HK1187613B

HK1187613B - Compounds as histamine h3 receptor ligands

Info

Publication number: HK1187613B
Application number: HK14100570.2A
Authority: HK
Inventors: Ramakrishna Nirogi; Anil Karbhari Shinde; Ramasastri Kambhampati; Amol Dinakar DESHPANDE; Adi Reddy Dwarampudi; Narasimhareddy GANGADASARI; Sangram Keshari SARAF; Vishwottam Nagaraj KANDIKERE; Pradeep Jayarajan; Ishtiyaque Ahmad; Mohmadsadik Abdulhamid MULLA; Venkateswarlu Jasti
Original assignee: Suven Life Sciences Limited
Priority date: 2011-02-23
Filing date: 2011-06-07
Publication date: 2015-08-21

Description

As histamine H3Receptor ligand compounds

Technical Field

The invention relates to the use for the treatment of histamine H₃Novel compounds of formula (I) and pharmaceutically acceptable salts thereof, and compositions comprising them, are disclosed.

Background

The histamine H3 receptor is a G protein-coupled receptor (GPCR) and is one of four histamine receptor families. The histamine H3 receptor was identified in 1983, and its cloning and characterization was completed in 1999. Histamine H₃Receptors are expressed to a higher degree in the central nervous system and to a lower degree in the peripheral nervous system.

Literature evidence suggests that histamine H3 receptors may be useful in the treatment of cognitive disorders (cognitive disorders) (British Journal of Pharmacology,2008,154(6), 1166-.

Patent publications US2009/0170869, US2010/0029608, US2010/0048580, WO2009/100120, WO2009/121812 and WO2009/135842 disclose a series of compounds as ligands for the histamine H3 receptor. Although some histamine H3 receptor ligands have been disclosed, no compounds have been proposed so far in the market in this research field, and there is still a need and room for finding new drugs with new chemical structures for the treatment of diseases affected by the histamine H3 receptor (scope).

Summary of The Invention

The invention relates to novel histamine H of formula (I)₃A receptor ligand compound or a pharmaceutically acceptable salt thereof,

wherein the content of the first and second substances,

at each occurrence, R₁Independently selected from hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cyano or-C (O) -NH₂

L is alkyl or

X is C, O or N-R₂；

Y is C or N;

a is-C (O) -or-CH₂；

R₂Is hydrogen, alkyl, -C (O) -alkyl or-S (O)₂-an alkyl group;

"r" is an integer from 0 to 1;

"p" is an integer of 0 to 3.

The present invention relates to the use of a therapeutically effective amount of a compound of formula (I) for the manufacture of a medicament for the treatment of conditions involving the histamine H3 receptor.

In particular, the compounds of the invention are useful for the treatment of various disorders, such as cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders, and pain.

In another aspect, the present invention relates to pharmaceutical compositions comprising a therapeutically effective amount of at least one compound of formula (I) and pharmaceutically acceptable salts thereof, in admixture with pharmaceutically acceptable excipients.

In another aspect, the invention relates to methods for using compounds of formula (I).

In another aspect, the invention also relates to processes for the preparation of compounds of formula (I) and pharmaceutically acceptable salts thereof.

Representative compounds of the present invention include those described in detail below and pharmaceutically acceptable salts thereof. The invention should not be construed as being limited to them.

N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide dihydrochloride;

2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino ] -1- (morpholin-4-yl) ethanone hydrochloride;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluoro-phenyl ] -2- (morpholin-4-yl) acetamide dihydrochloride;

n- [4- (1-cyclobutylpiperidin-4-yloxy) benzyl ] morpholin-4-ylamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -3-fluorophenyl ] -2- (morpholin-4-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-methylphenyl ] -2- (3, 3-difluoropyrrolidin-1-yl) acetamide;

2- (1-tert-butyl-piperidin-4-yloxy) -2-trifluoromethyl-phenyl ] -N- [4- (1-tert-butyl-piperidin-4-yloxy) -acetamide;

n- [4- (1-cyclopentylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide;

2- (4-chloro-1-cyclobutyl-piperidin-4-yloxy) -2-trifluoromethylphenyl ] -N- [4- (morpholin-4-yl) -acetamide;

2- (pyrrolidin-1-yl) -N- [4- (1-isopropylpiperidin-4-yloxy) -phenyl ] -N- [4- (1-isopropylpiperidin-4-yloxy) acetamide;

2- (pyrrolidin-1-yl) -N- [4- (1-cyclobutyl-piperidin-4-yloxy) -2-methylphenyl ] -acetamide;

2- (1-methyl-4- (1-cyclopentyl-piperidin-4-yloxy) -phenyl ] -acetamide;

2- (1-methyl-4- (tert-butyl) -piperidin-4-yloxy) -phenyl ] -N- [4- (piperidin-1-yl) -acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -N-methyl-2- (morpholin-4-yl) acetamide;

n- [4- (1-cyclopentylpiperidin-4-yloxy) -2-methylphenyl ] -2- (R-2-methylpyrrolidin-1-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-methylphenyl ] -2- (R-2-methylpyrrolidin-1-yl) acetamide;

2- (4-chloro-1-cyclobutyl-piperidin-4-yloxy) -2-methoxyphenyl ] -N- [4- (morpholin-4-yl) acetamide;

2- [4- (1-tert-butyl-piperidin-4-yloxy) -2-trifluoromethylphenyl ] -N- [4- (4-hydroxy-piperidin-1-yl) -acetamide;

2- (4-hydroxy-piperidin-1-yl) -N- [4- (1-cyclobutyl-piperidin-4-yloxy) phenyl ] -acetamide;

n- [4- (1-cyclopentylpiperidin-4-yloxy) -2-fluorophenyl ] -2- (morpholin-4-yl) acetamide dihydrochloride;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (pyrrolidin-1-yl) acetamide;

n- [4- (1-isopropylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide;

n- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (4-isopropyl [1,4] diazepan-1-yl) acetamide;

2- (2-hydroxymethyl-morpholin-4-yl) -N- [4- (1-cyclobutyl-piperidin-4-yloxy) phenyl ] -acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -3- (morpholin-4-yl) propionamide;

n- [4- (1-cyclopentylpiperidin-4-yloxy) phenyl ] -2- (piperidin-1-yl) acetamide dihydrochloride;

n- [4- (1-cyclopentylpiperidin-4-yloxy) phenyl ] -2- (pyrrolidin-1-yl) acetamide dihydrochloride;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (piperidin-1-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-trifluoromethylphenyl ] -2- (pyrrolidin-1-yl) acetamide dihydrochloride;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -N- (2-morpholin-4-ylethyl) acetamide;

[4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] - (2-morpholin-4-ylethyl) amine;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide L (+) tartrate;

n- [2- (1-cyclobutylpiperidin-4-yloxy) pyridin-5-yl ] -N- [2- (morpholin-4-yl) ethyl ] acetamide;

n- [2- (1-cyclobutylpiperidin-4-yloxy) pyridin-5-yl ] -2- (piperidin-1-yl) acetamide;

n- [2- (1-cyclobutylpiperidin-4-yloxy) pyridin-5-yl ] -2- (morpholin-4-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -N- [2- (morpholin-4-yl) ethyl ] acetamide;

n- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl ] -N- [2- (morpholin-4-yl) ethyl ] acetamide L (+) tartrate;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (1-acetylpiperazin-4-yl) acetamide dihydrochloride;

2- (4-hydroxy-piperidin-1-yl) -N- [4- (1-tert-butylpiperidin-4-yloxy) -phenyl ] -acetamide;

n- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl ] -2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide;

2- (morpholin-4-yl) N- [4- (1-cyclobutyl-piperidin-4-yloxy) benzyl ] -acetamide;

2- (morpholin-4-yl) -N- [4- (1-cyclobutyl-piperidin-4-yloxy) -2-fluorobenzyl ] -acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (3-hydroxyazetidin-1-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -2- (3-methoxyazetidin-1-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -2- (2-hydroxymethylpyrrolidin-1-yl) acetamide;

n- [ 2-chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide;

n- [ 2-chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (piperidin-1-yl) acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (tetrahydropyran-4-yloxy) acetamide;

2- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenylamino ] -1- (morpholin-4-yl) ethanone; and

n- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -N- (2-morpholin-4-ylethyl) acetamide;

Detailed Description

Unless otherwise indicated, the following terms used in the specification and claims have the meanings given below:

the term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "alkyl" refers to a straight or branched chain hydrocarbon group having from one to eight carbon atoms, consisting solely of carbon and hydrogen atoms, free of unsaturation, and which is attached to the remainder of the molecule by a single bond. Exemplary "alkyl" groups include methyl, ethyl, n-propyl, isopropyl, and the like.

The term "alkoxy" refers to an alkyl group attached to the rest of the molecule through an oxygen bond. Exemplary "alkoxy" groups include methoxy, ethoxy, propoxy, isopropoxy, and the like.

The term "haloalkyl" refers to a straight or branched alkyl group containing one to three carbon atoms. Exemplary "haloalkyl" groups include fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, fluoroethyl, difluoroethyl, and the like.

The term "haloalkoxy" refers to a straight or branched chain alkoxy group containing one to three carbon atoms. Exemplary "haloalkoxy" groups include fluoromethoxy, difluoromethoxy, trifluoromethoxy, trifluoroethoxy, fluoroethoxy, difluoroethoxy, and the like.

The term "hydroxyalkyl" means that the hydroxyl group is directly bonded to the alkyl chain. Exemplary "hydroxyalkyl" groups include hydroxymethyl, hydroxyethyl, and the like.

The terms "treating", "treatment" or "treatment" have all meanings such as prophylactic, prophylactic and palliative.

The phrase "pharmaceutically acceptable salt" means that the substance or composition must be compatible chemically and/or toxicologically with the other ingredients comprising the formulation, the mammal being treated therewith.

The phrase "therapeutically effective amount" is defined as an amount of a compound of the invention that (i) treats or prevents a particular disease, condition, or disorder (ii) alleviates (alenuate), ameliorates (ameliorate), or eliminates (elimate) one or more symptoms of a particular disease, condition, or disorder (iii) prevents or delays the onset of one or more symptoms of a particular disease, condition, or disorder described herein.

Commercial reagents were used without further purification. The room temperature is 25-40 ℃. Unless otherwise specified, all mass spectra were performed using ESI conditions.¹H-NMR was recorded on a 400MHz Bruker instrument. Deuterated chloroform, methanol or dimethyl sulfoxide is used as a solvent. TMS was used as an internal reference standard. Chemical shift values are represented as () values in parts per million. The following abbreviations are used for multiplicity of NMR signals: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, qui = quintet, h = heptad, dd = doublet, dt = doublet triplet, tt = triplet, m = multiplet. Chromatography refers to column chromatography performed using 100-200 mesh silica gel and performed under nitrogen pressure (flash chromatography).

Pharmaceutical composition

For use in therapy, the compounds of formula (I) will generally be formulated into pharmaceutical compositions according to standard pharmaceutical practice.

The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable excipients. The pharmaceutically acceptable excipient is a carrier or diluent. Thus, the active compounds of the present invention may be formulated for oral, intranasal, or parenteral (e.g., intravenous, intramuscular, or subcutaneous). Such pharmaceutical compositions and methods of making them are well known in The art (The Science and Practice of Pharmacy, d.b. troy, 21 st edition, Williams & Wilkins, 2006).

The dosage of the active compound may vary depending on, for example, the route of administration, the age and weight of the patient, the nature and severity of the disease to be treated and similar factors. Thus, any reference herein to a pharmacologically effective amount of a compound of formula (I) refers to the aforementioned factors. For oral or parenteral administration to the average adult, the suggested dose of the active compounds of the invention is used for the treatment of the above-mentioned conditions.

Preparation method

The compounds of formula (I) may be prepared by scheme I as shown below.

Scheme I

In scheme I above, B is OH, Cl or Br; all other symbols are as defined above.

Coupling a compound of formula (1) with a compound of formula (2) to form a compound of formula (I). The reaction is preferably carried out in a solvent such as tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, preferably by using dichloromethane and dimethylformamide. The reaction may be carried out in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate, diisopropylethylamine, sodium bicarbonate, sodium hydroxide or a mixture thereof, preferably by using potassium carbonate and diisopropylethylamine. The reaction can be carried out in a coupling agent such as O- (benzotriazol-1-yl) -N, N, N ', N' -tetramethylureaThe tetrafluoroborate salt is affected in the presence of the salt. The reaction is carried out at a temperature of 25 ℃ to 85 ℃ based on the choice of solvent and base. The duration of the reaction may be 4 to 18 hours, preferably 10 to 14 hours.

The compounds of formula (1) and formula (2) may be commercially available or may be prepared by conventional methods or by modification using known methods.

The compounds of formula (I) can also be prepared by using scheme II shown below.

Scheme II

In scheme II above, all symbols are as defined above.

Converting the compound of formula (1) into a compound of formula (3). Coupling a compound of formula (3) with a compound of formula (4) to form a compound of formula (I).

In the first step of the above preparation, the compound of formula (1) is converted into the compound of formula (3). The reaction is preferably carried out in a solvent such as tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or mixtures thereof, preferably by using dichloromethane. The reaction can be effected in the presence of a base such as triethylamine, potassium carbonate, diisopropylethylamine, pyridine, and the like, or mixtures thereof, preferably by using triethylamine. The reaction is carried out at a temperature of-10 ℃ to 10 ℃ based on the choice of solvent and base. The duration of the reaction may be 0.5 to 2 hours, preferably 45 minutes to 1.5 hours.

In the second step of the above preparation, the compound of formula (3) is coupled with the compound of formula (4) to form the compound of formula (I). The reaction is preferably carried out in a solvent such as tetrahydrofuran, acetonitrile, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, preferably by using acetonitrile. The reaction may be effected in the presence of a base such as triethylamine, potassium carbonate, diisopropylethylamine, pyridine, and the like, or mixtures thereof, preferably by using potassium carbonate. The reaction is carried out at a temperature of 25 ℃ to 85 ℃ based on the choice of solvent and base. The duration of the reaction may be 3 to 7 hours, preferably 4 to 6 hours.

The compounds of formula (1) and formula (4) may be commercially available or may be prepared by conventional methods or by modification using known methods.

The compounds of formula (I) can also be prepared by using scheme III shown below.

Scheme III

In scheme III above, all symbols are as defined above.

Coupling a compound of formula (5) with a compound of formula (4) to form a compound of formula (6). Converting the compound of formula (6) to a compound of formula (I).

In the first step of the above preparation, the compound of formula (5) is coupled with the compound of formula (4) to form the compound of formula (6). The reaction is preferably carried out in a solvent such as acetonitrile, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide and the like or a mixture thereof, preferably by using acetonitrile. The reaction may be effected in the presence of a base such as triethylamine, potassium carbonate, diisopropylethylamine, pyridine, and the like, or mixtures thereof, preferably by using potassium carbonate. The reaction is carried out at a temperature of 25 ℃ to 70 ℃ based on the choice of solvent and base. The duration of the reaction may be 3 to 7 hours, preferably 4 to 6 hours.

In the second step of the above preparation, the compound of formula (6) is subjected to deprotection followed by reductive alkylation to form the compound of formula (I). The deprotection reaction is preferably carried out in a solvent such as acetonitrile, tetrahydrofuran, toluene, ethyl acetate, dichloromethane, dimethylformamide, methanol, ethanol, isopropanol, etc., or a mixture thereof, preferably by using an alcohol solvent or dichloromethane. The reaction can be effected in the presence of an acid such as trifluoroacetic acid, sulfuric acid, acetic acid, perchloric acid, hydrochloric acid, and the like, or mixtures thereof, preferably by using trifluoroacetic acid. The reaction is carried out at a temperature of 25 ℃ to 60 ℃. The duration of the reaction may be 4 to 10 hours, preferably 4 to 8 hours. After deprotection, the isolated base is treated with a carbonyl compound such as acetone, cyclobutanone or cyclopentanone in the presence of a solvent such as tetrahydrofuran, acetic acid, dichloromethane, dichloroethane or the like or mixtures thereof, and preferably by using dichloroethane in the presence of acetic acid. The reaction is effected in the presence of a reducing agent such as sodium triacetoxyborohydride, sodium cyanoborohydride, lithium aluminum hydride, sodium borohydride and the like or mixtures thereof, preferably by using sodium triacetoxyborohydride. The reaction is carried out at a temperature of from 10 ℃ to 40 ℃. The duration of the reaction may be 4 to 16 hours.

The compounds of formula (4) and formula (5) may be commercially available or may be prepared by conventional methods or by modification using known methods.

If necessary, any one or more than one of the following steps may be performed,

i) converting a compound of formula (I) into another compound of formula (I) or

ii) forming a pharmaceutically acceptable salt.

Process (i) can be carried out by further chemical modification using known reactions such as oxidation, reduction, protection, deprotection, rearrangement, halogenation, hydroxylation, alkylation, alkylsulfation, demethylation, O-alkylation, O-acylation, N-alkylation, N-alkenylation, N-acylation, N-cyanation, N-sulfonylation, coupling and the like.

In process (ii), pharmaceutically acceptable salts may be conveniently prepared by reaction with a suitable acid or acid derivative.

Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art and include those described in j.pharm.sci.,1977,66,1-19, for example acid addition salts with inorganic acids such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid and with organic acids such as succinic, maleic, acetic, fumaric, citric, malic, tartaric, benzoic, p-toluic, p-toluenesulphonic, methanesulphonic or benzenesulphonic acid.

Examples

The novel compounds of the present invention were prepared according to the following experimental procedure using suitable materials and suitable conditions.

Preparation 1: preparation of 4- [ (1-cyclobutyl-4-piperidinyl) oxy ] aniline

Step (i): preparation of 1-cyclobutyl-4-piperidinol

A solution of 4-piperidinol (80g, 0.792 moles) and cyclobutanone (67.2g, 0.96 moles) in dichloroethane (1L) was treated portionwise with sodium triacetoxyborohydride (251.1g, 1.184 moles) and the mixture was stirred at room temperature for 5 hours. The reaction mixture was quenched in cold water (1L) and the resulting mass was basified with a base solution (1ye solution). The layers were separated and the aqueous layer was extracted with dichloromethane (2X 500 mL). The combined organic layers were washed with water, dried over sodium sulfate and concentrated to give 100g of the title compound (yield: 81.46%).

¹H-NMR( ppm)：1.55-2.02(13H，m)，2.64-2.74(2H，m)，3.68-3.70(1H，m)；

Mass (m/z): 155.9(M + H)⁺。

Step (ii): preparation of 1-cyclobutyl-4- (4-nitrophenoxy) piperidine

To a stirred solution of sodium hydride (24.76 g, 60% in mineral oil, 0.619 mole) in dimethylformamide (100 mL) was added 1-cyclobutyl-4-piperidinol (80g, 0.516 mole, obtained in the above step) in dimethylformamide (300mL) at 10 ℃ under nitrogen atmosphere. The material was stirred for 1 hour. To the above reaction mass was added dropwise a solution of 4-fluoronitrobenzene (87.3g, 0.619 mole) in dimethylformamide (300mL) at room temperature. After completion of the reaction, the mass was quenched in cold water (2L) and stirred for 1 hour. The solid obtained was separated and dissolved in ethyl acetate (1L). The ethyl acetate layer was washed with water, dried over sodium sulfate and concentrated in vacuo. The residue thus obtained was purified by flash chromatography (methanol: chloroform, 2: 8) to obtain 99.7g (yield: 70%) of the title compound.

¹H-NMR( ppm)：1.67-1.71(2H，m)，1.83-1.91(4H，m)，2.00-2.08(4H，m)，2.11-2.19(2H，m)，2.51-2.60(2H，m)，2.71-2.78(1H，m)，4.44-4.46(1H，m)，6.93-6.95(2H，d，J＝9.2Hz)，8.17-8.20(2H，d，J=9.2 Hz)；

Mass (m/z): 277.3(M + H)⁺。

Step (iii): preparation of 4- [ (1-cyclobutyl-4-piperidinyl) oxy ] aniline

Hydrogen was bubbled through a solution of 1-cyclobutyl-4- (4-nitrophenoxy) piperidine (94.9g, 0.344 moles, obtained in the above step) and 10% Pd/C (95g) in methanol (2L) at room temperature for 5 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated under vacuum to obtain 81g of the title compound (yield: 95.7%).

¹H-NMR( ppm)：1.62-2.07(12H，m)，2.62-2.76(3H，m)，3.43-3.47(2H，m)，4.13-4.17(1H，m)，6.61-6.63(2H，d，J=8.7 Hz)，6.75-6.77(2H，d，J=8.7Hz)；

Mass (m/z): 247.5(M + H)⁺。

Preparation 2: preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine

Step (i): preparation of 4- (4-cyanophenoxy) piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-hydroxybenzonitrile (15 g, 0.126 mol), potassium carbonate (28.89 g, 0.208 mol) and tert-butyl 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylate (57.62 g, 0.162 mol) in dimethylformamide (150 mL) was stirred at 100 ℃ while monitoring the progress of the reaction by thin layer chromatography. After completion of the reaction, the reaction mass was quenched in water (400 mL) and extracted with ethyl acetate (3 × 300 mL). The obtained ethyl acetate layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography using (ethyl acetate: hexane, 1: 9) to obtain 21.25g of the title compound (yield: 55.8%).

¹H-NMR(ppm):1.47(9H,s),1.74-1.80(2H,m),1.91-1.96(2H,m)3.33-3.40(2H,m),3.66-3.72(2H，m)，4.53-4.57(1H，m)，6.94-6.96(2H，d，J=8.78Hz)，7.57-7.59(2H，d，J＝8.75Hz)；

Mass (m/z): 303.4(M + H)⁺。

Step (ii): preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzonitrile

To a stirred solution of tert-butyl 4- (4-cyanophenoxy) piperidine-1-carboxylate (21.25 g, 0.0704 moles) in dichloromethane (300mL) was added trifluoroacetic acid (81.4 g, 0.714 moles) and the reaction mass was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under vacuum and the residue thus obtained was basified with 10% caustic (caustic) alkali solution. The reaction mass was extracted twice with ethyl acetate and the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product thus obtained was treated with cyclobutanone (5.18 g, 0.074 mol), acetic acid (4.89 g, 0.0815 mol) in dichloroethane (100 mL) and stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (35.06 g, 0.165 mole) was added to the reaction mass in one portion and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water and basified with an alkaline solution. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under vacuum and the residual material was further purified by flash chromatography (dichloromethane: triethylamine, 9.5: 0.5) to obtain 10.92g of the title compound (yield: 60.5%).

¹H-NMR(ppm):1.67-1.76(2H,m),1.88-1.97(2H,m),2.04-2.14(6H,m)2.49(2H,bs),2.64-2.68(2H，m)，2.85-2.91(1H，m)，4.47-4.49(1H，m)，6.92-6.94(2H，d，J＝8.8Hz)，7.56-7.58(2H，d，J＝8.8Hz)；

Mass (m/z): 257.4(M + H)⁺。

Step (iii): preparation of 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine

To a stirred solution of lithium aluminium hydride (3.74 g, 0.098 mol) in dry tetrahydrofuran (30 mL) at 10 ℃ to 15 ℃ under a nitrogen atmosphere was added a solution of 4- (1-cyclobutylpiperidin-4-yloxy) benzonitrile (8.22 g, 0.032 mol) in dry tetrahydrofuran (50 mL). The resulting mass was stirred at ambient temperature for an additional 20 minutes and then refluxed for 4 hours. After completion of the reaction, the mass was cooled to 10-15 ℃, quenched with water and basified with 4N sodium hydroxide solution. The reaction mass was filtered through celite and the filter cake was washed with ethyl acetate. The separated organic layer was dried over sodium sulfate and concentrated under reduced pressure to obtain 7.17g of the title compound (yield: 86.2%).

¹H-NMR(ppm):1.65-1.72(2H，m)，1.82-1.88(4H，m)，1.96-2.05(4H，m)，2.14(2H，bs)，2.62(2H，bs)，2.66-2.75(1H，m)，3.79(2H，m)，4.29-4.31(1H，m)，6.85-6.88(2H，d，J＝8.5Hz)，7.20-7.21(2H，d，J＝8，5Hz)；

Mass (m/z): 261.4(M + H)⁺。

Preparation 3: preparation of 4- [4- (2-chloroacetylamino) -3-fluorophenoxy ] piperidine-1-carboxylic acid tert-butyl ester

Step (i): preparation of 4- (3-fluoro-4-nitrophenoxy) piperidine-1-carboxylic acid tert-butyl ester

3-fluoro-4-nitrophenol (5 g, 0.032 moles), potassium carbonate (6.34 g, 0.047 moles) and tert-butyl 4- (toluene-4-sulfonyloxy) piperidine-1-carboxylate (14 g, 0.04 moles) in dimethylformamide (50 mL) were stirred at 100 ℃. After completion of the reaction, the mass was quenched in water (100 mL) and extracted with ethyl acetate (2 × 100 mL). The obtained organic layer was washed with a brine solution, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography using (ethyl acetate: hexane, 0.5: 9.5) to obtain 9.23g of the title compound (yield: 85%).

¹H-NMR(ppm):1.47(9H,s),1.75-1.82(2H,m),1.94-1.99(2H,m),3.35-3.41(2H,m),3.67-3.73(2H，m)，4.54-4.59(1H，m)，6.72-6.77(2H，m)，8.07-811(1H，m)；

Mass (m/z): 341.3(M + H)⁺。

Step (ii): preparation of 4- (4-amino-3-fluorophenoxy) piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (3-fluoro-4-nitrophenoxy) piperidine-1-carboxylate (9.22 g, 0.027 mol) was hydrogenated over 10% Pd/C (9.22 g) in methanol (92.2 mL) by bubbling hydrogen at ambient temperature for 5 hours. The mixture was filtered through a celite pad, and the filtrate was concentrated under vacuum to obtain 7.54g of the title compound (yield: 90%). The product was used in the next step without further purification.

¹H-NMR(ppm):1.47(9H,s),1.75-1.82(2H,m),1.94-1.99(2H,m),3.35-3.41(2H,m),3.67-3.73(2H，m)，4.54-4.59(1H，m)，6.23-6.35(3H，m)；

Mass (m/z): 311.6(M + H)⁺。

Step (iii): preparation of 4- [4- (2-chloroacetylamino) -3-fluorophenoxy ] piperidine-1-carboxylic acid tert-butyl ester

Tert-butyl 4- (4-amino-3-fluorophenoxy) piperidine-1-carboxylate (7.54 g, 0.024 mol) was dissolved in dichloromethane (100 mL) and triethylamine (3.6 g, 0.036 mol) was added at room temperature. To the resulting mass was added dropwise a solution of chloroacetyl chloride (2.9 g, 0.026 mol) in dichloromethane (15 mL) at room temperature. After completion of the reaction, the organic material was washed with water, dried over sodium sulfate and concentrated under reduced pressure to obtain a crude residue, which was further purified by flash chromatography using (ethyl acetate: hexane, 1: 5) to obtain 5.94g of the title compound (yield: 64%).

¹H-NMR(ppm):1.47(9H,s)，1.72-1.76(2H,m),1.89-1.94(2H,m),3.313.37(2H,m)，3.65-3.71(2H,m)，４.21(2H，s)，4.0-4.44(1H，m)，6.70-6.74(2H，m)，8.03-8.07(1H，t，J＝8Hz)，8.32(1H，s)，

Mass (m/z): 387.2(M + H)⁺，389.1(M+H)⁺。

Example 1: preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) -acetamide dihydrochloride

Step (i): preparation of 2-chloro-N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] acetamide

To a solution of 4- [ (1-cyclobutyl-4-piperidinyl) oxy ] aniline (81 g, 0.329 mol, obtained in preparation 1) in dichloromethane (1L) was added triethylamine (66.5 g, 0.658 mol) at 0 ℃ under nitrogen atmosphere. The resulting mass was then treated dropwise with a solution of chloroacetyl chloride (44.6 g, 0.395 mol) in dichloromethane (1L) at 0 ℃ and stirred for 1 hour at 0 ℃. The reaction mixture was washed with water, dried over sodium sulfate and concentrated in vacuo, and the crude compound thus obtained was purified by flash chromatography (methanol: chloroform, 2: 8) to obtain 76.1g (yield: 72%) of the title compound.

¹H-NMR(ppm):1.55-1.99(12H,m),2.49-2.67(3H,m),4.19(2H,s),4.26-4.28(1H,m),6.88-6.90(2H，d，J＝8.9Hz)，7.44-7.46(2H，d，J＝8.9Hz)，10.13(1H，s)；

Mass (m/z): 323.2(M + H)⁺。

Step (ii): preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide

A mixture of 2-chloro-N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] acetamide (76.0 g, 0.236 mol, obtained in the above step), morpholine (30.8 g, 0.353 mol) and potassium carbonate (98 g, 0.71 mol) in acetonitrile (1.5L) was stirred at reflux temperature for 5 hours. The mixture was partitioned between ethyl acetate (1L) and water (1L). The layers were separated and the aqueous layer was extracted with ethyl acetate (2X 500 mL). The combined organic layers were washed twice with water, dried over sodium sulfate and concentrated in vacuo. The crude compound was purified by flash chromatography using (methanol: chloroform, 2: 8) to obtain 71g (yield: 80%) of the title compound.

¹H-NMR(ppm):1.53-1.99(12H,m),2.46-2.68(7H,m),3.06(2H,s),3.60-3.63(4H,m),４.２4-4.28(1H，m)，6.85-6.88(2H，d，J＝8.9Hz)，7.47-7.50(2H，d，J＝8.9Hz)，9.5(1H，s)；

Mass (m/z): 374.2(M + H)⁺。

Step (iii): preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) -acetamide dihydrochloride

A stirred solution of N- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (morpholin-4-yl) acetamide (70 g, 0.187 mol) in diethyl ether (2.3L) and methanol (350 mL) was treated with 31.5% w/v methanol hydrochloride (54.36 mL, 0.469 mol). The reaction mass is stirred at room temperature for a further 2 to 3 hours. The solvent was poured off, and the resulting solid material was washed with diethyl ether (3X 250 mL) and dried under reduced pressure to obtain 70g of the title compound (yield: 83.9%).

IR(cm^-1):2983,2934,2499,1688,1604,1553,1509,1243,1234,1120,830；

¹H-NMR(ppm)：1.63-1.75(2H，m)，1.89-2.01(2H，m)，2.11-2.15(4H，m)，2.34-2.39(2H，m)，2.80-2.90(2H，m)，3.17-3.20(2H，s)，3.21-3.26(2H，m)，3.43-3.54(2H，m)，3.69-3.73(1H，m)，3.90-3.92(2H，m)，4.15-4.16(2H，m)，4.20-4.22(2H，m)，4.48-4.50(1H，m)，6.97-7.03(2H，m)，7.51-7.54(2H，m)，10.57(1H，bs)，10.78(1H，bs)，11.11(1H，bs)；

Mass (m/z): 374.2(M + H)⁺。

HPLC: 99.54 percent; M.P: 249.2-251.5 ℃; salt content: 16.09% (as dihydrochloride); example 2: preparation of 2- [4- (1-cyclobutyl-piperidin-4-yloxy) phenylamino ] -1- (morpholin-4-yl) ethanone hydrochloride

Step (i): preparation of 2- [4- (1-cyclobutyl-piperidin-4-yloxy) phenylamino ] -1- (morpholin-4-yl) ethanone

A mixture of 4- (1-cyclobutylpiperidin-4-yloxy) aniline (0.5 g, 0.002 mol), 2-chloro-1- (morpholin-4-yl) ethanone (0.5 g, 0.003) and potassium carbonate (0.56 g, 0.004 mol) in dimethylformamide (25 ml) was stirred at reflux temperature. After completion of the reaction, the mixture was concentrated under reduced pressure and the residue was partitioned between ethyl acetate (250 mL) and water (250 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure. The crude compound was purified by flash chromatography (chloroform: triethylamine, 9.5: 0.5) to obtain 0.3g (yield: 40%) of the title compound.

Step (ii): preparation of 2- [4- (1-cyclobutyl-piperidin-4-yloxy) phenylamino ] -1- (morpholin-4-yl) ethanone hydrochloride

A stirred solution of 2- [4- (1-cyclobutylpiperidin-4-yloxy) phenylamino ] -1- (morpholin-4-yl) ethanone (0.3 g, 0.804 mmol) in diethyl ether (20 mL) is treated with 15% methanol hydrochloride (0.23 mL, 0.965 mmol). The reaction mass was stirred at room temperature for a further 1 hour. The solvent was poured off, and the resulting solid was washed with diethyl ether (2X 10 mL) and dried under reduced pressure to obtain 0.28g of the title compound (yield: 85%).

¹H-NMR(ppm):1.65-1.75(2H,m),1.96-2.01(2H,m),2.08-2.17(4H,m),2.36-2.37(2H，m)，2.80-2.90(2H，m)，3.15-3.19(1H，m)，3.34-3.48(5H，m)，3.55-3.67(4H，m)，4.22-4.26(3H，m)，4.45-4.48(1H，m)，4.64-4.68(1H，m)，6.99-7.01(2H，d，J＝8Hz)，7.19-7.21(2H，m)，11.15(1H，bs)；

Mass (m/z): 374.4(M + H)⁺。

Example 3: preparation of N- [4- (1-cyclobutyl-piperidin-4-yloxy) -2-fluorophenyl ] -2- (morpholin-4-yl) acetamide dihydrochloride

Step (i): preparation of 4- [ 3-fluoro-4- (2- (morpholin-4-yl) acetylamino) phenoxy ] piperidine-1-carboxylic acid tert-butyl ester

4- [4- (2-chloroacetylamino) -3-fluorophenoxy group at reflux temperature]A mixture of tert-butyl piperidine-1-carboxylate (3.31 g, 0.0085 mol, obtained in preparation 3), morpholine (0.89 g, 0.01 mol) and potassium carbonate (1.75 g, 0.012 mol) in acetonitrile (30 mL) was stirred for 5 hours. The mixture was concentrated under reduced pressure and the residue thus obtained was partitioned between ethyl acetate (50 mL) and water (50 mL). The resulting aqueous phase was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine solution, dried over sodium sulfate and concentrated. The crude compound was purified by flash chromatography (ethyl acetate: hexane, 3: 7) to obtain 3.1g of the title compound (yield: 83.5%).¹H-NMR(ppm):1.47(9H，s)，1.71-1.75(2H，m)，1.89-1.92(2H，m)，2.62-2.64(4H，t，J＝4Hz)，3.16(2H，s)，3.30-3.36(2H，m)，3.65-3.71(2H，m)，3.77-3.79(4H，t，J＝4Hz)，4.39-4.42(1H，m)，6.69-6.71(2H，d，J＝8Hz)，8.14-8.18(1H，t，J＝8Hz)，9.27(1H，s)；

Mass (m/z): 438.2(M + H)⁺。

Step (ii): preparation of N- [4- (1-cyclobutyl-piperidin-4-yloxy) -2-fluorophenyl ] -2- (morpholin-4-yl) acetamide

To a stirred solution of tert-butyl 4- [ 3-fluoro-4- (2- (morpholin-4-yl) acetylamino) phenoxy ] piperidine-1-carboxylate (3.1 g, 0.007 mol, obtained in the above step) in dichloromethane (25 mL) was added trifluoroacetic acid (8.1 g, 0.071 mol) and the reaction mass was stirred at room temperature overnight. After completion of the reaction, the solvent was evaporated under vacuum and the residue thus obtained was basified with 10% caustic solution. The reaction mass was extracted twice with ethyl acetate, the combined organic layers were dried over sodium sulfate and evaporated under reduced pressure. The crude product thus obtained was treated with cyclobutanone (0.6 g, 0.008 mol) in dichloroethane (30 mL) and stirred at room temperature for 4 hours. Sodium triacetoxyborohydride (3 g, 0.014 mol) was added to the reaction mass in one portion and the mixture was stirred at room temperature for 2 hours. The reaction mixture was quenched in water and basified with an alkaline solution. The layers were separated and the aqueous layer was extracted twice with dichloromethane. The combined organic layers were dried over sodium sulfate, concentrated under vacuum and the residual material was further purified by flash chromatography (dichloromethane: triethylamine, 9.5: 0.5) to obtain the title compound 1.52g (yield: 55%).

¹H-NMR(ppm):1.64-1.68(3H,m),1.70-1.73(2H,m),1.82-1.91(4H,m),1.96-2.05(4H,m)，2.14-2.15(2H，m)，-2.62-2.64(4H，m)，3.16(2H，s)，3.77-3.79(4H，t，J＝4.0Hz)，4.25-4.26(1H，m)，6.68-6.70(2H，m)，8.12-8.16(1H，t，J＝8.0Hz)，9.20(1H，bs)；

Mass (m/z): 392.2(M + H)⁺。

Step (iii): preparation of N- [4- (1-cyclobutyl-piperidin-4-yloxy) -2-fluorophenyl ] -2- (morpholin-4-yl) acetamide dihydrochloride

Methanol hydrochloride (2.08 mL, 0.009 mol, 15% w/v) was added to a stirred solution of N- [4- (1-cyclobutylpiperidin-4-yloxy) -2-fluorophenyl ] -2- (morpholin-4-yl) acetamide (1.52 g, 0.004 mol) in diethyl ether (5 vol) and the reaction mass was stirred at room temperature for a further 2 to 3 hours. The solvent was poured off, and the resulting solid was washed with diethyl ether (2X 10 mL) and dried under reduced pressure to obtain 1.6g of the title compound (yield: 86.2%).

¹H-NMR(ppm):1.63-1.72(2H,m),1,92-2.02(2H,m),2.13-2.21(4H,m),2.35-2.36(3H，m)，2.80-2.89(2H，m)，3.15-3.26(4H，m)，3.56-3.70(2H，m)，3.77-3.80(2H，m)，3.90-3.91(2H，m)，3.93-4.21(2H，m)，4.55-4.76(1H，m)，6.83-6.89(1H，m)，7.04-7.07(1H，m)，7.58-7.60(1H，m)，10.39(1H，bs)，10.55(1H，bs)，11.05(1H，bs)；

Mass (m/z): 392.2(M + H)⁺。

Example 4: preparation of N- [4- (1-cyclobutylpiperidin-4-yloxy) benzyl ] morpholin-4-ylamide

A solution of morpholine-4-carbonyl chloride (0.45 g, 0.003 mol), 4- (1-cyclobutylpiperidin-4-yloxy) benzylamine (0.5 g, 0.002 mol, obtained in preparation 2) and triethylamine (0.4 g, 0.004 mol) in dichloromethane (20 mL) was stirred at room temperature. After completion of the reaction, the reaction mass was quenched in water and extracted with dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure to obtain a crude compound, which was further purified by flash chromatography (ethyl acetate: methanol, 98: 2) to obtain the title compound 0.45g (yield: 60%).

¹H-NMR(ppm):1.66-1.78(2H，m)，1.75-1.78(2H，m)，2.07-2.19(6H，m)，2.59(2H，bs)，2.67-2.69(2H，m)，2.93-2.97(1H，m)，3.34-3.36(4H，t，J＝4.8)，3.67-3.69(4H，t，J＝4.5)4.35-4.36(2H，d，J＝5.14)，4.41(1H，bs)4.66(1H，bs)，6.84-6.86(2H，d，J＝8.4)7.21-7.23(2H，d，J＝8.4)；

Mass (m/z): 374.3(M + H)⁺。

Examples 5 to 39:

the compounds of examples 5 to 39 were prepared by following the procedure as described in examples 1 to 4 with some non-critical variations:

examples 40 to 51

The compounds of examples 40 to 51 can be prepared by the skilled person by following the procedure as described above.

40.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-methylphenyl]-2- (4-hydroxypiperidin-1-yl) acetamide
		41.	N- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl]-2- (R-2-hydroxymethylpyrrolidin-1-yl) acetamide
42.	N [4- (1-cyclobutyl-piperidin-4-yloxy) benzyl]-2- (morpholin-4-yl) acetamide
		43.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorobenzyl]-2- (morpholin-4-yl) acetamide
44.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl]-2- (3-hydroxyazetidin-1-yl) acetamide

45.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl]-2- (3-methoxyazetidin-1-yl) acetamide
		46.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl]-2- (2-hydroxymethylpyrrolidin-1-yl) acetamide
47.	N- [ 2-chloro-4- (1-cyclobutylpiperidin-4-yloxy) phenyl]-2- (morpholin-4-yl) acetamide
		48.	N- [ 2-chloro-4- (1-cyclobutyl-piperidin-4-yloxy)Phenyl radical]-2- (piperidin-1-yl) acetamide
49.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl]-2- (tetrahydropyran-4-yloxy) acetamide
		50.	2- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenylamino]-1- (morpholin-4-yl) ethanone
51.	N- [4- (1-Cyclobutylpiperidin-4-yloxy) -2-fluorophenyl]-N- (2-morpholin-4-ylethyl) acetamide

Biological assay

Example 52: binding and functional assays for the human or rat histamine H3 receptor

The compounds can be evaluated according to the following procedure.

Materials and methods:

the receptor source is as follows: rat brain frontal cortex (front core) or recombinant human cDNA expressed in CHO cells

Radioligand: [³H]R-alpha-methyl histamine

Final ligand concentration- [3.0nM ]

Non-specific determinants: r-alpha-methyl histamine (100 uM)

Reference compound: r-alpha-methyl histamine

Positive control: r-alpha-methyl histamine

Incubation conditions were as follows:

increasing concentrations of test compound or standard were mixed with 5mM MgCl at room temperature₂And membrane receptor and radioligand in 50mM TRIS-HCl (pH 7.4) for 60 min. The reaction was terminated by rapid vacuum filtration onto a glass fiber filter. Radioactivity trapped on the filter is measured and compared to control values to determine any interaction of the test compound with the cloned human or rat receptor binding site.

Example numbering	K_i(nM)
		1.	8.7
2.	6.4
		3.	14.9
7.	14.8
		10.	8.4
11.	1.9
		12.	7.5
13.	3.3
		14.	4.9
15.	4
		16.	2.4
19.	6.4
		21.	1.1
22.	8.3
		24.	1.0
25.	4.05
		26.	6.7
27.	4.1
		28.	3.8
29.	1.6
		37.	9.73
38.	6.6
		39	5.39

Reference documents: millipore data sheet.

Example 53: pharmacokinetic Studies in rodents

Male Wistar rats (230- "280 g") obtained from NIN (National Institute of Nutrition, Hyderabad, India) were used as experimental animals. Three animals were housed in each cage. Animals were kept fasted overnight and maintained on a 12 hour light/dark cycle. Three rats were administered the New Chemical Entity (NCE) orally (3 or 10 mg/kg) and intravenously (1 or 5 mg/kg) on days 0 and 2.

Blood was collected via the jugular vein at each time point. Blood was stored at 2-8 ℃ until analysis. The concentration of NCE compounds in blood was determined using the LC-MS/MS method. Planning time points: pre-dose, 0.08, 0.25, 0.5, 1, 2, 4, 6, 8 and 24 hours post-dose (n = 3). NCE compounds were quantified in blood by the partially validated LC-MS/MS method using acetonitrile precipitation technique. NCE compounds were quantified in a calibrated range of 1-2000ng/mL in blood. Study samples were analyzed using calibration samples within a batch and quality control samples across batches.

Pharmacokinetic parameters were calculated by a non-compartmental model using the software winnonlin version 5.0.1.

Example 54: rodent brain penetration study.

Male Wistar rats (230- "280 g") obtained from NIN (National Institute of Nutrition, Hyderabad, India) were used as experimental animals. Three animals were housed in each cage. Animals were given any water and food throughout the experiment and maintained on a 12 hour light/dark cycle.

The New Chemical Entity (NCE) was dissolved in a suitable vehicle and administered orally (3 or 10 mg/kg). At about T_max(i.e., 0.5 hours, 1.0 hour, and 2.0 hours), the animals were sacrificed. Blood and brain tissue were collected and the brain was homogenized to yield 20% w/v. Blood was stored at 2-8 ℃ and brain homogenate was frozen at-20 ℃ until analysis. The concentration of NCE in blood and brain was quantified using the LC-MS/MS method.

NCE was quantified in blood and brain homogenates by a partially validated LC-MS/MS method using acetonitrile precipitation technique. NCE compounds were quantified in a calibrated range of 1-500ng/mL in blood and brain homogenates. Study samples were analyzed using calibration samples within a batch and quality control samples across batches. Calculation of the brain-to-blood ratio (C)_Brain/C_{Blood, blood-enriching agent and method for producing the same}) The range of (1).

Example 55: object recognition task model

The cognitive enhancing properties of the compounds of the invention were evaluated by using this model.

Male Wistar rats (230- "280 g) obtained from the National Institute of Nutrition, Hyderabad, India were used as experimental animals. Four animals were housed in each cage. Animals were kept 20% food deprivation (food depletion) one day ago and given water ad libitum throughout the experiment, with a 12 hour light/dark cycle maintained. In addition, rats were habituated to a separate arena (arena) for 1 hour without any object present.

One group of 12 rats received the vehicle (1mL/Kg) orally and another group of animals received the compound of formula (I) orally or intraperitoneally 1 hour prior to familiarity with the trial (T1) and selection trial (T2).

The experiments were carried out in a 50X 50cm open field consisting of polyacrylate (acrylic). In the familiarity phase (T1), rats were placed individually in an open field for 3 minutes, where two identical objects (plastic bottles, 12.5cm height x 5.5cm diameter) (a 1 and a 2) covered with yellow masking tape (masking tape) were placed individually in two adjacent corners, 10cm from the wall. After 24 hours from the long-term memory test trial (T1), the same rats were placed in the same field as they were in the T1 trial. The rats of the selection phase (T2) were allowed to explore the open field for 3 minutes in the presence of a familiar object (a3) and a new object (b) (brown glass bottle, 12cm in height, 5cm in diameter). Familiar objects appear similar in texture, color and size. During the T1 and T2 trials, the exploration of each object (defined as sniffing, licking, chewing or moving the tentacle while moving the nose towards the object to a distance of less than 1 cm) was recorded separately by a stopwatch. Sitting on an object is not considered an exploratory activity, but this is rarely observed.

T1 is the total time taken to explore the familiar object (a 1+ a 2).

T2 is the total time spent exploring the familiar and new objects (a 3+ b).

Object recognition tests were performed as described in Ennaceur, A., Delaour, J.,1988, A new one-tertiary test for biological students of memory in rates-Behavioural data, Behav.

Example 56: morris water maze

A water maze device consisting of a circular pool (1.8 m diameter, 0.6m high) built in black plexiglass (Perspex, TSEsystems, germany) filled with water (24 ± 2 ℃) and located under a wide-angle camera for tracking animals. 10cm below the water surface by 1cm²The plexiglas platform was placed in the center 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 did not provide an in-maze clue to guide escape behavior. Instead, the training room provides several powerful extramaze visual cues to help form the spatial map necessary for learning escape. An automatic tracking system [ Videomoto 2(5.51), TSE systems, Germany was used]. This program analyzes video images acquired via a digital camera and image acquisition board (image acquisition board) that determines path length, swimming speed and number of times each water maze quadrant is entered and the duration of swimming spent therein.

Example 57: inhibition of food intake

This model was used to evaluate the anti-obesity properties of the compounds of the invention.

The experiment consisted of 6 days. Rats were acclimatized to an 18 hour fasting and 6 hour feeding regime. Animals were placed in a group of three in cages provided with a fasting grid (fasting grill) and fasted for 18 hours. After 18 hours of fasting, the rats were separated and placed individually in cages. The rats were provided with a weighed amount of feed for 6 hours, and the feed intake (feed intake) was measured for 1 hour, 2 hours, 4 hours, and 6 hours.

The rats were regrouped again and fasted for 18 hours. The above procedure was then carried out for 5 days. The average cumulative food intake of the rats on the last 3 days was calculated. Animals were randomized based on their food intake on the previous three days. Rats were orally treated with test compound or vehicle on the day of the experiment. After 60 minutes, the rats were provided with feed and the food intake was measured for 1 hour, 2 hours, 4 hours and 6 hours. The food intake of rats treated with test compounds was compared to the vehicle-treated group using the asymmetric t-test.

Example numbering	Inhibition of food intake
		13.	30mg/kg, orally administered
16.	Not less than 30mg/kg, orally administered
		21.	Not less than 30mg/kg, orally administered
22.	60mg/kg, orally administered

Claims

1. A compound of the general formula (I):

wherein the content of the first and second substances,

at each occurrence, R₁Independently selected from hydrogen, hydroxy, fluoro, methyl, methoxy, trifluoromethyl or-CH₂-OH；

L is

X is C, O or N-R₂；

Y is C;

a is-C (O) -or-CH₂；

R₂Is hydrogen, methyl, ethyl, isopropyl or-C (O) -CH₃；

"r" is an integer from 0 to 1;

"p" is an integer of 0 to 3.

2. The compound according to claim 1, selected from the following compounds and pharmaceutically acceptable salts thereof:

n- [4- (1-cyclobutylpiperidin-4-yloxy) benzyl ] morpholin-4-ylamide;

2- (1-methyl-4- (1-cyclopentyl-piperidin-4-yloxy) -phenyl ] -acetamide;

n- [4- (1-cyclobutylpiperidin-4-yloxy) phenyl ] -2- (piperidin-1-yl) acetamide;

n- [4- (1-cyclopropylpiperidin-4-yloxy) phenyl ] -N- [2- (morpholin-4-yl) ethyl ] acetamide L (+) tartrate; and

n- [4- (1-Cyclobutylpiperidin-4-yloxy) phenyl ] -2- (1-acetylpiperazin-4-yl) acetamide dihydrochloride.

3. A pharmaceutical composition comprising a compound according to any one of claims 1 to 2 and a pharmaceutically acceptable excipient.

4. A pharmaceutical composition according to claim 3 for the treatment of cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders and pain.

5. A process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises:

(a) coupling the compound of formula (1) with a compound of formula (2) to form a compound of formula (I), wherein all substitutions are as defined in claim 1,

(b) optionally converting said compound of formula (I) into a pharmaceutically acceptable salt thereof.

6. A process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises:

(a) converting the amine compound of formula (1) to a compound of formula (3),

(b) coupling a compound of formula (3) with a compound of formula (4) to form a compound of formula (I), wherein all substitutions are as defined in claim 1,

(c) optionally converting said compound of formula (I) into a pharmaceutically acceptable salt thereof.

7. A process for the preparation of a compound of formula (I) as claimed in claim 1, which comprises:

(a) coupling a compound of formula (5) with a compound of formula (4) to form a compound of formula (6),

(b) converting a compound of formula (6) to form said compound of formula (I), wherein all substitutions are as defined in claim 1,

8. Use of a compound according to any one of claims 1 to 2 for the preparation of a medicament for the treatment of disorders involving histamine H₃The use in medicine of a disease of a receptor.

9. The use of a compound according to claim 8 for the treatment of cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders, and pain.

10. Use of a compound of formula (I) as defined in claims 1 and 2 for the preparation of a medicament for the treatment of disorders involving H₃Receptor or acceptor H₃Use of a receptor for the treatment of a disorder of the central nervous system.