Title of Invention	A SUBSTITUTED BENZIMIDAZOLE COMPOUNDS OF FORMULA (I) AND PREPARATION THEREOF
Abstract	Present invention provides a substituted benzimidazole compound or pharmaceutically acceptable salt thereof with antihypertensive activity, wherein 5th position is substituted by an electron releasing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. The present invention also provides a process for preparing substituted benzimidazole compound using an economical route. (Scheme I) The Benzimidazole derived angiotensin II receptor antagonists of the present invention are more potent than other commercially available drugs.

Title of Invention

A SUBSTITUTED BENZIMIDAZOLE COMPOUNDS OF FORMULA (I) AND PREPARATION THEREOF

Abstract

Present invention provides a substituted benzimidazole compound or pharmaceutically acceptable salt thereof with antihypertensive activity, wherein 5th position is substituted by an electron releasing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. The present invention also provides a process for preparing substituted benzimidazole compound using an economical route. (Scheme I) The Benzimidazole derived angiotensin II receptor antagonists of the present invention are more potent than other commercially available drugs.

Full Text	Field of Invention: Present Invention relates to a substituted benzimidazole compound with antihypertensive activity, wherein 5th position is substituted by an electron releasing group and 2nd position is substituted by an alkyl group. More particularly the present invention relates to substituted benzimidazole based compounds with optimized substitutions at 5th and 2nd positions wherein optimization is done with respect to substituted or unsubstituted alklysulfamoyl or Nitro group at 5th position and any one of ethyl, n-propyl, n-butyl and ethoxymethyl froup at 2nd position. The Benzimidazole derived angiotensin II receptor antagonists of the present invention are more potent than commercially available drugs like candesartan and losartan. Background and Prior art: The Renin-Angiotensin system (RAS) is a hormone system that helps regulate blood pressure and blood volume in the body. The system can be activated when there is a loss of blood volume or a drop in blood pressure. The Renin-Angiotensin system is involved in homeostasis to control systemic blood pressure, body fluid volume, and electrolyte balance and aldosetrone system. Angiotensin II is the effecter hormone which mediates all these controls by acting on ATI receptors. Angiotensin II converting enzyme inhibitors such as captopril, enalapril, etc., are the first kind of drug used in treatment of hypertension controlled by RAS. However due to side effects associated with use of these agents like dry cough and angioedema search for compounds acting at the receptor level was undertaken .Sarlesin and sarmesin are the first such compounds derived by modifying native Ang II. But due to their metabolic instability, poor oral bioavailability and partial agonist activity owing to their peptidic nature various research groups searched for non-peptide Ang II receptor antagonists. Furukawa et al disclosed the first of its kind compounds (S-8305 and S-8306). This development revolutionized the development of more potent such nonpeptide compounds. Losartan is the protypical Ang II receptor antagonist which was further taken up as lead by various research groups. A large number of such compounds have been reported in literature prepared by replacing the imidazole nucleus of losartan with various kinds of appropriately substituted heterocyclic heads appended to biphenyl system containing acidic function. Kubo et al reported a new series of Ang II receptor antagonists prepared by replacing imidazole nucleus of losartan with benzimidazole. Various substitutions have been carried out in benzo ring of the benzimidazole nucleus. 7-carboxylic acid derivatives (e.g., Candesartan) and 6-substituted derivatives (e.g., BIBR 277) emerged as the compound more potent than losartan. 4-position in benzo ring has not been found to be conducive to binding as any substituent at this position block the interaction of imidazole ring nitrogen with receptor site. Although much work has been carried out at 6-position and 7-position but on the basis of very limited data set it has been reported that 5-substituted benzimidazole derivatives are less potent than the corresponding 6-substituted ones. Taking 5-position as a potential site for modification we initially synthesized 5-nitro benzimidazole derivatives which displayed activity greater than the reference compounds, candesartan and losartan. The higher activity of this 5-nitro derivative as Ang II receptor antagonist may be due to interaction with a receptor pocket which may be filled up with appropriate electron withdrawing groups (such as nitro group) and remained unexploited by other research groups. On the basis of this data, present invention proposes a new binding site in the drug receptor interaction model. Statement of Invention Accordingly present invention provides a substituted benzimidazole compound with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. (Formula Removed) The present invention also provides a particular compound of formula (II) wherein the group X is t-butyl; Y is n-butyl; Z is NHSO2- and A is 2'-carboxy biphenyl-4-yl methyl. (Formula Removed) The present invention also provides an economic process for the preparation of compounds of the formula (I) comprising the steps of: a. Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003-.006 M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5) and 4-8 ml of pyridine for 1 hour ; b. keeping the solution at room temperature; c. pouring the solution obtained ,dropwise into ice cold water to obtain red precipitate; d. filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid (compound 6); e. subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic acid obtained in step(iv) to chlorosulfonation; f. adding alkyl amine to obtain compound of formula (II). 4'-Chloromethyl-biphenyl-2-carboxylic acid (5) is prepared by a process comprising the steps of: a. fusing 0,45-0.55 M KOH at 180-200 C; b. adding finely powdered 9-H fluoren-9-one in 4-8 portions with vigorous stirring at 180-200 C for 20-40 minutes to obtain a hot slurry; c. mixing the hot slurry in with ice cold water with vigorous stirring; d. filtering the solution obtained in step (iii); e. acidifying said filtrate with HC1; f. filtering, washing and drying the solution obtained in step (e); g. recrystallizing a compound 3 from CC14; h. dissolving .01-.015 M of compound 3 in sulphuric acid; i. adding .02-.05 M of acetamide in one portion; j. adding .002-.007 M of paraformaldehyde in small portions; k. heating the solution obtained in step (x) at 40-60 C with stirring; 1. mixing the hot solution with ice cold water to obtain a compound 4; m, refluxing compound 4 with .063M phosphorous oxychloride, .03M of dimethylformarnide and 2 ml of xylene for 5-8 hours; n. cooling, washing and evaporating the solution to obtain a light yellow compound 5. Detailed description of the Invention The present invention provides a substituted benzimidazole compound with antihypertensive activity by substituting electron withdrawing group and alkyl group at 5th and 2nd position respectively and optimizing these substitutions with respect to 5th and 2nd positions, (un)substituted sulfamoyls or Nitro group may be substituted at 5th position. Here to further explore the new binding pocket the inventors of the present invention have designed a new series of compounds by isosterically replacing nitro group with (un)substituted sulfamoyls with a view that sulfonyl group can mimic well the nitro group where as the alkyl group may find an additional pocket making the drug receptor binding stronger, evaluated their Ang II receptor blocking activity and have found that the benzimidazole derivatives of the formula (I) exhibit excellent Ang II receptor antagonism in vitro as well as reduce the mean arterial blood pressure in DOCA induced hypertensive rats. Accordingly the present invention provides benzimidazole derivatives of following formula (I): (Formula Removed) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. The present invention also provides a process for synthesizing the pendent biphenyl moiety with significant yields. The present invention also provides a method for treating hypertension by administering a benzimidazole derivative. Present invention particularly relates to a substituted benzimidazole compound or pharmaceutically acceptable salt thereof with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. An embodiment of the present invention provides a process for preparing substituted benzimidazole compound using an economical route. (Scheme I) Scheme I (Scheme Removed) Reference numerals (scheme I): 2-Butyl-1 H-benzimidazole Biphenyl-2-carboxylic acid 4 4'-(Acetylamino-methyl)-biphenyl-2-carboxylic acid 5 4'-Chloromethyl-biphenyl-2-carboxylic acid 6 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-carboxylic acid 7 4'-(2-Butyl-5-chlorosulfonyl-benzimidazol-l-ylmethyl)-biphenyl- 2-carboxylic acid 1 (R = H) 4'-(2-Butyl-5-sulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic acid 1 (R = i-Pr) 4'-(2-Butyl-5-isopropylsulfamoyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid 1 (R = n-Butyl) 4'-(2-Butyl-5-butylsulfamoyl-benzimidazol-l-ylmethyl)-biphenyl- 2-carboxylic acid 1 (R = t-Butyl) 4'-(2-Butyl-5-tert-butylsulfamoyl-benzimidazol-1 -ylmethyl)- biphenyl-2-carboxylic acid 1 (R = c-Hexyl) 4'-(2-Butyl-5-cyclohexylsulfamoyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid The process comprises following steps: (i) Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003- .006 M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5) and 4-8 ml of pyridine for 1 hour; (ii) keeping the solution at room temperature; (iii) pouring the solution obtained ,dropwise into ice cold water to obtain red precipitate; (iv) filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid (compound 6); (v) subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic acid obtained in step(iv) to chlorosulfonation; (vi) adding alkyl amine to obtain compound of formula (II). One another embodiment of the present invention provides a process for preparing substituted benzimidazole compound using an economical route wherein alkyl amine of step (vi) is selected from isopropyl amine, n-butyl amine, t-butyl amine and cyclohexylamine. The present invention also provides a process for preparing substituted benzimidazole compound using an economical route wherein a strong ammonia solution is added to the product obtained in step (v). Yet another embodiment of the present invention provides a process for preparing substituted benzimidazole compound such as herein described wherein the compound 5 is prepared by a process comprising the steps of: (i) fusing 0.45-0.55 M KOH at 180-200 C; (ii) adding finely powdered 9-H fluoren-9-one in 4-8 portions with vigorous stirring at 180-200 C for 20-40 minutes to obtain a hot slurry; (iii) mixing the hot slurry in with ice cold water with vigorous stirring; (iv) filtering the solution obtained in step (iii); (v) acidifying said filtrate with HC1; (vi) filtering, washing and drying the solution obtained in step (v); (vii) recrystallizing a compound 3 from CC14; (viii) dissolving .01-.015 M of compound 3 in sulphuric acid; (ix) adding .02-.05 M of acetamide in one portion; (x) adding .002-.007 M of paraformaldehyde in small portions; (xi) heating the solution obtained in step (x) at 40-60 C with stirring; (xii) mixing the hot solution with ice cold water to obtain a compound 4; (xiii) refluxing compound 4 obtained in step (xii) with .063M phosphorous oxychloride, .03M of dimethylformamide and 2 ml of xylene for 5-8 hours; (xiv) cooling, washing and evaporating the solution to obtain a light yellow compound 5. The novel compounds disclosed in the invention by formula (I) can be prepared using the reactions and techniques described (Scheme I) in this section. Briefly, substituted benzimidazole (2) is coupled with compound (5) in the presence of a base to produce a compound (6). Subsequently, the resulting 6 is subjected to chlorosulfonation followed by addition of alkyl amine to obtain compound 1 of the present invention. Starting material 2 is obtained by simple condensation of o-phenylene diamine with valeric acid. Condensation reaction is performed without the aid of any solvent as valeric acid itself provides a liquid medium for the reaction. Refluxing of the reactants followed by basification of the cooled reaction mixture provided 2. The bases employed in the recovery of compound 2 include sodium hydroxide or ammonia solution. Starting material 5 is obtained from 9H-flourenone through a three step process. In the first step 9H-flourenone is subjected to potash fusion at a temperature of 180-200 C to provide an intermediate 3. This reaction is carried out as reported in literature. The second step involves acetamidomethylation of 3 to produce intermediate 4. The third step involves aliphatic substitution reaction in which acetamido group is replaced by chloro group to provide starting material 5. The invention is further elaborated with the help of following examples. However, these examples should not be construed to limit the scope of the invention. Examples The following examples illustrate the preparation of compounds and intermediates of this invention in more details. All the reactions were monitored and product purity in each reaction was ascertained by thin layer chromatographic method specifically developed for the reactant(s) and product(s) in the particular reaction. Structure of each product is ascertained by spectral analysis. In infra red spectral data position of stretching and bending bands is represented in "cm"1". In NMR spectral data position of each signal is represented in "8". In mass spectral data each peak corresponding to a particular molecule or its fragment is represented in "m/e ratio". Example 1 o-Phenylendiamine 27 g and pentanoic acid (0.5M) were placed in round bottom flask and refluxed for 7 hours. The reaction mixture was cooled and basified (pH 7-8) with 20% sodium hydroxide solution with continuous stirring. The crude product was dissolved in 95% ethanol and digested with activated charcoal for 45 minutes. Boiling water was then added to the filtrate till slight turbidity appeared. The solution was made clear by addition of few drops of ethanol and kept for recrystallization . The product (2) was obtained as white, needle shaped crystals. Yield 29 g (74%), mp. 162°C. IR (KBr): Broad N-H stretch (3600-3200); Aromatic C-H stretch (3100, 3050); Aliphatic C-H stretch (2900, 2800); N-H scissoring (1500); C - N stretching (1240, 1220); N-H wagging (880) and Out of plane C-H bend (700). NMR (CDC13): 10.3 (1H, s, br); 7.5 (2H, m); 7.2 (2H, m); 2.95 (2H, t, J - 7.5 Hz); 1.84 (2H, qv, J= 7.5 Hz); 1.40 (2H, sx, J = 7.5 Hz); 0.88 (3H, t, J = 7.5 Hz). MASS (El): 174 (M peak); 132 (Base peak). Example 2 30 g (0.53M) of potassium hydroxide was fused at 180-200°C in a two necked round bottom flask fitted with a mechanical stirrer. 10 g (0.055M) of finely powdered 9(H)-fluorenone was added in about 6 portions over 30 minutes with vigorous stirring and the temperature was maintained at 180-200°C for further 30 minutes. The hot slurry was then poured in ice cold water with vigorous stirring. The resulting suspension was filtered at pump. The filtrate was acidified with cone, hydrochloric acid resulting in precipitation of the product, which was filtered under suction, washed with distilled water and dried in air. The product (3) was recrystallized from carbon tetrachloride. Yield 9 g (81%), m.p. IR (KBr): Broad O-H stretch (3600 - 2750); Aromatic C-H stretch (3060, 3020); Carboxylic C=O stretch (1760); C-O-H in plane bend (1400); Out of plane O-H bend (940) and Aromatic out of plane C-H bend (750). NMR (CDC13): 9.03 (1H, s, br); 7.9 (1H, d, J = 9.0 Hz); 7.4 (1H, m); 7.36 (7H, m). MASS (El): 198 (M and base peak). Example 3 2 g of (0.01 M) of 3 obtained as in example 2 was dissolved in 12.12 ml of cone, sulfuric acid. 1.78g (0.03M) of acetamide was added in one portion and then 0.150 g (0.005M) of paraformaldehyde was added in small portions. The solution was heated at 55°C along with stirring for 3 hours. The hot mixture was poured over ice cold water resulting in separation of product (4) as yellow solid which was filtered at pump. Yield 900 mg (33.2%), mp. 145°C. IR (KBr): Broad band for O-H and N-H stretch (3610-2300); Aromatic C-H stretch (3070); Aliphatic C-H stretch (2925); C=O stretch (Amide I band) (1713);C=C stretching (1630); N-H bend (Amide II band) (1611); C-O-H bending (1375); Amide III band (1296); Out of plane O-H bend (917); N-H wagging (849) and Aromatic out of plane C-H stretch (738). NMR(CDC13): 8.10 (lH,s); 7.67 (lH,m); 7.47 (3H,m); 7.30 (4H, m); 6.1 (1H, s); 4.42(2H,s)and 2.10(3H,s) MASS (El): 269 (M) and 180 (Base peak). Example 4 700 mg (0.0026M) of compound 4 obtained in example 3, 0.794 g (0.063M) of phosphorous oxychloride, 2 ml (0.03M) of dimethylformamide and 2 ml of xylene were was taken in a round bottom flask and refluxed for 7 hours. The solution was cooled, washed with water and evaporated to give a light yellow crystalline product. Yield 200 rag (31.25%), mp. 127°C. IR (KBr): Broad band for O-H stretch (3580-2500); Aromatic C-H stretch (3037); Aliphatic C-H stretch (2875 and 2800); C=O stretch (1713); Ring C=C stretching (1603); CH2 scissoring (1457); C-O-H bending (1368); Out of plane O-H bend (966); Aromatic out of plane C-H stretch (738) and Aliphatic C-C1 stretch (650). NMR (CDC13): 9.40 (1H, s); 7.70 (1H, d, J = 8); 7.49 (3H, m); 7.32 (2H, d, J - 9); 7.29 (2H,d,J = 9) and 4.01(2H, s). MASS (El): 209 (Base peak). Example 5 1g (0.004M) of 2, 1g (0.005M) of 5 and 6ml of pyridine (previously dried over KOH pellets) were taken in a round bottom flask fitted with a reflux condenser. The mixture was refluxed for 1 hour. The solution was kept to achieve room temperature (20°C). Then it was poured drop wise with constant stirring into 200ml of ice cold water resulting in brick red precipitates. The product 6 was filtered at vacuum pump to afford the product as brick red crystalline powder. Yield (1.102g) 65.3%, mp.l20°C. 1R (KBr): Broad band for O-H stretch (3600-2500); Aromatic C-H stretch (3054); Aliphatic C-H stretch (2924 and 2859); CO stretch (1710); Ring C=C stretching (1604 and 1452); C-O-H bending (1425); Aromatic out of plane C-H stretch (738). NMR (CDC13): 9.6 (1H, s, br); 7.74 (1H, m); 7.67-7.44 (4H, m); 7.40-7.20 (4H, m); 7.10-6.96 (1H, m); 6.87-6.79 (2H, m); 4.0 (2H, s); 2.94 (2H, t, J = 7.5 Hz); 1.80 (2H, qv, J = 7.5 Hz); 1.36 (2H, sx, J = 7.5 Hz) and 0.88 (3H, t, J = 7.5 Hz). Example 6 1.2 ml (0.018 M) chlorosulfonic acid was cooled to 10-15°C in a dry two necked 100 ml round bottom flask. 1g (0.0026M) of 6 was added with continuous stirring over a period of half an hour. Stirring was further continued for 3.5 hour maintaining the temperature at 10-15 C. Formation of sulfonyl chloride derivative 7 was ascertained by TLC data. TLC Data: Chloroform: Methanol (98: 2), Rf value 5 (0.35); 6 (0.78) and Cyclohexane : Ethylacetate (25 : 75), Rf value 5 (0.42); 6 (0.58). This reaction mixture was used as such without product isolation to synthesize the target compounds of the invention. Example 7 Part A To the reaction mixture of 7 at temperature of 10°C was added 10ml (0.163M) strong ammonia solution drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dilute HCI and solid was filtered at pump to afford the product 1 (R=Hydrogen atom) as brown amorphous powder. Yield (0.824g) 63%, mp. 150°C. IR (KBr): Broad O-H and N-H stretch (3600-2500); N-H stretch (1° amide) (3142); CO stretch (1712); N-H bend (1537); SO (asymmetric) stretch (1320); SO (asymmetric) stretch (1170); N-H wagging (819) and C-S stretch (621). NMR (d6-DMSO): 8.1 (1H, b, m); 8.07-8.01 (1H, m), 7.76-7.73 (1H, m); 7.61-7.49 (6H, m); 7.44-7.31 (2H, m); 7.29-7.26 (3H, m); 4.02 (2H, d, J = 6 Hz); 3.02 (2H, t, J - 7 Hz); 1.88 (2H, qv, J = 7 Hz); 1.44 (2H, sx, J = 7 Hz) and 0.95 (3H, t, J = 7 Hz). GC-MS: 132 (Base peak) Part B To the reaction mixture of 7 at temperature of 30°C was added 5ml of 90% isopropyl amine (0.0625M) drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at same temperature. The reaction mixture was acidified with dil. HCI and solid was filtered at pump to afford the product as reddish brown amorphous powder. Yield (0.682g) 51%, mp. 155°C. 1R (KBr): O-H (free) stretch (3650); Broad O-H and N-H stretch (3700 - 2200); N-H Stretching (2° amide) (3275); Aromatic C-H stretch (3061); Aliphatic C-H stretch (2937); C=O stretch (1711); C-H bending of gem-dimethyl groups (1382, 1365); S=O asymmetric stretch (1370);S=0 symmetric stretch (1161) and C-S stretch (615). NMR (d6-DMSO): 8.05-7.90 (3H, br, m); 7.76-7.74 (1H, m); 7.73-7.26 (9H, m); 4.0 (2H, d, J=6); 3.70 (1H, sp, J=7.5 Hz); 3.24 (3H, t, J=7 Hz); 1.43 (6H, d, J = 7.5 Hz); 1.45 (2H, sx, J = 7 Hz); 1.95 (1H, qv, J = 7 Hz) and 0.99 (3H, t, J = 7 Hz). Part C To the reaction mixture of 7 at temperature of 10°C was added 5ml of n-butyl amine (0.0503M) drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at same temperature. The reaction mixture was acidified with dil. HCI and solid was filtered at pump to afford the product as reddish brown amorphous powder. Yield (0.692g) 50.5%, mp. 190°C. 1R (KBr): same as that in part B except that the bending vibrational band for gem-dimethyl groups was absent. NMR (d6-DMSO): 8.06-8.18 (1H, br, m); 7.75-7.62 (3H, m); 7.55-7.31 (9H, m); 4.04 (2H, d, J = 6 Hz); 3.21 (4H, m); 1.71 (4H, m); 1.41 (4H, m) and 0.96 (6H, m). Part D To the reaction mixture of 7 at temperature of 10°C was added 5ml (0.047M) t-butyl amine drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dil.HCI and solid was filtered at pump to afford the product as brownish amorphous powder. Yield (0.583g) 41%, mp. 150°C. 1R (KBr): Same as that in part B. NMR (d6-DMSO): 8.0-7.32 (13H, br, m); 4.0 (2H, d, J = 6 Hz); 3.02 (3H, t, J = 7 Hz); 2.1 (9H, s); 1.93 (2H, qv, J = 7 Hz); 1.47 (2H, sx, J = 7 Hz) and 0.99 (3H, t, J = 7 Hz). Part E To the reaction mixture of 7 at temperature of 10°C was added 5ml (0.0432M) cyclohexylamine drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dil.HCI and solid was filtered at pump to afford the product as brownish amorphous powder. Yield (0.583g) 41%, mp. 170°C. 1R (KBr): Same as that in part B except that the gem-dimethyl group bending vibrational band was replaced by CH2 bending in cyclohexane at 1454. NMR (d6-DMSO): 8.1-7.58 (8H, br, m); 7.64-7.31 (5H, br, m); 4.02 (2H, d, J - 6 Hz); 4.4 (1H, m); 3.25 (2H, t, J = 7 Hz); 2.27-1.17 (10H, m); 1.95 (2H, qv, J = 7 Hz); 1.43 (2H, sx, J - 7 Hz) and 0.96 (3H, t, J = 7 Hz). Angiotensin II receptor antagonistic activity vitro ATi receptor blocking activity The activity of the compound represented by formula (1) was evaluated on endothelium removed isolated rat aortic ring using force transducers and BIOPAC four-channel recorder. The activity was expressed as pA2 values. In vivo effect on hypertension Dose standardization was done in DOCA induced hypertensive rats and all the compounds of formula (1) reduced the hypertension significantly. (Formula Removed) Reference numerals (scheme I): 2 3 4 5 2-Butyl-1 H-benzimidazole Biphenyl-2-carboxylic acid 4' -(Acetylamino-methyl)-biphenyl-2-carboxylic acid 4' -Chloromethyl-biphenyl-2-carboxylic acid 6 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-carboxylic acid 7 4'-(2-Butyl-5-chlorosulfonyl-benzimidazol-l-ylmethyl)-biphenyl- 2-carboxylic acid 1 (R = H) 4'-(2-Butyl-5-sulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic acid 1 (R = i-Pr) 4'-(2-Butyl-5-isopropylsulfamoyl-benzimidazol-l-ylmethy])- biphenyl-2-carboxylic acid 1 (R = n-Butyl) 4'-(2-Butyl-5-butylsulfamoyl-benzimidazol-l-ylmethyl)-biphenyl- 2-carboxylic acid 1 (R = t-Butyl) 4'-(2-Butyl-5-tert-butylsulfamoyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid 1 (R = c-Hexyl) 4'-(2-Butyl-5-cyclohexylsulfamoyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid Table I: Infra red spectral data of the intermediate and claimed compounds. The vibrational frequencies are expressed in cm'1. (Table Removed) Table II: NMR spectral data of the intermediate and claimed compounds. The chemical shift values are expressed in 5 and coupling constant (J) values in Hz. (Table Removed) Table III: Mass spectral data of the intermediate and claimed compounds (BP = Base Peak) (Table Removed) Table IV: TLC data of the intermediate and claimed compounds (Table Removed) Table V: The comparative angiotensin II antagonism of the target and reference compounds (Table Removed) Table VI: Effect of target and reference compounds on mean arterial blood pressure (MABP) (Table Removed) We claim: 1. A substituted benzimidazole compound with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro group; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group. (Formula Removed) (I) 2. The compound of formula (II) as claimed in claim 1, wherein R is selected from (Formula Removed) H, isopropyl, n-butyl, t-butyl and cyclo-hexyl. 3. The compound of formula (III) as claimed in claims 1-2 wherein the group X is t-butyl; Y is n-butyl; Z is NHSO2- and A is 2'-carboxy biphenyl-4-yl methyl. (Formula Removed) 4. A process for the preparation of a substituted benzimidazole compound with antihypertensive activity, of formula (I) comprising the steps of: (i) Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003- .006 M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5) and 4-8 ml of pyridine for 1 hour ; (ii) keeping the solution at room temperature; (iii) pouring the solution obtained ,dropwise into ice cold water to obtain red precipitate; (iv) filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)- biphenyl-2-carboxylic acid (compound 6); (v) subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic acid obtained in step(iv) to chlorosulfonation; (vi) adding alkyl amine to obtain compound of formula (II). 5. The process as claimed in claim 4, wherein alkyl amine of step (vi) is selected from isopropyl amine, n-butyl amine, t-butyl amine and cyclohexylamine. 6. The process as claimed in claim 4, wherein a strong ammonia solution is added to the product obtained in step (v). 7. The process as claimed in claim 4, wherein the step of chlorosulfonation comprises: (i) cooling 0.015-0.020 M chlorosulfonic acid to 10-15 C; (ii) adding 0.0025-0.0030 M of 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl- 2-carboxylic acid to the chlorosulfonic acid of step (i) with continous stirring for 20-40 minutes; (iii) stirring the solution obtained in step (ii) for 3-4 hours to obtain 4'-(2-Butyl-5- sulfamoyl-benzimidazol-1 -ylmethyl)-biphenyl-2-carboxylic acid. 8. The process as claimed in claim 4, wherein 2-butyl-1 -H-benzimidazole (compound 2) is prepared by a process comprising the steps of: (i) reacting o-phenylendiamine, with petanoic acid ; (ii) adding 15-25% NaOH solution with continous stirring; (iii) dissolving the solution obtained in step (ii) in ethanol, digesting with activated charcoal to obtain 2-butyl-1 -H-benzimidazole. 9. The process as claimed in claim 4, wherein the compound 5 is prepared by a process comprising the steps of: (i) fusing 0.45-0.55 M KOH at 180-200 C; (ii) adding finely powdered 9-H fluoren-9-one in 4-8 portions with vigorous stirring at 180-200 C for 20-40 minutes to obtain a hot slurry; (iii) mixing the hot slurry in with ice cold water with vigorous stirring; (iv) filtering the solution obtained in step (iii); (v) acidifying said filtrate with HC1; (vi) filtering, washing and drying the solution obtained in step (v); (vii) recrystallizing a compound 3 from CC14; (viii) dissolving .01-.015 M of compound 3 in sulphuric acid; (ix) adding .02-.05 M of acetamide in one portion; (x) adding .002-.007 M of paraformaldehyde in small portions; (xi) heating the solution obtained in step (x) at 40-60 C with stirring; (xii) mixing the hot solution with ice cold water to obtain a compound 4; (xiii) refluxing compound 4 obtained in step (xii) with .063M phosphorous oxychloride, .03M of dimethylformamide and 2 ml of xylene for 5-8 hours; (xiv) cooling, washing and evaporating the solution to obtain a light yellow compound 5. 10. A substituted benzimidazole compound with antihypertensive activity substantially as herein described with reference to forgoing examples. 11. A process for preparing a substituted benzimidazole compound with antihypertensive activity substantially as herein described with reference to forgoing examples.

Full Text

Field of Invention:
Present Invention relates to a substituted benzimidazole compound with antihypertensive activity, wherein 5th position is substituted by an electron releasing group and 2nd position is substituted by an alkyl group. More particularly the present invention relates to substituted benzimidazole based compounds with optimized substitutions at 5th and 2nd positions wherein optimization is done with respect to substituted or unsubstituted alklysulfamoyl or Nitro group at 5th position and any one of ethyl, n-propyl, n-butyl and ethoxymethyl froup at 2nd position. The Benzimidazole derived angiotensin II receptor antagonists of the present invention are more potent than commercially available drugs like candesartan and losartan.
Background and Prior art:
The Renin-Angiotensin system (RAS) is a hormone system that helps regulate blood pressure and blood volume in the body. The system can be activated when there is a loss of blood volume or a drop in blood pressure. The Renin-Angiotensin system is involved in homeostasis to control systemic blood pressure, body fluid volume, and electrolyte balance and aldosetrone system. Angiotensin II is the effecter hormone which mediates all these controls by acting on ATI receptors. Angiotensin II converting enzyme inhibitors such as captopril, enalapril, etc., are the first kind of drug used in treatment of hypertension controlled by RAS. However due to side effects associated with use of these
agents like dry cough and angioedema search for compounds acting at the receptor level was undertaken .Sarlesin and sarmesin are the first such compounds derived by modifying native Ang II. But due to their metabolic instability, poor oral bioavailability and partial agonist activity owing to their peptidic nature various research groups searched for non-peptide Ang II receptor antagonists. Furukawa et al disclosed the first of its kind compounds (S-8305 and S-8306). This development revolutionized the development of more potent such nonpeptide compounds. Losartan is the protypical Ang II receptor antagonist which was further taken up as lead by various research groups. A large number of such compounds have been reported in literature prepared by replacing the imidazole nucleus of losartan with various kinds of appropriately substituted heterocyclic heads appended to biphenyl system containing acidic function. Kubo et al reported a new series of Ang II receptor antagonists prepared by replacing imidazole nucleus of losartan with benzimidazole. Various substitutions have been carried out in benzo ring of the benzimidazole nucleus. 7-carboxylic acid derivatives (e.g., Candesartan) and 6-substituted derivatives (e.g., BIBR 277) emerged as the compound more potent than losartan. 4-position in benzo ring has not been found to be conducive to binding as any substituent at this position block the interaction of imidazole ring nitrogen with receptor site. Although much work has been carried out at 6-position and 7-position but on the basis of very limited data set it has been reported that 5-substituted benzimidazole derivatives are less potent than the corresponding 6-substituted ones. Taking 5-position as a potential site for modification we initially synthesized 5-nitro benzimidazole derivatives which displayed activity greater than the reference compounds, candesartan and losartan. The higher activity of this 5-nitro derivative as
Ang II receptor antagonist may be due to interaction with a receptor pocket which may be filled up with appropriate electron withdrawing groups (such as nitro group) and remained unexploited by other research groups. On the basis of this data, present invention proposes a new binding site in the drug receptor interaction model.
Statement of Invention
Accordingly present invention provides a substituted benzimidazole compound with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group.
(Formula Removed)
The present invention also provides a particular compound of formula (II) wherein the group X is t-butyl; Y is n-butyl; Z is NHSO2- and A is 2'-carboxy biphenyl-4-yl methyl.
(Formula Removed)
The present invention also provides an economic process for the preparation of
compounds of the formula (I) comprising the steps of:
a. Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003-.006
M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5) and 4-8
ml of pyridine for 1 hour ;
b. keeping the solution at room temperature;
c. pouring the solution obtained ,dropwise into ice cold water to obtain red
precipitate;
d. filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid (compound 6);
e. subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2- carboxylic
acid obtained in step(iv) to chlorosulfonation;
f. adding alkyl amine to obtain compound of formula (II).
4'-Chloromethyl-biphenyl-2-carboxylic acid (5) is prepared by a process comprising the steps of:
a. fusing 0,45-0.55 M KOH at 180-200 C;
b. adding finely powdered 9-H fluoren-9-one in 4-8 portions with vigorous
stirring at 180-200 C for 20-40 minutes to obtain a hot slurry;
c. mixing the hot slurry in with ice cold water with vigorous stirring;
d. filtering the solution obtained in step (iii);
e. acidifying said filtrate with HC1;
f. filtering, washing and drying the solution obtained in step (e);
g. recrystallizing a compound 3 from CC14;
h. dissolving .01-.015 M of compound 3 in sulphuric acid;
i. adding .02-.05 M of acetamide in one portion;
j. adding .002-.007 M of paraformaldehyde in small portions;
k. heating the solution obtained in step (x) at 40-60 C with stirring;
1. mixing the hot solution with ice cold water to obtain a compound 4;
m, refluxing compound 4 with .063M phosphorous oxychloride, .03M of dimethylformarnide and 2 ml of xylene for 5-8 hours;
n. cooling, washing and evaporating the solution to obtain a light yellow compound 5.
Detailed description of the Invention
The present invention provides a substituted benzimidazole compound with antihypertensive activity by substituting electron withdrawing group and alkyl group at 5th and 2nd position respectively and optimizing these substitutions with respect to 5th and 2nd positions, (un)substituted sulfamoyls or Nitro group may be substituted at 5th position. Here to further explore the new binding pocket the inventors of the present invention have designed a new series of compounds by isosterically replacing nitro group with (un)substituted sulfamoyls with a view that sulfonyl group can mimic well the nitro group where as the alkyl group may find an additional pocket making the drug receptor binding stronger, evaluated their Ang II receptor blocking activity and have found that the benzimidazole derivatives of the formula (I) exhibit excellent Ang II receptor antagonism in vitro as well as reduce the mean arterial blood pressure in DOCA induced hypertensive rats.
Accordingly the present invention provides benzimidazole derivatives of following formula (I):
(Formula Removed)
wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group.
The present invention also provides a process for synthesizing the pendent biphenyl moiety with significant yields. The present invention also provides a method for treating hypertension by administering a benzimidazole derivative.
Present invention particularly relates to a substituted benzimidazole compound or pharmaceutically acceptable salt thereof with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group.
An embodiment of the present invention provides a process for preparing substituted benzimidazole compound using an economical route. (Scheme I)
Scheme I
(Scheme Removed)
Reference numerals (scheme I):
2-Butyl-1 H-benzimidazole Biphenyl-2-carboxylic acid
4 4'-(Acetylamino-methyl)-biphenyl-2-carboxylic acid
5 4'-Chloromethyl-biphenyl-2-carboxylic acid
6 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-carboxylic acid
7 4'-(2-Butyl-5-chlorosulfonyl-benzimidazol-l-ylmethyl)-biphenyl-
2-carboxylic acid
1 (R = H) 4'-(2-Butyl-5-sulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-2-
carboxylic acid
1 (R = i-Pr) 4'-(2-Butyl-5-isopropylsulfamoyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid
1 (R = n-Butyl) 4'-(2-Butyl-5-butylsulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-
2-carboxylic acid
1 (R = t-Butyl) 4'-(2-Butyl-5-tert-butylsulfamoyl-benzimidazol-1 -ylmethyl)-
biphenyl-2-carboxylic acid
1 (R = c-Hexyl) 4'-(2-Butyl-5-cyclohexylsulfamoyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid The process comprises following steps:
(i) Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003-
.006 M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5)
and 4-8 ml of pyridine for 1 hour; (ii) keeping the solution at room temperature; (iii) pouring the solution obtained ,dropwise into ice cold water to obtain
red precipitate; (iv) filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid (compound 6);
(v) subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-
carboxylic acid obtained in step(iv) to chlorosulfonation; (vi) adding alkyl amine to obtain compound of formula (II).
One another embodiment of the present invention provides a process for preparing substituted benzimidazole compound using an economical route wherein alkyl amine
of step (vi) is selected from isopropyl amine, n-butyl amine, t-butyl amine and cyclohexylamine. The present invention also provides a process for preparing substituted benzimidazole compound using an economical route wherein a strong ammonia solution is added to the product obtained in step (v).
Yet another embodiment of the present invention provides a process for preparing substituted benzimidazole compound such as herein described wherein the compound 5 is prepared by a process comprising the steps of:
(i) fusing 0.45-0.55 M KOH at 180-200 C;
(ii) adding finely powdered 9-H fluoren-9-one in 4-8 portions with
vigorous stirring at 180-200 C for 20-40 minutes to obtain a hot slurry; (iii) mixing the hot slurry in with ice cold water with vigorous stirring; (iv) filtering the solution obtained in step (iii); (v) acidifying said filtrate with HC1;
(vi) filtering, washing and drying the solution obtained in step (v); (vii) recrystallizing a compound 3 from CC14; (viii) dissolving .01-.015 M of compound 3 in sulphuric acid; (ix) adding .02-.05 M of acetamide in one portion; (x) adding .002-.007 M of paraformaldehyde in small portions; (xi) heating the solution obtained in step (x) at 40-60 C with stirring; (xii) mixing the hot solution with ice cold water to obtain a compound 4; (xiii) refluxing compound 4 obtained in step (xii) with .063M phosphorous
oxychloride, .03M of dimethylformamide and 2 ml of xylene for 5-8
hours; (xiv) cooling, washing and evaporating the solution to obtain a light yellow
compound 5.

The novel compounds disclosed in the invention by formula (I) can be prepared using the
reactions and techniques described (Scheme I) in this section. Briefly, substituted
benzimidazole (2) is coupled with compound (5) in the presence of a base to produce a
compound (6). Subsequently, the resulting 6 is subjected to chlorosulfonation followed
by addition of alkyl amine to obtain compound 1 of the present invention.
Starting material 2 is obtained by simple condensation of o-phenylene diamine with
valeric acid.
Condensation reaction is performed without the aid of any solvent as valeric acid itself
provides a liquid medium for the reaction. Refluxing of the reactants followed by
basification of the cooled reaction mixture provided 2.
The bases employed in the recovery of compound 2 include sodium hydroxide or
ammonia solution.
Starting material 5 is obtained from 9H-flourenone through a three step process.
In the first step 9H-flourenone is subjected to potash fusion at a temperature of 180-200
C to provide an intermediate 3. This reaction is carried out as reported in literature.
The second step involves acetamidomethylation of 3 to produce intermediate 4.
The third step involves aliphatic substitution reaction in which acetamido group is
replaced by chloro group to provide starting material 5.
The invention is further elaborated with the help of following examples. However, these examples should not be construed to limit the scope of the invention.
Examples
The following examples illustrate the preparation of compounds and intermediates of this
invention in more details. All the reactions were monitored and product purity in each reaction was ascertained by thin layer chromatographic method specifically developed for the reactant(s) and product(s) in the particular reaction. Structure of each product is ascertained by spectral analysis. In infra red spectral data position of stretching and bending bands is represented in "cm"1". In NMR spectral data position of each signal is represented in "8". In mass spectral data each peak corresponding to a particular molecule or its fragment is represented in "m/e ratio".
Example 1
o-Phenylendiamine 27 g and pentanoic acid (0.5M) were placed in round bottom flask and refluxed for 7 hours. The reaction mixture was cooled and basified (pH 7-8) with 20% sodium hydroxide solution with continuous stirring. The crude product was dissolved in 95% ethanol and digested with activated charcoal for 45 minutes. Boiling water was then added to the filtrate till slight turbidity appeared. The solution was made clear by addition of few drops of ethanol and kept for recrystallization . The product (2) was obtained as white, needle shaped crystals. Yield 29 g (74%), mp. 162°C.
IR (KBr): Broad N-H stretch (3600-3200); Aromatic C-H stretch (3100, 3050); Aliphatic C-H stretch (2900, 2800); N-H scissoring (1500); C - N stretching (1240, 1220); N-H wagging (880) and Out of plane C-H bend (700). NMR (CDC13): 10.3 (1H, s, br); 7.5 (2H, m); 7.2 (2H, m); 2.95 (2H, t, J - 7.5 Hz); 1.84
(2H, qv, J= 7.5 Hz); 1.40 (2H, sx, J = 7.5 Hz); 0.88 (3H, t, J = 7.5 Hz). MASS (El): 174 (M peak); 132 (Base peak).
Example 2
30 g (0.53M) of potassium hydroxide was fused at 180-200°C in a two necked round bottom flask fitted with a mechanical stirrer. 10 g (0.055M) of finely powdered 9(H)-fluorenone was added in about 6 portions over 30 minutes with vigorous stirring and the temperature was maintained at 180-200°C for further 30 minutes. The hot slurry was then poured in ice cold water with vigorous stirring. The resulting suspension was filtered at pump. The filtrate was acidified with cone, hydrochloric acid resulting in precipitation of the product, which was filtered under suction, washed with distilled water and dried in air. The product (3) was recrystallized from carbon tetrachloride. Yield 9 g (81%), m.p.
IR (KBr): Broad O-H stretch (3600 - 2750); Aromatic C-H stretch (3060, 3020); Carboxylic C=O stretch (1760); C-O-H in plane bend (1400); Out of plane O-H bend (940) and Aromatic out of plane C-H bend (750). NMR (CDC13): 9.03 (1H, s, br); 7.9 (1H, d, J = 9.0 Hz); 7.4 (1H, m); 7.36 (7H, m).
MASS (El): 198 (M and base peak).
Example 3
2 g of (0.01 M) of 3 obtained as in example 2 was dissolved in 12.12 ml of cone, sulfuric acid. 1.78g (0.03M) of acetamide was added in one portion and then 0.150 g (0.005M) of paraformaldehyde was added in small portions. The solution was heated at 55°C along with stirring for 3 hours. The hot mixture was poured over ice cold water resulting in separation of product (4) as yellow solid which was filtered at pump. Yield 900 mg (33.2%), mp. 145°C.
IR (KBr): Broad band for O-H and N-H stretch (3610-2300); Aromatic C-H stretch (3070); Aliphatic C-H stretch (2925); C=O stretch (Amide I band) (1713);C=C
stretching (1630); N-H bend (Amide II band) (1611); C-O-H bending (1375); Amide III band (1296); Out of plane O-H bend (917); N-H wagging (849) and Aromatic out of plane C-H stretch (738). NMR(CDC13): 8.10 (lH,s); 7.67 (lH,m); 7.47 (3H,m); 7.30 (4H, m); 6.1 (1H, s);
4.42(2H,s)and 2.10(3H,s)
MASS (El): 269 (M) and 180 (Base peak).
Example 4
700 mg (0.0026M) of compound 4 obtained in example 3, 0.794 g (0.063M) of phosphorous oxychloride, 2 ml (0.03M) of dimethylformamide and 2 ml of xylene were was taken in a round bottom flask and refluxed for 7 hours. The solution was cooled, washed with water and evaporated to give a light yellow crystalline product. Yield 200
rag (31.25%), mp. 127°C.
IR (KBr): Broad band for O-H stretch (3580-2500); Aromatic C-H stretch (3037); Aliphatic C-H stretch (2875 and 2800); C=O stretch (1713); Ring C=C stretching (1603); CH2 scissoring (1457); C-O-H bending (1368); Out of plane O-H bend (966); Aromatic out of plane C-H stretch (738) and Aliphatic C-C1 stretch (650). NMR (CDC13): 9.40 (1H, s); 7.70 (1H, d, J = 8); 7.49 (3H, m); 7.32 (2H, d, J - 9); 7.29
(2H,d,J = 9) and 4.01(2H, s). MASS (El): 209 (Base peak).
Example 5
1g (0.004M) of 2, 1g (0.005M) of 5 and 6ml of pyridine (previously dried over KOH pellets) were taken in a round bottom flask fitted with a reflux condenser. The mixture was refluxed for 1 hour. The solution was kept to achieve room temperature (20°C). Then it was poured drop wise with constant stirring into 200ml of ice cold water resulting in brick red precipitates. The product 6 was filtered at vacuum pump to afford the product as brick red crystalline powder. Yield (1.102g) 65.3%, mp.l20°C.
1R (KBr): Broad band for O-H stretch (3600-2500); Aromatic C-H stretch (3054); Aliphatic C-H stretch (2924 and 2859); CO stretch (1710); Ring C=C stretching (1604 and 1452); C-O-H bending (1425); Aromatic out of plane C-H stretch (738). NMR (CDC13): 9.6 (1H, s, br); 7.74 (1H, m); 7.67-7.44 (4H, m); 7.40-7.20 (4H, m);
7.10-6.96 (1H, m); 6.87-6.79 (2H, m); 4.0 (2H, s); 2.94 (2H, t, J = 7.5 Hz); 1.80 (2H, qv, J = 7.5 Hz); 1.36 (2H, sx, J = 7.5 Hz) and 0.88 (3H, t, J = 7.5 Hz).
Example 6
1.2 ml (0.018 M) chlorosulfonic acid was cooled to 10-15°C in a dry two necked 100 ml round bottom flask. 1g (0.0026M) of 6 was added with continuous stirring over a period of half an hour. Stirring was further continued for 3.5 hour maintaining the temperature at 10-15 C. Formation of sulfonyl chloride derivative 7 was ascertained by TLC data.
TLC Data: Chloroform: Methanol (98: 2), Rf value 5 (0.35); 6 (0.78) and Cyclohexane : Ethylacetate (25 : 75), Rf value 5 (0.42); 6 (0.58).
This reaction mixture was used as such without product isolation to synthesize the target compounds of the invention.
Example 7
Part A
To the reaction mixture of 7 at temperature of 10°C was added 10ml (0.163M) strong ammonia solution drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dilute HCI and solid was filtered at pump to afford the product 1 (R=Hydrogen atom) as brown amorphous powder. Yield (0.824g) 63%, mp. 150°C.
IR (KBr): Broad O-H and N-H stretch (3600-2500); N-H stretch (1° amide) (3142); CO stretch (1712); N-H bend (1537); SO (asymmetric) stretch (1320); SO (asymmetric)
stretch (1170); N-H wagging (819) and C-S stretch (621).
NMR (d6-DMSO): 8.1 (1H, b, m); 8.07-8.01 (1H, m), 7.76-7.73 (1H, m); 7.61-7.49 (6H,
m); 7.44-7.31 (2H, m); 7.29-7.26 (3H, m); 4.02 (2H, d, J = 6 Hz); 3.02 (2H, t, J - 7 Hz);
1.88 (2H, qv, J = 7 Hz); 1.44 (2H, sx, J = 7 Hz) and 0.95 (3H, t, J = 7 Hz).
GC-MS: 132 (Base peak)
Part B
To the reaction mixture of 7 at temperature of 30°C was added 5ml of 90% isopropyl amine (0.0625M) drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at same temperature. The reaction mixture was acidified with dil. HCI and solid was filtered at pump to afford the product as reddish brown amorphous powder. Yield (0.682g) 51%, mp. 155°C.
1R (KBr): O-H (free) stretch (3650); Broad O-H and N-H stretch (3700 - 2200); N-H Stretching (2° amide) (3275); Aromatic C-H stretch (3061); Aliphatic C-H stretch (2937); C=O stretch (1711); C-H bending of gem-dimethyl groups (1382, 1365); S=O asymmetric stretch (1370);S=0 symmetric stretch (1161) and C-S stretch (615).
NMR (d6-DMSO): 8.05-7.90 (3H, br, m); 7.76-7.74 (1H, m); 7.73-7.26 (9H, m); 4.0 (2H, d, J=6); 3.70 (1H, sp, J=7.5 Hz); 3.24 (3H, t, J=7 Hz); 1.43 (6H, d, J = 7.5 Hz); 1.45 (2H, sx, J = 7 Hz); 1.95 (1H, qv, J = 7 Hz) and 0.99 (3H, t, J = 7 Hz).
Part C
To the reaction mixture of 7 at temperature of 10°C was added 5ml of n-butyl amine (0.0503M) drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at same temperature. The reaction mixture was acidified with dil. HCI and solid was filtered at pump to afford the product as reddish brown amorphous powder. Yield (0.692g) 50.5%, mp. 190°C.
1R (KBr): same as that in part B except that the bending vibrational band for gem-dimethyl groups was absent. NMR (d6-DMSO): 8.06-8.18 (1H, br, m); 7.75-7.62 (3H, m); 7.55-7.31 (9H, m); 4.04
(2H, d, J = 6 Hz); 3.21 (4H, m); 1.71 (4H, m); 1.41 (4H, m) and 0.96 (6H, m). Part D
To the reaction mixture of 7 at temperature of 10°C was added 5ml (0.047M) t-butyl amine drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dil.HCI and solid was filtered at pump to afford the product as brownish amorphous powder. Yield (0.583g) 41%, mp. 150°C.
1R (KBr): Same as that in part B.
NMR (d6-DMSO): 8.0-7.32 (13H, br, m); 4.0 (2H, d, J = 6 Hz); 3.02 (3H, t, J = 7 Hz);
2.1 (9H, s); 1.93 (2H, qv, J = 7 Hz); 1.47 (2H, sx, J = 7 Hz) and 0.99 (3H, t, J = 7 Hz).
Part E
To the reaction mixture of 7 at temperature of 10°C was added 5ml (0.0432M) cyclohexylamine drop wise (Caution: vigorous reaction) with continuous stirring. After the addition was complete, stirring continued for another 30 minutes at the same temperature. The reaction mixture was acidified with dil.HCI and solid was filtered at pump to afford the product as brownish amorphous powder. Yield (0.583g) 41%, mp. 170°C.
1R (KBr): Same as that in part B except that the gem-dimethyl group bending vibrational band was replaced by CH2 bending in cyclohexane at 1454.
NMR (d6-DMSO): 8.1-7.58 (8H, br, m); 7.64-7.31 (5H, br, m); 4.02 (2H, d, J - 6 Hz); 4.4 (1H, m); 3.25 (2H, t, J = 7 Hz); 2.27-1.17 (10H, m); 1.95 (2H, qv, J = 7 Hz); 1.43 (2H, sx, J - 7 Hz) and 0.96 (3H, t, J = 7 Hz). Angiotensin II receptor antagonistic activity vitro ATi receptor blocking activity
The activity of the compound represented by formula (1) was evaluated on endothelium removed isolated rat aortic ring using force transducers and BIOPAC four-channel recorder. The activity was expressed as pA2 values. In vivo effect on hypertension
Dose standardization was done in DOCA induced hypertensive rats and all the compounds of formula (1) reduced the hypertension significantly.
(Formula Removed)

Reference numerals (scheme I):

2
3
4
5

2-Butyl-1 H-benzimidazole Biphenyl-2-carboxylic acid
4' -(Acetylamino-methyl)-biphenyl-2-carboxylic acid 4' -Chloromethyl-biphenyl-2-carboxylic acid

6 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-carboxylic acid
7 4'-(2-Butyl-5-chlorosulfonyl-benzimidazol-l-ylmethyl)-biphenyl-
2-carboxylic acid
1 (R = H) 4'-(2-Butyl-5-sulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-2-
carboxylic acid
1 (R = i-Pr) 4'-(2-Butyl-5-isopropylsulfamoyl-benzimidazol-l-ylmethy])-
biphenyl-2-carboxylic acid
1 (R = n-Butyl) 4'-(2-Butyl-5-butylsulfamoyl-benzimidazol-l-ylmethyl)-biphenyl-
2-carboxylic acid
1 (R = t-Butyl) 4'-(2-Butyl-5-tert-butylsulfamoyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid
1 (R = c-Hexyl) 4'-(2-Butyl-5-cyclohexylsulfamoyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid
Table I: Infra red spectral data of the intermediate and claimed compounds. The vibrational frequencies are expressed in cm'1.

(Table Removed)
Table II: NMR spectral data of the intermediate and claimed compounds. The chemical shift values are expressed in 5 and coupling constant (J) values in Hz.

(Table Removed)
Table III: Mass spectral data of the intermediate and claimed compounds (BP = Base Peak)

(Table Removed)
Table IV: TLC data of the intermediate and claimed compounds

(Table Removed)
Table V: The comparative angiotensin II antagonism of the target and reference compounds

(Table Removed)
Table VI: Effect of target and reference compounds on mean arterial blood pressure (MABP)

(Table Removed)

We claim:
1. A substituted benzimidazole compound with antihypertensive activity, of formula (I) wherein 5th position is substituted by an electron withdrawing group (Z) and 2nd position is substituted by an alkyl group (Y); wherein the Z is selected from substituted (X) or unsubstituted sulphomyl moiety and Nitro group; X is selected from alkyl and cyclo-alkyl group; alkyl group (Y) is selected from ethyl, n-propyl, n-butyl and ethoxymethyl; and A is a biphenyl group bearing a carboxy group.

(Formula Removed)
(I) 2. The compound of formula (II) as claimed in claim 1, wherein R is selected from
(Formula Removed)
H, isopropyl, n-butyl, t-butyl and cyclo-hexyl.
3. The compound of formula (III) as claimed in claims 1-2 wherein the group X is t-butyl; Y is n-butyl; Z is NHSO2- and A is 2'-carboxy biphenyl-4-yl methyl.
(Formula Removed)
4. A process for the preparation of a substituted benzimidazole compound with
antihypertensive activity, of formula (I) comprising the steps of:
(i) Mixing and refluxing .002-.005 M 2-butyl-l-H-benzimidazole, .003-
.006 M of 4'-Chloromethyl-biphenyl-2-carboxylic acid (compound 5)
and 4-8 ml of pyridine for 1 hour ; (ii) keeping the solution at room temperature; (iii) pouring the solution obtained ,dropwise into ice cold water to obtain
red precipitate; (iv) filtering the solution to obtain 4'-(2-Butyl-benzimidazol-l-ylmethyl)-
biphenyl-2-carboxylic acid (compound 6);
(v) subjecting 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-2-
carboxylic acid obtained in step(iv) to chlorosulfonation; (vi) adding alkyl amine to obtain compound of formula (II).
5. The process as claimed in claim 4, wherein alkyl amine of step (vi) is selected
from isopropyl amine, n-butyl amine, t-butyl amine and cyclohexylamine.
6. The process as claimed in claim 4, wherein a strong ammonia solution is added to
the product obtained in step (v).
7. The process as claimed in claim 4, wherein the step of chlorosulfonation
comprises:
(i) cooling 0.015-0.020 M chlorosulfonic acid to 10-15 C;
(ii) adding 0.0025-0.0030 M of 4'-(2-Butyl-benzimidazol-l-ylmethyl)-biphenyl-
2-carboxylic acid to the chlorosulfonic acid of step (i) with continous stirring
for 20-40 minutes; (iii) stirring the solution obtained in step (ii) for 3-4 hours to obtain 4'-(2-Butyl-5-
sulfamoyl-benzimidazol-1 -ylmethyl)-biphenyl-2-carboxylic acid.
8. The process as claimed in claim 4, wherein 2-butyl-1 -H-benzimidazole
(compound 2) is prepared by a process comprising the steps of:
(i) reacting o-phenylendiamine, with petanoic acid ; (ii) adding 15-25% NaOH solution with continous stirring; (iii) dissolving the solution obtained in step (ii) in ethanol, digesting with activated charcoal to obtain 2-butyl-1 -H-benzimidazole.
9. The process as claimed in claim 4, wherein the compound 5 is prepared by a
process comprising the steps of:
(i) fusing 0.45-0.55 M KOH at 180-200 C;
(ii) adding finely powdered 9-H fluoren-9-one in 4-8 portions with
vigorous stirring at 180-200 C for 20-40 minutes to obtain a hot slurry; (iii) mixing the hot slurry in with ice cold water with vigorous stirring; (iv) filtering the solution obtained in step (iii); (v) acidifying said filtrate with HC1;
(vi) filtering, washing and drying the solution obtained in step (v); (vii) recrystallizing a compound 3 from CC14; (viii) dissolving .01-.015 M of compound 3 in sulphuric acid; (ix) adding .02-.05 M of acetamide in one portion; (x) adding .002-.007 M of paraformaldehyde in small portions; (xi) heating the solution obtained in step (x) at 40-60 C with stirring; (xii) mixing the hot solution with ice cold water to obtain a compound 4; (xiii) refluxing compound 4 obtained in step (xii) with .063M phosphorous
oxychloride, .03M of dimethylformamide and 2 ml of xylene for 5-8
hours; (xiv) cooling, washing and evaporating the solution to obtain a light yellow
compound 5.
10. A substituted benzimidazole compound with antihypertensive activity
substantially as herein described with reference to forgoing examples.
11. A process for preparing a substituted benzimidazole compound with antihypertensive activity substantially as herein described with reference to forgoing examples.

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Patent Number

269611

Indian Patent Application Number

1151/DEL/2006

PG Journal Number

44/2015

Publication Date

30-Oct-2015

Grant Date

29-Oct-2015

Date of Filing

09-May-2006

Name of Patentee

PUNJABI UNIVERSITY

Applicant Address

PUNJABI UNIVERSITY, PATIALA 147002, PUNJAB

Inventors:

#	Inventor's Name	Inventor's Address
1	DHVANIT SHAH	DEPARTMENT OF PHARMACEUTICAL SCIENCE & DRUG RESEARCH, PUNJABI UNIVERSITY, PATIALA-147002, PUNJAB
2	NAVNEET KAUR	DEPARTMENT OF PHARMACEUTICAL SCIENCE & DRUG RESEARCH, PUNJABI UNIVERSITY, PATIALA-147002, PUNJAB
3	YOGITA BANSAL	DEPARTMENT OF PHARMACEUTICAL SCIENCE & DRUG RESEARCH, PUNJABI UNIVERSITY, PATIALA-147002, PUNJAB
4	GULSHAN BANSAL	DEPARTMENT OF PHARMACEUTICAL SCIENCE & DRUG RESEARCH, PUNJABI UNIVERSITY, PATIALA-147002, PUNJAB
5	PROF. MANJEET SINGH	DEPARTMENT OF PHARMACEUTICAL SCIENCE & DRUG RESEARCH, PUNJABI UNIVERSITY, PATIALA-147002, PUNJAB

PCT International Classification Number

C07D 237/00

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA