KR20070022094A - Sulfonamide compound - Google Patents

Abstract

The following compounds of formula I, prodrugs thereof, pharmaceutically acceptable salts or solvates thereof are described:

[Wherein R ¹ represents amino which may be substituted by ethyl or lower alkyl which may be substituted by halogen;

R ² And R ³ independently represents hydrogen or lower alkyl;

X represents cycloalkylene, lower alkylene or piperidindiyl, and

Z represents optionally substituted phenyl or optionally substituted heterocyclic group.

Description

Sulfonamide compound {SULFONAMIDE COMPOUND}

The present invention relates to novel compounds having NPYY5 receptor antagonist activity or pharmaceutical compositions containing them. In more detail, it relates to anti-obesity agents or appetite suppressants.

Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues, which was isolated in porcine brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.

It has been reported that NPY has, in the central nervous system, food intake stimulating activity, anti-convulsive activity, learning-promoting activity, anti-anxiety activity, anti-stress activity, and the like, central nervous system diseases such as depression, Alzheimer's disease and It can be seriously related to Parkinson's disease. NPY is thought to be associated with cardiovascular disease because it induces contraction of smooth muscle, such as blood vessels or cardiac muscle, in peripheral tissues. It is also known to be associated with metabolic diseases such as obesity, diabetes, and hormonal abnormalities (Non-Patent Document 1). Thus, NPY receptor antagonists are expected as a prophylactic or therapeutic agent for various diseases associated with the NPY receptor.

Subtypes of Y1, Y2, Y3, Y4, Y5, and Y6 have now been identified as NPY receptors (Non-Patent Document 2). It has been suggested that the Y5 receptor is at least related to feeding behavior, and its antagonists are expected as anti-obesity agents (Non-Patent Document 3).

Compounds having a structure similar to the compounds of the present invention and having NPY receptor antagonist activity are described in Patent Document 1. However, amino sulfonamide compounds or ethyl sulfonamide compounds in which amino is substituted with alkyl are not specifically described in this document.

Non-Patent Document 1: Trends in Pharmacological Sciences, Vol. 15, pp. 153 (1994)

Non-Patent Document 2: Trends in Pharmacological Sciences, Vol. 18, pp. 372 (1997)

Non-Patent Document 3: Peptides, Vol. 18, pp. 445 (1997)

Patent Document 1: WO 01/37826

Problem to solve in the present invention

It is an object of the present invention to provide novel compounds having excellent NPYY5 receptor antagonist activity and pharmaceutical compositions containing them.

Problem solving

The present invention provides:

1) Compounds of Formula I, pharmaceutically acceptable salts or solvates thereof:

[Wherein R ¹ is ethyl optionally substituted with halogen or amino optionally substituted with lower alkyl,

R ² And Each R ³ is independently hydrogen or lower alkyl,

X is cycloalkylene, lower alkylene or piperidindiyl,

Z is optionally substituted phenyl or optionally substituted heterocyclyl],

2) X is C2-C4 alkylene,

또는

or

The compound described in 1) above, a pharmaceutically acceptable salt or solvate thereof,

3) a compound as described above in 1) or 2) wherein Z is a pharmaceutically acceptable salt or solvate thereof:

(i) optionally substituted with one or more substituent (s) selected from morpholino, halogeno lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylene dioxy or halogeno lower alkylene dioxy substituted with lower alkyl Phenyl,

(ii) pyridyl optionally substituted with one or more substituent (s) selected from halogeno lower alkyl or halogeno lower alkoxy,

(iii) carbazolyl optionally substituted with lower alkyl or tetrahydrocarbazolyl optionally substituted with lower alkyl,

(iv) benzofuryl optionally substituted with one or more substituent (s) selected from lower alkoxy, lower alkoxycarbonyl or lower alkyl carbamoyl,

(v) cromenyl optionally substituted with oxo, or

(vi) cycloheptabenzofuryl,

4) R ² And R ³ The compounds described in any one of 1) to 3) above, all of which are hydrogen, pharmaceutically acceptable salts or solvates thereof,

5) a pharmaceutical composition containing the compound described in any one of 1) to 4), a pharmaceutically acceptable salt or solvate thereof,

6) NPYY5 receptor antagonists containing a compound as described in any one of 1) to 4), a pharmaceutically acceptable salt or solvate thereof.

Effects of the Invention

Compounds of the invention have NPYY5 receptor antagonist activity. Thus, the compounds of the present invention may be very useful as anti-obesity agents or appetite suppressants.

Best Mode for Carrying Out the Invention

"Halogen" in this description includes fluorine, chlorine, bromine and iodine. Fluorine is particularly preferred. Halogen moieties in “halogeno lower alkyl”, “halogeno lower alkylenedioxy”, “halogeno lower alkoxy”, “halogeno lower alkoxycarbonyl” or “halogeno lower alkyl carbamoyl” are also described above. same.

The term "lower alkyl" includes C1 to C10 straight or branched chain alkyl. Examples of "lower alkyl" are methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n- Heptyl, isoheptyl, n-octyl, isooctyl and n-nonyl, n-decyl.

"Morpholino substituted by lower alkyl", "halogeno lower alkyl", "lower alkoxy", "halogeno lower alkoxy", "lower alkoxycarbonyl", "halogeno lower alkoxycarbonyl", "lower alkylcarbons" The lower alkyl moiety in "bamoyl", "halogeno lower alkylcarbamoyl", "heterocyclyl substituted with lower alkyl" or "lower alkylcarbonyl" is as defined above.

R ² And Lower alkyl in "lower alkyl" at R ³ or "amino optionally substituted with lower alkyl" at R ¹ is preferably C1 to C3 alkyl, more preferably methyl.

The term "cycloalkyl" includes C3 to C8 cyclic alkyl, preferably C5 or C6 cyclic alkyl. For example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

The cycloalkyl moiety in the "cycloalkylcarbonyl" is the same as described above.

The term "cycloalkylene" includes C3 to C8 cyclic alkylenes, preferably C5 or C6 cyclic alkylenes. For example cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, cycloheptylene and cyclooctylene, preferably cyclohexylene, particularly preferably 1,4-cyclohexanediyl.

The term "lower alkylene" includes divalent groups comprising 1 to 6 methylenes, preferably 2 to 6 methylenes, more preferably 3 to 6 methylenes. For example methylene, ethylene, trimethylene, tetramethylene, pentamethylene and hexamethylene, particularly preferably tetramethylene.

The lower alkylene moieties in "lower alkylenedioxy" and "halogeno lower alkylenedioxy" are as described above and are preferably methylenedioxy or ethylenedioxy.

The term "lower alkenyl" includes C2 to C10, preferably C2 to C8, more preferably C3 to C6 straight or branched chain alkenyl, having one or more double bonds at any position possible. For example, vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl , Octenyl, nonenyl and decenyl.

 The lower alkenyl moiety in "lower alkenylcarbonyl" is as defined above.

The term "aryl carbonyl" includes benzoylcarbonyl and naphthylcarbonyl.

Examples of substituents of "optionally substituted phenyl" include halogen, hydroxy, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, carboxy, lower alkoxycarbonyl, halogeno lower alkoxycarbonyl, acyl, acyloxy , Carbamoyl, lower alkyl carbamoyl, halogeno lower alkyl carbamoyl, phenyl optionally substituted with substituent group a, heterocyclyl optionally substituted with substituent group a, wherein substituent group a is halogen, hydroxy, lower Alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, etc.), lower alkylenedioxy, halogeno lower alkylenedioxy, oxo and the like. Substituents may be substituted with one or more substituent (s) selected from the above substituents.

Preferred are heterocyclyl substituted by lower alkyl, lower alkyl, halogeno lower alkyl, lower alkoxy, halogeno lower alkoxy, carboxy, lower alkoxycarbonyl, halogeno lower alkoxycarbonyl, lower alkylenedioxy or halogeno lower Alkylenedioxy.

The term “heterocyclyl” includes heterocyclyl including one or more heteroatoms optionally selected from O, S and N in the ring. For example, 5- or 6-membered heteroaryl such as pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl , Oxazolyl, oxdiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl and thienyl; Non-aromatic heterocyclyls such as dioxanyl, tyranyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazoli Nil, pyrazolidinyl, pyrazolinyl, piperidyl, piperazinyl, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino, dihydropyridyl, tetrahydrofuryl, tetrahydropyranyl, Tetrahydrothiazolyl and tetrahydroisothiazolyl; Fused heterocyclyls consisting of two rings such as indolyl, isoindoleyl, indazolyl, indolinyl, indolinyl, isoindolinyl, quinolyl, isoquinolyl, cynolinyl, phthalazinyl, quinazoli Neil, naphthyridinyl, quinoxalinyl, purinyl, putridinyl, chromenyl, benzimidazolyl, benzisazolyl, benzoxazolyl, benzoxadiazolyl, benzisothiazolyl, benzothiazolyl, benzothiadia Zolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotriazolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, quinazolinyl, quinolyl, isoquinolyl, naphthyl Lidinyl, dihydropyridyl, tetrahydroquinolyl and tetrahydrobenzothienyl; And fused heterocyclyls consisting of three rings such as carbazolyl, tetrahydrocarbazolyl, acridinyl, xenyl, phenthiazinyl, phenoxatinyl, phenoxazinyl, dibenzofuryl, cyclohexabenzofuryl and Cycloheptabenzofuryl.

Preferred are pyridyl, carbazole, tetrahydrocarbazolyl, benzofuryl or cycloheptabenzofuryl.

Fused heterocyclyls condensed with rings other than heterocyclyl (eg benzofuryl) may be bonded to any of these rings.

 The heterocyclyl moiety in “heterocyclyl substituted with lower alkyl” is as described above and is preferably morpholine.

Substituents for “optionally substituted heterocyclyl” are the same as those for “optionally substituted phenyl”, which are optionally substituted with one or more substituents selected from them. Preferred are lower alkyl, halogeno lower alkyl, halogeno lower alkoxy, lower alkoxy, lower alkoxycarbonyl and lower alkyl carbamoyl, oxo and the like.

The heterocyclyl moiety in the "heterocyclyl optionally substituted with substituent group a" is preferably morpholino, morpholinyl, thiomorpholino, thiomorpholinyl or the like.

The term "acyl" means (1) C1 to C10, preferably C1 to C6, more preferably C1 to C4 straight or branched chain lower alkylcarbonyl or C2 to C10, preferably C2 to C8, more preferably C3 to C6 straight chain Or branched chain lower alkenylcarbonyl, (2) C4 to C9, preferably C4 to C7 cycloalkylcarbonyl, and (3) arylcarbonyl. For example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, acryloyl, propioloyl, methacryloyl, crotonoyl, cyclopropylcarba Carbonyl, cyclohexylcarbonyl, cyclooctylcarbonyl and benzoyl.

The "acyl" moiety in "acyloxy" is the same as described above.

The compounds of the present invention include any formable, pharmaceutically acceptable salts thereof. Examples of “pharmaceutically acceptable salts” include salts with mineral acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid; Salts with organic acids such as para-toluenesulfonic acid, methanesulfonic acid, oxalic acid and citric acid; Salts with organic bases such as ammonium, trimethylammonium and triethylammonium; Salts with alkali metals such as sodium and potassium; And salts with alkaline earth metals such as calcium and magnesium.

Compounds of the present invention include solvates thereof. Hydrates are preferred, and any number of solvent molecules can be coordinated with compound I.

When compound I of the present invention has an asymmetric carbon atom, it includes racemates, all enantiomers and all stereoisomers such as diastereomers, epimers and enantiomers thereof.

In addition, when the compound I of the present invention having a double bond forms the E isomer or the Z isomer, the compound I includes two isomers. When X is cycloalkylene, compound I includes both cis isomers and trans isomers.

For example, the compound (I) of the present invention can be synthesized by the method described in Patent Document 1 or the following method.

Wherein Hal is halogen and the other symbols are as defined above.

Step A

Substituent R ¹ for compound IV, corresponding to target compound in suitable solvent Compound V having a reaction with, if necessary, in the presence of a base to give compound II.

Examples of the solvent include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane hexane chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane acetone, acetonitrile and water And mixtures thereof. Preferred are dioxane dichloromethane and the like.

Examples of bases are sodium hydroxide, potassium hydroxide, lithium hydroxide and the like.

The reaction temperature is about 0 ° C to 50 ° C, preferably about 20 ° C to 30 ° C.

The reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.

As the compounds IV and V, known compounds or compounds synthesized by known methods from known compounds can be used.

Step B

Having substituents Z and R ³ corresponding to the target compound Compounds II and III are reacted in a suitable solvent.

Examples of the solvent include tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane hexane chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane acetone, acetonitrile and water And mixtures thereof. Preferred are dimethylformamide, tetrahydrofuran, ethyl acetate and the like.

If necessary, the reaction can be carried out with condensing agents such as 1,3-dicyclohexylcarbodiimide, 1-ethyl 3- (3-dimethylamino) carbodiimide (WSCD; Hydroxy benzotriazole, 3,4-dihydro-3-hydroxy-4-oxo 1,2,3-benzotriazine.

The reaction temperature is about 0 ° C to 50 ° C, preferably about 20 ° C to 30 ° C.

The reaction time is about 5 minutes to 30 hours, preferably about 5 to 20 hours.

The amino group may be protected in a conventional manner at a suitable step with a suitable protecting group. For example, phthalimide, lower alkoxycarbonyl, lower alkenyloxycarbonyl, halogenoalkoxycarbonyl, aryl lower alkoxycarbonyl, trialkylsilyl, lower alkylsulfonyl, halogeno lower alkylsulfonyl, arylsul Phonyl, lower alkylcarbonyl and arylcarbonyl can be used as protecting groups.

After protection, the reaction was carried out on the compound and the obtained compound was deprotected by treatment with acid or base in a suitable solvent for the appropriate step. Examples of solvents are tetrahydrofuran, dimethylformamide, diethyl ether, dichloromethane, toluene, benzene, xylene, cyclohexane hexane chloroform, ethyl acetate, butyl acetate, pentane, heptane, dioxane acetone, acetonitrile and mixtures thereof to be. Examples of bases are hydrazine, pyridine, sodium hydroxide and potassium hydroxide seed seeds, hydrochloric acid, trifluoroacetic acid and hydrofluoric acid.

All compounds of the present invention have NPYY5 receptor antagonist activity, and this antagonist activity can be confirmed by the following assay.

The cDNA sequence encoding the human NPY Y5 receptor (WO 96/16542) is cloned into the expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 8957). The obtained expression vector was transfected into a host CHO cell using a Lipofect AMINE reagent (trademark, Gibco BRL Co., Ltd.) according to an instruction protocol to obtain cells stably expressing the NPY Y5 receptor.

Cell membranes prepared from CHO cells expressing NPY Y5 receptor, compounds of the present invention and 50,000-70,000 cpm [ ¹²⁵ I] peptide YY (final concentration 100-140 pM: Amersham) were buffered (0.1% chow) at 25 ° C. for 2 hours. After incubation in 20 mM HEPES-Hanks buffer, pH 7.4) containing serum albumin, the mixture was filtered with free filter GF / B (0.5% polyethyleneimine and 0.25% bovine serum albumin treatment). After the glass filter was washed with assay buffer, the radioactivity on the glass filter was measured with a gamma counter. 50% inhibition concentration (IC ₅₀ value) for specific peptide YY binding of the compounds of the invention was determined. Of the prepared cell membrane 1μM NPYY5 agonist of: ^{([cPP 1 -7, NPY 19} -23, Ala 31, Aib 32, Gln 34] -h pancreatic polypeptide Coockson Tocris) and 50,000-70,000 cpm of ^[125 I] Peptide YY After incubation in the presence, radioactivity was measured on a glass filter to calculate 50% inhibitory concentration for nonspecific binding of the compounds of the invention.

Of all the compounds of the invention, the following compounds are particularly preferred.

In Formula I,

(A1) a compound in which R ¹ is unsubstituted ethyl (hereinafter referred to as "R ¹ is A1"),

(A2) R ¹ is a trifluoroethyl compound (hereinafter referred to as “R ¹ is A2”),

(A3) a compound in which R ¹ is dimethylamino (hereinafter referred to as "R ¹ is A3"),

(B1) R ² And R ³ is each independently hydrogen or methyl (hereinafter “R ² And R ³ is referred to as B1 "),

(B2) R ² And R ³ is all hydrogen (hereinafter “R ² And R ³ is referred to as B2 ″),

(C1) a compound in which X is cyclohexylene (hereinafter referred to as "X is C1"),

(C2) X is a dimethylene compound (hereinafter referred to as "X is C2"),

(C3) a compound in which X is tetramethylene (hereinafter referred to as "X is C3"),

(C4) a compound in which X is piperidindiyl (hereinafter referred to as "X is C4"),

(D1a) optionally one or more substituent (s) selected from morpholino, halogeno lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylenedioxy or halogeno lower alkylenedioxy, wherein Z is substituted with lower alkyl A compound that is substituted phenyl (hereinafter referred to as "Z is D1a"),

(D1b) Z is optionally substituted with one or more substituent (s) selected from dimethylmorpholino, trifluoromethyl, methoxy, methoxycarbonyl, methylenedioxy, difluoromethylenedioxy or tetrafluoroethylenedioxy A compound that is substituted phenyl (hereafter Z is "D1b"),

(D2a) A compound wherein Z is pyridyl optionally substituted with one or more substituent (s) selected from halogeno lower alkyl or halogeno lower alkoxy (hereinafter "Z is referred to as D2a"),

(D2b) A compound wherein Z is pyridyl optionally substituted with trifluoromethyl or trifluoroethoxy (hereinafter referred to as "Z is D2b"),

(D3a) A compound wherein Z is carbazolyl optionally substituted with lower alkyl or tetrahydrocarbazolyl optionally substituted with lower alkyl (hereinafter referred to as "Z is D3a"),

(D3b) A compound wherein Z is carbazolyl optionally substituted with ethyl or isopropyl or tetrahydrocarbazolyl optionally substituted with ethyl or isopropyl (hereinafter, Z is referred to as "D3b"),

(D4a) A compound wherein Z is benzofuryl optionally substituted with one or more substituent (s) selected from lower alkoxy, lower alkoxycarbonyl or lower alkyl carbamoyl (hereinafter referred to as "Z is D4a"),

(D4b) A compound wherein Z is benzofuryl optionally substituted with one or more substituent (s) selected from methoxy, methoxycarbonyl or isopropylcarbamoyl (hereinafter referred to as "Z is D4b"),

(D5) A compound wherein Z is chromenyl optionally substituted with oxo (hereinafter referred to as "Z is D5"),

(D6) a compound in which Z is cycloheptabenzofuryl (hereinafter referred to as "Z is D6"),

(E) R ¹ , R ² And R ³ , X and Z (R ¹ , R ² And A compound in which the combination of R ³ , X, Z) is any one of the following: a pharmaceutically acceptable salt or solvate thereof;

The compounds of the present invention are effective against all diseases associated with NPY Y5, in particular they are useful for preventing and / or treating obesity and inhibiting food intake. In addition, the compounds are effective in preventing and / or treating diseases in which obesity acts as a risk factor, such as diabetes, hypertension, hyperlipidemia, atherosclerosis and acute coronary syndromes.

In addition, the compounds of the present invention have the following good characteristics, for example:

a) weak CYP enzyme inhibition

b) high water solubility

c) good drug degradability such as high bioavailability

d) low toxicity such as anemia-inducing activity

e) high metabolic stability

f) high Y5 receptor selectivity.

The compounds of the present invention can be administered orally or parenterally as anti-obesity agents or appetite suppressants. For oral administration, it may be in any conventional form such as tablets, granules, powders, capsules, pills, solutions, syrups, oral tablets and sublingual tablets. When the compound is administered parenterally, any conventional form is preferred, for example, injections (eg intramuscular, intravenous), suppositories, intradermal preparations and vapors. Oral administration is particularly preferred because the compounds of the present invention exhibit high oral absorption.

An effective amount of a compound of the present invention may be mixed with various pharmaceutical additives suitable for the dosage form, such as excipients, binders, wetting agents, disintegrants, lubricants and diluents, to produce pharmaceutical compositions. If the composition is for injection, a suitable carrier and the active ingredient can be sterilized together to obtain a pharmaceutical composition.

Examples of excipients include lactose, saccharose, glucose, starch, calcium carbonate and crystalline cellulose. Examples of binders include methylcellulose, carboxymethylcellulose, hydroxypropylcellulose, gelatin and polyvinylpyrrolidone. Examples of disintegrants include carboxymethylcellulose, sodium carboxymethylcellulose, starch, sodium alginate, agar and sodium lauryl sulfate. Examples of lubricants include talc, magnesium stearate and macrogol. Cacao oil, macrogol, methylcellulose and the like can be used as the base material for suppositories. When the composition is produced in solution, emulsified injections or suspended injections, dissolution promoters, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents and the like can be added. Sweetening, flavoring and the like can be added for oral administration.

The dosage of the compound of the present invention as an anti-obesity agent or anorexia medicament is determined in consideration of the age and weight of the patient, the type and severity of the disease, the route of administration, etc., but a typical oral dosage for adults is 0.05-100 mg / kg / day, preferably 0.1 to 10 mg / kg / day. For parenteral administration, the dosage is highly variable depending on the route of administration, but usually the dosage is from 0.005 to 10 mg / kg / day, preferably from 0.01 to 1 mg / kg / day. Dosages may be administered once to several times per day.

The invention is also illustrated through the following examples, which are not intended to limit the scope of the invention.

In the Examples, each abbreviation means the following.

Me: methyl

Et: ethyl

iPr: Isopropyl

WSCD: 1-ethyl 3- (3-dimethylamino) carbodiimide

DMF: N, N-dimethylformamide

HOBt: 1-hydroxybenzotriazole

Example 1

(Step 1)

To a suspension of 20.0 g (171 mmol) of 5-amino valeric acid 1 in 200 ml of dioxane, 200 ml (400 mmol) of 2 mol / L NaOH solution were added under ice stirring. To this solution was added 33.0 g (257 mmol) of ethane sulfonyl chloride while stirring for 10 minutes under ice. The mixture was stirred at rt for 15 min. The reaction solution was concentrated to about half volume and water (200 ml) was added thereto. After 5 mol / L-HCl was added to make the acid, the mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. Ether and hexanes were added to the residue. The precipitated crystals were filtered to give 19.6 g of sulfonamide compound 2 (yield 55%).

(Step 2)

209 mg (1.00 mmol) of carboxylic acid 2 , 210 mg (1.00 mmol) of 3 -amino-N-ethyl carbazole 3 and 163 mg (1.21 mmol) of 1-hydroxybenzotriazole in 5 ml of N, N-dimethylformamide 231 mg (1.21 mmol) of 1-ethyl 3- (3-dimethylamino) carbodiimide hydrochloride were added to the solution. The mixture was stirred at rt for 15 h. Water was added to the reaction solution and the precipitated crystals were filtered off, washed with water and dried. The obtained crude crystals were purified by column chromatography (SiO ₂ 10 g, CHCl ₃ / MeOH = 50) and crystallized with diethyl ether to give 167 mg of compound Id-2 of the present invention (yield 42%).

Other compound I was synthesized in the same manner as described above. The structure and physical properties are as follows.

Experiment 1 Feeding Inhibition Activity

Guide cannula was implanted into the lateral ventricle of 7 week old rats (200-300 g) and fed freely. The rats were then fed freely for about a week.

The compound of the present invention was suspended in 0.5% HPMC solution (hydroxypropylmethylcellulose: 60 SH-50, Shin-Etsu Chemical Co., Ltd.) to a final concentration of 15 mg / ml.

Rats were orally administered 2 mL / kg of a suspension of the compound of the present invention (compound 30 mg / kg). In contrast, rats of the control group were orally administered the same amount of 0.5% HPMC.

NPYY5 agonists ([cPP ^{1 -7} , NPY ^{19 -23} , Ala ³¹ , Aib ³² , Gln ³⁴ ] -h pancreatic polypeptide: Tocris Coockson) were dissolved in physiological salt solution to 0.1 nmol / 10 μl. One hour after the compound of the present invention was given, 0.1 nmol of solution was injected into the head of the rat through the guide cannula. Immediately after infusion, the amount of feed remaining was measured.

The amount of feed remaining was measured 1, 2 or 4 hours after infusion of the agonist and the number of feed intakes was measured during that time. Feeding inhibition rate of the compound of the present invention was measured relative to feed intake of control rats. The results are as follows.

TABLE 1

Compound number Feeding inhibitory activity (%) 1 hours 2 hours 4 hours Ia-2 98 ** 77 ** 56 ** Ia-3 85 ** 78 ** 74 ** Ib-1 90 ** 95 ** 92 ** Id-1 5 37 49 ** Id-2 100 ** 100 ** 100 ** Id-4 100 ** 94 ** 95 ** Ie-3 56 62 * 21 Ig-1 67 44 48 ** Ii-1 42 38 * 31

                                          *: p <0.05, **: p <0.01

The results show that the compounds of the present invention significantly inhibited feed intake of rats.

Formulation Example 1 Tablet

15 mg of compound (Ia-1)

Starch 15 mg

Lactose 15 mg

Crystalline Cellulose 19 mg

3 mg polyvinyl alcohol

30 ml of distilled water

Calcium Stearate 3 mg

After mixing all the above materials except calcium stearate uniformly, the mixture was ground, granulated and dried to obtain granules of suitable size. Calcium stearate was added to the granules and then tablets were formed via compression molding.

Formulation Example 2 Capsules

10 mg of compound (Ib-1)

Magnesium Stearate 10 mg

Lactose 80 mg

After mixing the materials to produce a powder or granules, the obtained product was filled into capsules.

Formulation Example 3 Granules

30 g of compound (Ic-1)

Lactose 265 g

5 g of magnesium stearate

The materials were uniformly mixed and then shaped through compression molding, and the resultant was ground, granulated and sieved to produce a suitable volume of granules.

As shown in the above experiments, the compounds of the present invention have NPY Y5 receptor antagonistic activity. Thus, the compounds of the present invention are very useful as anti-obesity agents and appetite suppressants.

Claims (6)

Compounds of Formula (I), pharmaceutically acceptable salts or solvates thereof:

[Wherein R ¹ is ethyl optionally substituted with halogen or amino optionally substituted with lower alkyl, R ² And Each R ³ is independently hydrogen or lower alkyl, X is cycloalkylene, lower alkylene or piperidindiyl, Z is optionally substituted phenyl or optionally substituted heterocyclyl. The compound of claim 1, wherein X is C2-C4 alkylene,

or

Phosphorus compounds, pharmaceutically acceptable salts or solvates thereof. A compound according to claim 1 or 2, wherein Z is a pharmaceutically acceptable salt or solvate thereof: (i) optionally substituted with one or more substituent (s) selected from morpholino, halogeno lower alkyl, lower alkoxy, lower alkoxycarbonyl, lower alkylene dioxy or halogeno lower alkylene dioxy substituted with lower alkyl Phenyl, (ii) pyridyl optionally substituted with one or more substituent (s) selected from halogeno lower alkyl or halogeno lower alkoxy, (iii) carbazolyl optionally substituted with lower alkyl or tetrahydrocarbazolyl optionally substituted with lower alkyl, (iv) benzofuryl optionally substituted with one or more substituent (s) selected from lower alkoxy, lower alkoxycarbonyl or lower alkyl carbamoyl, (v) cromenyl optionally substituted with oxo, or (vi) cycloheptabenzofuryl, The compound according to any one of claims 1 to 3, wherein R ² And R ³ A compound that is both hydrogen, Pharmaceutically acceptable salts or solvates thereof. A pharmaceutical composition comprising a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or solvate thereof. NPYY5 receptor antagonists containing a compound according to any one of claims 1 to 4, a pharmaceutically acceptable salt or solvate thereof.