxy benzo~ycloalkyl azoles. These compounds are potentially useful in the treatment of leishinaniasis. Another objective of the present invention is to provide a process for the preparation of novel aryloxy benzocycloalkyl azoles of the general formula 4. Summary of the invention The present invention relates to novel aryloxy benzocycloalkyl azoles of general formula 4 wherein R is selected from the group consisting of R =H, Me, Cl, F and Er etc.; R 1 = CF3, COCH3, N02 etc.; X= HorN etc.; n=1 or 2. 3 R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 X=CH, N n =I, 2 I The compounds of general formula 4 are useful for the treatment of leishmkniasis. The I representative novel aryloxy benzocycloalkyl azoles 4a to 4y are nontoxic in bytotoxicity assay. Detailed description of the invention ,I 'i Accordingly, the present invention provides novel aryloxy benzocycloalky:l azoles of ! general formula 4, isomers, derivatives and salts thereof, R = H, Me, Cl,IF, Br,OCH3 R' = CF3, COQ-!3, N02 I X=CH,N n =I, 2 i wherein R is selected from a group consisting of H, halogen, alkyl or alk~xy ; R' is selected from a group consisting of CF3, COCH3, CHO, COOR, CN, N02, alKyl, alkoxy or amide; X is CH or N; n=l or 2. In an embodiment of the present invention wherein the structural formula c•hmprising; I X=CH, wherein R is selected from a group consisting of H, halogen, alkyl or alkoxy; R' I I is selected from a group consisting of CF3, COCH3, CHO, COOR, CN, "t\·p2, alkyl, alkoxy or amide; X is CH or N; n=l or 2 . .R C- c;t)n~ 1 ' r=I ~ =- N~N R'004 R= H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 n =I, 2 I In another embodiment of the. present invention wherein the structural • formula ' comprising; X=N, wherein R is selected from a group consisting of H, halogen.; alkyl or .I alkoxy; R' is selected from a group consisting of CF3, COCH3, c·Ho, COOR, C:N, N02, alkyl, alkoxy or amide; X is N; n=l or 2. 4 RO:;tF\ N ,,N. 'N R'v- ~0. 4 R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 n= 1, 2 In yet another embodiment of present invention wherein the subject novel compounds are the representative compounds of formula 4 are as follows:- 4a. 1-(1-( 4-Acetyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole. 4b. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl) -INimidazole. 4c. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-lH-imidazole. 4d. 1-( 1-( 4-Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole . . 4e. 1-(5-Methyl-1-{ 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- 1H-imidazole . 4f. 1-(5-Methyl-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole 4g. 1-(1-( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole. 4h. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- 1 H-imidazole. 4i. 1-(5-Chloro-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole. 4j. 1-(5-Fluoro-1-( 4-trifluoroinethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-lHimidazole. 4k. 1-(5-Fluoro-1-( 4-nitro-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 Himidazole. 41. 1-(1-( 4-Acetyl-phenoxy)-5-bromo-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole. 4m. 1-(5-Bromo-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)- 1 H-imidazole. 5 4n. I-(5-Bromo-I-( 4-nitro-phenoxy)-I ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-I Himidazole. 4o. I-( I-( 4-Acetyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-IH-[ I ,2,3 ~triazole. ' 4p. I-(1-( 4-Trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- iH- (I ,2,3]triazole. 1 4q. I-(1-( 4-Nitro-phenoxy)-I ,2,3,4~tetrahydronaphthalen-2-ylmethyl)-IH-[I ,2,3]t~iazole . 4r. I-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- • .;;';...._ I • IH-[I :2,3]triazole 4s. I-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-IH-imidazole. 4t. I-(I-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-IH-imidazole . 4u. I-(I-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-IH-imidazole. 4v. 1-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-lH-[ 1 ,2,3]triaiole. 4w. I-(1-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1H-[I,2,3]triazole. 4x. I-(1-(4-Nitro-phenoxy)-indan-2-ylmethyl)-IH-[ 1 ,2,3)triazole. 4y: 1-(6-methoxy-I-( 4-trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylfnethyl)I H-imidazole. In a further embodiment of the present invention the compounds of formulA 4 posses . ·' interesting pharmacological properties. In particular they are useful as antileishmamal agents. I In a further embodiment of the present invention wherein the compound exhitited more than 80% inhibition of parasites in vivo(L.donovani!Hamstermodel) at a do~e of 50 mg/kg x 5 i.p. dose concentration. In a further embodiment of the present invention wherein the CC5o of the compounds is ranging between 4.4 to 7 4.13 f.!g/ml. In a further embodiment of the present invention wherein the IC5o of the compounds is ! ranging between -0.34 to 3.39-f..lg/ml. In a further embodiment of the present invention wherein all the representative novel aryloxy benzocycloalkyl azoles 4a to 4y as claimed in claim I are nontoxic in cytotoxicity assay. In a further embodiment of the present invention wherein aryloxy benzocycloalkyl azoles 4a, . 4b, 4c, 4d, 4g, 4h, 4i, 4j, 4k, 4m, 4n, 4r, 4t, 4u, 4w and 4y exhibited I 6 Selective Index (SI) in the range of 11.8 to 112 based on potent antihistaminial activity against intracellular amastigotes of L. donovani residing within murine macrophages. In a further embodiment of the present invention wherein novel compound 4h, chemically, ( 1-( 5-Chloro-1-( 4-trifluoromethyl-phenoxy )-1 ,2,3 ,4-tetrahydronaphthalen-2- ylmethyl)-1H-imidazole, showed higher levels of in-vivo antileishmanial activity (82% inhibition of parasite multiplication) and 4c (1-(1-(4-Nitro-phenoxy)-1,2,3,4- tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole ), 4i (1-( 5-Chloro-1-( 4-nitro-phenoxy )- ~~. .... 1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole) and 4u (1-(1-( 4-Nitrophenoxy)- indan-2-ylmethyl)-1H-imidazole) exhibited medium levels of antiJeishmanial activity with 52.5%, 60.4% and 56.4 % inhibition respectively . in in vivo using ·Leishmania donovani I hamster model. .In a further another embodiment of the present invention novel 1-(1-( 4-Acetylphenoxy )-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole( 4a ), 1-(1-( 4- . Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4b ), 1- ( 1-( 4-Nitro-phenoxy)~ 1 ,2 ,3, 4-tetrahydronaphthalen-2-ylm~thyl )-1 H-imidazole ( 4c ), 1-( 1-( 4- Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4d), 1- ( 1-( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 Himidazole( 4g), 1 ;..(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2- ylmethyl)-1 H-imidazole( 4h), 1-( 5 .:Chloro-1-( 4-nitro-phenoxy )-1 ,2,3,4-tetrahydronaphthalen- 2-ylmethyl)-1 H-imidazole( 4i), · 1-( 5-Bronio-1-( 4-trifluoromethyl-phenoxy)-1 ,2,.3 ,4- tetrahydronaphthalen-2-ylmethyl)- ~ H-imidazole( 4m), 1-(5-Bromo-1-( 4-nitro-phenoxy)- 1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole( 4n), 1-(5-Chloro-1-( 4- trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-[1 ,2,3 ]triazole( 4r), 1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole( 4u) and 1-(6-methoxy-1-( 4- trifluorome.thyl-phenoxy)-1,2,3,4-tetrahydron5lphthalen-2-ylmethyl)-1H-imidazole (4y) exhibited potent antihistaminial activity against extracellular promastigotes and intracellular amastigote~ of L. donovani residing within murine macrophages. Accordingly the present invention relates to a process for the preparation of new aryloxy benzocycloalkyl azoles of general formula 4. In general, the compounds of formula 4 may be prepared by chemical reactions analogously known in the art, the choice of any specific route of preparation being dependent 7 upon a variety of factors e.g. general availability and cost of reactants. In preparing these compounds standard procedures and techniques which are well known and appreciated by those of ordinary skill in the art are utilized. For example, compounds of for;:nula 4 can conveniently.be made according to the general synthetic route outlined in scheme 1, which comprises of reacting an appropriately substituted pyrrolidinylmethyl ketone 1 wherein R = H, Me, Cl, F, Br or OCH3; n = I or 2 with imidazole/ triazole in water alcohol mixture to give the azolylmethyl ketone (2) wherein X = H or N followed by reaction with sodium ·:r--~ borohydride to give the amino alcohol (3) with TRANS stereoselectivity (8.5: 1.5). The potassium derivative of the amino alcohol 3 which is formed \Jy reacting 3 with potassium tertiary butoxide (KtBuO) in dimethyl sulfoxide (DMSO) is further reacted with appropriately substituted aryl fluoride in the presence of DMSO to give the corresponding . ~ compound of the formula 4 wherein R'=H, 4-CFJ, 4-COCHJ or 4-NOz and isolating the compounds by conventional methods. The procedure generally results in the TRA).J'S isomer in substantially pure form. For example, compounds of the formula (4) can conveniently be made according to the general synthetic route outlined in scheme 1. Scheme-l R ~~)0 .·. o imidazole/triazole ~) r::::=::1 .Q N R_!_ n I ~ · Step-1 1 _g N, ,,N O HCI X 0 la (n = 1), l b(n = 2) 2a, (n = 1), 2b(n = 2) _g. N, ,, R~~~·)nF\N .:. X . 0 aryl fluoride R'v- ~ 4 R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 X=CH, N n= I, 2 . 4a: R=H, n=2, R'= 4-COCH3, X=CH 4b: R=H, n=2, R'= 4-CF3, X="=CH Step-3 OH 3a(n = I), 3b(n = 2) 8 4c: R=H, n=2, R'= 4-N02, X=CH 4d: R=5-CH3, n=2, R'= 4-COCH3, X=CH 4e: R=5-CH3, n=2, R'= 4-CF3, X=CH 4f: R=5-CH3, n=2, R'= 4-N02, X=CH 4g: R=5-CI, n=2, R'= 4-COCH3, X=CH 4h: R=5-CI, n=2, R'= 4-CF3, X=CH 4i: R=5-Cl, n=2, R'= 4-N02, X=CH 4j: R=5-F, n=2, R'= 4-CF3, X=CH 4k: R=5-F, n=2, R'= 4-N02, X=CH 41: R=5-Br, n=2, R'= 4-COCH3, X=CH 4m: R=5-Br, n=2, R'= 4-CF3, X=CH 4n: R=5-Br, n=2, R'= 4-N02, X=CH 4o: R=H, n=2, R'= 4-COCHJ, X=N 4p: R=H, n=2, R'= 4-CF3, X=N 4q: R=H, n=2, R'= 4-N02, X=N 4r: R=Cl, n=2, R'= 4-CF3, X=N 4s: R=H, n=l, R'= 4-COCH3, X=CH 4t: R=H, n=l, R'= 4-CF3, X=CH 4u: R=H, n=I, R'=4-N02, X=CH 4v: R=H, n=I, R'= 4-COCH3, X=N 4w: R=H, n=l, R'= 4-CF3, X=N 4x: R=H, n=I, R',;, 4-N02, X=N 4y: R=6-0CH3, n~2, R'= 4-CF3, X=CH In yet another embodiment of present invention the novel aryloxy benzocycloalkyl · azoles have exhibited inhibition of parasites in-vitro at concentration ranging from 0.25 to 10 Jlg/ml. In a preferred embodiment of present invention all the novel aryloxy benzocycloalkyl azoles (4a-4y) were found nontoxic in cytotoxicity assay. In a further preferred embodiment of the present invention 1-( 5-Chloro-1-{ 4- trifluoromethyl-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-.imidazole( 4h), 1-(1- ( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4c), 1-(5-Chloro- 1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4i) and 1-(1- 9 (4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole(4u) emerged as most potent!compounds I in this series ( on the basis of significant SI). I In a still preferred embodiment of the present invention 4h, 4c, 4i arid 4u were assessed in vivo using Leishmania donovani I haemester model. The com,pound 4h, ' chemically, (1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2- ylmethyl)-1 H-imidazole, showed remarkable antileishmanial activity · (82% inpibition of . ' I parasite multiplication) and the other three compounds exhibited medium activity viz:- 4c. (52.5%), 4i. (60.4%) and 4u (56.4 %) inhibition respectively. In yet another embodiment of pre;;;ent invention the bioactivity of compound 4h, chemically, 1-( 5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2- ! ylmethyl)-1H-imidazole was comparable to tl\e reference compound Sodium stibogluconate. . ' . The following examples are given by the way of illustration and should net be construed to limit the scope of present invention. Example 1 Step-1 2-Imidazol-1-ylmethyl-indan-1-one (2a, R=H, n=1, X=CH). A mixture of 2-py~rolidin-1- ylmethyl-indan-1-one · (la, R=H, n=1)(4.11mmol) and imidazole (4.93mmol) in I ethanol:water (2:3) was heated for 6h at 90°C. The organic solvent was distilled o:ff and the compound was extracted with dichloromethane (5ml x 2). The organic layer w~s washed with water and dried over sodium sulphate and distilled to give 2a in 60.7% yield. MS (ESI) m/z: 21_3 ((M+1t, 100%); 1H NMR (200 MHz, CDCb): 8 2.73-2.77 (m, 1H, H-2), 7.87-3.19 (m, 3H, H-3, N-CH2), 4.48-4.55 (m, 1H, N-CH2), 6.79-6.92 (m, 1H, ArH), 7.32-7.79 (m, 6H, ArH); IR (Neat): 3428, 2927, 2365, 1597, 1352, 1245, 760cm-1 • Example 2 Step-1 2-Imidazol-l-ylmethyl-3,4-dihydro-2H-naphthalen-l-one (2b, R=H, n=2, X=CH)'~ A mixture of 2-pyrrolidin-l-ylmethyl-3,4-dihydro-2H-naphthalen-l-one(1b, R=H, n=2)(4.1 ]mmol) and imidazole (4.9;3mmol) in ethanol:water (2:3) was heated for 3 hat 90°C. The organic ,solvent was distilled off and the compound was extracted with dichloromethane (5ml x 2). The organic layer was washed with water and dried over sodium sulphate and distilled to give 2b in 9~.45% yield. 10 MS (ESI) rnlz: 227 (M+, 100%); 1H NMR (200 MHz, CDCh): 8 1.71-1.79 (m, ]IH, H-3), 2.06- . I! 2.11 (m, IH, H-3), 2.78-3.05 (m, 3H, H-4; H-2), 4.37-4.46 (m, 2H, NCH2), 6.9.~ {s, IH, ArH), 7.02 (s, IH, ArH), 7.16-7.36 {m, 2H, ArH), 7.44-7.49 {m, 2H, ArH), 8.02-8.06 (di IH, J=7.79Hz, ArH); IR (Neat): 3401, 3117, 2932, 1676, 1600, 1511, 1249, 1174cm-1• .~""~ Example3 Step-2 trans-2-Imidazol-1-ylmethyl-indan-1-ol (3a, R=H,n=I, X=CH). Sodium boroliydride (30 I mmol) was added in portions to a ~tirred and cooled solution of 2a (R =H, n= I, X =CH) (I 0 . i . mmol) in methanol (10 mL) over a.period of 30 minutes. The reaction mixture -~as fmther stirred at room temperature for 3 h. Methanol was distilled under reduced pr~ssure. The . t I residue was triturated with water (15 mL) and extracted with dichloromethane (10 mL x 3). ! The combined organic layer was dried over sodium sulphate and concentrated to give the I crude product which was purified by column chromatography using methanol:chldroform (1: . . ! 99) as an eluant to provide the trans hydroxyl compounds (3a) in 91.6% yielcL m.p.l07- 1090C; MS (ESI) n1/z: 215 ({M+1t, 40%); 1H NMR (200 MHz, CDCh): 8 2.61-3.14 (m, I 3H, H-2, H-3), 4.53-4.68 (m, 2H, N-CH2), 4.87-4.91 (d, 1H, J=7.4Hz, H-1), 6.93-7.02 (m, ! 2H, ArH), 7.16-7.53 (m, 5H, ArH); IR(KBr): 3381,3013,2931,1454,1218, I033,i767cm-1• I Example 4 Step-2 trans-2-Imidazol-1-ylmethyl-1,2,3,4-tetrahydro-2H-naphthalen-1-ol (3b,R=H,n=~ X=CH). Sodium borohydride (30 mmol) was added in portions to a stirred and cooled solution of i 2b(R=H,n=2, X=CH) (10 mmol) in methanol (10 mL) over a period of 30 min·Jtes. The reaction mixture was further stirred at room temperature for 3 h. Methanol was distiJled under reduced pressure. The residue was triturated with water (15 mL) and extrac:ted with . ! dichloromethane (1 0 mL x 3). The combined organic layer was dried over sodium [sulphate and concentrated to give the crude product which was purified by column chroma~ograJ:hy using methanol:chloroform (1: 99) as an eluant to provide the trans hydroxyl compounds ! (3b) in 99% yield (trans: cis); Yield 84% (trans); m.p.92-94°C; MS (ESI) rnlz: 229 C(M+ It, IOO%); 1 H NMR (200 MHz, CDCh): 8 1.48-1.52 {m, IH, H-2), 1.88-2.10 (m, 2ij, H-3), II 2.76-2.83 (m, 2H, H-4), 4.15-4.25 (m, 2H, N-CH2), 4.33-4.37 (d, 1H, J=8.97Hz, OH-CH), I I 6.91-7.22 (m; 5H, ArH), 7.45 (s, 1H, imidazole-H), 7.50-7.53 (s, 1H, imidazole-H); IR (KBr): 3116,2933,23.65, 1613, 1588, 1498, 1458,2138, 1108, 1082, 1039, 754cm-1. Example 5 Step-3 trans-(.1-( 4-Trifiuoromethy 1-phenoxy )-1 ,2,3,4-tetrahydronaph thalen-2-ylmetftyl)-lHimidazole (4b, R=H, n=2, R'= 4-CF3, X=CH). A solution of hydroxyl compound (3b, ... ~ R=H,n=2, X=CH)) (0,622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) !was added dropwise to stirred susp~nsion of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was allowed to stir at room temperature for 2min. 4-Fluorobenzotrifluoride (0.622mmol) in DMSO (O.?mL) was added dropwise to the reaction mixture under stirring. It The dark coloured reaction mixture was stirred for 15min to 1.5h for the compl~tion of the reaction. The reaction was discontinued and treated with water (15 mL) and extracted with • I ethyl acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6), i dried over sodium sulphate and concentrated to give the crude product \fhich was chromatographed on a silica gel column using chloroform or methanol:chloroform (1 :99%) as an eluent to get the desired trans ether (4b) in 77.9% yield MS (ESI) m/z: 37J ((M+1t, I . ' 100%); H NMR (200 MHz, CDCh): 8 1.65-1.77 (m, 1H, H-2), 2.08-2.17 (m, 11H, H-3), . i 2.59-2.61 (m, 1H, H-3), 2.88-2.98 (m, 2H, Ar-CH2), 3.92-4.15 (m, 2H, N-CH2), 5.1~1 1-5.19 (d, 1H, J=6.33Hz, 0-CH), 6.87-7.05 (m, 3H, ArH), 7.11 (s, 1H, .t\rH), 7.21-7.26 (m, 4H, ArH), 7.39 (s, 1H, ArH), 7.52-7.56 (d, 2H, J=8.41Hz, ArH); IR (Neat): 3400, 2929, 2368, 1598, 1351, 1081, 1036, 752cm-1. Anal. .Calcd. for C21H19F3N20: C, 67.74; H, 5.10;. N, 7.52. , . . Found: C, 67.66; H, 5.21; N, 7.47. 1 Example 6 Step-3 trans 1-(1-(4-Acetyl-phenoxy)-1,2,3,4-tetrahydronapltthalen-2-ylmethyl)-1 H-imidazole ( 4a, I R=H, R'=COCH3, n=2, X=CH). A solution of hydroxyl compound (3b, R=H, n=2; X=CH) (0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added dropwise te stirred I suspension of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was allow~d to stir at room temperature for 2min. 4-Fluoroacetophenone (0.622mmol) in DMSO · (0.5mL) was added dropwise to the above reaction mixture under stirring. The dark coloured 12 reaction mixture was stirred for 15min for the completion of the reaction. The reaction was discontinued and treated with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with water (1 0 mL x 6), dried over sodium sulphate and concentrated to give the crude product which was chromatographed on a silica gel column using chloroform or methanol:chloroform (1 :99%) as an eluent to get the desired trans ethers (4a) in 85% yield. MS (ESI) rnlz: 346 ((M+1t, 100%); 1H NMR (200 MHz, CDCh): 8 1.63-1.74 (m, 1H, H-2), 2.08-2.14 (m, 1H, H-3), 2.56-2.64 (m, 4H, H-3, COCH3), 2.86-2.94 (rri~2H, Ar-CH2), 4.00-4.09 (m, 2H, N-CH2), 5.15-5.19 (d, IH, J=6.38Hz, 0-CH), 6.86-6.89 (m, 2H,~ ArH), 7.11-7.27 (m, 2H, ArH), 7.36-7.39 (d, IH, J=6.08Hz, ArH), 7.48- 7.52 (d, 2H, J=8.14Hz, ArH), 7.91-7.95 (d, 2H, J=9.18Hz, ArH), 8.07-8.11 (d, 2H, J=8.26Hz, ArH); IR(Neat): 3115,2931,1677,1600,1511,1360,1249,1174, 753cm-1.i\nal. ti Calcd. For C22H22N202: C, 76.30; H, 6.35; N, 8.09. Found: C, 76.29; H, 6.38; N, 7.96. Similarly compounds 4c-4n and 4y were prepared using corresponding hydroxyl compounds (3) and substituted aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4- fluoronitrobenzene and 4-fluoroacetophenone . Example 7 Step-3. · trans-1-(1-( 4-Trifluoromethyl-phenoxy )-1 ,2,3,4~tet(ahydronaphthalen-2-ylmethyl)-1 H{ 1,2,3jtriazole (4p, R=H, R'=4-CF3, n=2, X=N). A sol~tion of hydroxyl compound (3b', R=H, n=2, X=N) (0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added dropwise . to stirred suspension of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was allowed to stir at room temperature for 2min. 4-Fluorobenzotrifluoride (0.622mmol) in DMSO (0.5mL) was added dropwise to the above reaction mixture under stirring, The dark coloured reaction mixture was stirred for 1.5h for the completion of the reaction. The reaction was discontinued and treated with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6), dried over sodium sulphate and concentrated to give ·the crude product which was chromatographed on a silica gel column using chloroform or methanol:chloroform (I :99%) as an eluent to get the desired trans ethers (4p) in 72.2% yield. MS (ESI) rnlz: 374 ((M+It, 100%), 375 ((M+2t, 22%); 1H NMR (200 MHz, CDCh): 8 1.67-1.74 (m, IH, H:·2), 2:09- 2.11 (m, 1H, H-3), 2.78-2.99 (m, 3H, H-3, Ar-CH2), 4.46-4.52 (m, 2H, N-CH2), 5.27-5.30 (d, 13 IH, J=6.72Hz, 0-CH), 6.93-6.98 (d, 2H, J=8.56Hz, ArH), 7.16-7.29 (m, 4H, ArH), 7.47-7.57 i ' (m, 3H, ArH), 7.71-7.74 (m, IH, ArH); IR (Neat): 3374, 2930, 1613, 1515, 1457, 1327, 1247, 1163, 1068, 755cm-1. Arlal. Calcd. For C2oH1sN30F3: C, 64.34; H, 4.8~; N, 11.26. Found: C, 64.72; H, 4.98; N, 10.97. I I . Similarly' compounds 4o, 4q, 4r were prepared using corresponding hydroxyl corrlpounds 1 (3b', R=H or Cl, n=2, X=N) and substituted aryl fluorides selected from the grou~ of 4- fluorobenzotrifluoride, 4-fluoronitrobenzene and 4-fluoroacetophenone (Step-3). : Example 8 Step-3 1-(1-(4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazo/e (4u, R=H, R'=4-N02, n=1, X=H) .. A solution of hydroxyl compound (3a, R=H, n=l, X=CH) (0.622mmol) in dimethyl sulphoxiJe (DMSO) (0.5mL) was added dropwise to stirred suspension of potassihm tertiary I ' butoxide (0.933mmol) in DMSO (0.5mL) and it was allowed to stir at room temp 1 eratureJor I 2min. 4-Fluoronitrobenzene (0.622mmol) in DMSO (0.5mL) was added dropwise to the . above reaction mixture under stirring. The dark coloured reaction mixture was i1stirred for 15min to 1.5h for the completion of the reaction. The reactiqn was discontinued ~nd treated with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combin~d organic layer was washed with water (1 0 mL x 6), dried over sodium sulphate and conc~ntrated to give th~ crude product which was chromatographed on a silica gel column using chloroform I or methanol:chloroform (1 :99%) as an eluent to get the desired trans ether ( 4u) in 82.1% yield. MS (ESI) m/z: 336 ((M+ It, 100%), 337 ((M+2t, 24%); 1H NMR (200 MHz, CDC~]): ' o 2.57-2.68 (dd, IH, J=l5.92Hz, J=5.06Hz, H-3), 2.92-3.01 (m, 1H, H-2), 3.18-3.3•) (dd, 1H, I J=15.92Hz, J=7.5Hz, H-3), 3.99-4.06 (m, 2H, N-CH2), 5.47-5.49 (d, 1H, J=4,08Hz, 0-CH), J . 6.68-6.72 (d, 2H, J=7.12Hz, ArH), 6.90 (s, IH, ArH), 7.06 (s, 1H, ArH), 7.19-7.39 (m, 3H, ArH), 7.45-7.53 (m, 2H, ArH), 8.06-8.11 (d, 2H, J=9.26Hz, ArH), 8.28-8.33 (d, 1H, . . 'I J=9.08Hz,. ArH); IR (Neat): 3421, 1594, 1511, 1341, 1252, 1220, 663cm-1: Anal. dalcd. For C,9H17N303: C, 68.05; H, 5.07; N, 12.53. Found: C, 68.12; H, 5.01; N, 12.19. Similarly compounds 4s-4t were prepared using hydroxyl compound (3a) and substituted I aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4-fluoronitroben.Zene and . ' 4-f1 uoroacetophenone. 14 Example 9 Step-3 J-(l-(4-Trijluoromethyl-phenoxy)-indan-2-ylmethyl)-JH-{1,2,3]triazole ( 4w, R=H, R'=4-CF3, n=1, X=N). A solution of hydroxyl compound (3a', R=H, n=l, X=N) (0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added dropwise to stirred suspension of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was allowed to stir at room temperature for 2min. 4-fluorobenzotrifluoride (0.622mmol) in DMSO (0.5mL) was added dropwise to the above reaction mixture under stirring. The dark coloured reaction mixture was stirred for I h for the completion of the reaction. The reaction was discontinued . and treated with water ( 15 mL) and extracted with ethyl· acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6), ~ried over sodium sulphate and concentrated to give the crude product which was chromatographed on a silica gel column using chloroform or methanol:chloroform (1:99%) as an eluent to get the desired trans ethers (4w) in 76% yield. MS (ESI) m/z: 360 ((M+1t, 100%); 1H NMR (200 MHz, CDCh): 8 2.70-2.81 (dd, IH, J=I5.4Hz, J=5.36Hz, H-3), 3.07-3.35 (m, 2H, H-2, H-3), 4.57-4.60 (d, 2H, J=6.94Hz, N-CH2), 5.69- 5.72 (d, IH, J=4.78Hz, 0-CH), 6.86-6.90 (d, 2H, J=8.68Hz, ArH ortho to 0), 7.19-7.38 (m, 4H, ArH), 7.47-7.58 (m, 3H, ArH), 7.73 (s, IH, ArH); IR (Neat): 3021, 2367, 1592, 1341, 1253, 769cm-1. Anal. Calcd. For C19H16N30F3: C, 63.50; H, 4.45; N, 11.69. Found: C, 63.32; H, 5.01; N, 12.05·. Similarly compound 4v-4x were prepared using hydroxyl compound (3a') and substituted aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4-fluoronitrobenzene and 4-fluoroacetophenone (step-3). The pharmacological evaluation of the test compounds of general formula 4 was carried out by the following protocol. Antileishmanial Activity Parasite: The Leishmania donovani promastigotes (MHOM/IN/Dd8; a WHO reference strain originally obtained from Imperial college, London in 1979 through the courtesy of Prof. P. C. C. Garnham Imperial College, London (U.K.)) were transfected with fire fly luciferase gene, 15 and the transfectants were maintained in medium 199 (Sigma Chemical Co,, USA) i supplemented with 10% foetal calf serum (GIBCO) and gentamycin ( 41Jg/ml) solutfon (Sigma) under pressure of G 418 (Sigma)(Ashutosh, Gupta Suman, Ramesh, Sundar S. arid Goyal N. Antimicrob. Agents and Chemother., 49 2005) 3776-3783). Preparation of Compounds: Stock solutions of compounds were initially prepared in DMSO at 1 Omg/rril cone. and further diluted two folds with fresh complete medium. Antipromastigote activity: I I The in vitro effect of the compounds on the growth of promastigotes was ~ssessed by I monitoring the luciferase activity of viable cells after treatment. The transgenic prcinastigotes of late log phase were seeded at lx 105 /2001Jl medium 199 well in 96 well fla1 bottomed I microtitre (MT) plates (CELLST AR) and incubated for 96 hr in medium alone, or in the . j presence of serial dilutions of drugs ( 0.25 - lO IJg/ml ) in DMSO. Parallel dilutions:', of DMSO I were used as controls. After incubation, an aliquot (50 !Jl) of promastigote suspehsion was aspirated from each well of a 96 well plate and mixed with an equal volume of stileady Glo1 ,, reagent (Promega) and luminescence was measured by a luminometer~ The values were expressed as relative luminescence unit (RLU). The inhibition of parasitic growth is determined by comparison of the luciferase activity of drug treated parasites wi:h that of ' I untreated controls by the general formula: : N-n x 100 Percentage Inhibition = N Where N is average relative luminescence unit (RLU) of control wells; and n is average RLU I, of treated wells. I • I Antiamastigote activity: .: I I For assessing the activity of compounds against the amastigote stage of the liparasite, I I mouse macrophage cell line (J-774A.l) infected with promastigotes expressing h,1ciferase I firefly reporter gene was used. Cells were seeded in a 96-well plate (1.5x1 04cell/1 O~!Jllwell) in RPMI-1640 containing 10% fetal calf serum and the plates were incubated at 'iJoc in a ! C02 incubator. After 24h, the medium was replaced with fresh medium cohtaining I I 16 . stationary-phase promastigotes (2.25x105/100J..tl/well). Promastigotes invades the macrophage and are transformed· into amastigote. The test material in appropriate concentrations (0.25-1 OJ..lg/ml). in complete medium was added after replacing the previous medium and the plates were incubated at 37°C in a C02 incubator for 72 hrs. After incubation, the drug-containing medium was decanted and 50J..ll PBS was added in each well and mixed with an equal volume of steady Glo reagent. After gentle shaking for 1-2 minute, the reading was taken in a luminometer. The inhibition of parasitic growth is determined by comparison· of the luciferase activity of drug treated parasites with that of untreated controls as described above. After assessing activity of compounds against amastigotes, Cytotoxicity assay were carried out using J-774 cell line. Cytotoxicity assay: The cell viability was determined using the MTT assay (Huber,W., Koella.J.C, Acta Tropica, 55 (1993) 257-261). Exponentially growing cells J774.A-1 (1 x104cells /100J..tl/well) were incubated with different drug concentrations (30ng-1 00 J..lg/ml) for 72 hours and were incubated at 37°c in a humidified mixture of C02 and 95 % air in an incubator. Stock solutions of compounds were initially dissolved in DMSO and further diluted three fold with fresh complete medium. After incubation, 25 J..ll of MTT reagent (5mg/ml) in PBS medium, followed by syringe filtration, was added to each well and incubated at 3 7 °C for 2 hours. At the end of the incubation period, the supernatant is removed by. tilting plate completely without disturbing cell layer and 150 J..ll of pure DMSO were added to each well. After 15 min. of shaking the readings were recorded as absorbance at 544 nm on a micro plate reader. The cytotoxic effects were expressed as 50% lethal dose, i.e. as the concentration of a comp.ound which provoked a 50% reduction in cell viability compared to cell in culture medium alone. Selective Index: The selective index (S.I.) were .calculated using the following equation S.I. = ICso (J-774 A-1 cells) I ICso (Leishmania amastigotes) In- Vivo Activity 17 The in-vivo ieishmanicidal activity was determined in golden hamsters (.Mesocricetus ·auretus) infected with MHOM/IN/80/Dd8 strain of L. donovani obtained through the ccurtesy ofP.C.C. Garnham, Imperial College, London (U.K.) in 1979. For in-vivo evaluation of compounds, the method of Beveridge [S.Bevridge,In: R.J Shnitzer,F.I.Hanoking (Eds), Experimental Chemotherapy, vol.l ,(1963),257-280.] as modified by Bhatnagar et al. [S.Bhatnagar, P.Y.Guru, J.C.Katiyar, R.Srivastava, A.Mukherjee, M.S.Akhtar, M.Seth, A.P.Bhaduri, Ind.JMed.Res. 89(1989) 439.] and Gupta et al.[ S.Gupta, S.Tiwari, A.P.Bhaduri and G.K.Jain, Ada Tropica, 84(2002),165-173.] was employed. Golden hamsters (of either sex) weighing 40-45g were infected intracardially with 1x 107 amastigotes per animal. The infection is well adapted to the hamster model and establishes itself in 15-20 days. Meanwhile, hamsters gain weight (65-75 g) and can be subjected to repeated spleen biopsies. Pretreatment spleen biopsy in all the animals was carried oot to assess the degree of infection. The animals with + 1 infection (5-15 amastigotes I 100 spleen cell nuclei) were included in the chemotherapeutic trials. The infecte~ animals are ·randomized into several groups on the basis of their parasitic burdens. Four to six animals were used for each test sample. Drug treatment by i.p. route is initiated after 2 days of biopsy and continued for 10 consecutive days. Post-treatment biopsies are done on day 7 of the last drug administration and amastigote counts are assessed by Giemsa staining. In~enshy of infection in both , treated and untreated animals , as also the initial count in treated animals is compared and the efficacy is expressed in terms of percentage inhibition (PI) using the following formula:- PI= ANAT x 100/INAT x TIUC Where PI is Percent Inhibition of amastigotes multiplication ANA T is Actual Number of Amastigotes in Treated animals INAT is Initial Number of Amastigotes in Treated animals and TIUC is Times Increase of parasites in Untreated Control animals. The compounds synthesized were tested in Leishmania donovani m hamster model at 50mg/kg x 10, i.p. dose as shown in Table-1. 18 Data of two replicates were pooled for calculation of mean percent inhibition. Standard drugs: Sodiurri stibogluconate (SSG) was used in each trial as experimental control. Data analysis 1. IC50 were calculated by Probit analysis (Finney. D.J, Probit Analysis (1971), ,Cambridge Univ. Press 3rdedn.). Criteria for significant activity: Compounds having IC5o 50 were picked up for in vivo evaluation. Table 1. In Vitro and in Vivo antileishmanial activity of Aryloxy benzocycloalkyl azoles ( 4):- Sl. Compound In vitro Assessment Cytotoxicity . Selective number Anti Anti Cone. 500/o index No. promastigo amastigot CCso (SI) te e activity. (Jlg/ml) activity ICso ICso (f.!g/ml) (Jlg/ml) I 4a 1.76 0.84 37.76 44.94 2 4b 0.28 0.551 15.98 29 .3 4c l.l3 0.56 53.03 94.69 4 4d 1.59 1.40 60.95 43.5 5 4e 0.60 1.40 4.04 2.88 6 4f 0.58 3.39 16.37 4.82 7 4g 1.86 0.538 23.16 43 19 In vivo activity (Dose- 50mg/kg x 5 i.p.) Percent inhibition 52.5 : 8 4h 0.31 0.66 74.13 112.1 82.08 9 4i 0.32 0.44 29.41 66.84 60.4 10 4j 0.22 1.32 16.47 12.47 II 4k 1.49 2.16 25.51 11.81 12 41 r.I2 2.54 16.83 6.62 13 4m 0.29 0.53 17.86 33.69 14 4n 0.289 0.34 13.58 40.0 15 4o INACTIVE INACTIVE - NI 16 4p 3.20 J INACTIVE - NI 17 4q 3.35 INACTIVE - NI 18 4r 2.89 0.71 21.33 30.04 19 4s 2.82 INACTIVE 69.95 NI 20 4t 0.39 1.04 13.20 12.7 21 4u 1.91 0.62. 54.79 88.37 56.4 22 4v INACTIVE ND - NI 23 4w 3.70 0.88 20.09 22.82 24 4x 3.75 INACTIVE - NI 25 4y 1.70 0.5 17.07 35.4 Stand. Sodium 946.62 33.99 99 2.9 89 stibogluconate 20 Advantages; Compound 4h has similar antileishmanial efficacy compared to the standard drug sodium stibogluconate and has significantly high selectivity index. All the representative novel aryloxy benzocycloalkyl azoles 4a to 4y are nontoxic m cytotoxicity assay. 21 We claim; 1. A Novel aryloxy benzocycloalkyl azoles of general formula 4, isomers, derivatives ·and salts thereof, R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 X=CH,N n=l,2 ~,.::.,_ wher~in R is selected from a group consisting of H, halogen, alkyl or alkoxy ; R'. is selected from a group consisting of CF3, COCH3, CHO, COOR, CN, N02, alkyl, alkoxy or amide; X is CH or N; n=l or 2. 2. A novel compound as claimed in claim I wherein the structural formula comprising; X=CH, wherein R is selected from a groupconsisting ofH, halogen, alkyl or alkoxy; R' is selected from a group consisting ofCF3, COCH3, CHO, COOR, CN, N02, alkyl, alkoxy or amide; X is CH or N; n=l or 2. R~:) R'-o: R·= H, Me, Cl, F, Br,OCH3 R' = CF 3, COCH3, N02 n =I, 2 3. A novel compound as claimed in claim I wherein the structural formula comprising; X=N, wherein R is selected from a group consisting of H, halogen, alkyl or alkoxy ; R' is selected from a group consisting ofCF3, COCH3, CHO, COOR, CN, N02• alkyl, alkoxy or amide; X is N; n=l or 2. R~A N ,,N 'N R'v- ~0 4 R = H, Me, Cl, F, Br,OCH3 R' = CF3, COCH3, N02 n = 1,2 22 4. A novel compounds as claimed in claim 1 wherein the representative cqmpounds of formula 4 comprising; I 4a. 1-( 1-( 4-Acety !-phenoxy )-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethy 1)-:1 Himidazole. 4b. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl) - ' 1H-imidazole. 4c. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Eimidazole. 4d. 1-(1-( 4-Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ytmethyl)- 1 if-imidazole. . i' I 4e. 1-(5-Methyl-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphtl1ftlen-2- ylmethyl)-1H-imidazole. 4f. 1-(5-Methyl-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole 4g. 1-(1 .:( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethy1)- 1H-imidazole. 4h. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2- ylmethyl)-1 H-imidazole. 4i. 1-(5-Chloro-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmetpyl)-J Himidazole. 4j. i -(5-Fluoro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthah~n-2- ylmethyl)-1H-imidazole. • i 4k. 1-(5-Fluoro-1-( 4-mtro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylme~yl)-1Himidazole. 41. 1-( 1-( 4-Acetyl-phenoxy)-5-bromo-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- 1, 1H-imidazole. I 4m. 1-(5-Bromo-1-(4-trifluoromethyl-phenoxy)-1,2,3,4-tetrahydronaphthal~n-2- ylmethyl)-lH-imidazole. I I 4n. 1-(5-Bromo-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmet~yl)-1 Himidazole. 23 4o. 1-(1-( 4-Acetyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-'1H[ 1 ,2,3 ]triazole. 4p. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-yJmethyl)- 1 H-[ 1 ,2 ,3 ]triazole. 4q. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H[ 1 ,2,3]triazole . 4r. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthilen-2- ;~.. .... ylmethyl)-1H-[1 ,2,3]triazole 4s. 1-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-1H-imidazol~. 4t. 1-( 1-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1 H-irp.idazole . 4u. 1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole. :. lt 4v. l-(l-(4-Acetyl-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3]triazole. 4w. 1-(1-(4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3]triazble. I I 4x. 1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3)triazole. ' 4y: 1-( 6-methoxy-1-( 4-trifluoromethyl-phenoxy )-1 ,2,3 ,4-tetrahydronaphtl\.alen-2- ylmethyl)-1 H-imidazole. 5. A novel compound as claimed in claim antleishmanial agents. wherein the compounds are useful as I 'I 6. A process for the preparation of novel aryloxy benzocycloalkyl azoles Qf general formula 4 which comprises; a. reacting a substituted pyrrolidinylmethyl ketone of general formula 1, • • I R~o O HCI imidazole/triazole R ~) n [=Step-1 ~N ... >('N 0 1 2 wherein R = H, halogen, alkyl or alkoxy; n = 1 or 2 with imidazole/ triazole in • I water alcohol mixture to give the azolylmethyl ketone (2) wherein X =CH'or N, . ' b. reacting the azolylmethyl ketone· (2) with a reducing agent selecte~ from a I group consisting of sodium borohydride, sodium triacetoxy borohydride, I, aluminium isopropoxide, aluminium hydrides to give the amino alcnhol (3, X=CH or N) with TRANS stereoselectivity (8.5: 1.5), 24 c. reacting the compound 3 with potassium tertiary butoxide (KtBuO), Sodium hydride(NaH), butyl lithium(BuLi) in dimethyl sulfoxide (DMSO), dimethyl formamide(DMF) and followed by addition of appropriately substituted aryl fluoride in the presence an aprotic solvent of DMSO, DMF to give the corresponding compound of the formula 4 in trans isomeric form; wherein R' = H,.4-CF3, 4-COCHJ or 4-N02 and isolating the compounds by conventional methods. 7. A process as claimed in claim 12 wherein the base us\d is selected from the group consisting of sodium hydride, potassium tertiary butoxide (KtBuO), butyl lithium. 8. A process as claimed in claim I2 wherein the novel aryloxy benzocycloalkyl azoles of general formula 4 are in substantially pure TRANS isomeric form. 9. A pharmaceutical composition comprising a pharmaceutically effective amount of the compound of formula 4 as claimed in claim I optionally along with the pharmaceutically acceptable excepient, diluent. 10. Novel aryloxy benzocycloalkyl azoles, process of preparation thereof, substantially as herein described with reference to the exampies accompanying the specification.

Full Text

FIELD OF INVENTION
The present invention relates to novel aryloxy benzocycloalkyl azoles. The presep.t invention ·
. I
particularly relates to the synthesis of novel aryloxy benzocycloalkyl azole deri\atives as of
formula 4 and their use _as potent antileishmanial. agents for the treatment 1of visceral
leishmaniasis.
R~~)n FI b N ,,N
.:. 'x
()
0
R'-
h
4
BACKGROUND OF INVENTION
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
·x=CH,N
n =I, 2
Leishmaniases are parasitic diseases transmitted by the bite of the infect.~d female
phlebotomine sand fly and manifest with visceral, cutaneous, and mucocutane~us forms.
I
They are a significant cause of morbidity and mortality in the developing coundies of the
world, and they affect about 2 million people per annum (TOR-Leishmaniasis 2007 Update)
mostly in tropical and subtropical regions, the geographical distribution being limited by the
I
. biotope of the insect vector (P.J. Guerin, P. Olliaro, S. Sundar, M. Boelaert, S.L.I Croft, P.
I
Desjeux, M.K.Wasunna, A.D. Bryceson, Lancet Infect. Dis. 2 (2002) 494-501). However,
. ' ~
official data underestimate the reality of the human affliction.
Of the various types, visceral leishmaniasis (VL), known as kala-azar (black fever) .)r Assam
',]
fever is caused by Leishmania donovani and is transmitted by phlebotomine s1md flies
i
(Phlebtomus argentipes). VL is characterized by irregular bouts of fever, substanti~l weight
loss, swelling of the spleen and liver, and anaemia (occasionally serious). If left untreated,
I .
• I
the fatality rate in developing_ countries can be as high as I 00% within 2 years. It is _preval·ent
mostly_ in eastern India and still remains problematic as early diagnosis is difftbult and
treatment often results in drug resistance.
Chemotherapy. for these parasitic diseases is generally ineffective. mainly duei
1
to the
emergence of drug-resistant strains and toxicity of the therapeutic agents. The pentavalent
2
antimonials are widely used as pnmary therapy ·whereas alternative drtigs include
I
amphotericin B, pentamidine, paromomycin, and azoles. Azole antifungal drug3 have been
used as antileishmanial agents since 1980s [J.A. Maertens, Clin. Microbiol. Infect. i 0 (2004)
I
1-10]. However, resistance to antimonials is common and treatments with amrhotericin B
and pentamidine are plagued by severe toxic side effects. Newly introduced first drally active
drug miltefosine is quite effective but shows teratogenic effects and cannot be used in the
pregnant women. Though th~re have been commendable research efforts towards ~lucidating
the basic biology of Leishmania parasites, little progress has been made in the field of
therapeutic interest (F. Chappuis, S. Sunder,· H. Ghalib. S.Rijai., R. W. Peeling, i Alavaran,
I
M. Boelaert, Nature Reviews Microbiology 5, Nov. 2007). Drug resistance, high t::>xicity and
high treatment costs necessitate the need for novel therapeutics.
In order to find new drugs with antileislunanial activity the aryloxy benzocycloa\kyl azoles
I
have been synthesized and screened in vitro (against promasdgote/ and intracellular
amastigotes) and in vivo (against Leishmania donovani./Haemester model).
OBJECTS OF THE INVENTION
' The main objective of the present invention IS to provide novel ',substituted
benzocycloalkyl azoles.
More particularly the present invention relates to the novel aryloxy benzo~ycloalkyl
azoles. These compounds are potentially useful in the treatment of leishinaniasis.
Another objective of the present invention is to provide a process for the preparation
of novel aryloxy benzocycloalkyl azoles of the general formula 4.
Summary of the invention
The present invention relates to novel aryloxy benzocycloalkyl azoles of general
formula 4 wherein R is selected from the group consisting of R =H, Me, Cl, F and Er etc.; R 1
= CF3, COCH3, N02 etc.; X= HorN etc.; n=1 or 2.
3
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
X=CH, N
n =I, 2
I
The compounds of general formula 4 are useful for the treatment of leishmkniasis. The
I
representative novel aryloxy benzocycloalkyl azoles 4a to 4y are nontoxic in bytotoxicity
assay.
Detailed description of the invention ,I
'i
Accordingly, the present invention provides novel aryloxy benzocycloalky:l azoles of
!
general formula 4, isomers, derivatives and salts thereof,
R = H, Me, Cl,IF, Br,OCH3
R' = CF3, COQ-!3, N02
I
X=CH,N
n =I, 2
i
wherein R is selected from a group consisting of H, halogen, alkyl or alk~xy ; R' is
selected from a group consisting of CF3, COCH3, CHO, COOR, CN, N02, alKyl, alkoxy
or amide; X is CH or N; n=l or 2.
In an embodiment of the present invention wherein the structural formula c•hmprising;
I
X=CH, wherein R is selected from a group consisting of H, halogen, alkyl or alkoxy; R'
I
I
is selected from a group consisting of CF3, COCH3, CHO, COOR, CN, "t\·p2, alkyl,
alkoxy or amide; X is CH or N; n=l or 2 .
.R C- c;t)n~ 1 ' r=I ~ =- N~N
R'004
R= H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
n =I, 2
I
In another embodiment of the. present invention wherein the structural • formula
'
comprising; X=N, wherein R is selected from a group consisting of H, halogen.; alkyl or .I
alkoxy; R' is selected from a group consisting of CF3, COCH3, c·Ho, COOR, C:N, N02,
alkyl, alkoxy or amide; X is N; n=l or 2.
4
RO:;tF\ N ,,N.
'N
R'v- ~0. 4
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
n= 1, 2
In yet another embodiment of present invention wherein the subject novel compounds
are the representative compounds of formula 4 are as follows:-
4a. 1-(1-( 4-Acetyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole.
4b. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl) -INimidazole.
4c. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-lH-imidazole.
4d. 1-( 1-( 4-Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole
.
. 4e. 1-(5-Methyl-1-{ 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-
1H-imidazole .
4f. 1-(5-Methyl-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole
4g. 1-(1-( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole.
4h. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-
1 H-imidazole.
4i. 1-(5-Chloro-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole.
4j. 1-(5-Fluoro-1-( 4-trifluoroinethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-lHimidazole.
4k. 1-(5-Fluoro-1-( 4-nitro-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 Himidazole.
41. 1-(1-( 4-Acetyl-phenoxy)-5-bromo-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole.
4m. 1-(5-Bromo-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-
1 H-imidazole.
5
4n. I-(5-Bromo-I-( 4-nitro-phenoxy)-I ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-I Himidazole.
4o. I-( I-( 4-Acetyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-IH-[ I ,2,3 ~triazole.
' 4p. I-(1-( 4-Trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)- iH-
(I ,2,3]triazole. 1
4q. I-(1-( 4-Nitro-phenoxy)-I ,2,3,4~tetrahydronaphthalen-2-ylmethyl)-IH-[I ,2,3]t~iazole .
4r. I-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-
• .;;';...._ I •
IH-[I :2,3]triazole
4s. I-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-IH-imidazole.
4t. I-(I-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-IH-imidazole .
4u. I-(I-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-IH-imidazole.
4v. 1-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-lH-[ 1 ,2,3]triaiole.
4w. I-(1-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1H-[I,2,3]triazole.
4x. I-(1-(4-Nitro-phenoxy)-indan-2-ylmethyl)-IH-[ 1 ,2,3)triazole.
4y: 1-(6-methoxy-I-( 4-trifluoromethyl-phenoxy)-I ,2,3,4-tetrahydronaphthalen-2-ylfnethyl)I
H-imidazole.
In a further embodiment of the present invention the compounds of formulA 4 posses .
·'
interesting pharmacological properties. In particular they are useful as antileishmamal agents.
I
In a further embodiment of the present invention wherein the compound exhitited more
than 80% inhibition of parasites in vivo(L.donovani!Hamstermodel) at a do~e of 50
mg/kg x 5 i.p. dose concentration.
In a further embodiment of the present invention wherein the CC5o of the compounds is
ranging between 4.4 to 7 4.13 f.!g/ml.
In a further embodiment of the present invention wherein the IC5o of the compounds is
!
ranging between -0.34 to 3.39-f..lg/ml.
In a further embodiment of the present invention wherein all the representative novel
aryloxy benzocycloalkyl azoles 4a to 4y as claimed in claim I are nontoxic in
cytotoxicity assay.
In a further embodiment of the present invention wherein aryloxy benzocycloalkyl
azoles 4a, . 4b, 4c, 4d, 4g, 4h, 4i, 4j, 4k, 4m, 4n, 4r, 4t, 4u, 4w and 4y exhibited
I
6
Selective Index (SI) in the range of 11.8 to 112 based on potent antihistaminial activity
against intracellular amastigotes of L. donovani residing within murine macrophages.
In a further embodiment of the present invention wherein novel compound 4h,
chemically, ( 1-( 5-Chloro-1-( 4-trifluoromethyl-phenoxy )-1 ,2,3 ,4-tetrahydronaphthalen-2-
ylmethyl)-1H-imidazole, showed higher levels of in-vivo antileishmanial activity (82%
inhibition of parasite multiplication) and 4c (1-(1-(4-Nitro-phenoxy)-1,2,3,4-
tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole ), 4i (1-( 5-Chloro-1-( 4-nitro-phenoxy )-
~~. ....
1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole) and 4u (1-(1-( 4-Nitrophenoxy)-
indan-2-ylmethyl)-1H-imidazole) exhibited medium levels of antiJeishmanial
activity with 52.5%, 60.4% and 56.4 % inhibition respectively . in in vivo using
·Leishmania donovani I hamster model. .In a further another embodiment of the present invention novel 1-(1-( 4-Acetylphenoxy
)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole( 4a ), 1-(1-( 4-
. Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4b ), 1-
( 1-( 4-Nitro-phenoxy)~ 1 ,2 ,3, 4-tetrahydronaphthalen-2-ylm~thyl )-1 H-imidazole ( 4c ), 1-( 1-( 4-
Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4d), 1-
( 1-( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 Himidazole(
4g), 1 ;..(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-
ylmethyl)-1 H-imidazole( 4h), 1-( 5 .:Chloro-1-( 4-nitro-phenoxy )-1 ,2,3,4-tetrahydronaphthalen-
2-ylmethyl)-1 H-imidazole( 4i), · 1-( 5-Bronio-1-( 4-trifluoromethyl-phenoxy)-1 ,2,.3 ,4-
tetrahydronaphthalen-2-ylmethyl)- ~ H-imidazole( 4m), 1-(5-Bromo-1-( 4-nitro-phenoxy)-
1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-imidazole( 4n), 1-(5-Chloro-1-( 4-
trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1 H-[1 ,2,3 ]triazole( 4r),
1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole( 4u) and 1-(6-methoxy-1-( 4-
trifluorome.thyl-phenoxy)-1,2,3,4-tetrahydron5lphthalen-2-ylmethyl)-1H-imidazole (4y)
exhibited potent antihistaminial activity against extracellular promastigotes and intracellular
amastigote~ of L. donovani residing within murine macrophages.
Accordingly the present invention relates to a process for the preparation of new aryloxy
benzocycloalkyl azoles of general formula 4.
In general, the compounds of formula 4 may be prepared by chemical reactions
analogously known in the art, the choice of any specific route of preparation being dependent
7
upon a variety of factors e.g. general availability and cost of reactants. In preparing these
compounds standard procedures and techniques which are well known and appreciated by
those of ordinary skill in the art are utilized. For example, compounds of for;:nula 4 can
conveniently.be made according to the general synthetic route outlined in scheme 1, which
comprises of reacting an appropriately substituted pyrrolidinylmethyl ketone 1 wherein R =
H, Me, Cl, F, Br or OCH3; n = I or 2 with imidazole/ triazole in water alcohol mixture to
give the azolylmethyl ketone (2) wherein X = H or N followed by reaction with sodium
·:r--~
borohydride to give the amino alcohol (3) with TRANS stereoselectivity (8.5: 1.5). The
potassium derivative of the amino alcohol 3 which is formed \Jy reacting 3 with potassium
tertiary butoxide (KtBuO) in dimethyl sulfoxide (DMSO) is further reacted with
appropriately substituted aryl fluoride in the presence of DMSO to give the corresponding
. ~
compound of the formula 4 wherein R'=H, 4-CFJ, 4-COCHJ or 4-NOz and isolating the
compounds by conventional methods. The procedure generally results in the TRA).J'S isomer
in substantially pure form.
For example, compounds of the formula (4) can conveniently be made according to
the general synthetic route outlined in scheme 1.
Scheme-l
R ~~)0 .·. o imidazole/triazole ~) r::::=::1 .Q N R_!_ n I ~
· Step-1 1 _g N, ,,N
O HCI X
0
la (n = 1), l b(n = 2) 2a, (n = 1), 2b(n = 2)
_g. N, ,, R~~~·)nF\N
.:. X
. 0 aryl fluoride
R'v- ~ 4
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
X=CH, N
n= I, 2 .
4a: R=H, n=2, R'= 4-COCH3, X=CH
4b: R=H, n=2, R'= 4-CF3, X="=CH
Step-3 OH
3a(n = I), 3b(n = 2)
8
4c: R=H, n=2, R'= 4-N02, X=CH
4d: R=5-CH3, n=2, R'= 4-COCH3, X=CH
4e: R=5-CH3, n=2, R'= 4-CF3, X=CH
4f: R=5-CH3, n=2, R'= 4-N02, X=CH
4g: R=5-CI, n=2, R'= 4-COCH3, X=CH
4h: R=5-CI, n=2, R'= 4-CF3, X=CH
4i: R=5-Cl, n=2, R'= 4-N02, X=CH
4j: R=5-F, n=2, R'= 4-CF3, X=CH
4k: R=5-F, n=2, R'= 4-N02, X=CH
41: R=5-Br, n=2, R'= 4-COCH3, X=CH
4m: R=5-Br, n=2, R'= 4-CF3, X=CH
4n: R=5-Br, n=2, R'= 4-N02, X=CH
4o: R=H, n=2, R'= 4-COCHJ, X=N
4p: R=H, n=2, R'= 4-CF3, X=N
4q: R=H, n=2, R'= 4-N02, X=N
4r: R=Cl, n=2, R'= 4-CF3, X=N
4s: R=H, n=l, R'= 4-COCH3, X=CH
4t: R=H, n=l, R'= 4-CF3, X=CH
4u: R=H, n=I, R'=4-N02, X=CH
4v: R=H, n=I, R'= 4-COCH3, X=N
4w: R=H, n=l, R'= 4-CF3, X=N
4x: R=H, n=I, R',;, 4-N02, X=N
4y: R=6-0CH3, n~2, R'= 4-CF3, X=CH
In yet another embodiment of present invention the novel aryloxy benzocycloalkyl ·
azoles have exhibited inhibition of parasites in-vitro at concentration ranging from 0.25 to 10
Jlg/ml.
In a preferred embodiment of present invention all the novel aryloxy benzocycloalkyl
azoles (4a-4y) were found nontoxic in cytotoxicity assay.
In a further preferred embodiment of the present invention 1-( 5-Chloro-1-{ 4-
trifluoromethyl-phenoxy)-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethyl)-1 H-.imidazole( 4h), 1-(1-
( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4c), 1-(5-Chloro-
1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H-imidazole( 4i) and 1-(1-
9
(4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole(4u) emerged as most potent!compounds
I
in this series ( on the basis of significant SI). I
In a still preferred embodiment of the present invention 4h, 4c, 4i arid 4u were
assessed in vivo using Leishmania donovani I haemester model. The com,pound 4h,
' chemically, (1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-
ylmethyl)-1 H-imidazole, showed remarkable antileishmanial activity · (82% inpibition of
. '
I
parasite multiplication) and the other three compounds exhibited medium activity viz:- 4c.
(52.5%), 4i. (60.4%) and 4u (56.4 %) inhibition respectively.
In yet another embodiment of pre;;;ent invention the bioactivity of compound 4h,
chemically, 1-( 5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-
!
ylmethyl)-1H-imidazole was comparable to tl\e reference compound Sodium stibogluconate.
. ' .
The following examples are given by the way of illustration and should net be construed
to limit the scope of present invention.
Example 1
Step-1
2-Imidazol-1-ylmethyl-indan-1-one (2a, R=H, n=1, X=CH). A mixture of 2-py~rolidin-1-
ylmethyl-indan-1-one · (la, R=H, n=1)(4.11mmol) and imidazole (4.93mmol) in
I
ethanol:water (2:3) was heated for 6h at 90°C. The organic solvent was distilled o:ff and the
compound was extracted with dichloromethane (5ml x 2). The organic layer w~s washed
with water and dried over sodium sulphate and distilled to give 2a in 60.7% yield. MS (ESI)
m/z: 21_3 ((M+1t, 100%); 1H NMR (200 MHz, CDCb): 8 2.73-2.77 (m, 1H, H-2), 7.87-3.19
(m, 3H, H-3, N-CH2), 4.48-4.55 (m, 1H, N-CH2), 6.79-6.92 (m, 1H, ArH), 7.32-7.79 (m, 6H,
ArH); IR (Neat): 3428, 2927, 2365, 1597, 1352, 1245, 760cm-1
•
Example 2
Step-1
2-Imidazol-l-ylmethyl-3,4-dihydro-2H-naphthalen-l-one (2b, R=H, n=2, X=CH)'~ A mixture
of 2-pyrrolidin-l-ylmethyl-3,4-dihydro-2H-naphthalen-l-one(1b, R=H, n=2)(4.1 ]mmol) and
imidazole (4.9;3mmol) in ethanol:water (2:3) was heated for 3 hat 90°C. The organic ,solvent was
distilled off and the compound was extracted with dichloromethane (5ml x 2). The organic layer
was washed with water and dried over sodium sulphate and distilled to give 2b in 9~.45% yield.
10
MS (ESI) rnlz: 227 (M+, 100%); 1H NMR (200 MHz, CDCh): 8 1.71-1.79 (m, ]IH, H-3), 2.06-
. I!
2.11 (m, IH, H-3), 2.78-3.05 (m, 3H, H-4; H-2), 4.37-4.46 (m, 2H, NCH2), 6.9.~ {s, IH, ArH),
7.02 (s, IH, ArH), 7.16-7.36 {m, 2H, ArH), 7.44-7.49 {m, 2H, ArH), 8.02-8.06 (di IH, J=7.79Hz,
ArH); IR (Neat): 3401, 3117, 2932, 1676, 1600, 1511, 1249, 1174cm-1•
.~""~
Example3
Step-2
trans-2-Imidazol-1-ylmethyl-indan-1-ol (3a, R=H,n=I, X=CH). Sodium boroliydride (30
I mmol) was added in portions to a ~tirred and cooled solution of 2a (R =H, n= I, X =CH) (I 0
. i
. mmol) in methanol (10 mL) over a.period of 30 minutes. The reaction mixture -~as fmther
stirred at room temperature for 3 h. Methanol was distilled under reduced pr~ssure. The
. t I
residue was triturated with water (15 mL) and extracted with dichloromethane (10 mL x 3).
!
The combined organic layer was dried over sodium sulphate and concentrated to give the
I crude product which was purified by column chromatography using methanol:chldroform (1:
. . !
99) as an eluant to provide the trans hydroxyl compounds (3a) in 91.6% yielcL m.p.l07-
1090C; MS (ESI) n1/z: 215 ({M+1t, 40%); 1H NMR (200 MHz, CDCh): 8 2.61-3.14 (m,
I 3H, H-2, H-3), 4.53-4.68 (m, 2H, N-CH2), 4.87-4.91 (d, 1H, J=7.4Hz, H-1), 6.93-7.02 (m,
!
2H, ArH), 7.16-7.53 (m, 5H, ArH); IR(KBr): 3381,3013,2931,1454,1218, I033,i767cm-1•
I
Example 4
Step-2
trans-2-Imidazol-1-ylmethyl-1,2,3,4-tetrahydro-2H-naphthalen-1-ol (3b,R=H,n=~ X=CH).
Sodium borohydride (30 mmol) was added in portions to a stirred and cooled solution of
i 2b(R=H,n=2, X=CH) (10 mmol) in methanol (10 mL) over a period of 30 min·Jtes. The
reaction mixture was further stirred at room temperature for 3 h. Methanol was distiJled
under reduced pressure. The residue was triturated with water (15 mL) and extrac:ted with
. ! dichloromethane (1 0 mL x 3). The combined organic layer was dried over sodium [sulphate
and concentrated to give the crude product which was purified by column chroma~ograJ:hy
using methanol:chloroform (1: 99) as an eluant to provide the trans hydroxyl compounds
!
(3b) in 99% yield (trans: cis); Yield 84% (trans); m.p.92-94°C; MS (ESI) rnlz: 229 C(M+ It,
IOO%);
1
H NMR (200 MHz, CDCh): 8 1.48-1.52 {m, IH, H-2), 1.88-2.10 (m, 2ij, H-3),
II
2.76-2.83 (m, 2H, H-4), 4.15-4.25 (m, 2H, N-CH2), 4.33-4.37 (d, 1H, J=8.97Hz, OH-CH),
I
I
6.91-7.22 (m; 5H, ArH), 7.45 (s, 1H, imidazole-H), 7.50-7.53 (s, 1H, imidazole-H); IR (KBr):
3116,2933,23.65, 1613, 1588, 1498, 1458,2138, 1108, 1082, 1039, 754cm-1.
Example 5
Step-3
trans-(.1-( 4-Trifiuoromethy 1-phenoxy )-1 ,2,3,4-tetrahydronaph thalen-2-ylmetftyl)-lHimidazole
(4b, R=H, n=2, R'= 4-CF3, X=CH). A solution of hydroxyl compound (3b,
... ~ R=H,n=2, X=CH)) (0,622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) !was added
dropwise to stirred susp~nsion of potassium tertiary butoxide (0.933mmol) in DMSO
(0.5mL) and it was allowed to stir at room temperature for 2min. 4-Fluorobenzotrifluoride
(0.622mmol) in DMSO (O.?mL) was added dropwise to the reaction mixture under stirring.
It
The dark coloured reaction mixture was stirred for 15min to 1.5h for the compl~tion of the
reaction. The reaction was discontinued and treated with water (15 mL) and extracted with
• I
ethyl acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6),
i
dried over sodium sulphate and concentrated to give the crude product \fhich was
chromatographed on a silica gel column using chloroform or methanol:chloroform (1 :99%)
as an eluent to get the desired trans ether (4b) in 77.9% yield MS (ESI) m/z: 37J ((M+1t,
I . '
100%); H NMR (200 MHz, CDCh): 8 1.65-1.77 (m, 1H, H-2), 2.08-2.17 (m, 11H, H-3),
. i
2.59-2.61 (m, 1H, H-3), 2.88-2.98 (m, 2H, Ar-CH2), 3.92-4.15 (m, 2H, N-CH2), 5.1~1 1-5.19 (d,
1H, J=6.33Hz, 0-CH), 6.87-7.05 (m, 3H, ArH), 7.11 (s, 1H, .t\rH), 7.21-7.26 (m, 4H, ArH),
7.39 (s, 1H, ArH), 7.52-7.56 (d, 2H, J=8.41Hz, ArH); IR (Neat): 3400, 2929, 2368, 1598,
1351, 1081, 1036, 752cm-1. Anal. .Calcd. for C21H19F3N20: C, 67.74; H, 5.10;. N, 7.52.
, .
. Found: C, 67.66; H, 5.21; N, 7.47. 1
Example 6
Step-3
trans 1-(1-(4-Acetyl-phenoxy)-1,2,3,4-tetrahydronapltthalen-2-ylmethyl)-1 H-imidazole ( 4a,
I
R=H, R'=COCH3, n=2, X=CH). A solution of hydroxyl compound (3b, R=H, n=2; X=CH)
(0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added dropwise te stirred
I
suspension of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was
allow~d to stir at room temperature for 2min. 4-Fluoroacetophenone (0.622mmol) in DMSO ·
(0.5mL) was added dropwise to the above reaction mixture under stirring. The dark coloured
12
reaction mixture was stirred for 15min for the completion of the reaction. The reaction was
discontinued and treated with water (15 mL) and extracted with ethyl acetate (10 mL x 3).
The combined organic layer was washed with water (1 0 mL x 6), dried over sodium sulphate
and concentrated to give the crude product which was chromatographed on a silica gel
column using chloroform or methanol:chloroform (1 :99%) as an eluent to get the desired
trans ethers (4a) in 85% yield. MS (ESI) rnlz: 346 ((M+1t, 100%); 1H NMR (200 MHz,
CDCh): 8 1.63-1.74 (m, 1H, H-2), 2.08-2.14 (m, 1H, H-3), 2.56-2.64 (m, 4H, H-3, COCH3),
2.86-2.94 (rri~2H, Ar-CH2), 4.00-4.09 (m, 2H, N-CH2), 5.15-5.19 (d, IH, J=6.38Hz, 0-CH),
6.86-6.89 (m, 2H,~ ArH), 7.11-7.27 (m, 2H, ArH), 7.36-7.39 (d, IH, J=6.08Hz, ArH), 7.48-
7.52 (d, 2H, J=8.14Hz, ArH), 7.91-7.95 (d, 2H, J=9.18Hz, ArH), 8.07-8.11 (d, 2H,
J=8.26Hz, ArH); IR(Neat): 3115,2931,1677,1600,1511,1360,1249,1174, 753cm-1.i\nal.
ti
Calcd. For C22H22N202: C, 76.30; H, 6.35; N, 8.09. Found: C, 76.29; H, 6.38; N, 7.96.
Similarly compounds 4c-4n and 4y were prepared using corresponding hydroxyl compounds
(3) and substituted aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4-
fluoronitrobenzene and 4-fluoroacetophenone .
Example 7
Step-3. ·
trans-1-(1-( 4-Trifluoromethyl-phenoxy )-1 ,2,3,4~tet(ahydronaphthalen-2-ylmethyl)-1 H{
1,2,3jtriazole (4p, R=H, R'=4-CF3, n=2, X=N). A sol~tion of hydroxyl compound (3b',
R=H, n=2, X=N) (0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added
dropwise . to stirred suspension of potassium tertiary butoxide (0.933mmol) in DMSO
(0.5mL) and it was allowed to stir at room temperature for 2min. 4-Fluorobenzotrifluoride
(0.622mmol) in DMSO (0.5mL) was added dropwise to the above reaction mixture under
stirring, The dark coloured reaction mixture was stirred for 1.5h for the completion of the
reaction. The reaction was discontinued and treated with water (15 mL) and extracted with
ethyl acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6),
dried over sodium sulphate and concentrated to give ·the crude product which was
chromatographed on a silica gel column using chloroform or methanol:chloroform (I :99%)
as an eluent to get the desired trans ethers (4p) in 72.2% yield. MS (ESI) rnlz: 374 ((M+It,
100%), 375 ((M+2t, 22%); 1H NMR (200 MHz, CDCh): 8 1.67-1.74 (m, IH, H:·2), 2:09-
2.11 (m, 1H, H-3), 2.78-2.99 (m, 3H, H-3, Ar-CH2), 4.46-4.52 (m, 2H, N-CH2), 5.27-5.30 (d,
13
IH, J=6.72Hz, 0-CH), 6.93-6.98 (d, 2H, J=8.56Hz, ArH), 7.16-7.29 (m, 4H, ArH), 7.47-7.57
i
' (m, 3H, ArH), 7.71-7.74 (m, IH, ArH); IR (Neat): 3374, 2930, 1613, 1515, 1457, 1327,
1247, 1163, 1068, 755cm-1. Arlal. Calcd. For C2oH1sN30F3: C, 64.34; H, 4.8~; N, 11.26.
Found: C, 64.72; H, 4.98; N, 10.97. I
I
. Similarly' compounds 4o, 4q, 4r were prepared using corresponding hydroxyl corrlpounds
1
(3b', R=H or Cl, n=2, X=N) and substituted aryl fluorides selected from the grou~ of 4-
fluorobenzotrifluoride, 4-fluoronitrobenzene and 4-fluoroacetophenone (Step-3). :
Example 8
Step-3
1-(1-(4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazo/e (4u, R=H, R'=4-N02, n=1, X=H) ..
A solution of hydroxyl compound (3a, R=H, n=l, X=CH) (0.622mmol) in dimethyl
sulphoxiJe (DMSO) (0.5mL) was added dropwise to stirred suspension of potassihm tertiary
I '
butoxide (0.933mmol) in DMSO (0.5mL) and it was allowed to stir at room temp
1
eratureJor
I
2min. 4-Fluoronitrobenzene (0.622mmol) in DMSO (0.5mL) was added dropwise to the .
above reaction mixture under stirring. The dark coloured reaction mixture was i1stirred for
15min to 1.5h for the completion of the reaction. The reactiqn was discontinued ~nd treated
with water (15 mL) and extracted with ethyl acetate (10 mL x 3). The combin~d organic
layer was washed with water (1 0 mL x 6), dried over sodium sulphate and conc~ntrated to
give th~ crude product which was chromatographed on a silica gel column using chloroform
I
or methanol:chloroform (1 :99%) as an eluent to get the desired trans ether ( 4u) in 82.1%
yield. MS (ESI) m/z: 336 ((M+ It, 100%), 337 ((M+2t, 24%); 1H NMR (200 MHz, CDC~]):
' o 2.57-2.68 (dd, IH, J=l5.92Hz, J=5.06Hz, H-3), 2.92-3.01 (m, 1H, H-2), 3.18-3.3•) (dd, 1H,
I
J=15.92Hz, J=7.5Hz, H-3), 3.99-4.06 (m, 2H, N-CH2), 5.47-5.49 (d, 1H, J=4,08Hz, 0-CH),
J
. 6.68-6.72 (d, 2H, J=7.12Hz, ArH), 6.90 (s, IH, ArH), 7.06 (s, 1H, ArH), 7.19-7.39 (m, 3H,
ArH), 7.45-7.53 (m, 2H, ArH), 8.06-8.11 (d, 2H, J=9.26Hz, ArH), 8.28-8.33 (d, 1H,
. . 'I
J=9.08Hz,. ArH); IR (Neat): 3421, 1594, 1511, 1341, 1252, 1220, 663cm-1: Anal. dalcd. For
C,9H17N303: C, 68.05; H, 5.07; N, 12.53. Found: C, 68.12; H, 5.01; N, 12.19.
Similarly compounds 4s-4t were prepared using hydroxyl compound (3a) and substituted
I
aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4-fluoronitroben.Zene and
. '
4-f1 uoroacetophenone.
14
Example 9
Step-3
J-(l-(4-Trijluoromethyl-phenoxy)-indan-2-ylmethyl)-JH-{1,2,3]triazole ( 4w, R=H,
R'=4-CF3, n=1, X=N). A solution of hydroxyl compound (3a', R=H, n=l, X=N)
(0.622mmol) in dimethyl sulphoxide (DMSO) (0.5mL) was added dropwise to stirred
suspension of potassium tertiary butoxide (0.933mmol) in DMSO (0.5mL) and it was
allowed to stir at room temperature for 2min. 4-fluorobenzotrifluoride (0.622mmol) in
DMSO (0.5mL) was added dropwise to the above reaction mixture under stirring. The
dark coloured reaction mixture was stirred for I h for the completion of the reaction. The
reaction was discontinued . and treated with water ( 15 mL) and extracted with ethyl·
acetate (10 mL x 3). The combined organic layer was washed with water (10 mL x 6),
~ried over sodium sulphate and concentrated to give the crude product which was
chromatographed on a silica gel column using chloroform or methanol:chloroform
(1:99%) as an eluent to get the desired trans ethers (4w) in 76% yield. MS (ESI) m/z: 360
((M+1t, 100%); 1H NMR (200 MHz, CDCh): 8 2.70-2.81 (dd, IH, J=I5.4Hz,
J=5.36Hz, H-3), 3.07-3.35 (m, 2H, H-2, H-3), 4.57-4.60 (d, 2H, J=6.94Hz, N-CH2), 5.69-
5.72 (d, IH, J=4.78Hz, 0-CH), 6.86-6.90 (d, 2H, J=8.68Hz, ArH ortho to 0), 7.19-7.38
(m, 4H, ArH), 7.47-7.58 (m, 3H, ArH), 7.73 (s, IH, ArH); IR (Neat): 3021, 2367, 1592,
1341, 1253, 769cm-1. Anal. Calcd. For C19H16N30F3: C, 63.50; H, 4.45; N, 11.69. Found:
C, 63.32; H, 5.01; N, 12.05·.
Similarly compound 4v-4x were prepared using hydroxyl compound (3a') and substituted
aryl fluorides selected from the group of 4-fluorobenzotrifluoride, 4-fluoronitrobenzene
and 4-fluoroacetophenone (step-3).
The pharmacological evaluation of the test compounds of general formula 4 was
carried out by the following protocol.
Antileishmanial Activity
Parasite:
The Leishmania donovani promastigotes (MHOM/IN/Dd8; a WHO reference strain
originally obtained from Imperial college, London in 1979 through the courtesy of Prof. P. C.
C. Garnham Imperial College, London (U.K.)) were transfected with fire fly luciferase gene,
15
and the transfectants were maintained in medium 199 (Sigma Chemical Co,, USA)
i
supplemented with 10% foetal calf serum (GIBCO) and gentamycin ( 41Jg/ml) solutfon (Sigma)
under pressure of G 418 (Sigma)(Ashutosh, Gupta Suman, Ramesh, Sundar S. arid Goyal N.
Antimicrob. Agents and Chemother., 49 2005) 3776-3783).
Preparation of Compounds:
Stock solutions of compounds were initially prepared in DMSO at 1 Omg/rril cone. and
further diluted two folds with fresh complete medium.
Antipromastigote activity:
I
I
The in vitro effect of the compounds on the growth of promastigotes was ~ssessed by
I
monitoring the luciferase activity of viable cells after treatment. The transgenic prcinastigotes
of late log phase were seeded at lx 105 /2001Jl medium 199 well in 96 well fla1 bottomed
I
microtitre (MT) plates (CELLST AR) and incubated for 96 hr in medium alone, or in the
. j
presence of serial dilutions of drugs ( 0.25 - lO IJg/ml ) in DMSO. Parallel dilutions:', of DMSO
I
were used as controls. After incubation, an aliquot (50 !Jl) of promastigote suspehsion was
aspirated from each well of a 96 well plate and mixed with an equal volume of stileady Glo1
,,
reagent (Promega) and luminescence was measured by a luminometer~ The values were
expressed as relative luminescence unit (RLU). The inhibition of parasitic growth is
determined by comparison of the luciferase activity of drug treated parasites wi:h that of
' I
untreated controls by the general formula:
:
N-n x 100
Percentage Inhibition =
N
Where N is average relative luminescence unit (RLU) of control wells; and n is average RLU
I,
of treated wells. I
• I
Antiamastigote activity: .:
I
I
For assessing the activity of compounds against the amastigote stage of the liparasite,
I
I mouse macrophage cell line (J-774A.l) infected with promastigotes expressing h,1ciferase
I
firefly reporter gene was used. Cells were seeded in a 96-well plate (1.5x1 04cell/1 O~!Jllwell)
in RPMI-1640 containing 10% fetal calf serum and the plates were incubated at 'iJoc in a
!
C02 incubator. After 24h, the medium was replaced with fresh medium cohtaining
I
I
16
. stationary-phase promastigotes (2.25x105/100J..tl/well). Promastigotes invades the
macrophage and are transformed· into amastigote. The test material in appropriate
concentrations (0.25-1 OJ..lg/ml). in complete medium was added after replacing the previous
medium and the plates were incubated at 37°C in a C02 incubator for 72 hrs. After
incubation, the drug-containing medium was decanted and 50J..ll PBS was added in each well
and mixed with an equal volume of steady Glo reagent. After gentle shaking for 1-2 minute,
the reading was taken in a luminometer. The inhibition of parasitic growth is determined by
comparison· of the luciferase activity of drug treated parasites with that of untreated controls
as described above.
After assessing activity of compounds against amastigotes, Cytotoxicity assay were carried
out using J-774 cell line.
Cytotoxicity assay:
The cell viability was determined using the MTT assay (Huber,W., Koella.J.C, Acta Tropica,
55 (1993) 257-261). Exponentially growing cells J774.A-1 (1 x104cells /100J..tl/well) were
incubated with different drug concentrations (30ng-1 00 J..lg/ml) for 72 hours and were
incubated at 37°c in a humidified mixture of C02 and 95 % air in an incubator. Stock
solutions of compounds were initially dissolved in DMSO and further diluted three fold with
fresh complete medium. After incubation, 25 J..ll of MTT reagent (5mg/ml) in PBS medium,
followed by syringe filtration, was added to each well and incubated at 3 7 °C for 2 hours. At
the end of the incubation period, the supernatant is removed by. tilting plate completely
without disturbing cell layer and 150 J..ll of pure DMSO were added to each well. After 15
min. of shaking the readings were recorded as absorbance at 544 nm on a micro plate reader.
The cytotoxic effects were expressed as 50% lethal dose, i.e. as the concentration of a
comp.ound which provoked a 50% reduction in cell viability compared to cell in culture
medium alone.
Selective Index:
The selective index (S.I.) were .calculated using the following equation
S.I. = ICso (J-774 A-1 cells) I ICso (Leishmania amastigotes)
In- Vivo Activity
17
The in-vivo ieishmanicidal activity was determined in golden hamsters (.Mesocricetus
·auretus) infected with MHOM/IN/80/Dd8 strain of L. donovani obtained through the ccurtesy
ofP.C.C. Garnham, Imperial College, London (U.K.) in 1979.
For in-vivo evaluation of compounds, the method of Beveridge [S.Bevridge,In: R.J
Shnitzer,F.I.Hanoking (Eds), Experimental Chemotherapy, vol.l ,(1963),257-280.] as
modified by Bhatnagar et al. [S.Bhatnagar, P.Y.Guru, J.C.Katiyar, R.Srivastava,
A.Mukherjee, M.S.Akhtar, M.Seth, A.P.Bhaduri, Ind.JMed.Res. 89(1989) 439.] and Gupta
et al.[ S.Gupta, S.Tiwari, A.P.Bhaduri and G.K.Jain, Ada Tropica, 84(2002),165-173.] was
employed.
Golden hamsters (of either sex) weighing 40-45g were infected intracardially with 1x 107
amastigotes per animal. The infection is well adapted to the hamster model and establishes
itself in 15-20 days. Meanwhile, hamsters gain weight (65-75 g) and can be subjected to
repeated spleen biopsies. Pretreatment spleen biopsy in all the animals was carried oot to
assess the degree of infection. The animals with + 1 infection (5-15 amastigotes I 100 spleen
cell nuclei) were included in the chemotherapeutic trials. The infecte~ animals are
·randomized into several groups on the basis of their parasitic burdens. Four to six animals
were used for each test sample. Drug treatment by i.p. route is initiated after 2 days of biopsy
and continued for 10 consecutive days. Post-treatment biopsies are done on day 7 of the last
drug administration and amastigote counts are assessed by Giemsa staining. In~enshy of
infection in both , treated and untreated animals , as also the initial count in treated animals is
compared and the efficacy is expressed in terms of percentage inhibition (PI) using the
following formula:-
PI= ANAT x 100/INAT x TIUC
Where PI is Percent Inhibition of amastigotes multiplication
ANA T is Actual Number of Amastigotes in Treated animals
INAT is Initial Number of Amastigotes in Treated animals and
TIUC is Times Increase of parasites in Untreated Control animals.
The compounds synthesized were tested in Leishmania donovani m hamster model at
50mg/kg x 10, i.p. dose as shown in Table-1.
18
Data of two replicates were pooled for calculation of mean percent inhibition.
Standard drugs: Sodiurri stibogluconate (SSG) was used in each trial as experimental
control.
Data analysis
1. IC50 were calculated by Probit analysis (Finney. D.J, Probit Analysis (1971),
,Cambridge Univ. Press 3rdedn.).
Criteria for significant activity:
Compounds having IC5o 50 were picked
up for in vivo evaluation.
Table 1. In Vitro and in Vivo antileishmanial activity of Aryloxy
benzocycloalkyl azoles ( 4):-
Sl. Compound In vitro Assessment Cytotoxicity . Selective
number Anti Anti Cone. 500/o index
No.
promastigo amastigot CCso (SI)
te e activity. (Jlg/ml)
activity
ICso
ICso (f.!g/ml)
(Jlg/ml)
I 4a 1.76 0.84
37.76 44.94
2 4b 0.28 0.551
15.98 29
.3 4c l.l3 0.56
53.03 94.69
4 4d 1.59 1.40
60.95 43.5
5 4e 0.60 1.40
4.04 2.88
6 4f 0.58 3.39
16.37 4.82
7 4g 1.86 0.538
23.16 43
19
In vivo
activity
(Dose-
50mg/kg x 5
i.p.)
Percent
inhibition
52.5
:
8 4h 0.31 0.66
74.13 112.1 82.08
9 4i 0.32 0.44
29.41 66.84 60.4
10 4j 0.22 1.32
16.47 12.47
II 4k 1.49 2.16
25.51 11.81
12 41 r.I2 2.54
16.83 6.62
13 4m 0.29 0.53
17.86 33.69
14 4n 0.289 0.34
13.58 40.0
15 4o INACTIVE INACTIVE - NI
16 4p 3.20 J
INACTIVE - NI
17 4q 3.35 INACTIVE - NI
18 4r 2.89 0.71
21.33 30.04
19 4s 2.82
INACTIVE 69.95 NI
20 4t 0.39 1.04
13.20 12.7
21 4u 1.91 0.62.
54.79 88.37 56.4
22 4v INACTIVE ND - NI
23 4w 3.70 0.88
20.09 22.82
24 4x 3.75 INACTIVE - NI
25 4y 1.70 0.5
17.07 35.4
Stand. Sodium 946.62 33.99 99 2.9 89
stibogluconate
20
Advantages;
Compound 4h has similar antileishmanial efficacy compared to the standard drug sodium
stibogluconate and has significantly high selectivity index.
All the representative novel aryloxy benzocycloalkyl azoles 4a to 4y are nontoxic m
cytotoxicity assay.
21

We claim;
1. A Novel aryloxy benzocycloalkyl azoles of general formula 4, isomers, derivatives
·and salts thereof,
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
X=CH,N
n=l,2 ~,.::.,_
wher~in R is selected from a group consisting of H, halogen, alkyl or alkoxy ; R'. is
selected from a group consisting of CF3, COCH3, CHO, COOR, CN, N02, alkyl, alkoxy
or amide; X is CH or N; n=l or 2.
2. A novel compound as claimed in claim I wherein the structural formula comprising;
X=CH, wherein R is selected from a groupconsisting ofH, halogen, alkyl or alkoxy;
R' is selected from a group consisting ofCF3, COCH3, CHO, COOR, CN, N02, alkyl,
alkoxy or amide; X is CH or N; n=l or 2.
R~:)
R'-o: R·= H, Me, Cl, F, Br,OCH3
R' = CF 3, COCH3, N02
n =I, 2
3. A novel compound as claimed in claim I wherein the structural formula comprising;
X=N, wherein R is selected from a group consisting of H, halogen, alkyl or alkoxy ;
R' is selected from a group consisting ofCF3, COCH3, CHO, COOR, CN, N02• alkyl,
alkoxy or amide; X is N; n=l or 2.
R~A N ,,N
'N
R'v- ~0 4
R = H, Me, Cl, F, Br,OCH3
R' = CF3, COCH3, N02
n = 1,2
22
4. A novel compounds as claimed in claim 1 wherein the representative cqmpounds of
formula 4 comprising;
I 4a. 1-( 1-( 4-Acety !-phenoxy )-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethy 1)-:1 Himidazole.
4b. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl) -
'
1H-imidazole.
4c. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Eimidazole.
4d. 1-(1-( 4-Acetyl-phenoxy)-5-methyl-1 ,2,3,4-tetrahydronaphthalen-2-ytmethyl)-
1 if-imidazole. . i'
I
4e. 1-(5-Methyl-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphtl1ftlen-2-
ylmethyl)-1H-imidazole.
4f. 1-(5-Methyl-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1Himidazole
4g. 1-(1 .:( 4-Acetyl-phenoxy)-5-chloro-1 ,2,3 ,4-tetrahydronaphthalen-2-ylmethy1)-
1H-imidazole.
4h. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-
ylmethyl)-1 H-imidazole.
4i. 1-(5-Chloro-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmetpyl)-J Himidazole.
4j. i -(5-Fluoro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthah~n-2-
ylmethyl)-1H-imidazole.
• i
4k. 1-(5-Fluoro-1-( 4-mtro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylme~yl)-1Himidazole.
41. 1-( 1-( 4-Acetyl-phenoxy)-5-bromo-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-
1,
1H-imidazole.
I
4m. 1-(5-Bromo-1-(4-trifluoromethyl-phenoxy)-1,2,3,4-tetrahydronaphthal~n-2-
ylmethyl)-lH-imidazole.
I
I
4n. 1-(5-Bromo-1-( 4-nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmet~yl)-1 Himidazole.
23
4o. 1-(1-( 4-Acetyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-'1H[
1 ,2,3 ]triazole.
4p. 1-(1-( 4-Trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-yJmethyl)-
1 H-[ 1 ,2 ,3 ]triazole.
4q. 1-(1-( 4-Nitro-phenoxy)-1 ,2,3,4-tetrahydronaphthalen-2-ylmethyl)-1H[
1 ,2,3]triazole .
4r. 1-(5-Chloro-1-( 4-trifluoromethyl-phenoxy)-1 ,2,3,4-tetrahydronaphthilen-2-
;~.. ....
ylmethyl)-1H-[1 ,2,3]triazole
4s. 1-(1-( 4-Acetyl-phenoxy)-indan-2-ylmethyl)-1H-imidazol~.
4t. 1-( 1-( 4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1 H-irp.idazole .
4u. 1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-imidazole. :.
lt
4v. l-(l-(4-Acetyl-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3]triazole.
4w. 1-(1-(4-Trifluoromethyl-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3]triazble.
I
I
4x. 1-(1-( 4-Nitro-phenoxy)-indan-2-ylmethyl)-1H-[1 ,2,3)triazole. '
4y: 1-( 6-methoxy-1-( 4-trifluoromethyl-phenoxy )-1 ,2,3 ,4-tetrahydronaphtl\.alen-2-
ylmethyl)-1 H-imidazole.
5. A novel compound as claimed in claim
antleishmanial agents.
wherein the compounds are useful as
I
'I
6. A process for the preparation of novel aryloxy benzocycloalkyl azoles Qf general
formula 4 which comprises;
a. reacting a substituted pyrrolidinylmethyl ketone of general formula 1,
• • I
R~o
O HCI
imidazole/triazole R ~) n [=Step-1 ~N ... >('N
0
1 2
wherein R = H, halogen, alkyl or alkoxy; n = 1 or 2 with imidazole/ triazole in
• I
water alcohol mixture to give the azolylmethyl ketone (2) wherein X =CH'or N,
. '
b. reacting the azolylmethyl ketone· (2) with a reducing agent selecte~ from a
I
group consisting of sodium borohydride, sodium triacetoxy borohydride,
I,
aluminium isopropoxide, aluminium hydrides to give the amino alcnhol (3,
X=CH or N) with TRANS stereoselectivity (8.5: 1.5),
24
c. reacting the compound 3 with potassium tertiary butoxide (KtBuO), Sodium
hydride(NaH), butyl lithium(BuLi) in dimethyl sulfoxide (DMSO), dimethyl
formamide(DMF) and followed by addition of appropriately substituted aryl
fluoride in the presence an aprotic solvent of DMSO, DMF to give the
corresponding compound of the formula 4 in trans isomeric form; wherein R'
= H,.4-CF3, 4-COCHJ or 4-N02 and isolating the compounds by conventional
methods.
7. A process as claimed in claim 12 wherein the base us\d is selected from the group
consisting of sodium hydride, potassium tertiary butoxide (KtBuO), butyl lithium.
8. A process as claimed in claim I2 wherein the novel aryloxy benzocycloalkyl azoles
of general formula 4 are in substantially pure TRANS isomeric form.
9. A pharmaceutical composition comprising a pharmaceutically effective amount of the
compound of formula 4 as claimed in claim I optionally along with the
pharmaceutically acceptable excepient, diluent.
10. Novel aryloxy benzocycloalkyl azoles, process of preparation thereof,
substantially as herein described with reference to the exampies accompanying the
specification.

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http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=MKAzKSOQuTzhBnBpfjUrXw==&loc=+mN2fYxnTC4l0fUd8W4CAA==

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Patent Number

271474

Indian Patent Application Number

610/DEL/2008

PG Journal Number

09/2016

Publication Date

26-Feb-2016

Grant Date

23-Feb-2016

Date of Filing

11-Mar-2008

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	KALPANA BHANDARI	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE POST BOX NO 173,LUCKNOW 226 001 INDIA
2	SHRADDHA PALNE	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE POST BOX NO 173,LUCKNOW 226 001 INDIA
3	NISHI	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE POST BOX NO 173,LUCKNOW 226 001 INDIA
4	SUMAN GUPTA	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE POST BOX NO 173,LUCKNOW 226 001 INDIA
5	NAGARAPU SRINIVAS	CENTRAL DRUG RESEARCH INSTITUTE, CHATTAR MANZIL PALACE POST BOX NO 173,LUCKNOW 226 001 INDIA

PCT International Classification Number

C07D233/28

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA