FORM 2
THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See section 10)
ANTIHISTAMINIC COMPOUNDS
SUN PHARMACEUTICAL INDUSTRIES LTD.
A company incorporated under the laws of India having their office at ACME PLAZA, ANDHERI-KURLA ROAD, ANDHERI (E), MUMBAI-400059. MAHARASHTRA, INDIA

The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

ANTIHISTAMINIC COMPOUNDS
The present invention relates to antihistaminic compounds which are (E)-oxime ether derivatives of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-11-ones (earlier referred to as 4-aza-5-oxo-10,1 1-dihydro-dibenzo[a,d]cycloheptenes), compound of formula I,

wherein R, R1 and R2 are as defined in the later part of the text.
The compounds of the present invention are antihistaminic compounds useful in the treatment of histamine mediated disorders.
PRIOR ART
United States Patent No. 3,458,524 (referred to herein as '524, Indian reference not available) discloses oxime ethers of general formula II, their synthesis from aza-5-oxo-dibenzo[a,d]cycloheptenes or their 10, 11-dihydro analogs, and their use as antihistaminic agents, wherein X is independently carbon or nitrogen and R is lower alkyl. Also, the patent exemplifies the synthesis of a compound of formula IA1 (X is N in position 1, n=2 and R is CH3 in formula II) as per scheme 1.


Synthesis of compound of formula IA1 was achieved by the following two methods (scheme1):
(a) Conversion of ketone of formula IIIA to an oxime of formula IVA, and its subsequent
alkylation with 2-(dimethylamino)ethyl chloride, or
(b) by reaction of ketone of formula mA with 2-(dimethylamino)ethoxyamine of formula V.

The '524 does not disclose the geometry of compound of formula IA1, or for that matter the geometry of the compounds claimed of generic formula II. It is possible that by either of the methods (a & b, vide supra) described in the said patent, and exemplified for compound of formula IA1, there is the possibility of obtaining two geometric isomers of formulas Ia1 & Ia'1 which represent (E)-isomer & (Z)-isomer respectively of compound of formula IA1.

Both these isomers are expected to be co-produced by the methods (a & b) described. The oxime IVA prepared (route a) is not purified as per the procedure described in the said patent, and would contain both E & Z oximes of formulas IVa & IVa' respectively. This was indeed found to be the case when we prepared in our laboratory the oxime as described in '524.

HPLC analysis of several batches of the oxime preparation as described in '524 revealed that it was a mixture of E & Z isomers of formulas IVa & IVa' in the ratio averaging about 58:42.

The condensation of ketone of formula IIIA with 2-(dimethylamino)ethoxyamine of formula V (scheme1, method 'b') is also not expected to be specific although there could be some selectivity towards the formation of E isomer Ial. This was in fact found to be the case when we prepared in our laboratory the oxime ether as described in '524 from ketone IIIA and 2-(dimethylarnino)ethoxyamine (V). Analysis of the crude products by HPLC obtained from different batches by the method described in '524 revealed that they were indeed mixtures of E and Z isomers of formulas Ia1 and Ia'1 respectively in the ratio of about 64: 36.
BACKGROUND OF THE INVENTION:
It is very well known that the pharmacodynamic or pharmacokinetics profiles sometimes markedly differ for different geometric isomers of the same molecule. The antihistaminic activity of the individual geometric isomers viz. the E & Z isomers, of formulas Ia1 & Ia'1 respectively, is not reported hitherto in literature. We felt that it is important to understand the geometrical isomer that would predominantly contribute to the antihistaminic activity. Hence, the pure isomeric oximes of formulas IVa & IVa' were separated and individually alkylated so as to obtain pure E & Z compounds of formulas Ia1 and Ia'1, respectively. Incidentally it was found that alkylation of oxime of the pure E isomer of formula IVa led to the formation of two side products besides the expected alkylated product of formula Ia1. These two side products were separated by chromatography and characterized as nitfone of formula VI and a tetracyclic compound of formula VII, respectively (scheme 2).


On the other hand alkylation on pure Z isomer of formula IVa' with 2-(dimethylamino)ethyl chloride under similar conditions produced the Z-alkylated product of fromula Ia'1 alongwith minor side product of formula VII, without appreciable formation of nitrone of formula VI. (Scheme 3)

We anticipated that the side products viz. nitrone of formula VI, and tetracyclic compound of formula VII could also be present to some extent alongwith the expected products of formula Ia1 & Ia'1 in the preparation of IA1 (by method 'a') as described in '524 by conversion of ketone of formula IIIA to an oxime of formula IVA, and its subsequent alkylation with 2-(dimethylamino)ethyl chloride of formula V. Indeed when we carried out the oxime preparation and alkylated the resulting oxime of formula IVA with 2-(dimethylamino)ethyl chloride as per the process described '524, and when the resulting crude alkylated product was analyzed by

HPLC, three products were observed viz. the E & Z -alkylated products of formulas Ia1 and Ia'1 alongwith the nitrone of formula VI in the ratio of about 4.1: 1.0: 1.1, respectively.
The pure E & Z isomers of formulas Ia1 and Ia'1 were isolated and tested individually for antihistaminic activity in both in-vitro and in-vivo. Interestingly we discovered that the antihistaminic activity of the pure E isomer of formula Ia1, in both in-vitro and in-vivo was significantly higher than that of the corresponding Z isomer of formula Ia'1 (Table 1). We also isolated and tested the pure nitrone of formula VI and the tetracyclic compound of formula VII for their antihistaminic activity. Both these products were also found to possess antihistaminic activity, albeit much lower than that of the (E)-oxime ether of formula Ia1 (Table 1). From our observations, it is apparent that the biological activities described in '524 for compounds of formula II are not for a pure single isomer but for mixtures of compounds, viz. the E & Z isomers, and the nitrone.
Table-1

Encouraged by this interesting finding that the pure E isomer of formula Ia1 is markedly more potent in comparison to the corresponding Z isomer of formula Ia'1, we have synthesized a number of (E)-oxime ether derivatives of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-11-ones, compounds of formula I. These compounds were found to have antihistaminic activity.
OBJECT OF THE INVENTION
The object of the present invention is to provide antihistaminic compounds of formula I and pharmaceutically acceptable salts thereof.

SUMMARY OF INVENTION
wherein R in formula I is selected from
The present invention provides (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-11-one, compound of formula I


wherein R', R", R"', R3, R4, R5, R6 & R7 are selected from
hydrogen, alkyl (C1 to C6 linear, branched or cyclo), tricylic fused ring such as adamantyl, unsaturated alkyl (C1 to C6 linear, branched or cyclo), heterocyclic (containing one or more of hetero atoms viz. N, S, O), aryl, heteroaryl (containing one or more of hetero atoms viz. N, S, 0), alkylaryl, optionally further wherein any of R', R", R"', R3, R4, R5, R6 & R7 groups above may be further substituted with one or more groups selected from saturated or unsaturated alkyl (C1 to C6 linear, branched or

cyclo), alkoxy(C1 to C6 linear, branched or cyclo), halo, haloalkyl, haloalkoxy, alkylaryl, hydroxy, amino and its derivatives such as amide or carbamate; carboxylic acids, C1-C6 alkylcarboxylic acids, acrylic acids, propargylic acids and their derivatives such as amides or substituted amides with alkyl (C1-C5), Substitution
or aryl substitution or cyclic amides (C1 to C7), esters (C1 to C7), N-hydroxyamides,
or N-C1 to C5 alkoxyamides;
m is 0 to 2;
E is selected from 0, S, NH, NR8 wherein R8 maybe C1-C6 linear branched or cyclo
alkyl group, C=O, C02, SO2 and S=O; and
B is selected from -(CH2)P- wherein p=2 to 7; and
-CH(R9)-(CH2)x-D- CH(R10)- (CH2)y- wherein D is O, NR8, S or SO2; x and y are
independently 1 to 6; and R8, R9 & R10 are independently H, (C1-C6 linear, branched
or cyclo) alkyl group;
optionally B is part of arylheterocycles containing one or more of hetero atoms (viz.,
N, S, O);
R2 and R2 are selected from hydrogen, halogen, saturated or unsaturated C1-C6 linear, branched or cyclo alkyl group, haloalkyl, C1-C6 linear, branched or cyclo alkoxy or haloalkoxy, amino and its derivatives such as amide or carbamate; carboxylic acids, C1-C6 alkyl carboxylic acids, acrylic acids, propargylic acids and their derivatives as defined above;
and n is 2 to 6; and pharmaceutically acceptable salts thereof.
More particularly the present invention provides (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-11-one, compound of formula I wherein R in formula I is selected from



R', R", R'", R3, R4, R5, R6 & R7 are selected from hydrogen, alkyl (C1 to C6 linear,
branched or cyclo), tricylic fused ring such as adamantyl, unsaturated alkyl (C1 to C6
linear, branched or cyclo), aryl, alkylaryl, optionally further wherein any of R', R",
R'", R3, R4, R5, R6 & R7 groups above may be further substituted with one or more
groups selected from alkoxy, halo, haloalkyl, haloalkoxy, free carboxyl, hydroxy or
amino groups;
m is 0 to 2;
E is selected from C=O, CO2 and SO2; and
B is selected from -(CH2)P- wherein p=2 to 7; and
-CH(R9)-(CH2)X-D- CH(R10)- (CH2)y- wherein D is O, NR8, S or SO2; x and y are
independently 1 to 6; and R8, R9 & R10 are independently H, (C1-C6 linear, branched
or cyclo) alkyl group;
optionally B is part of arylheterocycles containing one or more of hetero atoms (viz.,
N,S,0);
R1 and R2 are selected from hydrogen, halogen, alkyl (C1-C6 linear, branched or cyclo),.
alkoxy (C1-C6 linear, branched or cyclo), haloalkoxy or haloalkyl; and
n is 2 to 6 and pharmaceutically acceptable salts thereof.

DETAILED DESCRIPTION OF THE INVENTION:
wherein R, R1 and R2 are as described above.
The compound of formula I, wherein R is

Accordingly, the present invention provides compound of formula I

referred to herein as formula Ia.
More particularly, the compounds of formula Ia are as given below in Table 2:
Table 2



The compound of formula I wherein R is

referred to herein as formula Ib.
More particularly, the compounds of formula Ib are as given below in Table 3:
Table 3


The compound of formula I wherein R is

referred to herein as formula Ic.
More particularly, the compounds of formula Ic are as given below in Table 4:
Table 4

All compounds are as iodide salts
The compound of formula I wherein R is

referred to herein as formula Id.
More particularly, the compounds of formula Id are as given below in Table 5:
Table 5


The compound of formula I wherein R is

referred to herein as formula Ie.
More particularly, the compounds of formula Ie are as given below in Table 6:
Table 6



The compound of formula I wherein R is
referred to herein as formula If.
The compound of formula I wherein R is

More particularly, the compounds of formula If are as given below in Table 7:

referred to herein as formula Ig.
The compound of formula I wherein R is

More particularly, the compounds of formula Ig are as given below in Table 8:

referred to herein as formula Ih; and wherein

R is referred to herein as formula Ii.
More particularly, the compounds of formula Ih and Ii are as given below in Table 9:

Compounds of the present invention may be prepared using different routes. For instance, by a process comprising (a) reacting ketone of formula III with hydroxylamine or salts of hydroxylamine to yield oxime of formula IV(E/Z); (b) purifying the oxime of formula IV(E/Z) with a suitable solvent to obtain pure (E)-oxime of formula IV; and (c) treating the pure (E)-oxime of formula IV with an alkylating agent, optionally further derivatizing the alkylated compound, to yield compound of formula I.

In one embodiment of the process of the present invention step (a) of the process comprises reaction of ketone of formula III with hydroxylamine or its acid addition salts in an alcoholic solvent such as ethanol or methanol, using an organic or an inorganic base, preferably an inorganic base such as alkali metal hydroxides or carbonates or acetates to yield oxime of formula IVE/Z.
In one embodiment of the process of the present invention step (b) comprises purifying the oxime of formula IVE/Z obtained in step (a) with a suitable solvent preferably an aprotic solvent, more preferably a ketonic solvent, to get pure (E)-oxime of formula IV.
In one embodiment of the process of the present invention step (c) the antihistaminic compounds of the general formula I are obtained by a simple and an efficient process comprising reaction of oxime of formula IV with a suitable alkylating agent. The alkylated compound could, if required, be further derivatized to compounds of the general formula I as described above.
Preferably the process of the present invention step (c) comprises reaction between the oxime of formula IV with an alkylating agent in the presence of a base and a facilitator, in an inert aprotic solvent, at desired temperature for requisite time. The resulting crude (E)-oxime ether is purified by standard methods.
The base used in the process of the present invention step (c) may be an organic base or an inorganic base, preferably an inorganic base selected from alkali metal hydroxides, such as potassium hydroxide.

The inert aprotic solvent used in the process of the present invention step (c) may be an hydrocarbon solvent, preferably an aromatic hydrocarbon solvent such as toluene.
The facilitator used in the process of the present invention step (c) may be a quaternary ammonium salt or a cyclic or acyclic polyethers, preferably an acyclic polyether such as poly(ethylene glycol)-400 (PEG-400).
Series of compounds may be prepared by routes as illustrated below:

wherein L is a leaving group selected from halo, or an alkyl or arylsulfonate group for e.g.
methanesulfonate or p-toluenesulfonate and the like.
The starting material for the preparation of IV may be prepared as in Belgian patent Number
647,043

wherein L is a leaving group selected from halide, or an alkyl/arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like.


wherein L is a leaving group selected from halide, or an alkyl/arylsulfonate group for e.g. methanesulfonate or p-toluenesulfonate and the like.

wherein Lisa leaving group selected from a halide, aryloxy siich as 4-nitrophenoxy and the like.

wherein X is a halide, and Visa group displaceable by amine such as imidazolyl, aryloxy such as 4-nitrophenoxy, and the like.


wherein L is a leaving group selected from halide, X is halide or aiyloxy such as 4-nitrophenoxy and the like arid X and Y are as defined above

Another aspect of the present invention relates to formulation of compound of formula I in suitable form, which can be administered to the patient.

Compounds of the present invention can be provided as a pharmaceutical composition for use in the treatment of histamine mediated diseases. The composition comprises compound of formula I and pharmaceutically acceptable ingredients.
Such compositions may be prepared by admixing compound of formula I and pharmaceutically
acceptable ingredients. Usually the compositions are adapted for oral administration. However,
they may be adapted for other modes of administration, for example parenteral administration,
sublingual, transdermal or opthalrnic administration.
The compositions may be in the form of tablets, capsules, powders, granules, nasal spray, aerosols, lozenges, ointments, creams, transdermal patches, reconstitutable powders, or liquid preparations, such as oral or sterile solutions or suspensions.
In order to obtain consistency of administration it is preferred that a composition of the invention is in the form of a unit dose.
Unit dose presentation forms for oral administration may be tablets and capsules and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrrolidone; fillers, for example lactose, sugar, maize-starch, calcium phosphate, sorbitol or glycine; tabletting lubricants, for example magnesium stearate; disintegrants, for example starch, polyvinylpyrrolidone, sodium starch glycollate or microcrystalline cellulose; or pharmaceutically acceptable wetting agents such as sodium lauryl sulphate.
The compositions are preferably in a unit dosage form in an amount appropriate for the relevant daily dosage.
The solid oral compositions may be prepared by conventional methods of blending, filling or tabletting known to those skilled in this art. Repeated blending operations -may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art. The tablets may be coated according to

methods well known in normal pharmaceutical practice.
Oral liquid preparations may be in the form of, for example, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, gelatin, hydroxyethyl cellulose, carboxymethylcellulose, aluminum stearate gel, hydrogenated edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as esters of glycerine, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid; and if desired conventional flavoring or coloring agents.
For parenteral administration, fluid unit dosage forms are prepared utilizing the compound and a sterile vehicle, and, depending on the concentration used, can be either suspended or dissolved in the vehicle. In preparing solutions the compound can be dissolved in water for injection and filter sterilized before filling into a suitable vial or ampoule and sealing. Advantageously, adjuvants such as a local anaesthetic, a preservative and buffering agent can be dissolved in the vehicle. To enhance the stability, the composition can be frozen after filling into the vial and the water removed under vacuum.
For ophthalmic administration, sterile solution or suspension can be prepared. Ophthalmic solution can be prepared by dissolving the compound in water for injection along with suitable preservative, chelating agent, osmogen, viscosity enhancing agent, antioxidant and buffering agent. Solution is aseptically filtered and filled into suitable vials or bottles of suitable material. Similarly suspension can be prepared by aseptically dispersing the sterile compound in a sterile aqueous vehicle containing suitable preservative, chelating agent, osmogen, suspending agent, anti-oxidant and buffering agent. Preservative-free unit doses can also be prepared in similar way for solution as well as suspension and aseptically filled into unit dose containers.

Compositions may contain from 0.01 % to 99.0% by weight of the active material, depending upon the method of administration.
Composition may, if desired, be in the form of a pack accompanied by written or printed instructions for use.
The compound of formula I on being formulated is useful for various histamine mediated diseases. IC50's were determined for the compounds prepared by the present invention (using Guinea pig ileum functional assay method) for the estimation of antihistaminic potency (Table 10).
The invention is further illustrated but not restricted by the description in the following examples.
Examples
Example 1
Preparation of oxime of formula IVa:
To a suspension of 8-chloro-5}6-dihydro-benzo[5,6]cyclohepta[1,2-b] pyridin -11-one (formula IIIA) (100g, 0.410 mol) in ethanol (3500ml), hydroxylamine hydrochloride (171.25g, 2.46 mol) is added over a period of 20 minutes at ambient temperature and stirred for further 10 minutes. A solution of sodium hydroxide (103.49g, 2.587 mol) in water is then added and the mixture heated under reflux for 18.5 hrs. Cooled to 10-15° C and quenched with water (6000ml). The precipitated solid is filtered and dried to get the crude oxime containing mixture of (E) and (Z)-oximes.
The crude oxime mixture (lOOg) is suspended in acetone-(3500ml) and stirred for 2 hrs at ambient temperature. The solid is filtered and dried to get. pure (E)-isomer of 8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-ll-one oxime (formula IVa) (HPLC purity >97.0%). The mother liquor is concentrated and the residue is purified by flash chromatography to get the pure (Z)-isomer of 8-chloro-5,6-dihydro-benzo[5,6]cyclohepta[l,2-b] pyridin-11-one oxime of formula IVa'.

Example 2
a) Preparation of (E)~oxime ether of Ia1.
To a suspension of (E)- 8-chloro-5,6-dihydro-benzo[5,6]cycloheptat[1,2-b]pyridin-11-one oxime (formula IVa) (5g, 0.019mol) in a mixture of toluene (60ml)- PEG-400 (20ml), is introduced at ambient temperature powdered potassium hydroxide (7.59gms, 0.135mol) and stirred for 10 minutes. 2-(Dimethylamino)ethyl chloride (11g, 0.095mol) is then added and stirred at ambient temperature for 24 hrs. Water is added, organic layer separated and the aqueous layer re-extracted with toluene (3x30ml). Combined organic layer is washed successively with water and brine, arid degassed under reduced pressure to a get dark brown viscous liquid (6.15g). The crude material is purified by flash column chromatography to get pure compound of formula Ia1 as the major component and pure tetracyclic compound of formula VII in minor quantity.
MP. of Ia1: 78-80o C
H-NMR of Ia1 (CDC13, δppm): 8.55(dd, Jl=4.64, J2=1.55Hz, 1H), 7.47(dd, J,-7.73m, J2=1.46Hz, 1H), 7.45(d, J=8.09Hz, 1H), 7.17-7.26, (m,3H), 4.41 (t, 6.10Hz,2H), 3.16-3.05(m, 4H), 2.64(t, J=6.08Hz, 2H), 2.22(s, 6H)
13C-NMR of lal (CDC13, Sppm): 156.37(s), 151.87(s), 148.39(d), 140.09(s), 139.08(d), 135.37(s), 134.98(s), 132.28(s), I31.39(d), 128.90(d), 126.65(d), 124.45(d), 74.04(t), 58.54(t), 46.53(2q), 32.84(t), 32.12(t)
1H-NMR of VII (CDCI3, δppm): 8.16(d, J=8.40Hz,1H), 8.07(dd, J1=5.35, J2=2.7Hz,1H), 7.27(dd, J1=8.42, J2-2.23Hz,1H), 7.17(d, J=2.18Hz,1H), 6.53-6.49(m,2H), 3.91(s,2H), 3.02-3.09 (brm, 4H), 2.29(s, 6H)
13C-NMR of VII (CDC13, δppm): 139.97(s), 137.06(s), 134.33(2s), 133.41(5), 131.32(8), 130.20(d), 129.43(s), 128.27(d), 127.33{d), 121.29(d), 116.96(d), 112.95(d), 57.08(0, 45.94(2q), -35.67(t),33.50(t)

Compounds Ia2 to Ia6 are prepared in the same manner as for Ia1, using the corresponding 2-chloroethylamine or its derivatives.
b) Preparation of (Z)-oxime ether of Ia'l: The (Z)-oxime ether of the formula Ia'1 is prepared by following the procedure described above for Ia1, using the (Z)-oxime of formulaa IVa' in place of the (E)-oxime IVa.
1H-NMR of Ia'1 (CDCI3, δppm): 8.51(dd, J1=4.85, J2=1.52Hz, 1H), 7.60(d, J=8.31Hz, 1H), 7.58(dd, J1=7.65,-J2=1.46Hz,1H), 7.24-7.09(m, 3H),4.35(t, J=5.96Hz, 2H), 3.18-3.00(m, 4H), 2.68(t, J=5.90Hz, 2H), 2.24(s, 6H).
13C-NMR of Ia'1 (CDCl3j δppm): 156.19(s), 153.86(5), 147.77(d), 140.18(s), 136.32(d), 135.66(s), 134.26(s), 131.83(s), 131.32(d), 130.76(d), 127.18(d), 124.43(d), 71.15(t), 58.19(t), 46.13(2q),33.62(t), 30.31 (t).
c) Preparation of nitrone of formula VI: To a stirred mixture of oxime of formula IVa (0.0193mol) and anhydrous potassium carbonate (0.116mol) in acetone (60ml), is added 2-(dimethylamino)ethyl chloride (0.079mol) and the mixture refluxed for 8 hours. The solids were filtered and the filtrate is concentrated. The residue is taken up in ehtyl acetate, washed with water, concentrated and degassed. The syrupy residue is purified by column chromatography to get pure nitrone VI.
1H-NMR of VI (CDCl3, δppm): 8.50(dd, J1=4.73, J2=1.54Hz, 1H), 7.91 (d, J=8.42Hz, 1H), 7.58(dd, J=7.74,1.48Hz, 1H), 7.30-7.14(m,3H), 4.48-2.25(br, 8H),1.99(s, 6H).
13C-NMR of VI (CDCl3 δppm): 153.08(s), 147.83(d), 143.77(s), 139.87(s), 137.72(d), 136.25(s), 135.20(s), 131.60(d), 130.71 (s), 130.16(d), 126.56(d), 124.87(d), 59.84(t), 57.47(t), 45.80(2q), 32.27(t), 30.71(t)

Example 3
Preparation of Ia7 to Ia9
These compounds are prepared by alkylation of Ia5 with the corresponding alkyl halide in acetone using anhydrous potassium carbonate as a base.
Preparation of Ia10 to Ia16
Compounds Ia10 to Ia16 are prepared by alkylation of Ia6 with the corresponding alkyl halide
or haloalklyester in acetone using anhydrous potassium carbonate as a base.
Example 4
Preparation of Ia17
This compound is prepared by hydrolysis of Ia16 with potassium hydroxide in ethanol.
Example 5
Preparation of Ia19
A mixture of 3,4,5-trimethoxybenzaldehyde (0.0033 mol) and Ia5 (0.0033 rnol) in toluene (20ml) is refluxed azeotropically for 21 hours with a catalytic amount of p-toluenesulfonic acid. Cooled to ambient temperature and water is added. The organic layer is separated and the aqueous layer is extracted with toluene (2x15ml). Combined organic layer is washed successively with water and brine, and degassed under reduced pressure to obtain the crude imine. Sodium borohydride (0.046mol) is added portionwise to the solution of the crude imine in methanol (10ml) at 10-15°C. After stirring for 30 minutes the reaction mixture is concentrated under reduced pressure. The residue is quenched with water and extracted with ethyl acetate (3x15ml). Combined extract is washed successively with water and brine and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get the pure product of formula Ia19
Similarly are prepared.compounds of formulas Ia18 & Ia20 to Ia25 using the corresponding oxo compounds.

Example 6
Preparation of Ia26
Methyl iodide (0.001mol) is added into the stirred mixture of potassium carbonate (0.0015mol) and Ia19 (0.001mol) in acetone (20ml) at 10-15°C over a period of 5 minutes. After stirring at 15° C for 30 minutes the mixture is concentrated under reduced pressure, water is added and extracted in methylene chloride (3x10 ml). The organic extract is washed with water and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get compound of formula Ia26.
Similarly are prepared compounds of formulas Ia27 to Ia32 using the corresponding oxime ethers and methyl iodide.
Compounds Ia33 to Ia35 are prepared using the corresponding oxime ethers cinnamyl chloride.
Compound Ia36, Ia43 & Ia44 are prepared by similar alkylation of Ia6, Ia23 & Ia20
respectively, with 2-chloroethanol
Compounds Ia38 & Ia39 are prepared by similar alkylation of Ia6 & Ia8 respectively, with 3-chloro-1,2-propanediol.
Example 7
Preparation of Ia37
To a solution of Ia6 (0.002mol) in 2-propanol (15ml) is added propylene oxide (0.01mol) at 0-5°
C. The mixture is stirred for 12 hours and concentrated under reduced pressure. The crude
product obtained is purified by flash chromatography to obtain pure compound of formula Ia37.
Similarly are prepared compounds of formulas Ia40, Ia41 & Ia42 from Ia8, Ia9 & Ia19
respectively using propylene oxide.

Example 8
Preparation of Ib1 to Ib3
These compounds are prepared in a similar manner as for lal using the corresponding (2-
chloroethyl) cyclic amines.
Example 9
Preparation Ic1 to Ic6
These compounds are prepared in the same manner as Ia26, from the corresponding (dialkyamino)ethyl oxime ethers using molar excess of the corresponding alkyl halide to obtain the corresponding quaternary salts Ic1 to Ic6.
Example 10
Preparation of Id1
Methyl chloroformate (0.00248mol) is added to a stirred mixture of compound of formula Ia5 (0.001mol) and anhydrous potassium carbonate (0.004mol) in tetrahydrofuran (10ml) at ambient temperature and stirred for 2 hours. The mixture is concentrated under reduced pressure, quenched with water and extracted with methylene chloride. The extract is washed with brine and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get pure Id1.
Similarly compound of formula Id2 is prepared using ethyl chloroformate in the place of methyl chloroformate.
Similarly compound of formula Id3 is prepared using acetic anhydride in the place of methyl chloroformate and pyridine as base.
Similarly are prepared compounds of formulas Id8, Id9 & Id10 using methanesulfonyl chloride in the place of methyl chloroformate and using pyridine as base from Ia5, Ia6 & Ia23, respectively.

Compound Id11 is prepared similarly as above from Ia5 and 4-toluenesulfonyl chloride in place of methanesulfonyl chloride
Example 11
Preparation of Id4
To a stirred solution of N-methylmorpholine (0.00165mol) and (2-chlorophenyl)acetic acid (0.00124mol) in methylene chloride (15ml), is added 2,2-dimethylpropionyl chloride (0.001030mol) at 0-5° C and stirred for 30mins. The mixture is then brought to ambient temperature, stirred for further 30 mins, and again cooled to 0-5° C. A solution of compound of formula Ia6 (0.00083mol) in methylene chloride is introduced into the reaction mixture at 0-5° C and then slowly brought to ambient temperature. It is quenched with water and is extracted with methylene chloride (3x15ml). Combined organic layer is washed with brine and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get the compound of formula Id4.
Similarly is prepared compound Id5 using Ia5 as starting material.
Compound Id6 & Id7 are prepared from Ia5 & Ia6 respectively, using (4-carbethoxy-3-ethoxyphenyI)acetic acid in the place of (2-chlorophenyl)acetic acid followed by hydrolysis of the ester.
Example 12
Preparation of Ie1
Cyclohexyl isocyanate (0.00132mol) is added to a solution of Ia5 (0.00132mol) in tetrahydrofuran (10ml) at ambient temperature. After stirring for 2 hrs, the reaction mixture is concentrated under reduced pressure and the residue is purified by flash column chromatography on silica gel to get pure Ie1.
Similarly are prepared compounds of formulas Ie2 to Ie23 by reacting Ia5 with the corresponding isocyanates.

Similarly are prepared compounds of formulas Ie24 to Ie34 by reacting Ia6 with the corresponding isocyanates.
Similarly are prepared compounds of formulas Ie35 to Ie37 by reacting Ia8 with the corresponding isocyanates.
Example 13
Preparation of If1
To a solution of formula Ia5 (0.002mol) in methylene chloride (15ml) and
diisopropylethylamine (0.003) is added portionwise 4-nitrophenyl chloroformate (0.002mol) at
ambient temperature. The mixture is stirred for 4 hours. The mixture is washed with water and
concnctrated and degassed to obtain the 4-nitrophcnyl carbamate derivative of Ia5 as a yellow
solid.
To a stirred solution of the above carbamate derivative in methylene chloride (10ml) at ambient temperature is added a solution of cis-2,6-dimethylpiperazine (0.00227mol) in methylene chloride (5ml), and stirred for 8 hours. Reaction mixture is quenched with water and extracted with methylene chloride. The organic extract is washed successively with 5% aqueous sodium hydroxide, water and brine and then degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get the compound of formula If1.
Similarly compound of formula If2 is prepared starting from compound Ia6.
Example 14
Preparation of Ig1
A mixture of cyclopentane-1,3-dione (0.00142mol) and Ia5 (0.00095mol) in toluene (15ml) is heated under reflux for 6 hours. Cooled mixture to ambient temperature, water is added and the organic layer is separated. The aqueous layer is extracted with ethyl acetate (2xl5ml). Combined organic extract is washed successively with aqueous sodium hydroxide solution

(0.5N, 1x15ml), water, and brine, and then degassed under pressure. The residue is purified by flash column chromatography to get the pure Ig1.
Similarly are prepared compounds Ig2 to Ig5 & Ig11 from Ia5 using the corresponding cyclic 1,3-diones.
Similarly are prepared compounds Ig6 to Ig10 from Ia6 using the corresponding cyclic 1,3-diones.
Example 15
Preparation of Ih1
A mixture of 3,4-dimethoxy-3-cyclobutene-1,2-dione (0.0063mol) and Ia5 (0.0063mol) in methanol (10ml) is stirred for 8 hrs at ambient temperature and then concentrated and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get pure Ih1.
Similarly are prepared compounds Ih2 & Ih3 from Ia5 using the corresponding squarate ester. Similarly are prepared compounds Ih4 to Ih6 from Ia6 using the corresponding squarate ester.
Compound Ii9 is prepared in a similar manner using Ia6 and 3-methoxy-4-(2,6-dichlorophenyl)amino-cyclobut-3-en-1,2-dione at reflux condition.
Example 16
Preparation of Ii1
Triethylamine (0.023mol) and 30% aqueous methylamine solution (0.0167mol) are added sequentially to a solution Ihl (0.00068mol) in methanol (15ml) at 0-5° C. The mixture is gradually brought to ambient temperature and then concentrated under reduced pressure. The residue is quenched with water and is extracted into methylene chloride (2x15 ml). Combined extract is washed with brine and degassed under reduced pressure. The residue is purified by flash column chromatography on silica gel to get the pure Ii1.

Similarly are prepared compounds Ii2 to Ii8 from Ih1 using the corresponding amino compound.
Example 17
IC50 determination using isolated guinea pig ileum functional assay
Terminal segment of ileum of junction of Dunken Hartley guinea pig, of about 10 cm from the ileo-caecal, separated from mesenteric attachments was immediately removed and placed in Tyrode solution of composition, NaCl 137.0mM, KC1 2.7 mM, CaCl2 1.8 mM, MgCl2 1.05 mM, NaHCO3 11.9 mM, NaH2PO4 0.42 mM and glucose 5.6 mM, maintained at 35° C. The lumen of the ileum was gently cleaned with Tyrode so as to remove any particle without affecting the mucosal layer of the tissue. Pieces of 1.5-2 .0 cm length were cut and placed in the organ bath of 20ml capacity, attaching one end to the tissue holder and other to the transducer by a fine cotton thread. The system was previously calibrated before start of each experiment. Tissue was kept under a resting tension of 0.5-0.75g. The bath solution was continuously bubbled with 95 % O2 and 5% CO2 and maintained at 35° C temperature. After an initial 30 min of equilibration time the baseline was recorded and non-cumulative responses with sub maximal dose of histamine (7.2 X 10-7M) were initially recorded untii the responses were reproducible. The contractions to this typical dose of histamine in absence (only vehicle) and presence of at least 3 different concentrations of the test compounds were recorded after 15min constant incubation time. The percentage inhibitions caused by different concentrations of test compounds were plotted against the log of molar concentrations of the test compounds for the determination of IC50-
Table 10 : IC50 values for selected compounds




We claim:
wherein R in formula I is selected from
1. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cycloheptatl[1,2-b]pyridin-11-one, compound of formula I


wherein R1, R", R'", R3, R4, R5, R6 & R7 are selected from
hydrogen, alkyl (C1 to C6 linear, branched or cyclo), tricylic fused ring such as adamantyl, unsaturated alkyl (C1 to C6 linear, branched or cyclo), heterocyclic (containing one or more of hetero atoms viz. N, S, O), aryl, heteroaryl (containing one or more of hetero atoms viz. N, S, O), alkylaryl, optionally further wherein any of R', R", R'", R3, R4, R5, Ra & R7 groups above may be further substituted with one or more groups selected from saturated or unsaturated alkyl(C1 to C6 linear, branched or

cyclo), alkoxy(C1 to C6 linear, branched or cyclo), halo, haloalkyl, haloalkoxy,
alkylaryl, hydroxy, amino and its derivatives such as amide or carbamate;
or wherein R', R", R'", R3, R4, R5, R6 & R7 may be selected from the groups
consisting of
carboxylic acids, C1-C6 alkylcarboxylic acids, acrylic acids, propargylic acids and
their derivatives such as amides or substituted amides with alkyl (Ci-Cs) substitution
or aryl substitution or cyclic amides (C1 to C7), esters (C1 to C5), N-hydroxyamides,
or N-C1 to C5 alkoxyamides;
m is 0 to 2;
E is selected from O, S, NH, NR8 wherein R8 maybe C1-C6 linear, branched or cyclo
alkyl group, C=O, CO2, SO2 and S=O; and
B is selected from -(CH2)P- wherein p=2 to 7; and
-CH(R9)-(CH2),-D- CH(R10)- (CH2)y- wherein D is O, NR8, S or SO2; x and y are
independently 1 to 6; and R8, R9 & R10 are independently H, (C1-C6 linear, branched
or cyclo) alkyl oup;
optionally B is part of arylheterocycles containing one or more of hetero atoms (viz.,
N, S, 0);
R1 and R2 are selected from hydrogen, halogen, saturated or unsaturated C1-C6 linear, branched or cyclo alkyl group, haloalkyl, C1-C6 linear, branched or cyclo alkoxy or haloalkoxy, amino and its derivatives such as amide or carbamate; carboxylic acids, C1-C6 alkyl carboxylic acids, acrylic acids, propargylic acids and their derivatives as defined above;
and n is 2 to 6;
and pharmaceutically acceptable salts thereof.
2. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-I 1-one, compound of formula I as claimed in claim 1 wherein R in formula I is selected from


R', R", R"', R3, R4, R5, R6 & R7 are selected from hydrogen, alkyl (C1 to C6 linear,
branched or cyclo), tricylic fused ring such as adamantyl, unsaturated alkyl (C1 to C6
linear, branched or cyclo), aryl, alkylaryl, optionally further wherein any of R', R",
R'", R3, R4, R5, R6 & R7 groups above may be further substituted with one or more
groups selected from alkoxy, halo, haloalkyl, haloalkoxy, free carboxyl, hydroxy or
amino groups;
m is 0 to 2;
E is selected from C=O, CO2 and SO2; and
B is selected from -(CH2)P- wherein p=2 to 7; and
-CH(R9)-(CH2)X-D- CH(R10)- (CH2)y- wherein D is O, NR8, S or SO2; x and y are
independently 1 to 6; and R8, R9 & R10 are independently H, (C1-C6 linear, branched
or cyclo) alkyl group;
optionally B is part of arylheterocycles containing one or more of hetero atoms (viz.,
N,S,0);
R1 and R2 are selected from hydrogen, halogen, alkyl (C1-C6 linear, branched or cyclo),
alkoxy (C1-C6, linear, branched or cyclo), haloalkoxy or haloalkyl; and
n is 2 to 6 and pharmaceutically acceptable salts thereof. 3. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-1 1-one,
compound of formula I as claimed in claim 1 wherein

R1 is hydrogen; R2 is 8-chloro; R' and R" are methyl; and n is 2; and pharmaceutically acceptable salts thereof.
4. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cycIohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; R' and R" are ethyl; and n is 2; and pharmaceutically acceptable salts thereof.
5. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; B is -(CH2)P- wherein p is 4; and n is 2; and pharmaceutically acceptable salts thereof.
6. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-11-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; R' and R" are C6H5CH=CH2; R'" is methyl; L is I; and n is 2;
and pharmaceutically acceptable salts thereof.
7. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is


R1 is hydrogen; R2 is 8-chloro; R' and R'" are methyl; E is SO2; and n is ; and pharmaceutically acceptable salts thereof.
8. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; R' is hydrogen; R'" is cyclohexyl; and n is 2; and pharmaceutically acceptable salts thereof.
9. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[l,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; R3, R4 and R5 are hydrogen; R' is hydrogen; m is 1 and n is 2;
and pharmaceutically acceptable salts thereof
10. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein R is

R1 is hydrogen; R2 is 8-chloro; R' and R'" are methyl; and n is 2; and pharmaceutically acceptable salts thereof.
11. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in claim 1 wherein


R1 is hydrogen; R2 is 8-chloro; R' is methyl; R6 is hydrogen; R7 is methyl; and n is 2; and pharmaceutically acceptable salts thereof.
12. (E)-oxime ether derivative of 5,6-dihydro-benzo[5,6]cyclohepta[1,2-b]pyridin-1 1-one, compound of formula I as claimed in any of claims 1 to 10 substantially as herein described and illustrated by examples 1 to 17.

Dated this 8th day of April, 2003.


DILIP SHANGHVI CHAIRMAN AND MANAGING DIRECTOR
SUN PHARMACEUTICAL INDUSTRIES LIMITED