NZ626089B2 - Phenylpyrrole derivative - Google Patents

Abstract

Provided is a compound or a pharmaceutically acceptable salt thereof which is useful for the prevention or treatment of diseases such as dementia, Alzheimer's disease, attention deficit hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, diabetes, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep-related movement disorder, insomnia, depression or allergic rhinitis. Specifically, provided is a phenylpyrrole derivative or a pharmaceutically acceptable salt thereof represented by formula (I). In formula (I), Q is a group represented by formula (A) or (B). , idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep-related movement disorder, insomnia, depression or allergic rhinitis. Specifically, provided is a phenylpyrrole derivative or a pharmaceutically acceptable salt thereof represented by formula (I). In formula (I), Q is a group represented by formula (A) or (B).

Description

DESCRIPTION PHENYLPYRROLE DERIVATIVE TECHNICAL FIELD The present invention relates to novel phenylpyrrole tives and pharmaceutical uses thereof, in particular, preventive or therapeutic agents for diseases associated with histamine H3 receptors.

BACKGROUND ART Histamine is ly stored within intracellular es in mast cells, lung, liver and gastric mucosa, etc. and released from the cell in response to external stimuli such as antigen-binding to an dy on the cell surface. For example, when mast cells are ated by an antigen entering from outside, histamine is released from the mast cells and stimulates histamine H1 (H1) receptors located on blood vessels or smooth muscles, thereby triggering an allergic reaction. Likewise, histamine released from ELC cells (enterochromaffin—like cells) on the gastric mucosa stimulates ine H2 (H2) receptors on the parietal cells to promote gastric acid secretion. Based on these facts, H1 and H2 receptor antagonists have been developed as therapeutic agents for allergic diseases and gastric ulcer, respectively, and currently find wide use as medicaments.

It has been found that histamine serves as a neurotransmitter and acts on histamine receptors (histamine H3 (H3) receptors) d on the central and peripheral nerves to exhibit various physiological functions. This receptor was cloned in 1999, and its gene sequence and amino acid sequence were determined. However, the amino acid sequence of H3 receptor has only 22% and 21.4% homology with those of H1 receptor and H2 receptor, respectively (see Non—Patent Document 1). H3 receptors which are present in the presynaptic ne have been shown to serve as autoreceptors that control the synthesis and release of histamine (see Non-Patent Document 2). In addition to that, H3 receptors have been shown to control the e of other neurotransmitters including choline, serotonin, ne, and noradrenaline (see Non—Patent Document 3). It has also been suggested that H3 receptors are active in the absence of agonists and this activity is able to be inhibited by nds acting as inverse agonists. These facts suggest that H3 receptor antagonists or inverse agonists enhance the release of H3 receptor-controlled neurotransmitters and may potentially serve as therapeutic agents for various diseases associated with al release thereof.

As a matter of fact, results of experiments with animal models show the ility that H3 receptor antagonists or inverse agonists can be used as eutic agents for dementia, Alzheimer’s disease (see Non—Patent nts 4 and 5), attention-deficient hyperactivity disorder (see Non—Patent Document 6), schizophrenia (see Non-Patent Document 7), epilepsy, central convulsion, etc.

It has been shown that H3 receptors are ed in the eating behavior (see Non— Patent Document 8) and metabolic diseases including obesity, diabetes mellitus, hyperlipidemia, etc. are also assumed as diseases for which H3 receptor nists or inverse agonists are ted.

It has been shown that histamine regulates the circadian rhythm in the brain and is responsible for maintaining the balance between waking and sleeping states (see Non-Patent Documents 9 and 10) and es associated with sleep disorders, including narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasornnia, sleep related movement disorder, insomnia, and sion, are also assumed as diseases for which H3 receptor antagonists or inverse agonists are indicated.

It has been shown that H3 receptors are present in sympathetic nerves on the nasal mucosa, and reported that the combined use of H3 and H1 receptor nists improved nasal congestion significantly (see Non-Patent Document 11). This tes the possibility that H3 receptor antagonists or inverse agonists are useful for treatment of such diseases as allergic rhinitis when they are used either alone or in combination with H1 receptor antagonists.

Outlines of H3 receptor antagonists or inverse agonists are found in several reviews (see Non-Patent Documents 12 to 15) to which reference may be had. In earlier years, there have been reported many imidazole compounds which were derived from histamine itself as a lead compound. However, those have yet to be developed as ments due to the concerns of the inhibition of the drug-metabolizing enzyme cytochrome P450 (CYP).

In recent years, non—imidazole H3 receptor antagonists or inverse agonists have been reported in many documents and patents (see Patent Documents 1 to 10).

Reports have also been made of histamine H3 receptor antagonists having 5- membered aromatic rings such as the pyrazole ring (see Patent Documents 11 to 14). In addition, there has been reported a histamine H3 receptor antagonist having an aryloxypiperidine skeleton that is tuted by an unsubstituted pyrrole (see Patent Document 15). However, there has been no report about nds having the structures disclosed hereinafter.

CITATION LIST PATENT DOCUMENTS Patent Document 1: International Patent Publication 097751 Patent Document 2: International Patent Publication W02005097778 Patent Document 3: ational Patent Publication W02005118547 Patent Document 4: International Patent Publication W02006014136 Patent Document 5: International Patent Publication 045416 Patent Document 6: International Patent Publication W0200604613l Patent Document 7: International Patent Publication WO2006059778 Patent Document 8: International Patent Publication WO2006061 193 Patent Document 9: International Patent Publication W0200610766l Patent nt 10: International Patent Publication WO2006103 057 Patent Document 11: International Patent Publication W02006103045 Patent Document 12: International Patent Publication W02007094962 Patent Document 13: ational Patent Publication WO2008072724 Patent nt 14: International Patent ation WO2009063953 Patent nt 15: ational Patent Publication WO2002012190 NON-PATENT DOCUMENTS Non-Patent Document 1: erg T.W. et a1., Molecular pharmacology, 55, 1101- 1107, 1999 Non—Patent nt 2: Arrang J~M. et a1., Nature, 302, 832-837, 1983 Non-Patent Document 3: Brown RB. et a1., Progress in Neurobiology, 63, 63 7-672, 2001 N0n~Patent Document 4: Huang Y—W. et a1., Behavioural Brain Research, 151, 287— 293, 2004 Non-Patent Document 5: Komater VA. et a1., Behavioural Brain Research, 159, 295-300, 2005 Non-Patent Document 6: Passani MB. et a1., Neuroscience and Biobehavioral Reviews, 24, 107-113, 2000 Non-Patent Document 7: Fox G.B. et a1., J. Pharmacol. Exp. Ther., 313, 176-190, 2005 Non-Patent Document 8: Hancock A.A. et a1., Curr. Opin. Investig. Drug, 4, 1190— 1 197 Non—Patent Document 9: Huang Z-L. et a1., Prog. Natr. Acad. Sci., 103, 4687-4692, 2006 Non-Patent Document 10: Babier AJ. et al., Br. J. Pharmacol., 143, 649-661, 2004 tent Document 11: McLeod R.L. et al., Am. J. Rhinol., 13, 391-399, 1999 Non-Patent Document 12: Schwartz J.C. et a1., Trends in Pharmacol. Sci., 7, 24-28, 1986 Non-Patent Document 13: Passani M.B. et a1., Trends in Pharmacol. Sci., 25, 618- 625, 2004 Non-Patent Document 14: Leurs R. et al., Nature Drug Discovery, 4, 107-122, 2005 Non—Patent Document 15: Leurs R. et a1., Drug Discovery Today, 10, 1613-1627, 2005 SUMMARY OF THE INVENTION TECHNICAL PROBLEM The present invention has as an object providing novel compounds or their pharmaceutically acceptable salts, which have a potent action for inhibiting the binding of histamine to the histamine H3 receptor and which are useful in the prevention or treatment of disorders due to the histamine H3 receptor, for e, such es as dementia, Alzheimer’s disease, ion-deficient hyperactivity disorder, schizophrenia, epilepsy, central sion, obesity, diabetes mellitus, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, minia, sleep related movement disorder, insomnia, and depression, or ic rhinitis, or compounds that at least provide a usefiil alternative.

SOLUTION TO PROBLEM To attain the above—stated object, the present inventors conducted intensive studies and found as a result that pyrrole derivatives having a carbonyl substituent at 3- position of the pyrrole ring ted potent inhibitory activity against the binding of histamine to the histamine H3 receptor. This finding has led to the completion of the present invention.

Hereinafter, the present invention will be described in detail. Embodiments of the present invention (compound embodiments will be called “the inventive compounds”) are as shown below.

Briefly, the present ion relates to: (1) A compound represented by formula (I) [Chemical formula 1] / n [wherein Q refers to a group ented by the following formula (A) or (B): cal formula 2] R: U R5 \NMO/ 0/ R6 (A) (B) R1 is hydroxyl, C1-C6 alkoxy, or NR1A R‘B; R1A and RIB, which may be the same or different, are each a hydrogen atom, C1—C6 alkyl or C3-C7 cycloalkyl, or R113‘ and R”3 are bonded together with the adjacent nitrogen atom to form a 3- to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C1-C6 alkyls); R2 is a hydrogen atom, a halogen atom, or C1-C6 alkyl; n is l or 2; R3 is a hydrogen atom, a halogen atom, or C1-C6 alkyl; R4 is C1—C6 alkyl (the C1-C6 alkyl may be substituted by one or two C3-C7 cycloalkyls) or C3- C7 cycloalkyl (the C3—C7 cycloalkyl may be substituted by one or two C1-C6 alkyls); R5 and R6, which may be the same or different, are each C1—C6 alkyl or C3—C7 cycloalkyl, or R5 and R6 are bonded er with the adjacent nitrogen atom to form a 3- to 7-membered ted heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C1-C6 alkyls)] or a pharmaceutically acceptable salt thereof. (2) A compound as recited in (1), wherein Q is represented by a (A): [Chemical formula 3] R100/ (wherein R4 is as defined in ( 1)) or a pharmaceutically acceptable salt thereof. (3) A compound as recited in (I) or (2), wherein R1 is NRIAR1B (wherein R1A and R”3 are as defined in (1)) or a pharmaceutically acceptable salt thereof. (4) A compound as recited in any one of (I) to (3), wherein R2 and R3 are each a hydrogen atom and n is l, or a pharmaceutically acceptable salt thereof. (5) A compound as recited in any one of (l) to (4), wherein R4 is C3—C7 cycloalkyl or a pharmaceutically acceptable salt f. (6) A pharmaceutical agent comprising as the active ingredient a compound as recited in any one of (1) to (5) or a pharmaceutically acceptable salt f. (7) A pharmaceutical agent as recited in (6) which is a histamine H3 receptor antagonist or inverse agonist. (8) A pharmaceutical agent as recited in (6) or (7) which is a preventive or therapeutic agent for dementia, Alzheimer’s e, ion-deficient hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, diabetes mellitus, hyperlipidemia, epsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related nt disorder, insomnia, depression, or allergic is.

ADVANTAGEOUS EFFECTS OF THE INVENTION The compounds of the present invention have an outstanding histamine H3 receptor nistic action.

DESCRIPTION OF EMBODIMENTS The terms and expressions used herein are as defined below.

The “halogen atom” as used herein refers to a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.

The “C1-C6 alkyl” as used herein refers to a linear or ed alkyl group having 1 to 6 carbon atoms and may be exemplified by such groups as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec—butyl, utyl, yl, isopentyl, neopentyl, or n—hexyl.

The “C3-C7 cycloalkyl” as used herein refers to a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group.

The “C1-C6 alkoxy” as used herein refers to a linear or branched alkoxy group having 1 to 6 carbon atoms and may be exemplified by such groups as methoxy, ethoxy, n- propoxy, isopropoxy, xy, isobutoxy, toxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, or n—hexyloxy.

‘ The “3— to 7-membered saturated heterocyclic ring” in the sion “bonded together with the adjacent nitrogen atom to form a 3- to ered saturated heterocyclic ring” refers to a saturated monocyclic ring or spiro ring that is composed of 3 to 7 ring forming atoms and which contains said adjacent nitrogen atom, with optional additional inclusion of a single hetero atom selected from among 0, N, and S; examples may include such groups as l-aziridinyl, l-azetidinyl, l—pyrrolidinyl, piperidino, l-azepanyl, morpholino, or 2-oxaazaspiro[3,3]heptan-6~y1.

Preferred embodiments of the inventive compounds are shown below.

One preferred embodiment of the compound of formula (1) according to the present invention is where Q is represented by a (A): [Chemical formula 4] “CL0/ (wherein R4 is C1~C6 alkyl (the C1-C6 alkyl may be substituted by one or two C3-C7 cycloalkyls) or C3-C7 cycloalkyl (the ycloalkyl may be substituted by one or two C1- C6 )).

In formula (A), R4 is preferably C3-C7 cycloalkyi, and more preferably cyclobutyl.

Another preferred embodiment of the compound of formula (I) according to the present ion is where R1 is NRIARH3 (wherein R1A and RIB, which may be the same or ent, are each a hydrogen atom, C1—C6 alkyl, or C3-C7 cycloalkyl; alternatively, RIA and R18 are bonded together with the adjacent nitrogen atom to form a 3— to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally tuted by one or two CI-C6 alkyls)).

Still another preferred ment of the compound of formula (I) according to the present invention is where R2 and R3 are each a hydrogen atom and n is l.

Profiles the compounds of the present invention preferably have include high drug efficacy, superior in vivo cs (good oral absorption and no accumulation in particular tissues), superior properties exhibited as pharmaceuticals, low toxicity, etc. Preferred compounds of the present invention are less likely to be recognized as a substrate for P— glycoprotein which is an efflux transporter that controls intracerebral migration of drugs and hence, those compounds are expected to have superior intracerebral ion.

The “pharmaceutically acceptable salt” as used herein encompasses, for example, salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, and nitric acid; salts with organic acids such as acetic acid, oxalic acid, succinic acid, lactic acid, tartaric acid, fumaric acid, maleic acid, citric acid, benzenesulfonic acid, methanesulfonic acid, p—toluenesulfonic acid, benzoic acid, camphorsulfonic acid, ethanesulfonic acid, glucoheptonic acid, gluconic acid, glutamic acid, ic acid, malic acid, malonic acid, ic acid, galactaric acid, and naphthalene—Z—sulfonic acid; salts with one or more metal ions such as lithium ion, sodium ion, potassium ion, m ion, magnesium ion, zinc ion, and aluminum ion; and salts with ammonia or amines such as arginine, lysine, piperazine, e, diethylamine, 4-phenylcyclohexylamine, 2- aminoethanol, and benzathine.

The compounds of the t invention may also occur in the form of various solvates. They may sometimes be in a hydrate form from the viewpoint of applicability as pharmaceuticals.

The compounds of the t invention encompass all possible forms including enantiomers, reomers, equilibrium compounds, mixtures thereof in any proportions, tes, and so on. Individual isomers can be obtained by known methods, for example, use of an optically active starting material or intermediate, optically selective or diastereoselective reaction in the tion of an intermediate or the final product, or chromatographic separation in the production of an intermediate or the final product.

The compounds of the present invention also encompass those in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms or sulfur atoms are replaced by their radioisotopes or stable es. These labeled nds are useful in, for example, s of metabolism and pharmacokinetics, or biological analyses in which they are used as receptor ligands.

The compounds of the present invention or pharmaceutically able salts thereof may be combined with one or more pharmaceutically acceptable carriers, excipients or diluents to formulate pharmaceutical preparations. Such carriers, excipients and diluents may include, for example, water, lactose, dextrose, fructose, sucrose, sorbitol, mannitol, polyethylene glycol, propylene glycol, starch, gum, gelatin, alginate, calcium silicate, calcium phosphate, cellulose, water syrup, methylcellulose, polyvinylpyrrolidone, alkyl parahydroxybenzosorbate, talc, magnesium stearate, stearic acid, glycerin, and various kinds of oil such as sesame oil, olive oil, and soybean oil.

Moreover, the above—mentioned carriers, excipients or ts may optionally be d with commonly used additives such as extenders, s, disintegrants, pH modifiers, solubilizers, etc. and then processed by usual pharmaceutical formulating procedures to prepare oral or parenteral pharmaceuticals such as tablets, pills, capsules, es, dusts, liquids/solutions, emulsions, suspensions, ointments, injections, and skin plasters. The compounds of the present ion may be given to adult patients at doses of 0.001 to 500 mg per administration, once or several times a day, by the oral or parenteral route. This dosage may be increased or decreased as appropriate for the type of e to be treated, the age, body weight and symptom of the patient, and so on.

Pharmaceuticals containing the compounds of the present invention or pharmaceutically acceptable salts thereof as the active ingredient are useful as histamine H3 receptor antagonists or inverse agonists.

What is more, ceuticals containing the compounds of the present invention or -1]- pharmaceutically able salts thereof as the active ingredient are useful as preventive or therapeutic agents for dementia, Alzheimer’s disease, attention-deficient hyperactivity disorder, schizophrenia, sy, central convulsion, obesity, diabetes us, hyperlipidemia, epsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, depression, or allergic is.

The compounds of the present invention can be produced by known techniques in organic chemistry. Methods according to the following on s are exemplary processes for producing the compounds of the present invention and are by no means intended to limit the same. In Reaction Schemes l to 4 set out below, R1, R2, R3, R4, R5, R6, and n are as defined above. In on, X, Y1 and Y2, which may be the same or different, each represent a leaving group such as a halogen atom (e.g. a chlorine atom, a bromine atom, or an iodine atom) or an organic yloxy group (e. g. a methanesulfonyloxy group, a benzenesulfonyloxy group, a p-toluenesulfonyloxy group, or a trifluoromethanesulfonyloxy group).

Described below is the process for producing a compound of the present invention that is depicted by Reaction-Scheme 1. This is a process for producing the inventive compound (IA) from a compound (1).

(Reaction Scheme 1) [Chemical formula 5] Y‘ R‘ 0 Cf (R2)n R‘ 3 R4N 3 th\/(4) RT \ X (2) x R‘EN N:,\ / Q00 (R2)n (1) [5199 ta] R60 Rlx\0 [Step 2a] (3) (IA) (Step 1a) Step 1a is for achieving condensation between the compound (1) and a nd (2) by coupling reaction to form a compound (3). The compounds (1) and (2) are either known or can be readily synthesized from known compounds.

In the case where Y1 is a g group such as a halogen atom or an organic sulfonyloxy group, the ng on may be carried out by a common method ing tion of the hydroxyl group of phenol either in a solvent or without a solvent in the presence or absence of a base. If necessary, an additive may be added, as exemplified by potassium iodide or sodium bromide. Examples of the base that may be used in the reaction under consideration include organic bases such as pyridine, triethylamine, and diisopropylethylamine; and inorganic bases such as potassium tert-butoxide, potassium carbonate, cesium carbonate, sodium hydrogencarbonate, sodium hydroxide, potassium hydroxide, and sodium hydride. es of the solvent that may be used in the reaction under consideration include alcohols such as methanol, ethanol, and isopropanol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4—dioxane; hydrocarbons such as toluene and e; halogenated hydrocarbons such as chloroform and romethane; amides such as N,N-dimethylformamide, N,N-dimethylacetamide, and N-methyl-2—pyrrolid0ne; ketones such as acetone and 2-butanone; dimethyl sulfoxide; acetonitrile; water; or mixed solvents thereof. The reaction temperature for the reaction under consideration generally ranges from 0 °C to 200 °C, preferably from 15 °C to 150 0C, and the reaction time generally ranges from 1 to 48 hours, preferably from 1 to 16 hours.

In the case where Y1 is a hydroxyl group, the coupling reaction under consideration may be exemplified by the Mitsunobu reaction; an example of the method for carrying out this reaction is one that is performed in a solvent in the presence of a reagent comprising an organophosphorus compound such as triphenylphosphine or tributylphosphine combined with an azo nd such as diethyl azodicarboxylate, diisopropyl azodicarboxylate, or di- tert-butyl azodicarboxylate, or alternatively, in the ce of a phosphorus ylide reagent such as cyanomethylene tributyl phosphorane. Examples of the solvent that may be used in the reaction under consideration include ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and 1,4-dioxane; hydrocarbons such as toluene and benzene; nated hydrocarbons such as chloroform and dichloromethane; amides such as N,N—dimethylformamide, N,N- dimethylacetamide, and N—rnethyl-Z—pyrrolidone; ketones such as acetone and 2—butan0ne; dimethyl sulfoxide; acetonitrile; water; or mixed solvents thereof. The reaction temperature for the reaction under eration generally ranges from 0 °C to 150 °C, ably from °C to 100 °C, and the reaction time generally ranges from 1 to 48 hours, preferably from 1 to 16 hours.

(Step 2a) Step 2a is for achieving condensation between the compound (3) and a compound (4) by coupling reaction to form a compound (IA) of the t invention. The compound (4) is either known or can be readily synthesized from a known compound. The cross—coupling reaction can be carried out by a common method that performs the on in a t in the presence of a catalyst and its ligand; for instance, it can be carried out according to the method described in Kunz et al., Synlett, 2003, vol. 15, pp. 2428-2439 or a modification thereof. The reaction under consideration is preferably performed in the presence of a base. Examples of the catalyst that may be used in the reaction under consideration e transition metal catalysts such as copper, nickel or palladium which are commonly used in the cross—coupling reaction, and more specifically they include copper(0), copper(l) iodide, copper(I) chloride, copper(l) oxide, copper(I) bromide triphenylphosphine complex, copper(l) trifluoromethanesulfonate benzene complex, copper(ll) sulfate, palladium(ll) acetate, is(triphenylphosphine)palladiurn(0), bis(triphenylphosphine)palladium(ll) chloride, [1 ,1 ’ — bis(diphenylphosphino)ferrocene]palladium(ll) dichloride, tris(dibenzy1ideneacetone)dipalladium(0), bis(acetylacetonato)nickel(II), etc. The ligand that may be used in the reaction under consideration is selected from ligands that are commonly used in a condensation reaction that uses metal catalysts and es include N,N’- dimethylethylenediamine, imethylcyclohexane-l ,2—diamine, 2-aminopyridine, 1,10- phenanthroline, 8—tetramethyl-l ,lO-phenanthroline, 2-hydroxybenzaldehyde oxime, ne glycol, triphenylphosphine, tri-tert-butylphosphine, etc. Examples of the base that may be used in the reaction under consideration include potassium carbonate, potassium phosphate, potassium hydroxide, potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, sodium acetate, sodium methoxide, tetrabutylammonium hydroxide, etc. Examples of the solvent that may be used in the reaction under consideration include alcohols such as methanol, ethanol, and panol; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, and oxane; hydrocarbons such as toluene and benzene; halogenated hydrocarbons such as chloroform and dichloromethane; amides such as N,N—dimethylforrnamide, N,N-dimethylacetamide, and N-methyl—Z— pyrrolidone; ketones such as acetone and 2—butanone; dimethyl sulfoxide; acetonitrile; water; or mixed solvents thereof. The reaction temperature for the reaction under consideration generally ranges from 0 °C to 200 °C, preferably from 40 °C to 150 °C, and the reaction time generally ranges from 1 to 48 hours, preferably from 1 to 16 hours.

Alternatively, the compound (IA) may be produced according to the method depicted by Reaction Scheme 2. ion scheme 2) cal formula 6] O O XOMe/ / R4 R3 N / Base or Acid R3 KEVOH ‘0 ii “we, R4 ‘0 i“ NV/\ n <R2>n / / 0 [Step 3a] O R‘ H [Step 43] o (Step 3a) Step 3a is such that the methoxycarbonyl group of a compound (5) which is a species of the inventive compound (IA) n R] is a methoxy group is converted to a ylic acid through hydrolysis to form an inventive compound (6) in which R1 is a hydroxy group. The hydrolysis reaction can be carried out by a common reaction of ester hydrolysis; for instance, it can be carried out in accordance with the s bed in T.

W. Greene and P. G. M. Wuts, Protective Groups in c Synthesis, fourth edition, John Wiley and Sons or modifications thereof, as ified by a method of performing the reaction either in a solvent or without a solvent in the presence of a strong acid, and a method of ming the reaction in a solvent in the presence of a base. The reaction temperature for the reaction under consideration generally ranges from 0 °C to 120 °C, preferably from °C to 80 °C, and the reaction time generally ranges from 1 to 48 hours, preferably from 1 to 12 hours.

(Step 4a) Step 4a is for achieving condensation between the compound (6) and an amine derivative (7) by cross-coupling reaction to form the inventive compound (IA). The amine compound (7) is either known or can be readily synthesized from a known compound. The cross-coupling on can be carried out by common methods of amidating carboxylic acids, which include a method in which a carboxylic acid is converted to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide and then d with amine, a method in which a mixed acid anhydride as obtained from a carboxylic acid and chlorocarbonic acid ester is reacted with amine, a method in which ylic acid is converted to an active ester such as l-benzotriazolyl ester or succinimidyl ester and then reacted with amine, and a method in which a carboxylic acid is reacted with amine in the presence of a dehydration condensation agent. All of these reactions may be med in a solvent in the presence or absence of a base. es of the dehydration condensation agent that may be used in the reaction under consideration include 3-(3- dimethylaminopropyl)—1~ethylcarbodiimide hydrochloride, dicyclohexylcarbodiimide, diphenylphosphorylazide, and carbonyldiimidazole, with an activator such as 1- hydroxybenzotriazole or hydroxysuccinimide being optionally used. Examples of the base that may be used in the reaction under eration include pyridine, triethylamine, diisopropylethylamine, potassium carbonate, sodium carbonate, and sodium -16— hydrogencarbonate. Examples of the solvent that may be used in the on under consideration include ethers such as tetrahydrofuran and 1,4-dioxane; hydrocarbons such as toluene and benzene; nated arbons such as chloroform and dichloromethane; amides such as N,N-dimethy1formamide, N,N—dimethy1acetamide, and N—methyl—Z— pyrrolidone; ketones such as acetone and none; dimethyl sulfoxide; acetonitrile; water; or mixed solvents thereof. Among them, preferred is toluene, tetrahydrofuran or N,N— dimethylformamide. The reaction temperature for the reaction under consideration generally ranges from 0 °C to 120 °C, preferably from 15 °C to 40 °C, and the on time generally ranges from 1 to 48 hours, preferably from 1 to 12 hours.

Described below is the process for producing a compound of the present invention that is depicted by Reaction Scheme 3. This is a process for producing a compound (IB) of the t invention from the compound (1).

(Reaction Scheme 3) [Chemical formula 7] RS‘NMYZ ,6 3 / R5 /\/\ / [Step 1b] r)’ O (1) R6 R1 0 \ V\<R2>n/ R5 P [Step 2b] ‘NMO / (”3) (Step 1b) Step 1b is for obtaining a compound (9) by coupling reaction between the compound (1) and a compound (8). The compound (8) is either known or can be readily sized from a known compound. The coupling reaction can be carried out by the same method as in step 121.

(Step 2b) Step 2b is for obtaining the inventive compound (IB) by condensation between the compound (9) and the compound (4) through coupling reaction. The coupling reaction can be d out by the same method as in step 221.

Alternatively, the compound (1B) may be produced by the method ed by Reaction Scheme 4.

(Reaction Scheme 4) [Chemical formula 8] O O R rgown,/, Base or Acid 3 R \\ N\’/\ \\ N/ ,rEVOH\’/ R5 l (R )n R5 | (R2)n R6 R6 (9) (10) (7) R3\\ N\//’\ ”*9 2 Q (R >n R6 <18) (Step 3b) Step 3b is such that the methoxycarbonyl group of the compound (9) which is a species of the inventive nd (1B) n R1 is a methoxy group is converted to a carboxylic acid through hydrolysis to form an inventive compound (10) in which R1 is a hydroxy group. The hydrolysis reaction can be carried out by the same method as in Step 3a.

(Step 4b) Step 4b is for obtaining the inventive compound (IB) by condensation between the compound (10) and the amine derivative (7) through coupling reaction. The coupling reaction can be carried out by the same method as in Step 4a. —18— EXAMPLES On the ing pages, the present invention is described specifically by means of working examples and tests, which are not intended to limit the scope of the invention.

The instrument data listed in the working examples were obtained by measurement with the following instruments.

MS spectrum: micromass Platform LC or micromass GCT NMR um: R] 600 MHz: JNM-ECA600 (JEOL Ltd, Japan) (Example 1) Preparation of methyl 1-{4-[(1~cyclobutylpiperidin—4—yl)oxy]phenyl}~1H—pyrrole—3- carboxylate (Compound No. 1) cal formula 9] A suspension of 1—cyclobutyl(4-iodophenoxy)piperidine (3 g; can be synthesized in accordance with the method described in WO2008072703), methyl 1H-pyrrole-3— carboxylic acid (1.75 g), N,N’—dimethylethylenediamine (0.592 g), copper iodide (0.32 g) and cesium carbonate (2.32 g) in e (8.4 mL) was stirred at 110 °C for 4 hours. The reaction mixture was left to cool to room temperature and, after adding chloroform, d through Celite (registered trademark). The filtrate was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (NH form silica gel; eluent: n-hexane/ethyl acetate = 88/12 - 0/100) to give the titled compound as a colorless solid (1.42 g). 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.61 - 1.74 (m, 2 H) 1.78 - 1.92 (m, 4 H) 1.95 - 2.08 (m, 4 H) 2.10 - 2.27 (m, 2 H) 2.62 (br. s., 2 H) 2.73 (t, J=8.05 Hz, 1 H) 3.82 (s, 3 H) 4.32 (br. 5., l H) 6.71 (dd, #289, 1.65 Hz, 1 H) 6.88 - 6.92 (m, 1 H) 6.93 - 6.99 (m, 2 H) 7.26 — 7.31 (m, 2 H) 7.58 (t, #186 Hz, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 355 le 2) ation of l-{4-[(1—cyclobuty1piperidin—4—yl)oxy]phenyl}-1H-pyrrole—3—carboxylic acid und No. 2) [Chemical formula 10] & N// To an ethanol (8 mL) solution of methyl 1—{4—[(1-cyclobutylpiperidin~4— yl)oxy]phenyl}-1H-pyrrolecarboxylate (1.4 g) synthesized in Example 1, 6 N aqueous sodium hydroxide on (1.32 mL) was added and the mixture was stirred at 60 °C for 4 hours. The reaction mixture was left to cool to room temperature and, after adding water, ted with chloroform. The aqueous layer was neutralized with hydrochloric acid and extracted with chloroform. The combined organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give the titled compound as a colorless amorphous substance (1.22 g). 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.52 - 3.32 (m, 15 H) 4.13 — 4.87 (m, 1 H) 6.76 (dd, J=2.89, 1.65 Hz, 1 H) 6.86 - 7.03 (m, 3 H) 7.31 (d, J=8.67 Hz, 2 H) 7.58 — 7.68 (m, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 341 (Example 3) Preparation of azetidin-l-yl (l-{4-[(1-cyclobutylpiperidin—4-yl)oxy]phenyl}-1H—pyrrol-3— yl)methanone (Compound No. 3) [Chemical formula 11] A suspension of 1-{4—[(1~cyclobutylpiperidinyl)oxy]phenyl}-1H-pyrrole—3- carboxylic acid (0.1 g) synthesized in e 2, 1-{3-(dimethylamino)propyl} ethylcarbodiimide hydrochloride (0.085 g), 1—hydroxybenzotriazole hydrate (0.067 g) and aziridine (0.034 g) in N,N—dimethylformamide (0.1 ml) was stirred at room temperature for 16 hours. Water was added to the reaction e and extraction was conducted with chloroform. The organic layer was concentrated under reduced pressure and the resulting residue was purified by silica gel column chromatography (NH form silica gel; eluent: n- hexane/ethyl acetate = 88/12 - 0/100) to give the titled nd as a colorless solid (0.056 1H NMR (600 MHZ, CHLOROFORM-d) 5 ppm 1.60 - 1.73 (m, 2 H) 1.76 — 1.93 (m, 4 H) 1.95 - 2.08 (m, 4 H) 2.10 — 2.22 (m, 2 H) 2.34 (t, J=7.64 Hz, 2 H) 2.54 - 2.68 (m, 2 H) 2.70 - 2.82 (m, 1 H) 4.11 - 4.23 (m, 2 H) 4.28 — 4.35 (m, 1 H) 4.37 ~ 4.55 (m, 2 H) 6.53 (dd, J=2.89, 1.65 Hz, 1 H) 6.83 — 7.00 (m, 3 H) 7.25 — 7.33 (m, 2 H) 7.44 (t, J=1.86 Hz, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 380 The same ure as described in Example 3 was repeated to give the compounds listed in the following Tables 1—1 and 1-2 (Compound Nos. 4 -13).

[Chemical formula 12] Q0.0“” -21..

[Table 1—1] Compound ESI/APCI Name NMR No. observe 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.60 < 1.74 (m, 2 H) 1.79 - 2.08 (m, 12 H) 2.08 - 2.27 (m, 2 H) 2.50 - 2.68 (m, 2 H) (1-{4»[(1-cyc|obutylpiperidin 2.69 - 2.83 (m, 1 H) 3.54 4 3.68 (m. 2 H) y!)oxy]phenyl)~1H—pyrroI-S-yl) 394 3.69 - 3.85 (m. 2 H) 4.17 - 4.46 (m, 1 H) (pyrrolidin—1—yl)methanol 6.59 - 6.67 (m, 1 H) 6.91 (s, 1 H) 6.94 (d, J=8.67 Hz, 2 H) 7.28 (d, J=8.67 Hz, 2 H) 7.44 - 7.49 (m, 1 H) 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.57 — 1.74 (m, 8 H) 1.78 ~ 1.94 (m, 4 (1-(4-[(1-cyclobutylpiperidin H) 1.95 - 2.08 (m, 4 H) 2.09 - 2.22 (m, 2 H) y|)oxy]pheny|)~1H-pyrrol-S-yl) 408 2.57 — 2.66 (m, 2 H) 2.69 - 2.81 (m, 1 H) (piperidinyl)methano| 359 ~ 3.76 (m, 4 H) 4.23 - 4.38 (m, 1 H) 6.41 (br. s, 1 H) 6.85 -6.92 (m, 1 H) 6.94 (d, J=8.67 Hz, 2 H) 7.23 - 7.32 (m, 3 H) 1H NMR (600 MHz, CHLOROFORM—d) 6 ppm 1.62 - 1.75 (m, 2 H) 1.78 — 1.94 (m, 4 H) 1.96 - 2.08 (m, 4 H) 2.10 — 2.22 (m, 2 H) (1-(4-[(1-cyclobutylpiperidin 2.55 - 2.66 (m, 2 H) 2.68 — 2.81 (m, 1 H) yl)oxy]phenyI}-N,N~dimethyl-1H~ 368 3.00 - 3.38 (m, 6 H) 4.19 - 4.43 (m, 1 H) pyrroIe-s-carboxamide 6.46 - 6.54 (m, 1 H) 6.86 4 6.91 (m,1 H) 6.94 (d, J=9.08 Hz, 2 H) 7.27 (d, J=8.67 Hz, 2 H) 7.36 (br. s. 1 H) 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.62 - 1.74 (m, 2 H) 1.79 -192 (m, 4 “1;:/ H) 1.96 - 2.07 (m, 4 H) 2.10 - 2.24 (m, 2 H) 1—{4-[(1—cyclobutylpiperidin 2.53 - 2.67 (m, 2 H) 2.69 4 2.79 (m, 1 H) yl)oxy]pheny|)-N-methyl~1H- 354 2.96 (d, J=4.95 Hz, 3 H) 4.19 — 4.38 (m, 1 H) e-s-carboxamide .63 - 5.84 (m, 1 H) 6.40 - 6.53 (m, 1 H) 6.87 — 6.92 (m, 1 H) 8.95 (d. J=9.08 Hz. 2 H) 7.23 — 7.31 m, 2 H 7.49 - 7.55 m, 1 H 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.62 - 1.74 (m, 2 H) 1.76 -1.92(m. 4 H) 1.96 - 2.08 (m, 4 H) 2.11 - 2.24 (m, 2 H) 1-{4-[(1-cyclobuty|piperidin 2.55 - 2.67 (m, 2 H) 2.69 - 2.30 (m, 1 H) ]phenyI}-1H-pyrrole~3- 340 4.25 - 4.41 (m, 1 H) 5.14 - 5.69 (m, 2 H) carboxamide 6.51 (dd, J=2.89, 1.65 Hz, 1 H) 6.90 - 6.98 (m, 3 H) 7.26 — 7.31 (m, 2 H) 7.55 (t, J=2.06 Hz, 1 H) [Table 1-2] nd 1 ESl/APCI R Name NMR No. observe 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.52 - 1.65 (m, 2 H) 1.69 - 1.85 (m, 4 +V/—\O 2 '53“ (m1 4 H) 2'03 ' 2‘15 (m' 2 H) (1~{4-[(1-cyclobutylpiperidin-4« . - 1 H) 9 \_/ yl)oxy]phenyl)-1H—pyrrol-S-yl) 410 . . (m, 2 H) 2.61 .272 (m, 3 56 _ 3 75 (m 8 H) 4 15 44 31 (m 1 H) (m°rph°””'4'y')mema”one 6:33 (dd, J=2.89, 1.65 Hz, 1H) 6.63 (t.

J=2.68 Hz, 1 H) 6.87 (d, J=9.08 Hz, 2 H) 7.18— 7.21 (m, 2 H) 7.25 gt, J=2.06 HZ,1H) 1H NMR (600 MHz, CHLOROFORM-d) d ppm 1.20 (d, J=5.78 Hz, 6 H) 1.60 - 1.75 (m, 2 H) /—( (1v(4~[(1—cyclobutylpiperidin 1.79 - 1.93 (m, 4 H) 1.95 - 2.08 (m, 4 H) yl)oxy]phenyl}-1H-pyrrol—3~y|) 2.10 - 2.24 (m, 2 H) 2.42 - 2.97 (m, 5 H) é—N 438 0 (2R,BS)-2,6-dimethylmorpholin- 3.52 — 3.72 (m, 2 H) 4.15 - 4.58 (m, 3 H) \__< 4-yl)methanone 6.34-6.46 (m,1 H) 5.91 (d, J=2.48 Hz, 1 H) 6.95 (d, J=9.08 Hz, 2 H) 7.27 (d, J=9.08 Hz. 2 H 7.32 d. J=1.65 Hz, 1 H 1H NMR (600 MHz, CHLOROFORM—d) 6 ppm 1.61 - 1.76 (m, 2 H) 1.78 - 1.93 (m, 4 +N<><>0 (1-{4-[(1-cyclobutylpiperidin H) 1.96 - 2.08 (m, 4 H) 2.12 - 2.22 (m, 2 H) yl)oxy]phenyl)—1H—pyrrol-S-yl) 2.53 - 2.68 (m, 2 H) 2.69 - 2.78 (m. 1 H) 11 422 (2-oxa-6—azaspiro[3.3]hepta 4.18 - 4.67 (m. 5 H) 4.76 - 4.87 (m, 4 H) yl)methanone 6.48 - 6.53 (m, 1 H) 6.89 - 6.93 (m. 1 H) 6.95 (d, J=9.08 Hz, 2 H) 7.27 (d, J=667 Hz, 2 H) 7.40 - 7.45 (m, 1 H) 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.45 (s, 9 H) 1.60 - 1.76 (m, 2 H) 1.78 - H N-tert-butyI{4-[(1- 1.93 (m, 4 H) 1.96 — 2.08 (m, 4 H) 2.10 - cyclobutylpiperidinyl)oxy] 2.23 m, 2 H 2.50 - 2.67 (m, 2 H) 2.70 - 12 396 phenyI}-1H-pyrroIe 2.80 (m, 1 H) 4.20 - 4.42 (m, 1 H) 5.57 - carboxamide 5.65 (m, 1 H) 6.38 - 6.44 (m, 1 H) 6.85 - 6.91 (m, 1 H) 6.94 (d, J=9.08 Hz, 2 H) 7.24 - 7.28 m, 2 H 7.45 - 7.49 m, 1 H 1H NMR (600 MHz, CHLOROFORM-d) 6 ppm 1.59 - 1.77 (m. 4 H) 1.79 -2.08 (m, 10 3t)»: N-cyclobutyI{4-[(1— H) 2.10 - 2.21 (m, 2 H) 2.35 - 2.46 (m. 2 H) cyclobutylpiperidin-4—yl)oxy] 2.51 — 2.66 (m, 2 H) 2.68 - 2.79 (m, 1 H) 13 394 phenyl)»1H—pyrrole 4.22 ~ 4.39 (m, 1 H) 4.50 — 4.66 (m, 1 H) carboxamide 5.78 - 5.92 (m, 1 H) 6.40 - 6.50 (m, 1 H) 6.66 - 6.92 (m, 1 H) 6.94 (d, J=8.67 Hz. 2 H) 7.27 (d, J=8.67 Hz, 2 H) 7.50 (bus, 1 H) (Example 4) Preparation of methyl 1-{4~[(1~cyclobutylpiperidin—4-yl)oxy]phenyl}-2,5—dimethyl-lH~ pyrrolecarboxylate (Compound No. 14) [Chemical formula 13] a N// The titled compound was prepared as a colorless amorphous substance by repeating the procedure of e 1, except that the methyl lH-pyrrolecarboxylic acid was replaced by methyl 2,5-dimethyl—lH-pyrrole—3—carboxylic acid. 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.60 - 1.73 (m, 2 H) 1.77 — 1.90 (m, 4 H) 1.93 (s, 3 H) 1.97 - 2.07 (m, 4 H) 2.08 - 2.20 (m, 2 H) 2.25 (s, 3 H) 2.53 - 2.78 (m, 3 H) 3.77 (s, 3 H) 4.33 (br. s., 1 H) 6.30 (d, J=1.24 Hz, 1 H) 6.88 - 6.96 (m, 2 H) 7.00 - 7.08 (m, 2 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 383 (Example 5) Preparation of [(1-cyclobutylpiperidin-4—yl)oxy]phenyl}-2,5-dimethyl-1H-pyrrol—3 - yl)(pyrrolidin—1—yl)methanone und No. 15) [Chemical formula 14] A mixture of the methyl 1-{4-[(1-cyclobuty1piperidiny1)oxy]phenyl}-2,5- dimethyl-1H-pyrrolecarboxylate (0.06 g) synthesized in Example 4 and pyrrolidine (0.112 g) was stirred in a sealed tube at 100 °C for 16 hours. The reaction mixture was left to cool to room temperature and concentrated under reduced pressure; the resulting residue was d by silica gel column chromatography (NH ative silica gel plate 0.5 mm; eluent: n—hexane/ethyl acetate = 50/50) to give the titled compound as a colorless solid. 1H NMR (600 MHZ, CHLOROFORM—d) 5 ppm 1.59 - 1.93 (m, 12 H) 1.95 (s, 3 H) 1.98 - 2.09 (m, 4 H) 2.17 (s, 3 H) 2.64 (br. s., 2 H) 2.74 (t, J=8.05 Hz, 1 H) 3.62 (d, J=9.91 Hz, 4 H) 4.34 (br. s., 1 H) 6.06 (s, 1 H) 6.88 — 6.98 (m, 2 H) 7.02 - 7.11 (m, 2 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 422 (Example 6) Preparation of [1 ~(4-{3-[(2R)-2—methylpyrrolidin—l—yl]propoxy}pheny1)-1H-pyrrol-3 - y1](pyrrolidiny1)methanone (Compound No. 16) _ 24 _ [Chemical formula 15] The titled compound was prepared as a colorless amorphous substance by repeating the procedure of e 1, except that the 1—cyclobutyl(4—iodophenoxy)piperidine was replaced by ~[3~(4—iodophenoxy)propyl]methylpyrrolidine (which can be synthesized in accordance with the method described in W02009063953) and the methyl 1H- pyrrolecarboxylic acid by 3-(pyrrolidin—1-ylcarbonyl)—1H-pyrrole. 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.08 (d, J=5.78 Hz, 3 H) 1.35 — 1.48 (m, l H) 1.63 - 1.83 (m, 2 H) 1.85 — 2.04 (m, 3 H) 2.11 (d, J=9.08 Hz, 1 H) 2.16 - 2.23 (m, l H) 2.25 - 2.33 (m, 1 H) 2.92 - 2.99 (m, 1 H) 3.17 (d, J=2.48 Hz, 1 H) 3.65 (br. s., 4 H) 3.73 (br. s., 4 H) 3.96 - 4.15 (m, 2 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.89 - 6.97 (m, 3 H) 7.27 - 7.32 (m, 2 H) 7.45 - 7.49 (m, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 382 (Example 7) Preparation of [(1—isopropylpiperidin—4—yl)oxy]phenyl}—1H—pyrrol-3—yl)(pyrroldin yl)methanone (Compound No. 17) [Chemical formula 16] raga:0O The titled compound was prepared as a colorless amorphous substance by repeating the procedure of Example 1, except that the methyl 1H-pyrrole—3—carboxylic acid was replaced by (1H-pyrrolyl)(pyrrolidin~1-yl)methanone and the l-cyclobutyl(4— i0dophen0xy)piperidine by 4—(4-iodophenoxy)isopropylpiperidine (which can be synthesized in accordance with the method described in 0893 73). 1H NMR (600 MHz, CHLOROFORM—d) 5 ppm 1.05 (d, J=6.61 Hz, 6 H) 1.74 - 2.07 (m, 8 H) 2.39 (br. s., 2 H) 2.66 — 2.84 (m, 3 H) 3.60 - 3.81 (m, 4 H) 4.24 - 4.34 (m, 1 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.87 — 7.00 (m, 3 H) 7.22 - 7.32 (m, 2 H) 7.47 (t, J=2.06 Hz, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 382 (Example 8) Preparation of 1~{4—[(1—isopropylpiperidin—4-yl)oxy]phenyl}—N~methyl-1H-pyrrole-3 - carboxamide (Compound No. 18) [Chemical formula 17] The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl role-3—carboxylic acid was replaced by N- methyl-1H—pyrrole-3—carboxamide and the 1~cyclobutyl—4-(4-iodophen0xy)piperidine by 4- (4-iodophenoxy)— 1 opylpiperidine. 1H NMR (600 MHZ, CHLOROFORM-d) 8 ppm 1.06 (d, J=6.61 Hz, 6 H) 1.82 (d, J=9.08 Hz, 2 H) 1.95 - 2.09 (m, 2 H) 2.39 (br. s., 2 H) 2.79 (br. s., 3 H) 2.96 (d, J=4.95 Hz, 3 H) 4.19 - 4.39 (m, 1 H) 5.59 - 5.86 (m, 1 H) 6.45 (dd, 1:289, 1.65 Hz, 1 H) 6.84 - 6.99 (m, 2 H) 7.17 — 7.32 (m, 2 H) 7.52 (t, J=2.06 Hz, 1 H) MS (ESl/APCI Dual) (Positive) m/z; (M+H)+ 342 (Example 9) Preparation of (1-{4-[(1-tert-butylpiperidinyl)oxy]phenyl}-1H-pyrrolyl)(pyrrolidin yl)methanone (Compound No. 19) [Chemical formula 18] awef O The titled compound was prepared as a colorless crystal by repeating the procedure of Example 1, except that the methyl lH-pyrrole—3-carboxy1ic acid was replaced by (1H- pyrrol~3~yl)(pyrrolidinyl)methanone and the 1-cyclobutyl-4~(4—iodophenoxy)piperidine by 1—tert-butyl(4-iodophenoxy)piperidine (which can be synthesized in accordance with the method described in W02008072724). 1H NMR (600 MHz, CHLOROFORM-d) 5 ppm 1.09 (s, 9 H) 1.81 (dd, J=8.46, 3.92 Hz, 2 H) 1.86 - 2.06 (m, 6 H) 2.41 (br. s., 2 H) 2.87 (br. s., 2 H) 3.56 - 3.80 (m, 4 H) 4.22 - 4.32 (m, 1 H) 6.63 (dd, J=3.10, 1.86 Hz, 1 H) 6.85 - 6.99 (m, 3 H) 7.23 - 7.31 (m, 2 H) 7.41 - 7.50 (m, 1 MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 396 (Example 10) Preparation of 1 —{4-[(1-tert-buty1piperidin~4—yl)oxy]phenyl}~N—methyl-lH—pyrrole-3 - carboxamide (Compound No. 20) [Chemical formula 19] The titled compound was prepared as a ess crystal by ing the ure of Example 1, except that the methyl lH-pyrrolecarboxylic acid was replaced by N- methyl-1H-pyrrole—3-carboxamide and the obutyl(4-iodophenoxy)piperidine by 1- tert-butyll(4-iodophenoxy)piperidine. 1H NMR (600 MHz, CHLOROFORM—d) 5 ppm 1.09 (s, 9 H) 1.81 (dd, J=8.46, 3.92 Hz, 2 H) 1.96 - 2.06 (m, 2 H) 2.41 (br. s., 2 H) 2.87 (br. s., 2 H) 2.96 (d, J=4.95 Hz, 3 H) 4.27 (br. s., 1 H) 5.69 - 5.82 (m, 1 H) 6.38 - 6.50 (m, l H) 6.86 - 7.00 (m, 3 H) 7.21 - 7.31 (In, 2 H) 7.52 (t, J=1.86 Hz, 1 H) MS (ESI/APCI Dual) (Positive) m/z; (M+H)+ 356 (Test 1: Rat H3 receptor g test) The frontal cortex dissected from rats was homogenized with a Teflon homogenizer in a 50 mM Tris—HCl buffer solution (pH 7.4) ning a protease inhibitor (Complete EDTA-free; Roche Diagnostics) and 5 mM EDTA. The homogenate was centrifuged at 48,000Xg for 15 minutes. The supernatant was removed and the pellet was suspended in a 50 mM Cl buffer solution (pH 7.4) containing 5 mM EDTA and centrifuged at 48,000><g for 15 minutes. The supernatant was removed and the pellet was suspended in a 50 mM Tris- HCl buffer solution (pH 7.4) containing 5 mM EDTA to give a membrane fraction. The membrane fraction (the protein content in the final reaction mixture: 75 pg), N-a- methyl[3H]histamine (PerkinElmer; final tration: 0.75 nM) and a test drug were mixed and subjected to reaction at room temperature for an hour. After the end of the reaction, the reaction mixture was suction filtered through a 96—well GF/C filter plate pretreated with 0.3% polyethyleneimine; the filters were then washed five times with a 50 mM Tris—HCl buffer solution (pH 7.4) ning 5 mM EDTA. After the washing, the filters were dried and a scintillator was added to e the residual radioactivity on the filter with TopCount (PerkinElmer).

The residual radioactivity in the presence of 10 uM thioperamide was taken as indicative of nonspecific g and the ence from the residual radioactivity in the absence of thioperamide was taken as indicative of specific binding. Each of the test drugs was dissolved and diluted in DMSO at varying concentrations to plot a dose—response curve from the corresponding al radioactivities; the concentration of test drug that inhibited the specific binding by 50% (ICso) was determined from this curve. The IC50 values of the example compounds are shown in Table 2 below.

[Table 2] Compound No. ICso (HM) iNt—‘wi—‘HFhWEhr—‘QNKDLIIUJUJP—‘r—‘DJH [\Ji—nu—nr—p—tv—dr—at—ti—dh-Aoxoooqoxmri—‘oomflmmfi‘w “\rwwinmkimooobw'mloiva-Akr4el“ (Test 2: [35$]GTP—-y—-s binding test) The frontal cortex dissected from rats was homogenized with a Teflon homogenizer in a 30 mM Cl buffer solution (pH 7.4) containing 2.5 mM calcium chloride dihydrate.

The homogenate was centrifuged at 48,000Xg for 15 s. The supernatant was removed and the pellet was suspended in a 30 mM Tris-HCl buffer solution (pH 7.4) ning 2.5 mM calcium chloride dihydrate and centrifuged at Xg for 15 minutes. The atant was removed and the pellet was suspended in a 30 mM Tris-HCl buffer solution (pH 7.4) containing 2.5 mM m chloride dihydrate and after incubation at 37 °C for 30 minutes, the suspension was centrifuged at 48,000Xg for 15 minutes. The resulting supernatant was removed and the pellet was suspended in a 20 mM HEPES buffer solution (pH 7.4) containing 100 mM sodium chloride and 10 mM magnesium chloride to give a membrane fraction. The membrane fraction (the protein content in the final reaction mixture: 20 ug), GDP (final concentration: 300 uM), adenosine deaminase (final concentration: 1 U/mL), R(— ethyl histamine (final concentration: 300 nM) and a test drug were mixed and subjected to reaction at 30 °C for 20 minutes. After the end of the reaction, [35$]GTP—y-S (final concentration: 0.3 nM) was added and the reaction was continued for an additional 90 minutes. After the end of the on, the reaction e was suction filtered through a 96-well GF/C filter plate, which was then washed three times with a 20 mM HEPES buffer solution (pH 7.4) containing 100 mM sodium chloride and 10 mM magnesium chloride.

After the washing, the filters were dried and a scintillator was added to measure the residual radioactivity on the filter with TopCount (PerkinElmer).

The residual radioactivity in the absence of R(—)-a-methyl histamine was taken as indicative of nonspecific g and the difference from the residual radioactivity in the presence of R(—)-0L—methyl histamine was taken as indicative of specific binding. Each of the test drugs was dissolved and diluted in DMSO at varying concentrations to plot a dose- response curve from the corresponding residual radioactivities; the concentration of test drug that inhibited the specific binding by 50% (IC5O) was ined from this curve. As it turned out, Compound Nos. 3 and 7 of the present invention showed high activities, i.e., IC50 of 100 nM or less.

(Test 3: Rat in vivo cokinetic study) SD rats were given a single oral stration of nd No. 3, 4 or 7 at a dose of 3 mg/kg and an hour after the administration, the compound’s distribution among the plasma, brain, and cerebrospinal fluid was checked. Quantification was effected by a high- performance chromatography/tandem mass spectrometer API 4000 (LC-MS/MS; AB Sciex).

As it turned out, Compound Nos. 3, 4 and 7 had good brain/plasma movement ratios of 4.5, 2.9 and 2.2, respectively, with the corresponding intracerebral concentrations of 78.2 ng/g, 7.06 ng/g and 408 ng/g. Both Compound Nos. 3 and 7 had a cerebrospinal fluid/plasma movement ratio of 0.3, with the corresponding cerebrospinal fluid concentrations of 5.75 ng/mL and 50.5 , respectively.

(Test 4: oprotein ate recognition test) LLC—GAS-COL300 cells (Human MDRl expressing system derived from pig kidney derived, cultured renal epithelial cell line LLC-PKl) were cultured on a transwell.

Immediately before the test, the culture medium was replaced by Hank’s balanced salt solution (HBSS) and the test was then conducted. A solution of an assay compound ed to a final tration of 10 uM was added to the donor side of LLC—GAS-COL3 00 cells and after the passage of a predetermined period of time, a specified quantity of cells was sampled from the acceptor side. The concentration of the assay compound in the sample was measured by LC-MS/MS. From the amounts of the compound that accumulated and passed into the acceptor side, membrane permeation ients (X106 crn/sec) were calculated for apical—+basa1 and basal—>apical directions and their ve ratio (efflux ratio) was determined to evaluate the P—glycoprotein substrate ition. The efflux ratio values of Example Compounds are listed in Table 3 below.

[Table 3] Compound No Efflux ratio INDUSTRIAL APPLICABILITY According to the present invention, there can be provided pharmaceutical products that have a potent action for inhibiting the binding to the histamine H3 receptor and which are useful in the prevention or treatment of disorders due to the histamine H3 receptor, for example, such diseases as dementia, Alzheimer’s disease, attention-deficient hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, diabetes mellitus, ipidemia, epsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement er, insomnia, and depression, or allergic rhinitis and this is expected to make a great contribution to the development of the pharmaceutical industry. -31_

Claims (11)

1. A compound represented by formula (1) [Chemical a 1] R3 / \\ N \/ l 2 (I) (R >n Q refers to a group represented by the following formula (A) or (B): [Chemical formula 2] R4 5 0/ R6 (A) (B) R1 is hydroxyl, C1-C6 alkoxy, or NR1A RIB; R1A and R“3 which may be the same or different, are each a hydrogen atom, C1-C6 alkyl or C3—C7 cycloalkyl, or R1A and R”3 are bonded er with the adjacent nitrogen atom to form a 3- to 7—membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C1-C6 alkyls); R2 is a hydrogen atom, a halogen atom, or C1—C6 alkyl; n is l or 2; R3 is a hydrogen atom, a halogen atom, or C1— C6 alkyl; R4 is C1-C6 alkyl (the C1-C6 alkyl may be substituted by one or two C3-C7 cycloalkyls) or C3- C7 cycloalkyl (the C3-C7 cycloalkyl may be substituted by one or two C1-C6 alkyls); R5 and R6, which may be the same or different, are each C1—C6 alkyl or C3—C7 cycloalkyl, or R5 and R6 are bonded together with the adjacent nitrogen atom to form a 3— to 7-membered saturated heterocyclic ring (the saturated heterocyclic ring being optionally substituted by one or two C1—C6 alkyls)] or a pharmaceutically acceptable salt thereof.

2. A nd according to claim 1, wherein Q is represented by formula (A): [Chemical formula 3] R’LN (wherein R4 is as defined in claim 1), or a ceutically able salt thereof.

3. A compound according to claim 1 or 2, wherein R1 is NRIAR1B (wherein R1A and R113 are as defined in claim 1, or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein Rzand R3are each a hydrogen atom and n is 1, or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4, wherein R4 is C3—C7 cycloalkyl, or a pharmaceutically acceptable salt thereof.

6. A compound according to claim 1 which is ed from the group consisting of the following or a ceutically able salt thereof: Methyl l - {4-[(1-cyclobuty1piperidin-4—yl)oxy]phenyl}—lH-pyrrole-3 ~carboxylate, l— {4-[(l ~cyclobuty1piperidin—4-yl)oxy]phenyl } — l H—pyrrole—3 ~carboxylic acid, Azetidin-l—yl(1-{4-[(l~cyclobutylpiperidin—4—y1)oxy]phenyl}~1H—pyrrolyl) methanone, (l— {4-[(1-cyclobuty1piperidin-4—yl)oxy]phenyl}—1H—pyrrol~3 -yl)(pyrrolidin— l -yl) ( l - {4-[(l -cyclobuty1piperidinyl)oxy]phenyl}- l H—pyrrol-3 -yl)(piperidinyl) methanol, (1 - {4—[(l -cyclobuty1piperidin—4-yl)oxy]phenyl}—N,N—dimethyl-1H—pyrrole—3 — carboxamide, 1- {4—[(1-cyclobutylpiperidin—4—yl)oxy]pheny1}-N—methy1-1H-pyrrolecarb0xamide, 1- {4-[(1-cyclobutylpiperidiny1)oxy]phenyl}-1H—pyrrole-3 —carboxamide, (1 — {4-[(1-cyclobuty1piperidin-4—yl)oxy]pheny1}—1H—pyrrol-3 —yl)(morpholin—4-yl) one, (1- {4-[(1—cyclobutylpiperidinyl)oxy]phenyl}—1H-pyrrol~3 2R,6S)-2,6— dimethylmorpholin—4-y1)methanone, (1 — {4-[(1 —cyclobutylpiperidinyl)oxy]phenyl}- lH-pyrrol—3 -yl)(2-oxa~6—azaspiro[3 .3] hepta—6—yl)methanone, N-tert-butyl—l-{4—[(1-cyclobutylpiperidinyl)oxy]phenyl}~1H-pyrrole—3—carb0xamide, N—cyclobutyl—1—{4-[(1-cyclobutylpiperidin—4-y1)oxy]phenyl}—1H—pyrrole~3 — carboxamide, Methyl 1- {4—[(1-cyclobutylpiperidin—4-yl)oxy]phenyl}—2,5—dimethyl-1H—pyrrole-3 - carboxylate, (1-{4-[(1-cyclobuty1piperidin-4—yl)oxy]pheny1}-2,5-dimethyl-1H-pyrrol-3 -yl) (pyrrolidinyl)methanone, [1—(4— {3 ~[(2R)—2—methylpyrrolidinyl]propoxy}phenyl)-1H—pyrroly1](pyrrolidin—1- y1)methanone , (1— {4—[(1-isopropylpiperidin—4-yl)oxy]phenyl}«1H-pyrrol-3 -yl)(pyrroldin- l -yl) methanone, 1 l-isopropylpipen'din-4—yl)oxy]phenyl}-N—methyl-1H—pyrrolecarboxamide, (1 - {4—[(l-tert—buty1piperidinyl)oxy]phenyl}-1H—pyrrol-3 —yl)(pyrrolidin-1~yl) methanone, and 1- -tert—buty1piperidinyl)oxy]phenyl}-N—methyl—lH—pyrrole—3-carboxamide.

7. A compound according to claim 1 which is 1—{4-[(1—cyclobuty1piperidin—4- y1)0xy]phenyl}-N-methyl-1H-pyrrole-3 - carboxamide represented by the following formula or a pharmaceutically acceptable salt thereof

8. A pharmaceutical agent comprising as the active ingredient a compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. A pharmaceutical agent according to claim 8 which is a histamine H3 receptor antagonist or inverse agonist.

10. A pharmaceutical agent according to claim 8 or 9 which is a preventive or therapeutic agent for dementia, Alzheimer’s disease, ion-deficient hyperactivity disorder, schizophrenia, epilepsy, central convulsion, obesity, es mellitus, hyperlipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, depression, or allergic is.

11. The use of a compound according to any one of claims 1 to 7, in the production of a medicament for treating or preventing dementia, Alzheimer’s e, attention-deficient ctivity disorder, schizophrenia, epilepsy, central sion, obesity, diabetes mellitus, ipidemia, narcolepsy, idiopathic hypersomnia, behaviorally induced insufficient sleep syndrome, sleep apnea syndrome, circadian rhythm disorder, parasomnia, sleep related movement disorder, insomnia, depression, or allergic rhinitis.