NZ703323B2

NZ703323B2 - Acrylamide compounds as histamine h3 receptor ligands

Info

Publication number: NZ703323B2
Application number: NZ703323A
Authority: NZ
Inventors: Adi Reddy Dwarampudi; Venkateswarlu Jasti; Ramakrishna Nirogi; Anil Karbhari Shinde
Original assignee: Suven Life Sciences Limited
Priority date: 2012-08-23
Filing date: 2012-12-05
Publication date: 2016-07-01

Abstract

The present invention relates to novel acrylamide compounds of formula (I), and their pharmaceutically acceptable salts and process of their preparation. The compounds of formula (I) are useful in the treatment of various disorders that related to Histamine H3 receptors, including cognitive deficits in schizophrenia, narcolepsy, obesity, attention deficit hyperactivity disorder, pain and/or alzheimer’s disease. s in schizophrenia, narcolepsy, obesity, attention deficit hyperactivity disorder, pain and/or alzheimer’s disease.

Description

ACRYLAMIDE COMPOUNDS AS HISTAMINE H3 RECEPTOR LIGANDS Field of Invention The present invention relates to novel acrylamide compounds of formula (I) and their pharmaceutically acceptable salts, for treatment of various disorders that are related to Histamine H3 receptors.

N N I O X Background of the Invention Histamine H3 receptor is a ein coupled receptor (GPCR) and one out of the four receptors of Histamine family. Histamine H3 or is identified in 1983 and its cloning and terization were done in 1999. Histamine H3 receptor is expressed to a larger extent in l nervous system and lesser extent in the peripheral s system.

Literature ce suggests that Histamine H3 or ligands can be used in treatment of cognitive disorders (British Journal of Pharmacology, 2008, 154(6), 1166-1181), dementia (Drug News ctive, 2010, 23(2), 99-103), attention t hyperactivity disorder, obesity (Indian Journal of Pharmacology, 2001, 33, 17-28), schizophrenia (Biochemical Pharmacology, 2007, 73(8), 1215-1224) and pain (Journal of Pharmacology and Experimental Therapeutics, 2011, 336(1), .

Patent publications WO 2007/137955, US 2009/0170869, US 2010/0029608, US 2010/0048580, WO 00120, and disclosed series of compounds as ligands at Histamine H3 receptors. While some Histamine H3 receptor ligands have been disclosed, no compound till date is launched in market in this area of research, and there still exists a need and scope to discover new drugs with novel chemical structures for treatment of disorders affected by Histamine H3 receptors.

Summary of the Invention In a first aspect, the invention provides a compound of the general formula (I): N N I O X wherein, at each occurrence, R1 is independently selected from hydrogen, halogen, alkyl or alkoxy; “A” is alkyl, lkyl or cycloalkylalkyl; “X” is CH or N; “Y” is CH2, O or S O; or its pharmaceutically acceptable salts.

The present invention relates to novel acrylamide Histamine H3 receptor ligands of the formula (I), N N I O X wherein, at each ence, R1 is independently selected from hydrogen, halogen, alkyl or alkoxy; “A” is alkyl, cycloalkyl or cycloalkylalkyl; “X” is C or N; “Y” is C, O or S O; or its ceutically acceptable salts.

The present invention relates to use of a therapeutically effective amount of compound of formula (I), to manufacture a medicament in the treatment of various disorders that are related to Histamine H3 receptors.

Specifically, the compounds of this invention are useful in the treatment of various disorders such as cognitive deficits in schizophrenia, narcolepsy, obesity, attention deficit hyperactivity disorder, pain or alzheimer’s disease.

In another aspect, the ion relates to pharmaceutical compositions containing a eutically effective amount of at least one compound of formula (I), or its their pharmaceutically acceptable salts thereof, in admixture with pharmaceutically acceptable excipient.

In still another , the ion further relates to the process for preparing compounds of formula (I) and their pharmaceutically acceptable salts.

In a particular ment, the invention provides a process for preparation of a nd of formula (I) as defined in the first , which comprises: (a) reductive amination of the compound of formula ( 1) with compound of formula (2) HN N A O O X in presence of a suitable solvent and reducing agent to form a compound of formula (I), n all tutions are as defined in the first aspect, (b) optionally converting the nd of formula (I) to their pharmaceutically acceptable salts.

In a further aspect, the invention also provides the use of an effective amount of a compound or pharmaceutically acceptable salt thereof according to the first aspect in the manufacture of a medicament for the treatment of cognitive deficits in schizophrenia, epsy, obesity, attention deficit hyperactivity disorder, pain or alzheimer’s disease.

In a further aspect, the invention also provides the use of a compound according to the first aspect in the cture of a medicament for the treatment of diseases related to Histamine H3 receptors. entative compounds of the present invention include those specified below and their pharmaceutically acceptable salts. The present invention should not be construed to be d to them. 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone fumarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](piperidinyl) propeneone hydrochloride salt; 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](1,1-dioxo thiomorpholinyl) propene one hydrochloride salt; 1-Cyclobutyl piperidinyloxy) pyridinyl](piperidinyl) propeneone L(+)- Tartarate salt; 3-[2-(1-Cyclobutyl piperidinyloxy) pyridinyl](morpholinyl) propeneone L(+)- Tartarate salt; luoro(1-isopropyl piperidinyloxy) phenyl](morpholinyl) -eneone L(+)-Tartarate salt; 3-[2-Fluoro(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methyl phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Isopropyl piperidinyloxy)methyl phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclopropylmethyl piperidinyloxy)methoxy phenyl](morpholinyl) prop eneone L(+)-Tartarate salt; 1-Isobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Isopropyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Isopropyl piperidinyloxy)methoxy phenyl](piperidinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](piperidinyl) propeneone artarate salt; 3-[4-(1-Cyclopropylmethyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[4-(1-Isobutyl piperidinyloxy) phenyl](morpholinyl) -eneone; 3-[3-Bromo(1-isopropyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-isobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-cyclopropylmethyl piperidinyloxy) ](morpholinyl) prop eneone; 3-[6-(1-Cyclopropylmethyl piperidinyloxy) pyridinyl](morpholinyl) propene one L(+)-Tartarate salt; 3-[6-(1-Isobutyl dinyloxy) pyridinyl](morpholinyl) propeneone L(+)- Tartarate salt; 3-[2-Chloro(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[2-Chloro(1-isopropyl dinyloxy) phenyl](morpholinyl) propeneone; 3-[2-Chloro(1-cyclopropylmethyl piperidinyloxy) phenyl](morpholinyl) prop eneone; or 3-[2-Chloro(1-isobutyl piperidinyloxy) phenyl](morpholinyl) propeneone.

Detailed Description of the Invention Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: The term “halogen” means fluorine, chlorine, bromine or iodine.

The term “alkyl” means straight chain or branched hydrocarbon radical consisting solely of carbon and hydrogen atoms, containing no ration, having from one to eight carbon atoms, and which is attached to the rest of the le by a single bond. Exemplary “alkyl” groups include methyl, ethyl, n-propyl, iso-propyl and the like.

The term y” means an alkyl group attached via an oxygen linkage to the rest of the molecule. Exemplary “alkoxy” groups include methoxy, ethoxy, propyloxy, iso-propyloxy and the like.

The term alkyl” means non-aromatic mono cyclic ring of 3 to 8 carbon atoms.

Exemplary alkyl” groups include cyclopropyl, cyclobutyl, cyclopentyl and the like.

The term “cycloalkylalkyl” means non-aromatic mono cyclic ring of 3 to 8 carbon atoms attached to an alkyl group. Exemplary “cycloalkylalkyl” groups include ropyl methyl, utyl methyl, cyclopentyl methyl and the like.

The phrase "pharmaceutically acceptable salts" indicates that the substance or composition must be compatible chemically and/or toxicologically, with the other ingredients sing a formulation, the mammal being d therewith.

The phrase "therapeutically effective amount" is defined as an amount of a compound of the present invention that (i) treats the particular disease, condition or disorder (ii) eliminates one or more symptoms of the ular disease, condition or er (iii) delays the onset of one or more ms of the particular disease, ion or disorder described herein.

Commercial reagents were utilized without r purification. Room temperature refers to 25 - 40 oC. Unless otherwise stated, all mass spectra were carried out using ESI conditions. 1H- NMR spectra were recorded at 400 MHz on a Bruker instrument. Deuterated chloroform, methanol or dimethylsulfoxide was used as solvent. TMS was used as internal reference standard.

Chemical shift values are expressed in parts per million (d) values. The following abbreviations are used for the multiplicity for the NMR signals: s=singlet, bs=broad singlet, d=doublet, t=triplet, q=quartet, qui=quintet, h=heptet, dd=double doublet, dt=double triplet, tt=triplet of triplets, m=multiplet. Chromatography refers to column chromatography performed using 100 - 200 mesh silica gel and executed under en pressure (flash chromatography) conditions.

Pharmaceutical compositions In order to use the compounds of formula (I) in therapy, they will normally be formulated into a pharmaceutical composition in ance with standard pharmaceutical ce.

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically able excipient. The pharmaceutically acceptable excipient is carrier or diluent. Thus, the active nds of the invention may be formulated for oral, intranasal or parenteral (e.g., intravenous, intramuscular or subcutaneous). Such pharmaceutical compositions and processes for preparing same are well known in the art (The Science and Practice of cy, D.B. Troy, 21st Edition, Williams & Wilkins, 2006).

The dose of the active compounds can vary depending on factors such as the route of administration, age and weight of t, nature and severity of the disease to be treated and similar factors. Therefore, any reference herein to a pharmacologically effective amount of the compounds of general a (I) refers to the aforementioned factors Methods of Preparation The compounds of formula (I) can be prepared by Scheme I as shown below.

HN N + A O O X N N O X Scheme I Reductive amination of the compound of formula (1) with compound of formula ( 2) to form compound of a (I). This reaction is preferably carried out in solve nt such as tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide, and the like or a mixture thereof and preferably by using dicloromethane. The reaction may be affected in the presence of a reducing agent such as diisobutylaluminum hydride, sodium triacetoxyborohydride, dimethylsulfide , sodium methoxyethoxy)aluminumhydride, sodium hydrosulfite, sodium borohydride, sodium cyanoborohydride and sodium dithionite and preferably by using sodium triacetoxyborohydride. The reaction is carried out at room ature. The duration of the reaction may range from 4 hours to 8 hours, preferably from a period of 5 hours to 7 hours.

Compounds of formula (1 ) can be prepared by using ations 1 & 2 or ca n be prepared by using conventional methods or by modifications using known process.

Compounds of formula (2 ) may be commercially available or can be prepared by conventional methods or by modification using known process.

The pharmaceutically acceptable salts forming a part of this invention may be prepared by ng the compound of formula (I) with 1-6 equivalents of a acids such as hydrochlo ric, hydrobromic, ic, , phosphoric acid, succinic, maleic, acetic, fumaric, citric, malic, tartaric, benzoic, p-toluic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. The most preferable salts of compounds of formula (I) are fumarate, L(+)-tartarate, hydrochloride, oxalate and sulfate.

Examples The novel compounds of the t invention were prepared ing to the following experimental procedures, using appropriate materials and appropriate conditions.

Preparation 1: Preparation of 3-[4-(Piperidinyloxy) phenyl](morpholinyl) prop eneone Step (i): ation of t-Butyl 4-(4-formyl phenoxy) piperidinecarboxylate A solution of 4-Hydroxybenzaldehyde (20.1 grams, 0.164 moles), ium carbonate (67.9 grams, 0.492 moles) and t-butyl 4-(toluenesulfonyloxy) piperidinecarboxylate (70 grams, 0.197 moles) in acetonitrile (1000 mL) was stirred for 18 hours at 80 oC. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was cooled to room ature and quenched on to chilled water (1000 mL). The compound was extracted with dichloromethane (3 x 500 mL). The resulting dichloromethane layer was washed with 10 % lye solution (100 mL), water (100 mL) and brine solution (100 mL). The organic phase was dried over sodium sulfate and concentrated under reduced re to afford the title compound (50.3 grams).

Yield: 100 %. 1H - NMR (d ppm): 1.48 (9H, s), 1.76 - 1.83 (2H, m), 1.96 - 2.04 (2H, m), 3.36 - 3.41 (2H, m), 40 3.68 - 3.73 (2H, m), 4.45 - 4.60 (1H, m), 6.96 - 7.02 (2H, m), 7.78 - 7.85 (2H, m), 9.89 (1H, s); Mass (m/z): 306.4 (M+H)+.

Step (ii): Preparation of 3-[4-(1-t-Butyloxycarbonyl piperidinyloxy) phenyl] propene- 1-oic acid A solution of t-Butyl 4-(4-formyl phenoxy) dinecarboxylate (50.2 grams, 0.164 moles, obtained in above step), malonic acid (50.6 grams, 0.486 moles) and piperidine (12.5 mL) in pyridine (250 mL) was stirred for 8 hours at 110 oC under nitrogen here.

The ss of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was concentrated and the resulting slurry was ated with n-hexane (200 mL) and stirred for 30 minutes. The solids, thus obtained, were washed with n-hexane (100 mL) and dried under vacuum to afford the title compound (39.1 grams).

Yield: 68 %. 1H - NMR (d ppm): 1.47 (9H, s), 1.76 - 1.80 (2H, m), 1.90 - 1.96 (2H, m), 3.35 - 3.40 (2H, m), 3.67 - 3.72 (2H, m), 4.53 - 4.60 (1H, m), 6.30 - 6.34 (1H, d, J = 15.32 Hz), 6.89 - 6.95 (2H, d, J = 8.64); 7.47 - 7.53 (2H, d, J = 8.64 Hz), 7.71 - 7.75 (1H, d, J = 15.33 Hz); Mass (m/z): 348.2 (M+H)+.

Step (iii): Preparation of 3-[4-(1-t-Butyloxycarbonyl piperidinyloxy) phenyl] (morpholinyl) propeneone To a stirred solution of 3-[4-(1-t-butyloxycarbonyl piperidinyloxy) phenyl] prop eneoic acid (38 grams, 0.109 moles, obtained in above step) and triethylamine (38.4 mL, 0.273 moles) in dichloromethane (500 mL) was added ethylchloroformate (13.6 mL, 0.142 moles) at 0 oC. The reaction mass was further stirred for 2 hours at 0 - 5 oC. Morpholine (19.2 mL, 0.219 moles) was added to above mass at 0 - 5 oC and the resulting mixture were stirred for 2 hours.

The progress of the reaction was red by thin layer chromatography. After completion of reaction, the mass was quenched by adding water (100 mL). Layers were separated and the organic layer was washed with brine solution (100 mL) and dried over sodium te. The organic phase was concentrated under vacuum to obtain the crude residue, which was further purified by flash tography using methanol:triethylamine:chloroform in the ratio of 1: 1: 98 to afford the title compound (34 grams).

Yield: 74 %. 1H - NMR (d ppm): 1.47 (9H, s), 1.76 - 1.81 (2H, m), 1.90 - 1.95 (2H, m), 3.32 - 3.39 (2H, m), 3.62 - 3.79 (10H, m), 4.49 - 4.55 (1H, m), 6.69 - 6.73 (1H, d, J = 15.92 Hz), 6.88 - 6.94 (2H, d, J = 8.64 Hz); 7.45 - 7.49 (2H, d, J = 8.64 Hz), 7.64 - 7.68 (1H, d, J = ; Mass (m/z): 417.3 (M+H)+.

Step (iv): Preparation of Piperidinyloxy) phenyl](morpholinyl) propene A solution of 3-[4-(1-t-Butyloxycarbonyl piperidinyloxy) phenyl](morpholinyl) propeneone (29.8 grams, 0.071 moles) in dichloromethane (400 mL) was treated with trifluoroacetic acid (55.6 mL, 0.726 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After completion of the reaction, the on mass was poured on to chilled water (500 mL) and basified with 40 % lye solution (pH ~ 9). The layers were separated and the aqueous layer was ted with dichloromethane (2 x 200 mL) and the combined organic phase was washed with water (150 mL), brine solution (150 mL) and dried over sodium sulphate. The organic phase was concentrated on rotavacuum to afford the title compound (21.2 grams).

Yield: 90 %. 1H - NMR (d ppm): 1.63 - 1.72 (2H, m), 2.00 - 2.04 (2H, m), 2.71 - 2.77 (2H, m), 3.12 - 3.18 (2H, m), 3.73 (8H, m), 4.39 - 4.44 (1H, m), 6.69 - 6.73 (1H, d, J = 15.32 Hz), 6.89 - 6.91 (2H, d, J = 8.64 Hz); 7.45 - 7.47 (2H, d, J = 8.64 Hz), 7.64 - 7.68 (1H, d, J = 15.32 Hz); Mass (m/z): 317.3 . ation 2: Preparation of pholinyl)[2-(piperidinyloxy) pyridinyl]- propeneone Step (i): Preparation of t-Butyl 4-(5-bromo pyridinyloxy) piperidinecarboxylate To a stirred on of sodium hydride (4.0 grams, 60 % dispersion in mineral oil, 0.1 moles) in tetrahydrofuran (50 mL) was added l 4-hydroxy piperidinecarboxylate (15 grams, 0.075 moles) in tetrahydrofuran (50 mL) at 10 oC under nitrogen atmosphere. The mass was stirred for 1 hour at room temperature. A solution of 2, 5-dibromo pyridine (11.8 grams, 0.05 moles) in tetrahydrofuran (50 mL) was added drop wise to the above reaction mass at room temperature and stirred for 4 hours at 65 oC. The progress of the reaction was monitored by thin layer chromatography. After completion of reaction, the mass was quenched on to chilled water (600 mL) and the compound was extracted with ethyl acetate (3 x 200 mL). The resulting organic layer was washed with water, dried over sodium sulfate and concentrated under vacuum. The residue, thus obtained, was purified by flash tography using ethyl acetate: n-hexane in the ratio of 1:9 to afford the title compound (15 grams).

Yield: 84 %. 1H - NMR (d ppm): 1.47 (9H, s), 1.68 - 1.74 (2H, m), 1.91 - 2.00 (2H, m), 3.24 - 3.31 (2H, m), 3.72 - 3.78 (2H, m), 5.14 - 5.18 (1H, m), 6.62 - 6.64 (1H, d, J = 8.78 Hz), 7.62 - 7.65 (1H, dd, J = 8.76 & 2.57 Hz), 8.15 - 8.16 (1H, d, J = 2.48 Hz); Mass (m/z): 357.1, 359.2 (M+H)+ .

Step (ii): Preparation of 1-t-Butyloxycarbonyl piperidinyloxy) pyridinyl] (morpholinyl) propeneone A solution of t-butyl 4-(5-bromo pyridinyloxy) piperidinecarboxylate (1 gram, 2.80 mmoles), 4-acryloylmorpholine (0.63 gram, 4.46 mmoles), palladium acetate (13 mg, 0.061 mmoles) tri(o-tolyl) phosphine (25.6 mg, 0.084 mmoles) and ium carbonate (0.62 g, 4.49 mmoles) in DMF (15 mL) was d for 3 hours at 140 oC. The progress of the reaction was monitored by thin layer chromtography. After completion of reaction, the mass was quenched on to chilled water (30 mL) and the product was extracted with ethyl acetate (3 x 15 mL). The resulting organic layer was washed with water, dried over sodium sulfate and concentrated under . The residue, thus obtained, was purified by flash chromatography using ethyl acetate: n- hexane in the ratio of 1:1 to afford the title compound (1.07 grams).

Yield: 80 %. 1H - NMR (d ppm): 1.47 (9H, s), 1.72 - 1.76 (2H, m), 1.98 - 2.03 (2H, m), 3.26 - 3.32 (2H, m), 3.58 - 3.80 (10H, m), 5.23 - 5.27 (1H, m), 6.33 - 6.37 (1H, d, J = 15.96 Hz), 6.72 - 6.76 (1H, m), 7.62 - 7.67 (1H, m), 7.76 - 7.79 (1H, m), 8.24 - 8.25 (1H, m); Mass (m/z): 418.3 .

Step (iii): Preparation of 1-(Morpholinyl)[2-(piperidinyloxy) pyridinyl]-prop eneone A solution of 3-[2-(1-t-Butyloxycarbonyl piperidinyloxy) pyridinyl] (morpholinyl) propeneone (0.7 grams, 0.0016 moles) in dichloromethane (20 mL) was treated with trifluoroacetic acid (1.3 mL, 0.016 moles) at room temperature. The reaction mass was stirred for 6 hours at room temperature. The progress of the reaction was monitored by thin layer chromatography. After tion of reaction, the reaction mass was poured on to chilled water (30 mL) and basified with 40 % lye solution (pH ~ 9). The layers were separated and the aqueous layer was further ted with dichloromethane (2 x 20 mL). The combined organic phase was washed with water (30 mL), brine solution (30 mL) and dried over sodium sulphate.

The organic phase was concentrated on rotavacuum to afford the title compound (0.48 grams).

Yield: 90 %. 1H - NMR ( d ppm): 1.72 - 1.76 (2H, m), 1.98 - 2.03 (2H, m), 3.26 - 3. 32 (2H, m), 3.58 - 3.80 (10H, m), 5.23 - 5.27 (1H, m), 6.33 - 6.37 (1H, d, J = 15.96 Hz), 6.72 - 6.76 (2H, m), 7.62 - 7.67 (1H, m), 7.76 - 7.79 (1H, m), 8.24 - 8.25 (1H, m); Mass (m/z): 318.3 (M+H)+.

Example 1: Preparation of 3-[4-(1-Cyclobutyl piperidinyloxy) ](morpholinyl) propeneone fumarate salt Step (i): ation of 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone Sodium triacetoxyborohydride (38.6 grams, 0.18 moles) was added in a single lot to a well stirred solution of 3-[4-(Piperidinyloxy) phenyl](morpholinyl) -eneone (19.1 grams, 0.060 moles, obtained in preparation 1) and cyclobutanone (6.8 mL, 0.09 moles) in dichloroethane (500 mL). The e was further stirred at room temperature for 6 hours. The progress of the reaction was monitored by thin layer chromatography. After tion of reaction, the mass was quenched on to water (1000 mL) and basified with 40 % lye solution (pH ~ 9). The layers were separated and the aqueous layer was extracted with dichloromethane (2 x 200 mL). The combined organic layer was washed with brine solution (250 mL), dried over sodium e, concentrated under vacuum and the residual mass was further purified by flash chromatography using methanol: triethylamine:chloroform in the ratio of 1.5: 0.25: 98.25 to obtain the title nd (17.4 grams).

Yield: 77 %. 1H - NMR (d ppm): 1.68 - 1.73 (2H, m), 1.80 - 1.95 (4H, m), 1.99 - 2.06 (4H, m), 2.19 - 2.24 (2H, m), 2.55 - 2.62 (2H, m), 2.70 - 2.79 (1H, m), 3.60 - 3.88 (8H, m), 4.29 - 4.35 (1H, m), 6.68 - 6.72 (1H, d), 6.88 - 6.93 (2H, m); 7.44 - 7.49 (2H, m), 7.64 - 7.68 (1H, d); Mass (m/z): 371.1 (M+H)+.

Step (ii): ation of 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone fumarate salt.

To a stirred solution of 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) -eneone (23.52 grams, 0.063 moles) in methanol (300 mL) was added a solution of fumaric acid (7.32 grams, 0.063 moles) in 30 mL methanol. The clear mass, thus obtained, was further stirred for 2-3 hours at room temperature. The solvent was evaporated to afford a solid mass. The solid mass was triturated with diethyl ether (3 x 100 mL) and dried under reduced pressure to obtain the title compound (29.54 grams).

Yield: 95 %. 1H - NMR ( d ppm): 1.60 - 1.65 (2H, m), 1.73 - 1.77 (2H, m), 2. 01 - 2.09 (6H, m), 2.49 - 2.52 (2H, m), 2.81 - 2.89 (2H, m), 3.14 - 3.19 (1H, m), 3.50 - 3.70 (8H, m), 4.50 - 4.60 (1H, m), 6.56 (2H, s), 6.97 - 6.99 (2H, d, J = 8.45 Hz), 7.07 - 7.10 (1H, d, J = 15.32 Hz), 7.43 - 7.47 (1H, d, J = .27 Hz), 7.63 - 7.65 (2H, d, J = 8.45 Hz); Mass (m/z): 371.3 (M+H)+. es 2-28: The compounds of Examples 2-28 were prepared by following the procedures as described in Example 1, with some non-critical variations 2. 3-[4-(1-Cyclobutyl piperidin 1H - NMR (d ppm): 1.60 - 1.74 (8H, m), 1.82 - 1.87 (2H, m), yloxy) phenyl](piperidinyl) 1.95 - 2.08 (6H, m), 2.29 (2H, bs), 2.64 (2H, bs), 2.78 - 2.82 propeneone hydrochloride (1H, m), 3.62 - 3.65 (4H, m), 4.39 (1H, m), 6.75 - 6.79 (1H, d, salt J = 15.3 Hz), 6.87 - 6.89 (2H, d, J = 8.63 Hz), 7.44 - 7.46 (2H, d , J = 8.63 Hz), 7.58 - 7.62 (1H, d, J = 15.3 Hz); Mass (m/z): 369.3 (M+H)+. 3. 3-[4-(1-Cyclobutyl piperidin 1H - NMR ( d ppm): 1.66 - 1.97 (6H, m), 2.07 (5H, s), 2.25 yloxy) phenyl](1,1-dioxo (2H, bs), 2.63 (2H, bs), 2.76 - 2.80 (1H, m), 2.86 - 2.89 (1H, thiomorpholinyl) propene- m), 3.10 (4H, m), 4.17 (4H, m), 4.40 (1H, bs), 6.69 - 6.73 (1H, 1-one hydrochloride salt d, J = 15.2 Hz), 6.89 - 6.91 (2H, d, J = 8.65 Hz), 7.46 - 7.48 (2H, d, J = 8.66 Hz), 7.69 - 7.73 (1H, d, J = 15.2 Hz); Mass (m/z): 419.2 (M+H)+. 4. 3-[2-(1-Cyclobutyl piperidin 1H - NMR (d ppm): 1.66 - 1.72 (8H, m), 1.80 - 1.85 (2H, m), yloxy) pyridinyl](piperidin- 1.95 - 2.03 (6H, m), 2.32 (2H, bs), 2.63 (2H, bs), 2.80 - 2.82 1-yl) propeneone L(+)- (1H, m), 2.88 (2H, s) 3.60 - 3.63 (4H, m), 3.82 (1H, m), 5.30 - Tartarate salt 5.32 (1H, d , J = 8.36 Hz), 5.55 - 5.59 (1H, d, J = 15.6 Hz), .94 - 5.98 (1H, d, J = 15.6 Hz), 6.52 - 6.54 (1H, d, J = 8.32 Hz), 6.75 (1H, s); Mass (m/z): 370.4 (M+H)+. . 3-[2-(1-Cyclobutyl din 1H - NMR (d ppm): 1.68 - 1.75 (2H, m), 1.80 - 1.95 (4H, m), yloxy) pyridinyl] 1.99 - 2.06 (4H, m), 2.19 - 2.24 (2H, m), 2.55 - 2.62 (2H, m), (morpholinyl) propene 2.70 - 2.79 (1H, m), 2.87 (2H, s), 3.60 - 3.88 (8H, m), 5.42 one L(+)-Tartarate salt (1H, m), 6.93 - 6.99 (1H, m), 7.09 - 7.13 (1H, m), 7.55 - 7.58 (1H, m), 8.08 - 8.10 (1H, m), 8.32 (1H, s); Mass (m/z): 372.4 (M+H)+. 6. 3-[2-Fluoro(1-isopropyl 1H - NMR (d ppm): 1.16 - 1.18 (2H, m), 1.20 - 1.27 (1H, m), piperidinyloxy) ] 1.38 - 1.41 (6H, m), 1.90 - 2.34 (4H, m), 3.30 - 3.69 (4H, m), (morpholinyl) propene 3.71 - 3.80 (7H, m), 4.53 (2H, m), 6.80 - 6.89 (2H, m), 7.06 - one L(+)-Tartarate salt 7.10 (1H, m), 7.67 - 7.71 (2H, m); Mass (m/z): 377.3 (M+H)+. 7. 3-[2-Fluoro(1-cyclobutyl 1H - NMR (d ppm): 1.60 - 1.70 (4H, m), 1.80 - 1.90 (2H, m), piperidinyloxy) phenyl] 1.99 - 2.09 (3H, m), 2.14 - 2.20 (2H, m), 2.40 - 2.51 (4H, m), (morpholinyl) propene 2.70 - 2.76 (2H, m), 3.00 - 3.09 (1H, m), 3.48 (2H, s), 3.60 - one L(+)-Tartarate salt 3.80 (6H, m), 4.53 (2H, m), 6.61 - 6.70 (2H, m), 6. 85 - 6.89 (1H, d , J = 15.56 Hz), 7.39 - 7.43 (1H, m), 7.65 - 7.69 (1H, d, J = 15.56 Hz); Mass (m/z): 389.4 (M+H)+. 8. 3-[4-(1-Cyclobutyl piperidin 1H - NMR (d ppm): 1.81 - 1.91 (3H, m), 2.11 - 2.33 (9H, m), yloxy)methyl phenyl] 2.41 (3H, s), 3.14 - 3.20 (4H, m), 3.71 (8H, s), 4 .43 (2H, s), (morpholinyl) propene 6.85 - 6.93 (3H, m), 7.67 - 7.69 (1H, d , J = 8.3 H z), 7.85 - one L(+)-Tartarate salt 7.89 (1H, d, J = 15. Hz); Mass (m/z): 385.4 (M+H)+. 9. 3-[4-(1-Isopropyl piperidin 1H - NMR ( d ppm): 1.38 - 1.40 (6H, d), 1.91 - 1.98 (1H, m), yloxy)methyl phenyl] 2.16 - 2.30 (4H, m), 2.42 (3H, s), 3.34 - 3.57 (3H, m), 3.71 (morpholinyl) propene (8H, s), 4.41 (2H, s), 4.75 (2H, m), 6.86 - 6.95 (3H, m), 7.69 - one L(+)-Tartarate salt 7.71 (1H, d, J = 8.45 Hz), 7.86 - 7.90 (1H, d, J = 15.28 Hz) Mass (m/z): 373.4 (M+H)+. . 3-[4-(1-Cyclobutyl piperidin 1H - NMR (d ppm): 1.60 - 1.65 (2H, m), 1.73 - 1.77 (2H, m), yloxy) phenyl](morpholin 2.01 - 2.09 (6H, m), 2.49 - 2.52 (2H, m), 2.81 - 2.89 (2H, m), yl) propeneone 3.14 - 3.19 (1H, m), 3.50 - 3.70 (8H, m), 4.46 (2H, s), 4.50 - artarate salt 4.60 (1H, m), 6.97 - 6.99 (2H, d, J = 8.45 Hz), 7.07 - 7.10 (1H, d, J = 15.32 Hz), 7.43 - 7.47 (1H, d, J = 15.27 Hz), 7.63 - 7.65 (2H, d, J = 8.45 Hz); Mass (m/z): 371.3 (M+H)+. 11. 3-[4-(1-Cyclobutyl piperidin 1H - NMR (d ppm): 1.86 - 1.93 (3H, m), 2.14 - 2.38 (9H, m), yloxy)methoxy phenyl] 3.15 - 3.25 (3H, m), 3.72 (8H, s), 3.92 (3H, s), 4. 46 (2H, s), (morpholinyl) propene 4.71 - 4.77 (1H, m), 7.06 - 7.10 (2H, m), 7.19 - 7.21 (1H, d, J one L(+)-Tartarate salt = 7.7 Hz), 7.35 (1H, s), 7.54 - 7.58 (1H, d, J = 15.37 Hz); Mass (m/z): 401.3 (M+H)+. 12. 3-[4-(1-Cyclopropylmethyl 1H - NMR (d ppm): 0.46 - 0.48 (2H, m), 0.78 - 0.83 (2H, m), dinyloxy)methoxy 1.15 - 1.19 (1H, m), 1.33 - 1.39 (2H, m), 2.17 - 2.26 (4H, m) phenyl](morpholinyl) prop- 3.07 - 3.10 (2H, m), 3.41 - 3.52 (2H, m) 3.72 (8H, s), 3.92 2-eneone L(+)-Tartarate salt (3H, s), 4.46 (2H, s), 4.69 (1H, m), 7.05 - 7.09 (2H, m), 7.20 - 7.22 (1H, d , J = 8.2 Hz), 7.35 (1H, s), 7.54 - 7.58 (1H, d, J = .37 Hz); Mass (m/z): 401.4 (M+H)+. 13. 3-[4-(1-Isobutyl piperidin 1H - NMR ( d ppm): 1.03 - 1.05 (6H, d), 2.13 - 2.15 (5H, m), yloxy)methoxy phenyl] 2.96 - 2.98 (2H, m), 3.39 - 3.45 (4H, m), 3.68 - 3.81 (8H, m), (morpholinyl) propene 3.88 (3H, s), 4.39 (2H, s), 4.65 (1H, m), 7.05 - 7. 09 (2H, m), one L(+)-Tartarate salt 7.15 - 7.17 (1H, d, J = 8.28 Hz), 7.31 (1H, s), 7.50 - 7.54 (1H, d, J = 15.36 Hz); Mass (m/z): 403.4 (M+H)+. 14. 3-[4-(1-Isopropyl piperidin 1H - NMR ( d ppm): 1.40 - 1.42 (6H, d), 1.92 - 1.96 (1H, m), yloxy)methoxy phenyl] 2.14 - 2.31 (4H, m), 3.48 - 3.49 (4H, m), 3.72 - 3. 93 (8H, s), olinyl) propene 3.93 (3H, s), 4.44 (2H, s), 4.80 - 4.82 (1H, m), 7.06 - 7.10 (2H, one L(+)-Tartarate salt m), 7.20 - 7.22 (1H, d, J = 7.76 Hz), 7.35 (1H, s) 7.54 - 7.58 (1H, d, J = 15.37 Hz); Mass (m/z): 389.4 (M+H)+. . 3-[4-(1-Isopropyl piperidin 1H - NMR ( d ppm): 1.36 - 1.38 (6H, d), 1.60 - 1.62 (4H, m), yloxy)methoxy phenyl] 1.69 - 1.70 (2H, m), 2.14 (4H, bs), 3.44 - 3.46 (4H, m), 3.53 - (piperidinyl) propeneone 3.56 (1H, m), 3.63 - 3.75 (4H, m), 3.89 (3H, s), 4.39 (2H, s), L(+)-Tartarate salt 4.64 - 4.66 (1H, m), 7.03 - 7.07 (2H, m), 7.14 - 7.16 (1H, d, J = 8.21 Hz), 7.29 (1H, s), 7.45 - 7.49 ( 1H, d, J = 15.53 Hz); Mass (m/z): 387.4 (M+H)+. 16. 3-[4-(1-Cyclobutyl din 1H - NMR (d ppm): 0.46 - 0.48 (2H, m), 0.81 - 0.83 (2H, m), yloxy)methoxy phenyl] 1.18 - 1.21 (2H, m), 1.34 - 1.30 (2H, d, J = 6.56 H z), 1.62 - (piperidinyl) propeneone 1.64 (4H, m), 1.73 - 1.75 (2H, m), 2.18 (4H, bs), 3 .08 - 3.10 L(+)-Tartarate salt (2H, m), 3.39 - 3.50 (1H, m), 3.67 - 3.73 (4H, m), 3.93 (3H, s), 4.45 (2H, s), 4.70 - 4.76 (1H, m), 7.07 - 7.11 (2H, m), 7.18 - 7.20 (1H, d, J = 8.23 Hz), 7.34 (1H, s), 7.49 - 7.53 ( 1H, d, J = .38 Hz); Mass (m/z): 399.5 (M+H)+. 17. 3-[4-(1-Cyclopropylmethyl 1H - NMR ( d ppm): 0.09 - 0.12 (2H, d), 0.50 - 0.54 (2H, d), dinyloxy) phenyl] 0.85 - 0.89 (1H, m), 1.81 - 1.90 (2H, m), 2.01 - 2.05 (2H, m), (morpholinyl) propene 2.27 - 2.28 (2H, d), 2.38 - 2.41 (2H, m), 2.83 - 2.89 (2H, m), one 3.62 - 3.72 (8H, m), 4.35 - 4.37 (1H, m), 6.68 - 6.72 (1H, d , J = 15.30 Hz), 6.88 - 6.90 (2H, m, J = 8.64 Hz), 7.44 - 7.46 (2H, m, J = 8.63 Hz), 7.63 - 7.67 (1H, d, J = 15.33 Hz); Mass (m/z): 371.2 (M+H)+. 18. 3-[4-(1-Isobutyl din 1H - NMR ( d ppm): 0.89 - 0.90 (6H, d), 1.73 - 1.84 (3H, m), yloxy) phenyl](morpholin 1.97 - 2.00 (2H, m), 2.08 - 2.10 (2H, d), 2.18 - 2.23 (2H, m), yl) propeneone 2.68 - 2.70 (2H, m), 3.62 - 3.72 (8H, m), 4.31 - 4.35 (1H, m), 6.68 - 6.71 (1H, d, J = 15.38 Hz), 6.87 - 6.89 (2H, m, J = 8.62 Hz), 7.44 - 7.46 (2H, m, J = 8.65 Hz), 7.63 - 7.67 (1H, d , J = .30 Hz); Mass (m/z): 373.4 (M+H)+. 19. 3-[3-Bromo(1-isopropyl 1H - NMR ( d ppm): 1.25 - 1.27 (6H, d), 2.01 - 2.06 (1H, m), piperidinyloxy) phenyl] 2.11-2.14 (2H, m), 2.61 - 2.68 (2H, m), 3.11 - 3.18 (2H, m), (morpholinyl) propene 3.23 - 3.27 (2H, m), 3.66 - 3.73 (8H, m), 4.79 - 4.80 (1H, m), one 6.71 - 6.75 (1H, d, J = 15.32 Hz), 6.90 - 6.92 (1H, d, J = 8.50 Hz), 7.42 - 7.44 (1H, dd, J = 8.49 Hz), 7.56 - 7.60 (1H, d, J = .33 Hz) 7.74 (1H, d, J = 1.56 Hz); Mass (m/z): 437.3, 439.2 (M+H)+ . . 3-[3-Bromo(1-cyclobutyl 1H - NMR (d ppm): 1.37 - 1.42 (2H, m), 1.57 - 1.61 (2H, m), piperidinyloxy) phenyl] 1.68 - 1.75 (2H, m), 1.84 (1H, m), 2.01 - 2.04 (2H, m), 2.13 - (morpholinyl) propene 2.15 (2H, m), 2.31 - 2.32 (2H, m), 2.75 - 2.80 (2H, m), 3.66 - one 3.72 (8H, m), 4.66 - 4.70 (1H, m), 6.69 - 6.73 (1H, d , J = .37 Hz), 6.88 - 6.90 (1H, d, J = 8.57 Hz), 7.38 - 7.41 (1H, dd, J = 8.34, 1.44 Hz), 7.56 - 7.60 (1H, d , J = 15.33 Hz) 7.74 (1H, d, J = 1.77 Hz); Mass (m/z): 449.3, 451.2 (M+H)+ . 21. 3-[3-Bromo(1-isobutyl 1H - NMR ( d ppm): 1.25 - 1.27 (6H, d), 1.62 - 1.71 (4H, m), piperidinyloxy) ] 1.94 - 1.99 (2H, m), 2.01 - 2.06 (1H, m), 2.21 - 2.39 (2H, m), (morpholinyl) propene 2.76 - 2.80 (2H, m), 3.67 - 3.72 (8H, m), 4.50 - 4.53 (1H, m), one 6.69 - 6.72 (1H, d, J = 15.36 Hz), 6.87 - 6.90 (1H, d, J = 8.55 Hz), 7.36 - 7.38 (1H, d, J = 8.39 Hz), 7.56 - 7.60 (1H, d, J = .35 Hz), 7.75 (1H, d, J = 1.86 Hz ); Mass (m/z): 451.2, 453.3 (M+H)+ . 22. 3-[3-Bromo(1- 1H - NMR ( d ppm): 0.29 - 0.31 (2H, d), 0.66 - 0.68 (2H, d), cyclopropylmethyl piperidin 1.11 - 1.15 (1H, m), 2.05 - 2.08 (2H, m), 2.38 - 2.42 (2H, m), yloxy) phenyl](morpholin 2.62 - 2.70 (2H, m), 3.03 - 3.10 (4H, m), 3.66 - 3.72 (8H, m), yl) propeneone 4.68 - 4.71 (1H, m), 6.70 - 6.73 (1H, d, J = 15.33 Hz), 6.89 - 6.91 (1H, d, J = 8.55 Hz), 7.39 - 7.41 (1H, d, J = 8.46 Hz), 7.56 - 7.60 (1H, d, J = 15.31 Hz) 7.74 - 7.75 (1H, d, J = 1.60 Hz); Mass (m/z): 449.3, 451.2 (M+H)+ . 23. 3-[6-(1-Cyclopropylmethyl 1H - NMR (d ppm): 0.44 - 0.47 (2H, m), 0.76 - 0.81 (2H, m), piperidinyloxy) nyl]- 1.16 - 1.19 (1H, m), 1.28 -1.30 (1H, m), 2.19 - 2.3 0 (4H, m), 1-(morpholinyl) propene 3.06 - 3.08 (2H, d), 3.35 - 3.49 (3H, bs), 3.72 - 3.76 (8H, m), one L(+)-Tartarate salt 4.42 (2H, s), 5.39 (1H, bs), 6.88 - 6.90 (1H, d, J = 8.64 Hz), 7.10 - 7.14 (1H, d, J = 15.46 Hz), 7.56 - 7.60 (1H, d, J = 15.46 Hz), 8.09 - 8.11 (1H, dd, J = 8.61, 2.21 Hz), 8.34 - 8.35 (1H, d, J = 2 Hz); Mass (m/z): 372.4 (M+H)+. 24. 3-[6-(1-Isobutyl piperidin 1H - NMR ( d ppm): 1.08 - 1.09 (6H, d), 1.28 - 1.30 (1H, m), yloxy) pyridinyl] 1.39 - 1.42 (1H, m), 2.18 - 2.31 (4H, m), 3.03 - 3.05 (2H, d), (morpholinyl) propene 3.35 - 3.49 (3H, m), 3.72 - 3.76 (8H, m), 4.47 (2H, s), 5.40 one L(+)-Tartarate salt (1H, bs), 6.88 - 6.90 (1H, d, J = 8.59 Hz), 7.11 - 7.15 (1H, d, J = 15.46 Hz), 7.56 - 7.60 (1H, d, J = 15.46 Hz), 8.0 9 - 8.12 (1H, dd , J = 8.52, 1.86 Hz), 8.34 - 8.35 (1H, d, J = 1.86 Hz); Mass (m/z): 374.4 (M+H)+. . 3-[2-Chloro(1-cyclobutyl 1H - NMR ( d ppm): 1.69 - 1.76 (4H, d), 1.82 - 1.94 (3H, m), piperidinyloxy) ] 2.00 - 2.09 (3H, m), 2.21 - 2.25 (2H, m), 2.59 - 2.63 (2H, m), (morpholinyl) propene 2.73 - 2.79 (1H, m), 3.70 - 3.76 (8H, m), 4.11- 4.16 (1H, bs), one 6.74 - 6.78 (1H, d, J = 15.41 Hz), 6.82 - 6.85 (1H, dd, J = 8.71, 2.2 Hz), 6.97 - 6.98 (1H, d, J = 2.23 Hz), 7.53 - 7.55 (1H, dd, J = 8.71 Hz), 7.99 - 8.03 (1H, d, J = 15.42 Hz); Mass (m/z): 405.3, 407.4 (M+H)+ . 26. 3-[2-Chloro(1-isopropyl 1H - NMR ( d ppm): 1.05 - 1.06 (6H, d), 1.78 - 1.85 (2H, m), piperidinyloxy) phenyl] 1.99 - 2.09 (2H, m), 2.38 - 2.43 (2H, t), 2.72 - 2. 78 (3H, m), (morpholinyl) propene 3.66 - 3.72 (8H, s), 4.30 - 4.33 (1H, m), 6.71 - 6.74 (1H, d, J = one 15.33 Hz), 6.79 - 6.81 (1H, dd, J = 8.71, 2.07 Hz), 6.94 - 6.95 (1H, d, J = 2.4 Hz), 7.49 - 7.52 (1H, d, J = 8.73 H z), 7.96 - 7.99 (1H, d, J = 15.39 Hz); Mass (m/z): 393.2, 395.2 (M+H)+ . 27. 3-[2-Chloro(1- 1H - NMR (d ppm): 0.13 - 0.19 (2H, m), 0.54 - 0.59 (2H, m), cyclopropylmethyl piperidin 0.90 - 0.91 (1H, m), 1.87 - 1.93 (2H, m), 2.04 - 2.09 (2H, m), yloxy) phenyl](morpholin 2.31 - 2.32 (2H, d), 2.43 (2H, m), 2.86 (2H, m), 3. 69 - 3.76 yl) propeneone (8H, m), 4.37 - 4.38 (1H, m), 6.74 - 6.78 (1H, d, J = 15.41 Hz), 6.83 - 6.86 (1H, dd, J = 8.72, 2.22 Hz), 6.98 - 6.99 (1H, d, J = 2.41 Hz), 7.54 - 7.56 (1H, d, J = 8.71 Hz), 8.00 - 8.03 (1H, d, J = 15.46 Hz); Mass (m/z): 405.3, 407.4 (M+H)+ . 28. hloro(1-isobutyl 1H - NMR ( d ppm): 0.93 - 0.94 (6H, d), 1.77 - 1.87 (3H, m), piperidinyloxy) phenyl] 2.00 - 2.04 (2H, m), 2.12 - 2.14 (2H,d), 2.23 - 2.2 8 (2H, t), (morpholinyl) propene 2.72 (2H, m), 3.70 - 3.76 (8H, s), 4.32 - 4.36 (1H, m), 6.74 - one 6.78 (1H, d , J = 15.45 Hz), 6.82 - 6.85 (1H, dd, J = 8.72, 2.35 Hz), 6.97 - 6.98 (1H, d, J = 2.24 Hz), 7.53 - 7.55 (1H, d, J = 8.76 Hz), 8.00 - 8.03 (1H, d, J = 15.41 Hz); Mass (m/z): 407.3, 409.2 (M+H)+ . ical Assays Example 29: Binding and onal assays for human or rat histamine H3 receptor Compounds can be evaluated according to the following procedures.

Materials and Methods: Receptor source: Rat brain frontal cortex or recombinant human cDNA sed in CHO cells Radioligand: [3H] R-a-methylhistamine Final ligand concentration - [3.0 nM] ecific inant: R-a-methylhistamine (100 µM) Reference compound: R-a-methylhistamine Positive control: R-a-methylhistamine Incubation conditions: Increasing concentrations of test compounds or standard were incubated with membrane receptors and radioligand in 5 mM MgCl2 and 50 mM TRIS-HCl (pH 7.4) for 60 minutes at room temperature. The reaction was terminated by rapid vacuum filtration onto the glass fiber filters.

Radioactivity trapped onto the filters was determined and compared to the control values in order to ascertain any interactions of the test compound(s) with either cloned human or rat receptor g site.

Example Number Ki (nM) 1. 1.32 2. 1.82 3. 1.40 4. 7.82 . 7.90 6. 17.49 7. 2.96 8. 6.34 9. 13.10 . 3.43 11. 77.18 18. 32.35 19. 16.97 . 5.97 22. 52.62 . 29.71 Example 30: Rodent cokinetic Study Male Wistar rats (230 - 280 grams) were used as exp erimental animals. Three to five s were housed in each cage. One day prior to dosing day, male wistar rats (225 - 250 grams) were anesthetized with isoflurane for surgical placement of jugular vein catheter. Animals were kept fasted over night and maintained on a 12 hours light/dark cycle. Three rats were dosed with compounds of formula (I) orally (3 mg/Kg) and intravenously (1 mg/kg) in two separate set of animals (n = 3 rats/ group).

At each time point, blood was collected by r vein. Blood was stored frozen at 4 °C until analysis. The concentrations of the compounds of formula (I) in blood were determined using LC-MS/MS method. Schedule time points: Pre dose 0.08 (only for i.v.) 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hours after dosing (n=3). The compounds of formula (I) were fied in blood by validated LC-MS/MS method using acetonitrile precipitation technique. The compounds of formula (I) were quantified in the calibration range of 1-100 0 ng/mL in blood. Study samples were analyzed using calibration samples in the batch and quality l samples spread across the batch.

Pharmacokinetic parameters Cmax, Tmax, AUCt, T1/2 and Bioavailability were calculated by non-compartmental model using software Pheonix WinNonlin version 6.0.1.

Example Strain/ Dose Vehicle Route of Cmax Tmax AUCt T1/2 Bioavailability Number Sex (mg/kg) administration (ng/mL) (h) (ng.hr/mL) (h) (%) 1. Wistar 3 Reagent Per-Oral 106 ± 5 0.50 ± 176 ± 10 1.56 29 ± 2 rats/ grade 0.00 ± Male water 0.43 1 Sterile Intravenous 214 ± 25 0.08 ± 208 ± 7 1.05 water for 0.00 ± injection 0.07 . Wistar 3 Reagent Per-Oral 128 ± 6 0.42 ± 184 ± 25 1.1 35 ± 5 rats/ grade 0.14 ± Male water 0.3 1 e enous 220 ± 10 0.08 ± 173 ± 13 0.6 water for 0.00 ± injection 0.20 7. Wistar 3 Reagent Per-Oral 57 ± 36 0.25 ± 49 ± 29 0.9 9 ± 5 rats/ grade 0.00 ± Male water 0.6 1 Sterile Intravenous 311 ± 0.08 ± 167 ± 47 0.6 water for 110 0.00 ± injection 0.2 . Wistar 3 Reagent Per-Oral 290 ± 32 0.25 ± 387 ± 38 0.85 58 ± 6 rats/ grade 0.00 ± Male water 0.14 1 Sterile Intravenous 285 ± 46 0.08 ± 222 ± 33 0.80 water for 0.00 ± injection 0.05 Example 31: Rodent Brain Penetration Study Male Wistar rats (230 - 280 grams) were used as experimental s. Three animals were housed in each cage. Animals were given water and food ad libitum throughout the experiment and maintained on a 12 hours light/dark cycle.

Brain penetration was determined in discrete manner in rats. One day prior to dosing day, male wistar rats (225 - 250 grams) were acclimatize d. After acclimatization, the rats were grouped according to the weight in each group, 3 s were kept in dual cage and d free access to food and water. At each time point (05, 1, and 2 hrs) n=3 animals were used.

The compounds of formula (I) were dissolved in water and administered orally a t (free base) 3 mg/kg. Blood samples were removed via, cardiac puncture by using light ether anesthesia the animals were sacrificed to collect brain tissue. Brain samples were homogenized and stored frozen at -20 °C until is. The concentrations of the nds of formula (I) in blood and brain were determined using LC-MS/MS method.

The compounds of formula (I) were quantified in blood and brain homogenate by validated LC-MS/MS method using acetonitrile precipitation technique. The compounds of formula (I) were quantified in the ation range of 1-100 0 ng/mL in blood and brain homogenate. Study samples were ed using calibration samples in the batch and quality control samples spread across the batch. Extents of brain to blood ratios were calculated (Cbrain/Cblood).

Example Strain/ Sex Dose Vehicle Route of Brain Penetration Number (mg/kg) administration @ 1 h post dose (Cbrain/Cblood) 1. Wister rats/ 3 Reagent Per-oral 1.40 Male grade water . Wister rats/ 3 Reagent Per-oral 0.92 Male grade water 7. Wister rats/ 3 Reagent Per-oral 2.51 Male grade water . Wister rats/ 3 Reagent Per-oral 1.36 Male grade water Example 32: Object Recognition Task Model The cognition enhancing properties of compounds of this invention were estimated using a model of animal cognition: the object ition task model.

Male Wister rats (230 - 280 grams) were used as exp erimental animals. Four s were housed in each cage. Animals were kept on 20 % food deprivation before one day and given water ad libitum throughout the experiment and maintained on a 12 hours light/dark cycle.

Also the rats were ated to individual arenas for 1 hour in the absence of any objects.

One group of 12 rats received vehicle (1 mL/Kg) orally and another set of animals received compound of the formula (I) either orally or i.p., before one hour of the familiar (T1) and choice trial (T2).

The experiment was carried out in a 50 x 50 x 50 cm open field made up of acrylic. In the familiarization phase, (T1), the rats were placed individually in the open field for 3 minutes, in which two identical objects ic bottles, 12.5 cm height x 5.5 cm diameter) covered in yellow g tape alone (a1 and a2) were positioned in two adjacent corners, 10 cm. from the walls.

After 24 hours of the (T1) trial for long-term memory test, the same rats were placed in the same arena as they were placed in T1 trial. Choice phase (T2) rats were allowed to explore the open field for 3 minutes in presence of one familiar object (a3) and one novel object (b) (Amber color glass bottle, 12 cm high and 5 cm in diameter). ar objects ted similar textures, colors and sizes. During the T1 and T2 trial, explorations of each object (defined as sniffing, licking, chewing or having moving vibrissae whilst directing the nose towards the object at a distance of less than 1 cm) were recorded separately by stopwatch. Sitting on an object was not regarded as exploratory ty, however, it was rarely observed.

T1 is the total time spent exploring the familiar objects (a1 + a2).

T2 is the total time spent exploring the familiar object and novel object (a3 +b).

The object recognition test was performed as described by Ennaceur, A., Delacour, J., 1988, A new one-trial test for neurobiological studies of memory in rats - Behavioural data, Behav.

Brain Res., 31, 47-59.

Some representative nds have shown positive effects indicating the increased novel object recognition viz; sed exploration time with novel object and higher mination index.

Example Exploration time mean – S.E.M (sec) Dose mg/kg, p.o. Inference Number Familiar object Novel object 1. 1 mg/kg 5.96 ± 1.03 14.86 ± 1.92 Active . 3 mg/kg 9.64 ± 2.22 15.53 ± 2.36 Active Example 33: Water Maze The water maze apparatus consisted of a circular pool (1.8 m diameter, 0.6 m high) constructed in black x (TSE systems, Germany) filled with water (24 ± 2°C) and positioned eath a wide-angled video camera to track animal. The 10 cm2 perspex platform, lying 1 cm below the water surface, was placed in the centre of one of the four imaginary quadrants, which remained constant for all rats. The black Perspex used in the construction of the maze and platform offered no intramaze cues to guide escape behavior. By contrast, the training room offered several strong extramaze visual cues to aid the formation of the spatial map necessary for escape learning. An automated tracking system, [Videomot 2 (5.51), TSE systems, Germany] was employed. This program es video images acquired via a digital camera and an image acquisition boards that determined path length, swim speed and the number of s and duration of swim time spent in each quadrant of the water maze.

Example Number al of Scopolamine Induced amnesia . 3 & 10 mg/kg, s.c.

Claims

We claim:

1. A compound of the general formula (I): N N I O X wherein, 10 at each ence, R1 is independently selected from en, halogen, alkyl or alkoxy; “A” is alkyl, cycloalkyl or cycloalkylalkyl; wherein cycloalkyl is a non-aromatic mono cyclic ring of 3 to 8 carbon atoms; “X” is CH or N; 15 “Y” is CH2, O or S O; or its ceutically acceptable salts.

2. The compound according to claim 1, which is selected from the group consisting of: 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone fumarate salt; 20 3-[4-(1-Cyclobutyl dinyloxy) phenyl](piperidinyl) propeneone hydrochloride salt; 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](1,1-dioxo thiomorpholinyl) propene one hydrochloride salt; 3-[2-(1-Cyclobutyl piperidinyloxy) pyridinyl](piperidinyl) -eneone L(+)- 25 Tartarate salt; 3-[2-(1-Cyclobutyl dinyloxy) pyridinyl](morpholinyl) propeneone L(+)- Tartarate salt; 3-[2-Fluoro(1-isopropyl piperidinyloxy) phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 30 3-[2-Fluoro(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methyl phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 5 1-Isopropyl dinyloxy)methyl phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone 10 L(+)-Tartarate salt; 3-[4-(1-Cyclopropylmethyl piperidinyloxy)methoxy phenyl](morpholinyl) prop eneone L(+)-Tartarate salt; 3-[4-(1-Isobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 15 3-[4-(1-Isopropyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Isopropyl piperidinyloxy)methoxy phenyl](piperidinyl) propeneone L(+)-Tartarate salt; 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](piperidinyl) propeneone 20 L(+)-Tartarate salt; 3-[4-(1-Cyclopropylmethyl dinyloxy) phenyl](morpholinyl) propeneone; 3-[4-(1-Isobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-isopropyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-cyclobutyl dinyloxy) phenyl](morpholinyl) propeneone; 25 3-[3-Bromo(1-isobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[3-Bromo(1-cyclopropylmethyl piperidinyloxy) phenyl](morpholinyl) prop eneone; 3-[6-(1-Cyclopropylmethyl piperidinyloxy) pyridinyl](morpholinyl) propene one L(+)-Tartarate salt; 30 3-[6-(1-Isobutyl dinyloxy) pyridinyl](morpholinyl) propeneone L(+)- Tartarate salt; 3-[2-Chloro(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[2-Chloro(1-isopropyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[2-Chloro(1-cyclopropylmethyl piperidinyloxy) ](morpholinyl) prop 35 one; 3-[2-Chloro(1-isobutyl dinyloxy) phenyl](morpholinyl) propeneone; 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 1-Cyclobutyl piperidinyloxy) ](piperidinyl) propeneone; 5 3-[4-(1-Cyclobutyl piperidinyloxy) phenyl](1,1-dioxo thiomorpholinyl) propene one; 3-[2-(1-Cyclobutyl piperidinyloxy) pyridinyl](piperidinyl) -eneone; 3-[2-(1-Cyclobutyl piperidinyloxy) nyl](morpholinyl) propeneone; 3-[2-Fluoro(1-isopropyl dinyloxy) phenyl](morpholinyl) propeneone; 10 3-[2-Fluoro(1-cyclobutyl piperidinyloxy) phenyl](morpholinyl) propeneone; 3-[4-(1-Cyclobutyl piperidinyloxy)methyl phenyl](morpholinyl) propeneone; 3-[4-(1-Isopropyl piperidinyloxy)methyl phenyl](morpholinyl) propeneone; 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propene one; 15 3-[4-(1-Cyclopropylmethyl dinyloxy)methoxy phenyl](morpholinyl) prop eneone; 3-[4-(1-Isobutyl piperidinyloxy)methoxy phenyl](morpholinyl) propeneone; 3-[4-(1-Isopropyl dinyloxy)methoxy phenyl](morpholinyl) propeneone; 3-[4-(1-Isopropyl piperidinyloxy)methoxy phenyl](piperidinyl) propeneone; 20 3-[4-(1-Cyclobutyl piperidinyloxy)methoxy phenyl](piperidinyl) -eneone; 3-[6-(1-Cyclopropylmethyl piperidinyloxy) pyridinyl](morpholinyl) propene one; 3-[6-(1-Isobutyl piperidinyloxy) pyridinyl](morpholinyl) propeneone; or their pharmaceutically acceptable salts.

3. The process for preparation of a compound of formula (I) as claimed in claim 1 or 2, which comprises: (a) reductive amination of the compound of formula ( 1) with compound of formula (2) HN N A O O X in presence of a suitable solvent and reducing agent to form a compound of formula (I), wherein all substitutions are as d in claim 1, 35 (b) optionally converting the compound of formula (I) to their ceutically acceptable salts.

4. A pharmaceutical composition comprising a compound according to any of claims 1 to 2 and pharmaceutically acceptable excipients.

5. The pharmaceutical composition according to claim 4, for the treatment of al conditions 10 ed through H3 receptor such as cognitive deficits in schizophrenia, narcolepsy, obesity, attention deficit hyperactivity disorder, pain or alzheimer’s disease.

6. Use of an effective amount of a compound or pharmaceutically able salt thereof according to any one of claims 1 to 2 in the cture of a medicament for the treatment of 15 cognitive deficits in phrenia, narcolepsy, obesity, attention deficit ctivity disorder, pain or alzheimer’s disease.

7. Use of a compound according to any one of the claims 1 to 2 in the manufacture of medicament for the treatment of diseases related to Histamine H3 receptors.

8. The use of compound according to the claim 7, for the treatment of clinical ions such as cognitive deficits in schizophrenia, narcolepsy, obesity, attention deficit hyperactivity disorder, pain or alzheimer’s disease.