WO2012147765A1

WO2012147765A1 - Benzimidazole derivative having npy y5 receptor antagonist action

Info

Publication number: WO2012147765A1
Application number: PCT/JP2012/061033
Authority: WO
Inventors: 直樹大森; 正彦藤岡; 友亮田村; 香奈渡辺
Original assignee: 塩野義製薬株式会社
Priority date: 2011-04-27
Filing date: 2012-04-25
Publication date: 2012-11-01

Abstract

Provided is a novel compound having an NPY Y5 receptor antagonist action. A compound represented by formula (I): (Chemical Formula 1) (in the formula, R¹ is a substituted or unsubstituted alkyl or the like; p and q are each independently 0 or 1, where p and q are not simultaneously 1; L is an oxygen atom or sulfur atom; and R², R³, R⁴, and R⁵ are each independently a hydrogen atom, a substituted or unsubstituted alkyl, or the like) has been found to have an NPY Y5 receptor antagonist action.

Description

Benzimidazole derivatives having NPY Y5 receptor antagonistic activity

The present invention relates to a novel benzimidazole derivative having NPY Y5 receptor antagonistic activity and useful as a pharmaceutical, particularly as an anti-obesity drug.

Obesity is defined as the accumulation of excess fat or adipose tissue in the body relative to lean body mass, and is recognized as the main risk factor for health problems. The body mass index (BMI) is a simple index of the height-weight ratio that is commonly used to classify an adult (over 15 years old) group or individual as overweight or obese. It is defined as the body weight (kg / m ² ) expressed in kilograms divided by the height squared in meters. According to the World Health Organization, BMI of 25 kg / m ² or more is “overweight” and 30 kg / m ² or more is “obese”. On the other hand, the Japanese Obesity Society designates BMI of 25 kg / m ² or more as “obesity”. This is because the number of obesity-related diseases including diabetes and dyslipidemia increases according to BMI, and the average value of the number of diseases becomes 1.0 or more at a BMI of 25 kg / m ² . According to a 2005 survey by the World Health Organization, around 1.6 billion people worldwide are overweight and at least 400 million are obese. Obesity is mainly caused by an increase in the ratio of caloric intake to physical activity and consumption in daily life. The number of obese people is increasing due to an increase in the intake of high fat and high sugar content foods in recent years, and it is predicted that more than 700 million people will be diagnosed with obesity worldwide in 2015.

Neuropeptide Y (hereinafter referred to as NPY) is a peptide consisting of 36 amino acid residues and was isolated from pig brain in 1982. NPY is widely distributed in the central nervous system and peripheral tissues of humans and animals.
In previous reports, NPY has been found to have feeding promoting action, anticonvulsant action, learning promoting action, anti-anxiety action, anti-stress action, etc. in the central nervous system, and depression, It may be deeply involved in central nervous system diseases such as Alzheimer's dementia and Parkinson's disease. In peripheral tissues, NPY causes contraction of smooth muscles such as blood vessels and myocardium, and is thus considered to be involved in cardiovascular disorders. Furthermore, it is known to be involved in metabolic diseases such as obesity, diabetes, and hormonal abnormalities (see Non-Patent Document 1). Therefore, a pharmaceutical composition having an NPY receptor antagonistic action is a preventive or therapeutic agent for various diseases involving the NPY receptor as described above.
To date, subtypes Y1, Y2, Y3, Y4, Y5, and Y6 have been discovered for NPY receptors (see Non-Patent Document 2). The Y5 receptor is involved in at least the feeding function, and it has been suggested that the antagonist becomes an anti-obesity drug (see Non-Patent Documents 3 to 5).

Patent Document 1 discloses a benzimidazole derivative having a substituent containing sulfamide, which has a growth hormone secretion promoting action and can be used as an anti-obesity drug.

Patent Document 2 discloses a benzimidazole derivative having a carboxyl group, which has an IL-8 and GROα chemokine inhibitory action and can be used as a therapeutic agent for inflammatory diseases. Patent Document 3 discloses a benzimidazole derivative having a carbonyl group, which has a β-secretase inhibitory action and can be used as an Alzheimer's therapeutic agent. Non-Patent Document 6 describes one compound of a benzimidazole derivative having an ORL1 antagonist activity.

Patent Document 4 discloses a condensed heterocyclic derivative having a substituent containing benzoxazole, which has a glucokinase activating action and can be used as a diabetic drug.
Patent Documents 5, 6, and 7 describe benzimidazole derivatives having an NPY Y5 receptor antagonistic action.
Patent Document 7 describes two compounds of a benzimidazole derivative having an NPY Y5 receptor antagonistic action.
Patent Document 8 describes a benzoxazole derivative having an NPY Y5 receptor antagonistic action.
Patent Document 9 describes a thiazole derivative having an NPY Y5 receptor antagonistic action.
Patent Document 10 describes a tricyclic derivative having an NPY Y5 receptor antagonistic action.

The above cited document does not describe or suggest that the compound of the present invention has an NPY 拮抗 Y5 receptor antagonistic action.

US Pat. No. 6,525,203 International Publication No. 2007/009774 International Publication No. 2006/099379 International Publication No. 2008/136444 International Publication No. 2005/80348 International Publication No. 2007/1255952 International Publication No. 2009/054434 International Publication No. 2008/134228 US 2006/0293341 US Pat. No. 6,124,331

An object of the present invention is to provide a novel benzimidazole derivative having an excellent NPY Y5 receptor antagonistic action.

As a result of intensive studies, the present inventors have succeeded in synthesizing a novel benzimidazole derivative having an excellent NPY Y5 receptor antagonistic action. Moreover, it discovered that this compound showed the strong eating suppression effect. Furthermore, the present inventors have also found that the compounds of the present invention have little inhibition on drug metabolizing enzymes, and have good metabolic stability and water solubility. The compound of the present invention has low toxicity and is sufficiently safe for use as a medicine.

That is, the present invention relates to the following.
(1)
Formula (I):

(Where
R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted amino;
p and q are each independently 0 or 1, provided that p and q are not 1 at the same time,
L is an oxygen atom or a sulfur atom,
R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen or cyano. Or a pharmaceutically acceptable salt thereof.
(2)
R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano, or a pharmaceutically acceptable salt thereof. .
(3)
The compound or a pharmaceutically acceptable salt thereof according to the above (1) or (2), wherein L is an oxygen atom.
(4)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), wherein q is 0.
(5)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (3), wherein p and q are 0.
(6)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (5), wherein R ¹ is substituted or unsubstituted alkyl.
(7)
The compound or a pharmaceutically acceptable salt thereof according to any one of the above (1) to (6), wherein R ³ is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano.
(8)
A pharmaceutical composition comprising the compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof.
(9)
The pharmaceutical composition according to (8) above, which has an NPY Y5 receptor antagonistic action.
(10)
The compound according to any one of the above (1) to (7) or a pharmaceutically acceptable salt thereof for use in the treatment and / or prevention of a disease involving the NPY Y5 receptor.
(11)
A method for treating and / or preventing a disease involving NPY Y5 receptor, which comprises administering the compound according to any one of (1) to (7) above or a pharmaceutically acceptable salt thereof.

The compound of the present invention exhibits an NPY Y5 receptor antagonistic action, and is associated with drugs, particularly diseases involving NPY Y5, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, It is very useful as a medicine for the treatment or prevention of hypertension, cerebral overflow, congestive heart failure or sleep disorder. In addition, since the compound of the present invention exhibits an effective anti-feeding action, it is very useful for weight management, weight loss, and weight maintenance after weight loss in obesity. Furthermore, it is very useful as a medicament for the treatment or prevention of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndromes.

The terms used in this specification are explained below. In addition, in this specification, each term has the same meaning, unless otherwise specified, when used alone or in combination with other terms.

“Alkyl” means a straight or branched hydrocarbon group having 1 to 10 carbon atoms. Examples include alkyl having 1 to 6 carbon atoms, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 3 carbon atoms, and the like. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, hexyl, isohexyl, n-heptyl, isoheptyl, n-octyl, isooctyl , N-nonyl, n-decyl and the like.
“Alkyl” in R ¹ includes methyl, ethyl, isopropyl, tert-butyl and the like. In particular, ethyl, isopropyl and tert-butyl are preferable, and isopropyl and tert-butyl are more preferable.
Examples of “alkyl” in R ² , R ³ , R ⁴ and R ⁵ include methyl, ethyl, isopropyl, tert-butyl and the like. In particular, isopropyl is preferred.

“Alkenyl” means a straight or branched hydrocarbon group having 2 to 10 carbon atoms having one or more double bonds at an arbitrary position. Examples include alkenyl having 2 to 8 carbon atoms and alkenyl having 3 to 6 carbon atoms. Examples thereof include vinyl, propenyl, isopropenyl, butenyl, isobutenyl, prenyl, butadienyl, pentenyl, isopentenyl, pentadienyl, hexenyl, isohexenyl, hexadienyl, heptenyl, octenyl, nonenyl, decenyl and the like.

“Alkynyl” means a linear or branched hydrocarbon group having 2 to 10 carbon atoms having one or more triple bonds at any position. Examples include alkynyl having 2 to 6 carbon atoms, alkynyl having 2 to 4 carbon atoms, and the like. Examples include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl, nonynyl, decynyl and the like. In addition to one or more triple bonds at any position, alkynyl may further have a double bond.

“Cycloalkyl” means a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic saturated hydrocarbon groups. Examples of the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In particular, cycloalkyl having 3 to 6 carbon atoms and cycloalkyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the cyclic saturated hydrocarbon group having 3 to 8 carbon atoms include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring, Cyclopentene ring) and the like, and non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to come from a cyclic saturated hydrocarbon group having 3 to 8 carbon atoms.
For example, the following groups are also exemplified by cycloalkyl and are included in cycloalkyl. These groups may be substituted at any substitutable position.

As “cycloalkyl” in R ¹ , cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like are preferable.

“Cycloalkenyl” is a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms, and a group obtained by further condensing one or two 3- to 8-membered rings to these cyclic unsaturated aliphatic hydrocarbon groups. Means. Examples of the cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms include cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclohexadienyl and the like. In particular, cycloalkenyl having 3 to 6 carbon atoms and cycloalkenyl having 5 or 6 carbon atoms are preferable.
Examples of the ring condensed with the C 3-8 cyclic unsaturated aliphatic hydrocarbon group include carbocycles (aromatic carbocycles (eg, benzene ring, naphthalene ring etc.), non-aromatic carbocycles (eg cycloalkane ring). (Example: cyclohexane ring, cyclopentane ring, etc.), cycloalkene ring (example: cyclohexene ring, cyclopentene ring, etc.)), heterocycle (aromatic heterocycle (pyridine ring, pyrimidine ring, pyrrole ring, imidazole ring, etc.) And non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.) The bond is assumed to come from a cyclic unsaturated aliphatic hydrocarbon group having 3 to 8 carbon atoms. .
For example, the following groups are also exemplified as cycloalkenyl and are included in cycloalkenyl. These groups may be substituted at any substitutable position.

The alkyl part of “alkyloxy” and “alkylsulfonyl” has the same meaning as the above “alkyl”.

“Halogen” includes fluorine, chlorine, bromine and iodine. In particular, fluorine and chlorine are preferable.

“Haloalkyl” and “haloalkyloxy” mean groups in which 1 to 5 (preferably 1 to 3) of the above “halogens” are substituted on the alkyl part of the above “alkyl” and “alkyloxy”. .
As the “haloalkyl” in R ² , R ³ , R ⁴ and R ⁵ , difluoromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and the like are preferable.
As “haloalkyloxy” in R ² , R ³ , R ⁴ and R ⁵ , difluoromethyloxy, trifluoromethyloxy, 2,2,2-trifluoroethyloxy and the like are preferable.

As the substituent of “substituted alkyl”, “substituted alkenyl”, “substituted alkynyl”, “substituted cycloalkyl”, “substituted alkyloxy”, “substituted alkylsulfonyl” or “substituted cycloalkenyl”, halogen, hydroxy, mercapto, Nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or Unsubstituted heterocyclyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted amidino, group represented by the formula: —O—R ¹⁰ , formula: —O—C (═O) a group represented by -R ^10, wherein: -C = O) group represented by ^{-R 10,} wherein: -C (= O) groups represented by ^{-O-R 10,} wherein: or a group represented by the formula represented by ^{-S-R _10:} In -SO 2 ^{-R 10} And the groups shown where R ¹⁰ is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl or amidino. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

“Substituted or unsubstituted cycloalkyl”, “substituted or unsubstituted cycloalkenyl”, and “substituted or unsubstituted heterocyclyl” are oxo, thioxo or substituted or unsubstituted imino at any substitutable position. May be substituted.

As the substituent of “substituted amino”, “substituted carbamoyl”, “substituted sulfamoyl”, “substituted amidino” or “substituted imino”, hydroxy, cyano, formyl, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R, group represented by formula: —C (═O) —R, formula: —C (═O) — A group represented by OR, or a group represented by the formula: —SO ₂ —R, wherein R is alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl; Can be mentioned. With these substituents, 1 to 2 arbitrary positions where substitution is possible may be substituted.
Examples of the substituent of “substituted amino” in R ¹ include monomethyl, monoethyl, dimethyl, diethyl and the like. In particular, dimethyl is preferable.

Substituents for “substituted aryl”, “substituted heteroaryl” or “substituted heterocyclyl” include halogen, hydroxy, mercapto, nitro, nitroso, cyano, azide, formyl, substituted or unsubstituted amino, carboxy, alkyl, Haloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl, amidino, group represented by formula: —O—R ¹⁰ , formula: —O—C (═O) — A group represented by R ¹⁰ , a group represented by the formula: —C (═O) —R ¹⁰ , a group represented by the formula: —C (═O) —O—R ¹⁰ , a group represented by the formula: —S—R ¹⁰ group or _expression: group (wherein ^{R 10} represented by -SO 2 ^{-R 10} is alkyl, haloalkyl, alkenyl, alkynyl, consequent Alkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, carbamoyl, sulfamoyl or amidino), and the like. With these substituents, 1 to several arbitrary positions where substitution is possible may be substituted.

“Aryl” means a monocyclic or polycyclic aromatic carbocyclic group, and a group obtained by further condensing one or two 3- to 8-membered rings on these monocyclic or polycyclic aromatic carbocyclic groups Means. Examples of the monocyclic or polycyclic aromatic carbocyclic group include phenyl, naphthyl, anthryl, and phenanthryl. Particularly preferred is phenyl.
Rings condensed with monocyclic or polycyclic aromatic carbocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene ring). And non-aromatic heterocyclic rings (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic carbocyclic group.
For example, the following groups are also exemplified as aryl and are included in aryl. These groups may be substituted at any substitutable position.

“Heteroaryl” means a monocyclic or polycyclic aromatic heterocyclic group having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and monocyclic or polycyclic A group obtained by further condensing one or two 3- to 8-membered rings on an aromatic heterocyclic group.
As the “monocyclic aromatic heterocyclic group”, a 5- or 6-membered heteroaryl is particularly preferable. For example, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazolyl, triazinyl, tetrazolyl, isoxazolyl, Examples include oxazolyl, oxadiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, furyl, thienyl and the like.
The “polycyclic aromatic heterocyclic group” is particularly preferably a heteroaryl fused with a 5- or 6-membered ring, such as indolyl, isoindolyl, indazolyl, indolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, Naphthyridinyl, quinoxalinyl, purinyl, pteridinyl, benzimidazolyl, benzisoxazolyl, benzoxazolyl, benzoxadiazolyl, benzoisothiazolyl, benzothiazolyl, benzothiadiazolyl, benzofuryl, isobenzofuryl, benzothienyl, benzotria Bicyclic aromatic heterocyclic groups such as zolyl, imidazopyridyl, triazolopyridyl, imidazothiazolyl, pyrazinopyridazinyl, oxazolopyridyl, thiazolopyridyl; carbazolyl, Kurijiniru, xanthenyl, phenothiazinyl, phenoxathiinyl, cycloalkenyl, phenoxazinyl, heterocyclic groups such as the aromatic tricyclic dibenzofuryl and the like. In the case of a polycyclic aromatic heterocyclic group, any ring may have a bond.
Rings condensed with monocyclic or polycyclic aromatic heterocyclic groups include non-aromatic carbocycles (eg, cycloalkane rings (eg, cyclohexane ring, cyclopentane ring, etc.), cycloalkene rings (eg, cyclohexene). Ring, cyclopentene ring, etc.)) and non-aromatic heterocycles (for example, piperidine ring, piperazine ring, morpholine ring, etc.). The bond is assumed to be from a monocyclic or polycyclic aromatic heterocyclic group.
For example, the following groups are also exemplified as heteroaryl, and are included in heteroaryl. These groups may be substituted at any substitutable position.

“Heterocyclyl” refers to non-aromatic heterocyclic groups having one or more heteroatoms arbitrarily selected from O, S and N in the ring, and to these non-aromatic heterocyclic groups This means a group in which one or two 3- to 8-membered rings are condensed.
It contains a monocyclic non-aromatic heterocyclic group or a polycyclic non-aromatic heterocyclic group.
Specific examples of `` monocyclic non-aromatic heterocyclic group '' include dioxanyl, thiylyl, oxiranyl, oxathiolanyl, azetidinyl, thianyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidino, piperidino, piperazinyl, piperazinoyl , Morpholinyl, morpholino, oxadiazinyl, dihydropyridyl, thiomorpholinyl, thiomorpholino, tetrahydrofuryl, tetrahydropyranyl, tetrahydrothiazolyl, tetrahydroisothiazolyl, oxazolidyl, thiazolidyl and the like.
Specific examples of the “polycyclic non-aromatic heterocyclic group” include indolinyl, isoindolinyl, chromanyl, isochromanyl and the like. In the case of a polycyclic non-aromatic heterocyclic group, any ring may have a bond.
For example, the following groups are also included in heterocyclyl.

In the compounds of the present invention, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted amino. In particular, substituted or unsubstituted alkyl is preferable.
In the compound of the present invention, p and q are 0 or 1, provided that p and q are not 1 at the same time. As the combination of p and q, (p, q) = (0,0), (1,0), (0,1) can be considered, and among them, (p, q) = (0,0) The combination of is preferable.
R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted Or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen or cyano, including a hydrogen atom, alkyl, alkylsulfonyl, halogen, Haloalkyl, haloalkyloxy or cyano are preferred. R ² and R ⁵ are particularly preferably hydrogen, R ³ is particularly preferably halogen, haloalkyl or haloalkyloxy, and R ⁴ is particularly preferably hydrogen or halogen.
The substituent of “substituted alkyl” in R ³ is preferably halogen. In particular, fluorine is preferable. As the substituent of “substituted alkyloxy” in R ³ , halogen is preferable. In particular, fluorine is preferred.

In the compound of the present invention, particularly preferred embodiments are shown below.
Formula (I):

Or the pharmaceutically acceptable salt thereof, the following embodiments (IA) to (IC) are exemplified.
(IA)
R ¹ is substituted or unsubstituted alkyl or substituted amino;
p and q are each independently 0 or 1, provided that p and q are not 1 at the same time and L is an oxygen atom;
A compound or a pharmaceutically acceptable salt thereof, wherein R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano.
(IB)
R ¹ is substituted or unsubstituted alkyl;
p is 1, q is 0,
L is an oxygen atom,
A compound or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁴ and R ⁵ are each independently a hydrogen atom or halogen, and R ³ is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano. .
(IC)
R ¹ is substituted or unsubstituted alkyl;
p and q are 0,
L is an oxygen atom,
A compound or a pharmaceutically acceptable salt thereof, wherein R ² , R ⁴ and R ⁵ are each independently a hydrogen atom or halogen, and R ³ is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano. .

The compound of the present invention is not limited to a specific isomer, but all possible isomers (eg, keto-enol isomer, imine-enamine isomer, diastereoisomer, optical isomer, rotational isomer, etc.) ), Racemates or mixtures thereof.

One or more hydrogen, carbon and / or other atoms of the compounds of the present invention may be replaced with hydrogen, carbon and / or isotopes of other atoms, respectively. Examples of such isotopes are ² H, ³ H, ¹¹ C, ¹³ C, ¹⁴ C, ¹⁵ N, ¹⁸ O, ¹⁷ O, ³¹ P, ³² P, ³⁵ S, ¹⁸ F, ¹²³ I and ^{Like 36} Cl, hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, iodine and chlorine are included. The compounds of the present invention also include compounds substituted with such isotopes. The compound substituted with the isotope is also useful as a pharmaceutical, and includes all radiolabeled compounds of the compound of the present invention. A “radiolabeling method” for producing the “radiolabeled product” is also encompassed in the present invention, and is useful as a metabolic pharmacokinetic study, a study in a binding assay, and / or a diagnostic tool.

The radioactive label of the compound of the present invention can be prepared by a method well known in the art. For example, the tritium-labeled compound represented by the formula (I) can be prepared by introducing tritium into the specific compound represented by the formula (I) by, for example, catalytic dehalogenation reaction using tritium. This method reacts a tritium gas with a precursor in which the compound of formula (I) is appropriately halogen-substituted in the presence of a suitable catalyst such as Pd / C, in the presence or absence of a base. Including that. Suitable methods for preparing other tritium labeled compounds include the document Isotopes in the Physical and Biomedical Sciences, Vol. 1, Labeled Compounds (Part A), Chapter 6 (1987). ^{The 14} C-labeled compound can be prepared by using a raw material having ¹⁴ C carbon.

Examples of the pharmaceutically acceptable salt of the compound of the present invention include a compound represented by the formula (I), an alkali metal (for example, lithium, sodium, potassium, etc.), an alkaline earth metal (for example, calcium, barium, etc.). , Magnesium, transition metals (eg, zinc, iron, etc.), ammonia, organic bases (eg, trimethylamine, triethylamine, dicyclohexylamine, ethanolamine, diethanolamine, triethanolamine, meglumine, ethylenediamine, pyridine, picoline, quinoline, etc.) and amino acids Salts, or inorganic acids (eg, hydrochloric acid, sulfuric acid, nitric acid, carbonic acid, hydrobromic acid, phosphoric acid, hydroiodic acid, etc.) and organic acids (eg, formic acid, acetic acid, propionic acid, trifluoroacetic acid, Citric acid, lactic acid, tartaric acid, oxalic acid, maleic acid, Mar acid, mandelic acid, glutaric acid, malic acid, benzoic acid, phthalic acid, ascorbic acid, benzenesulfonic acid, p- toluenesulfonic acid, methanesulfonic acid, and salts with ethanesulfonic acid, etc.). Particularly, salts with hydrochloric acid, sulfuric acid, phosphoric acid, tartaric acid, methanesulfonic acid and the like can be mentioned. These salts can be formed by a commonly performed method.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a solvate (for example, hydrate etc.) and / or a crystal polymorph, and the present invention includes such various solvates and crystals. Also includes polymorphs. The “solvate” may be coordinated with any number of solvent molecules (for example, water molecules) with respect to the compound of the present invention. When the compound of the present invention or a pharmaceutically acceptable salt thereof is left in the air, it may absorb moisture and adsorbed water may adhere or form a hydrate. In addition, the crystalline polymorph may be formed by recrystallizing the compound of the present invention or a pharmaceutically acceptable salt thereof.

The compound of the present invention or a pharmaceutically acceptable salt thereof may form a prodrug, and the present invention includes such various prodrugs. A prodrug is a derivative of a compound of the invention that has a group that can be chemically or metabolically degraded and is a compound that becomes a pharmaceutically active compound of the invention in vivo by solvolysis or under physiological conditions. Prodrugs include compounds that are enzymatically oxidized, reduced, hydrolyzed and converted to the compounds of the present invention under physiological conditions in vivo, compounds that are hydrolyzed by gastric acid, etc., and converted to the compounds of the present invention, etc. Include. Methods for selecting and producing suitable prodrug derivatives are described, for example, in Design of Prodrugs, Elsevier, Amsterdam 1985. Prodrugs may themselves have activity.

When the compound of the present invention or a pharmaceutically acceptable salt thereof has a hydroxyl group, for example, a compound having a hydroxyl group and an appropriate acyl halide, an appropriate acid anhydride, an appropriate sulfonyl chloride, an appropriate sulfonyl anhydride, and a mixed anion. Examples thereof include prodrugs such as acyloxy derivatives and sulfonyloxy derivatives produced by reacting with hydride or reacting with a condensing agent. For example, CH ₃ COO—, C ₂ H ₅ COO—, t-BuCOO—, C ₁₅ H ₃₁ COO—, PhCOO—, (m-NaOOCPh) COO—, NaOOCCH ₂ CH ₂ COO—, CH ₃ CH (NH ₂ ) COO—, CH ₂ N (CH ₃ ) ₂ COO—, CH ₃ SO ₃ —, CH ₃ CH ₂ SO ₃ —, CF ₃ SO ₃ —, CH ₂ FSO ₃ —, CF ₃ CH ₂ SO ₃ —, p— CH ₃ —O—PhSO ₃ —, PhSO ₃ —, and p—CH ₃ PhSO ₃ — can be mentioned.

Below, the general manufacturing method of this invention compound is demonstrated. In addition, this invention compound can be manufactured based on the knowledge of organic chemistry also by methods other than the synthesis method shown below.
Process A

Wherein R ² , R ³ , R ⁴ and R ⁵ are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Alkyloxy, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen, or cyano.)

Compound a3 can be obtained by reacting a solution of compound a1 with compound a2 and reacting with methyl iodide.
Examples of the solvent include tetrahydrofuran, DMF, DMA and the like.
The compound a2 can be used in an amount of 1 to 3 equivalents with respect to the compound a1.
Methyl iodide can be used in an amount of 1 to 5 equivalents relative to compound a1.
The reaction temperature is 0 ° C. to room temperature.
The reaction time is 0.1 hour to 12 hours, preferably 1 hour to 5 hours.

Process B

(Wherein P ¹ is a silyl-based protecting group, and other symbols are as defined above.)
Compound a5 can be obtained by reacting a solution of compound a3 with compound a4 in the presence of a base.
Examples of the solvent include DMF, NMP, THF, DMA and the like.
Examples of compound a4 include 2- (chloromethoxy) ethyltrimethylsilane, BOC ₂ O, MOMCl, and the like, and 1 to 3 equivalents can be used with respect to compound a3.
Examples of the base include sodium hydride, triacylamine, DIEA and the like, and 1 to 5 equivalents can be used with respect to compound a3.
The reaction temperature is 50 ° C. to heating under reflux, preferably under heating under reflux.
The reaction time is 0.1 to 5 hours, preferably 0.5 to 2 hours.

Process C

Compound a6 can be obtained by reacting a solution of compound a5 with peracid.
Examples of the solvent include dichloromethane and dichloroethane.
Examples of the peracid include m-chloroperbenzoic acid, hydrogen peroxide solution, t-butyl hydroperoxide NaBO _{3 and the} like, and 1 to 10 molar equivalents can be used with respect to the compound a5.
The reaction temperature is −20 ° C. to 60 ° C., preferably 0 ° C. to 50 ° C.
The reaction time is 1 to 5 hours.

Process D

Wherein L is an oxygen atom or sulfur atom, Z is a leaving group such as alkylsulfonyl, R ¹ is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted Cycloalkyl, substituted or unsubstituted cycloalkenyl or substituted amino, and other symbols are as defined above.)
Compound a9 can be obtained by reacting a solution of compound a7 with compound a8 (for example, compound a6 obtained in Step C) in the presence of a base.
Examples of the solvent include DMF, NMP, THF, DMA and the like.
1 to 3 equivalents of compound a8 can be used with respect to compound a7.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents can be used with respect to compound a7.
The reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
The reaction time is 1 to 24 hours, preferably 3 to 12 hours.

Process E

(The symbols in the formula are as defined above.)
Compound (I ′) can be obtained by deprotecting compound a9 with an acid.
Examples of the acid include trifluoroacetic acid, hydrochloric acid, sulfuric acid and the like.
The reaction temperature is 0 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time is 0.1 to 12 hours, preferably 1 to 12 hours.

Process F

(In the formula, ^Ra is substituted or unsubstituted alkyl, and other symbols are as defined above.)
Compound a11 can be obtained by reacting compound a10 with alcohol in the presence of sulfuric acid.
Examples of the alcohol include methanol and ethanol.
The reaction temperature is 50 ° C. to heating under reflux.
The reaction time is 1 to 24 hours, preferably 5 to 12 hours.

Process G

(Wherein P ³ is a silyl-based protecting group, and other symbols are as defined above.)
Compound a14 can be obtained by reacting a solution of compound a11 with compound a13 in the presence of a base.
Examples of the solvent include DMF, NMP, THF, DMA and the like.
Examples of compound a11 include tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, and the like, and 1 to 3 equivalents can be used with respect to compound a11.
Examples of the base include imidazole, triethylamine, DIEA and the like, and 1 to 5 equivalents can be used with respect to compound a11.
The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
The reaction time is 1 to 24 hours.

Process H

(The symbols in the formula are as defined above.)
Compound a15 can be obtained by reacting compound a14 with a reducing agent.
Examples of the solvent include tetrahydrofuran, methanol and the like.
Examples of the reducing agent include lithium aluminum hydride, sodium borohydride, lithium borohydride and the like, and 1 to 5 molar equivalents can be used with respect to compound a14.
The reaction temperature is 0 ° C. to room temperature.
The reaction time is 0.2 to 48 hours, preferably 1 to 24 hours.

Process I

(In the formula, Ts is a tosyl group, and other symbols are as defined above.)
Process 1
Compound a16 can be obtained by reacting a solution of compound a15 with tosyl chloride in the presence of a base.
Examples of the solvent include methylene chloride, dichloroethane, THF, and the like.
Tosyl chloride can be used at 1 to 3 equivalents relative to compound a15.
Examples of the base include DIEA, triethylamine, pyridine and the like, and 1 to 3 equivalents can be used with respect to compound a7.
The reaction temperature is 0 ° C. to room temperature.
The reaction time is 0.2 to 12 hours, preferably 0.5 to 5 hours.

Process J

Compound a18 can be obtained by reacting a solution of compound a16 with compound a17 in the presence of a base.
Examples of the solvent include DMF, NMP, acetonitrile, DMA and the like.
Examples of the base include cesium carbonate and potassium carbonate, and 1 to 5 equivalents can be used with respect to compound a16.
The reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
The reaction time is 1 to 24 hours, preferably 3 to 12 hours.
Using the compound a18 thus obtained, the compound of the present invention can be obtained according to steps D and E while appropriately performing protection and deprotection as necessary.

Process K

Compound a21 can be obtained by reacting a solution of compound a19 with compound a20 in the presence of an acid and reacting with a reducing agent.
Examples of the solvent include methylene chloride and chloroform.
1 to 3 equivalents of compound a20 can be used with respect to compound a19.
Examples of the acid include acetic acid and the like, and 1 to 3 equivalents can be used with respect to the compound a7.
Examples of the reducing agent include sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride and the like, and 1.5 to 3 equivalents can be used.
The reaction temperature is 0 ° C. to 50 ° C., preferably room temperature.
The reaction time is 1 to 24 hours, preferably 3 to 12 hours.

Process L

Compound a23 can be obtained by reacting a solution of compound a21 with compound a22 in the presence of a base.
Examples of the solvent include methylene chloride, DMF, THF, and the like.
Examples of the base include triethylamine, DIEA, pyridine and the like, and 1 to 3 equivalents can be used with respect to compound a21.
The reaction temperature is 0 ° C. to room temperature.
The reaction time is 0.1 to 5 hours.

Process M

Compound a24 can be obtained by reacting the solution of compound a23 with a peracid.
Examples of the solvent include dichloromethane, chloroform, ethyl acetate and the like.
Examples of the peracid include m-chloroperbenzoic acid, hydrogen peroxide solution, t-butyl hydroperoxide and the like, and 1 to 3 equivalents can be used with respect to compound a23.
The reaction temperature is −20 ° C. to 50 ° C., preferably 0 ° C. to room temperature.
The reaction time is 1 to 5 hours.

Process N

Compound a25 can be obtained by reacting a solution of compound a24 with tetrabutylammonium fluoride.
Examples of the solvent include tetrahydrofuran.
Tetrabutylammonium fluoride can be used in an amount of 1 to 5 equivalents based on compound a24.
The reaction temperature is from room temperature to 100 ° C, preferably from 50 ° C to 80 ° C.
The reaction time is 1 to 5 hours.

Process O
By reacting Compound a25 obtained in Step N with Compound a6 obtained in Step C (or Compound a8 described in Step D) according to Step D, and then deprotecting according to Step E, Inventive compounds can be obtained.
Process P

(The symbols in the formula are as defined above.)
Compound a27 can be obtained by reacting a solution of compound a26 with compound a8 (for example, compound a6 obtained in Step C) in the presence of a base.
Examples of the solvent include DMF, NMP, THF, DMA and the like.
1 to 3 equivalents of compound a8 can be used with respect to compound a26.
Examples of the base include sodium hydride and the like, and 1 to 5 equivalents can be used with respect to compound a7.
The reaction temperature is room temperature to heating under reflux, preferably 50 ° C. to 100 ° C.
The reaction time is 1 to 24 hours, preferably 3 to 12 hours.
Process Q
Using the compound a27 thus obtained, the compound of the present invention can be obtained according to Step E.

The compound of the present invention thus obtained can be purified by crystallization with various solvents. Solvents used include alcohol (methanol, ethanol, isopropyl alcohol, n-butanol, etc.), ether (diethyl ether, diisopropyl ether, etc.), acetic acid methyl ester, acetic acid ethyl ester, chloroform, methylene chloride, tetrahydrofuran, N, N— Examples include dimethylformamide, toluene, benzene, xylene, acetonitrile, hexane, dioxane, dimethoxyethane, water, or a mixed solvent thereof. After dissolving in these solvents under heating to remove impurities, the temperature may be gradually lowered and the precipitated solid or crystals may be collected by filtration.

The compounds of the present invention prevent NPY Y5 related diseases in general, such as eating disorders, obesity, anorexia nervosa, sexual disorders, reproductive disorders, depression, epileptic seizures, hypertension, cerebral hyperemia, congestive heart failure or sleep disorders And / or effective treatment. It is particularly useful for the prevention and / or treatment of obesity and weight management in obesity. It is also effective for the prevention and / or treatment of diseases in which obesity is a risk factor, such as diabetes, hypertension, dyslipidemia, arteriosclerosis, and acute coronary syndrome.
Furthermore, the compound of the present invention has not only an NPY Y5 receptor antagonistic action but also a usefulness as a medicine, and has any or all of the following excellent features.
a) The inhibitory action against CYP enzymes (for example, CYP1A2, CYP2C9, CYP3A4, etc.) is weak.
b) Good pharmacokinetics such as high bioavailability and moderate clearance.
c) Low toxicity such as anemia-inducing action.
d) High metabolic stability.
e) High water solubility.
f) High brain transferability.
g) Does not cause gastrointestinal disorders (eg, hemorrhagic enteritis, gastrointestinal ulcer, gastrointestinal bleeding, etc.).

Furthermore, it is considered that the compound of the present invention has low affinity for NPY Y1 and Y2 receptors and has high Y5 receptor selectivity. NPY induces a sustained vasoconstrictive action in the periphery, but this action is mainly mediated by the Y1 receptor. Since the Y5 receptor is not involved in such an action at all, it is unlikely to induce side effects based on peripheral vasoconstriction, and the compound of the present invention considered to have high Y5 receptor selectivity is used as an active ingredient. The pharmaceutical composition to be used can be suitably used as a safe medicine.

The pharmaceutical composition containing the compound of the present invention as an active ingredient suppresses food intake and exhibits an anti-obesity effect. Therefore, side effects such as indigestion as seen in drugs that exhibit anti-obesity effects by inhibiting digestion and absorption, and central side effects such as antidepressant effects such as serotonin transporter inhibitors that exhibit anti-obesity effects Not doing so is one of the features of the pharmaceutical composition.

When administering the pharmaceutical composition of the present invention, it can be administered either orally or parenterally. Oral administration may be prepared and administered in a commonly used dosage form such as tablets, granules, powders, capsules, pills, liquids, syrups, buccals or sublinguals according to conventional methods. For parenteral administration, any commonly used dosage forms such as injections such as intramuscular administration and intravenous administration, suppositories, percutaneous absorption agents, inhalants and the like can be suitably administered. Since the compound according to the present invention has high oral absorbability, it can be suitably used as an oral preparation.

Various pharmaceutical additives such as excipients, binders, wetting agents, disintegrants, lubricants, diluents and the like suitable for the dosage form are mixed with an effective amount of the compound of the present invention as necessary to obtain a pharmaceutical composition. can do. In the case of an injection, it may be sterilized with an appropriate carrier to form a preparation.

Excipients include lactose, sucrose, glucose, starch, calcium carbonate, crystalline cellulose and the like. Examples of the binder include methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, gelatin, and polyvinyl pyrrolidone. Examples of the disintegrant include carboxymethyl cellulose, carboxymethyl cellulose sodium, starch, sodium alginate, agar powder or sodium lauryl sulfate. Examples of the lubricant include talc, magnesium stearate, and macrogol. As a suppository base, cacao butter, macrogol, methyl cellulose or the like can be used. In addition, when preparing as liquid or emulsion or suspension injections, commonly used solubilizers, suspending agents, emulsifiers, stabilizers, preservatives, isotonic agents, etc. are added as appropriate. You may do it. In the case of oral administration, flavoring agents, fragrances and the like may be added.

The dosage of the pharmaceutical composition of the present invention is preferably set in consideration of the age, weight, type and degree of disease, route of administration, etc. of the patient. 100 mg / kg / day, preferably in the range of 0.1 to 10 mg / kg / day. In the case of parenteral administration, although it varies greatly depending on the administration route, it is usually 0.005 to 10 mg / kg / day, preferably 0.01 to 1 mg / kg / day. This may be administered once to several times a day.

The pharmaceutical composition of the present invention can also be used in combination with other anti-obesity drugs (pharmaceutical compositions containing compounds having an anti-obesity action, drugs that can be used for weight management in obesity or obesity, etc.). For example, by using a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, it can be used for prevention and / or treatment of obesity, weight management in obesity, and the like. The pharmaceutical composition containing the compound of the present invention can be used in combination with a pharmaceutical composition containing a compound having an anti-obesity action for the prevention and / or treatment of obesity or weight management in obesity. it can. Moreover, the administration therapy of the pharmaceutical composition of the present invention can be used in combination with diet therapy, drug therapy, exercise and the like.

For example, the following methods are also within the scope of the present invention.
Prevention of obesity or obesity-related diseases, comprising administering a pharmaceutical composition containing a compound having an anti-obesity action in combination with the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof. Or a method of weight management in treatment or obesity.
A pharmaceutical composition containing a compound having an anti-obesity action is administered to a patient undergoing prevention or treatment by administration of the compound of the present invention, a pharmaceutically acceptable salt thereof or a solvate thereof. A method for the prevention or treatment of obesity or obesity-related diseases or weight management in obesity.

As an aspect of this invention compound, what has the following groups in the following general formula (IV) is mentioned.

(In the above table, Et represents ethyl, i-Pr represents isopropyl, and t-Bu represents tert-butyl.)

R ^a, combination of ^{R b} and p are the following ^(R ^{a, R} b, p), compound.
(R ^a , R ^b , p) = (R ^a1 , R ^b1 , p ¹ ), (R ^a1 , R ^b1 , p ² ), (R ^a1 , R ^b2 , p ¹ ), (R ^a1 , R ^b2 , p ² ), (R ^a1 , R ^b3 , p ¹ ), (R ^a1 , R ^b3 , p ² ), (R ^a1 , R ^b4 , p ¹ ), (R ^a1 , R ^b4 , p ² ), (R ^a1 , R ^b5 , p ¹ ), (R ^a1 , R ^b5 , p ² ), (R ^a1 , R ^b6 , p ¹ ), (R ^a1 , R ^b6 , p ² ), (R ^a1 , R ^b7 , p ¹ ), (R ^a1 , R ^b7 , p ² ), (R ^a1 , R ^b8 , p ¹ ), (R ^a1 , R ^b8 , p ² ), (R ^a1 , R ^b9 , p ¹ ), (R ^a1 ^{^{^{^{, R b9, p 2),}}}} (R a1, R b10, p 1), (R a1, R b10, p 2), (R a1, R b11, p 1), (R a ^{^{^{^{, R b11, p 2),}}}} (R a1, R b12, p 1), (R a1, R b12, p 2), (R a1, R b13, p 1), (R a1, R b13, p 2 ), (R ^a1 , R ^b14 , p ¹ ), (R ^a1 , R ^b14 , p ² ), (R ^a1 , R ^b15 , p ¹ ), (R ^a1 , R ^b15 , p ² ), (R ^a1 , R ^b16 , p ¹ ), (R ^a1 , R ^b16 , p ² ), (R ^a1 , R ^b17 , p ¹ ), (R ^a1 , R ^b17 , p ² ), (R ^a1 , R ^b18 , p ¹ ) , (R ^a1 , R ^b18 , p ² ), (R ^a1 , R ^b19 , p ¹ ), (R ^a1 , R ^b19 , p ² ), (R ^a2 , R ^b1 , p ¹ ), (R ^a2 , R ^{^{^{^{b1, p 2), (R}}}} a2, R b2, p 1), (R a2, R b2, p 2), (R a2 ^{^{^{^{R b3, p 1), (}}}} R a2, R b3, p 2), (R a2, R b4, p 1), (R a2, R b4, p 2), (R a2, R b5, p 1) , (R ^a2 , R ^b5 , p ² ), (R ^a2 , R ^b6 , p ¹ ), (R ^a2 , R ^b6 , p ² ), (R ^a2 , R ^b7 , p ¹ ), (R ^a2 , R ^{^{^{^{b7, p 2), (R}}}} a2, R b8, p 1), (R a2, R b8, p 2), (R a2, R b9, p 1), (R a2, R b9, p 2), (R ^a2 , R ^b10 , p ¹ ), (R ^a2 , R ^b10 , p ² ), (R ^a2 , R ^b11 , p ¹ ), (R ^a2 , R ^b11 , p ² ), (R ^a2 , R ^b12 ^{^{^{^{, p 1), (R a2}}}} , R b12, p 2), (R a2, R b13, p 1), (R a2, R b13, p 2), ^{^{^{^{R a2, R b14, p 1}}}} ), (R a2, R b14, p 2), (R a2, R b15, p 1), (R a2, R b15, p 2), (R a2, R b16, p ¹ ), (R ^a2 , R ^b16 , p ² ), (R ^a2 , R ^b17 , p ¹ ), (R ^a2 , R ^b17 , p ² ), (R ^a2 , R ^b18 , p ¹ ), (R ^{^{^{^{a2, R b18, p 2)}}}} , (R a2, R b19, p 1), (R a2, R b19, p 2), (R a3, R b1, p 1), (R a3, R b1, p ² ), (R ^a3 , R ^b2 , p ¹ ), (R ^a3 , R ^b2 , p ² ), (R ^a3 , R ^b3 , p ¹ ), (R ^a3 , R ^b3 , p ² ), (R ^a3 , R ^b4 , p ¹ ), (R ^a3 , R ^b4 , p ² ), (R ^a3 , R ^b5 , p ¹ ), (R ^a3 , R ^{^{^{^{b5, p 2), (R}}}} a3, R b6, p 1), (R a3, R b6, p 2), (R a3, R b7, p 1), (R a3, R b7, p 2), (R ^a3 , R ^b8 , p ¹ ), (R ^a3 , R ^b8 , p ² ), (R ^a3 , R ^b9 , p ¹ ), (R ^a3 , R ^b9 , p ² ), (R ^a3 , R ^b10 , P ¹ ), (R ^a3 , R ^b10 , p ² ), (R ^a3 , R ^b11 , p ¹ ), (R ^a3 , R ^b11 , p ² ), (R ^a3 , R ^b12 , p ¹ ), ( R ^a3 , R ^b12 , p ² ), (R ^a3 , R ^b13 , p ¹ ), (R ^a3 , R ^b13 , p ² ), (R ^a3 , R ^b14 , p ¹ ), (R ^a3 , R ^b14 , ^{^{^{^{p 2), (R a3,}}}} R b15, p 1), (R a3, R b15, p 2), (R a3, R b16, p ^{^{^{^{), (R a3, R b16}}}} , p 2), (R a3, R b17, p 1), (R a3, R b17, p 2), (R a3, R b18, p 1), (R a3, ^{^{^{^{R b18, p 2), (}}}} R a3, R b19, p 1), (R a3, R b19, p 2).
EXAMPLES The present invention will be described in more detail below with reference to examples and test examples of the present invention, but the present invention is not limited thereto.

Me: methyl Et: ethyl Bu: butyl Ph: phenyl PPh ₃ and TPP: triphenylphosphine AcOEt: ethyl acetate DMA: N, N-dimethylacetamide DMF: N, N-dimethylformamide TFA: trifluoroacetic acid DMSO: dimethyl sulfoxide THF : Tetrahydrofuran DIEA, Hunig's Base: N, N-diisopropylethylamine IPA: 2-propanol TBAF: tetrabutylammonium fluoride SEM: 2- (trimethylsilyl) ethoxymethyl Pd ₂ (dba) ₃ : tris (dibenzylideneacetone) di palladium OAc: acetate groups mCPBA: metachloroperbenzoic acid MOMCl: chloromethyl methyl ether _Boc 2 O: di -tert-butyl NMP: 1-methylpyrrolidine - - On NaBO _3: Sodium perborate LAH: lithium aluminum hydride DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene DCM: methylene chloride TEA: Triethylamine

The NMR analysis obtained in each example was performed at 300 MHz and measured using d ₆ -DMSO and CDCl ₃ .
In the specification, RT represents a retention time in LC / MS: liquid chromatography / mass spectrometry.
The measurement conditions for LC / MS analysis are as follows.
Column: Shim-pack XR-ODS (2.2 μm, id 50 × 3.0 mm) (Shimadzu)
Flow rate: 1.6 mL / min UV detection wavelength: 254 nm
Mobile phase: [A] is 0.1% formic acid-containing aqueous solution, [B] is 0.1% formic acid-containing acetonitrile solution Gradient: Linear gradient of 10% -100% solvent [B] in 3 minutes, 1 minute 100% solvent [B] was maintained.

Example 1 First Step of Synthesis of Compound I-024

Compound 2 (680 mg, 3.82 mmol) was added to a suspension of compound 1 (500 mg, 3.47 mmol) in tetrahydrofuran (5 mL), and the mixture was stirred at room temperature for 3 hours. Methyl iodide (0.31 ml, 5.00 mmol) was added and stirred at room temperature for 3 hours. AcOEt (30 ml) was added and washed with 1 mol / L citric acid solution and water. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 3 (669 mg, yield 96%).

Second step

Sodium hydride (160 mg, 4.01 mmol) was added to a DMF (10 mL) solution of compound 3 (380 mg, 2.47 mmol) obtained in the first step under ice cooling, and the mixture was stirred for 5 minutes. To the reaction solution, 2- (chloromethoxy) ethyltrimethylsilane (0.652 ml, 3.67 mmol) was added dropwise and stirred for 30 minutes. AcOEt (30 ml) was added, and the mixture was washed with water and saturated brine. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by column chromatography (hexane: AcOEt = 100: 0 → 70: 30) to obtain Compound 4 (946 mg, yield 86%) as a mixture of isomers.

Third step

To a solution of compound 4 (475 mg, 1.44 mmol) obtained in the second step in methylene chloride (10 ml) was added 3-chloroperbenzoic acid (69%, 791 mg, 3.16 mmol) under ice-cooling. The mixture was stirred at room temperature for 2 hours, and stirred at 40 ° C. for 30 minutes. Chloroform was added and washed with a 2 mol / L potassium carbonate aqueous solution. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. Purification by column chromatography (hexane: AcOEt = 100: 0 → 50: 50) gave Compound 5 (586 mg, quantitative) as a mixture of isomers.

Fourth step

To a solution of compound 6 (100 mg, 0.271 mmol) in DMF (1 ml) was added sodium hydride (33 mg, 0.406 mmol), and the mixture was stirred at room temperature for 5 minutes. A DMF solution (1 ml) of compound 5 (166 mg, 0.406 mmol) obtained in the third step was added dropwise and stirred at 80 ° C. for 10 hours. AcOEt (5 ml) was added and washed with water. The organic layer was evaporated under reduced pressure and purified by column chromatography (hexane: AcOEt = 50: 50) to obtain Compound 7 (74.9 mg, yield 43%) as a mixture of isomers.

5th process

Trifluoroacetic acid (2 ml) was added to compound 7 (100 mg, 0.40 mmol) obtained in the fourth step and stirred at room temperature for 5 hours. The solvent was evaporated under reduced pressure, AcOEt (10 ml) was added, and the organic layer was washed with 2 mol / L potassium carbonate aqueous solution. The organic layer was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by LC / MS to obtain Compound I-024 (31 mg, yield 70%).

Example 2 Compound I-014 Synthesis First Step

Sodium hydride (60%, 1.08 g, 27.2 mmol) was added to a solution of compound 8 (5 g, 22.7 mmol) in DMF (50 ml), and 2- (chloromethoxy) ethyltrimethylsilane (5.63 ml, 31.31) was added. 7 mmol) was added and stirred at room temperature for 3 hours. Water was added to the reaction solution and extracted with AcOEt. The organic layer was washed with water and dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain Compound 9 (6.52 g, yield 82%).

Second step

Sodium hydride (60%, 42 mg, 1.05 mmol) was added to a DMF (5 ml) solution of compound 10 (130 mg, 0.37 mmol), and the mixture was stirred at room temperature for 10 minutes. Compound 9 (185 mg, 0.53 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours. Water was added to the reaction solution and extracted with AcOEt. The organic layer was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 50: 50) to obtain Compound 11 (113 mg, yield 46%).

Third step

Trifluoroacetic acid (1 ml) was added to a solution of compound 11 (111 mg, 0.17 mmol) obtained in the second step in methylene chloride (1 ml), and the mixture was stirred at room temperature for 5 hours. The reaction solution was added to water and neutralized with a saturated aqueous sodium hydrogen carbonate solution. Extraction was performed with chloroform, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 0: 100) to obtain Compound I-014 (56 mg, yield 81%).

Example 3 First Step of Synthesis of Compound 19

To a solution of compound 12 (20 g, 139 mmol) in ethanol (200 ml) was added sulfuric acid (8 ml), and the mixture was stirred at 85 ° C. for 10 hours. After cooling to room temperature, about half of the solvent was distilled off under reduced pressure and added dropwise to a saturated aqueous sodium bicarbonate solution. Extraction was performed with AcOEt, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over magnesium sulfate and evaporated under reduced pressure to obtain Compound 13 (25.1 g).

Second step

To a solution of compound 13 (23.9 g, 139 mmol) obtained in step 1 in DMF (80 ml), imidazole (14.2 g, 208 mmol) and tert-butyldimethylchlorosilane (23 g, 153 mmol) are added, and then at room temperature for 18 hours. Stir. Water was added to the reaction mixture, and the mixture was extracted with diethyl ether. The organic layer was washed with water, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain the desired product 14 (41.7 g).

Third step

To a solution of compound 14 (10 g, 35 mmol) obtained in step 2 in tetrahydrofuran (100 ml) was added lithium aluminum hydride (2.7 g, 70 mmol) under ice cooling, and the mixture was stirred for 1.5 hours. Water (2.5 ml), 2 mmol / L sodium hydroxide aqueous solution, and water (7.5 ml) were added, and the mixture was stirred at room temperature for 1 hour. The insoluble material was filtered through Celite, and the solvent was distilled off under reduced pressure to obtain Compound 15 (6.7 g, yield 78%).

Fourth step

To a methylene chloride solution of compound 15 (2.9 g, 11.7 mmol) obtained in step 3, Hunig base (3.1 ml, 17.5 mmol) and tosyl chloride (2.7 g, 14 mmol) were added. Under ice-cooling, 1,4-diazabicyclo [2.2.2] octane (1.3 g, 11.7 mmol) was added, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. A solution of the obtained residue (5.1 g), cesium carbonate (11.4 g, 35 mmol), and compound 16 (2 g, 14.6 mmol) in DMF (30 ml) was stirred at 80 ° C. for 4 hours. Water was added to the reaction solution and extracted with AcOEt. The organic layer is washed with water, the organic layer is dried over magnesium sulfate, the solvent is distilled off under reduced pressure, and the residue is purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 85: 15). Gave compound 17 (2.9 g, 69% yield).

5th process

Sodium hydride (0.42 g, 10.5 mmol) was added to a DMF (60 ml) solution of compound 17 (2.9 g, 8.1 mmol) obtained in step 4, and the mixture was stirred at room temperature for 5 minutes. Paramethoxybenzyl chloride (1.21 ml, 8.86 mmol) was added dropwise to the reaction solution. The mixture was stirred at room temperature for 2 hours, and water was added to the reaction solution. The produced white solid was collected by filtration to obtain Compound 18 (3.72 g, yield 95%).

6th process

Tetrahydrofuran (4 ml) and 1 mol / L tetrabutylammonium fluoride in tetrahydrofuran (11 ml, 11 mmol) were added to compound 18 (3.7 g, 7.7 mmol) obtained in step 5, and the mixture was stirred at 70 ° C. for 3 hours. . Water was added to the reaction solution, and the produced white solid was collected by filtration. The obtained white solid was washed with water, hexane-AcOEt = 5/1 to obtain Compound 19 (2.8 g, 99%).

Example 4 First Step of Synthesis of Compound 22

To a solution of compound 28 (US2004 / 204427) (6.8 g, 14.9 mmol) in methylene chloride (70 ml) was added dropwise triethylamine (4.1 ml, 29 mmol). Isopropylsulfonyl chloride (2 ml, 17.9 mmol) was added under dry ice-acetone cooling. The temperature was raised slowly over 5 hours. After confirming disappearance of the raw materials, water was added. Extraction was performed with chloroform, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 40: 60) to obtain Compound 20 (2.7 g, yield 55%).

Second step

Sodium hydride (60%, 0.41 g, 10.3 mmol) was added to a DMF (50 ml) solution of compound 21 (2.7 g, 7.95 mmol) obtained in step 1. DMF (30 ml) was added to the reaction solution, and after stirring at room temperature for 10 minutes, paramethoxybenzyl chloride (1.18 ml, 8.66 mmol) was added. After stirring overnight at room temperature, water was added. Extracted with AcOEt and the organic layer was washed with water. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 50: 50) to give compound 21 (2.8 g, yield 77%).

Third step

Tetrahydrofuran (4 ml) and 1 mol / L tetrabutylammonium fluoride in tetrahydrofuran (7 ml) were added to compound 21 (2.7 g, 6.1 mmol) obtained in step 1, and the mixture was stirred at 75 ° C. for 1 hour. After cooling to room temperature, water was added and extracted with AcOEt. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 0: 100) to obtain Compound 22 (1.79 g, yield 86%).

Example 5 First Step of Synthesis of Compound 27

Parabenzaldehyde (2.1 ml, 17.4 mmol) and acetic acid (2 ml) were added to a methylene chloride solution of compound 19 (4 g, 17.4 mmol), and the mixture was stirred at room temperature for 15 minutes. Sodium triacetoxyborohydride (5.5 g, 26.2 mmol) was added to the reaction solution, and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was distilled off under reduced pressure to obtain Compound 23 (6.7 g). To a solution of compound 23 in methylene chloride (70 ml) was added triethylamine (6.5 ml, 47 mmol). Under ice cooling, Compound 24 (3 ml, 24.2 mmol) was added dropwise and stirred for 3 hours. Compound 24 was added, and after stirring for 15 minutes, a saturated aqueous sodium hydrogen carbonate solution was added. The mixture was extracted with chloroform, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane: AcOEt = 100: 0 → 75: 25) to give compound 25 (7.0 g, yield 89%).

Second step

To a solution of compound 25 (6.9 g, 15.1 mmol) obtained in the first step in methylene chloride (70 ml) was added metachloroperbenzoic acid (4.2 g, 16.8 mmol) under ice cooling for 2 hours. Stir. Saturated aqueous sodium hydrogen carbonate solution was added, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was purified by amino column chromatography (hexane: AcOEt = 100: 0) to obtain Compound 26 (5.0 g, yield 71%).

Third step

Tetrahydrofuran (10 ml) and 1 mol / L tetrabutylammonium fluoride in tetrahydrofuran (12 ml) were added to compound 26 (5.0 g, 10.7 mmol) obtained in the second step, and the mixture was stirred at 75 ° C. for 30 minutes. Water was added to the reaction solution and extracted with AcOEt. The organic layer was dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was precipitated with a mixed solvent of chloroform and hexane and collected by filtration to obtain Compound 27 (3.5 g, yield 92%).

The following compounds were synthesized according to the above examples.

Hereinafter, biological test examples of the compound of the present invention will be described.
Test Example 1 Affinity for Mouse NPY Y5 Receptor A cDNA sequence encoding the mouse NPY Y5 receptor (see Biochim. Biophys. Acta 1328: 83-89, 1997) was expressed in the expression vector pME18S (Takebe et al. Mol. Cell. Biol., 8, 466-472). The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
Membrane preparations prepared from CHO cells expressing the mouse NPY Y5 receptor were assayed together with the compounds of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM, manufactured by GE Healthcare). The solution was incubated in a solution (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter. Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].
The compound according to the present invention inhibited the binding of peptide YY (NPY and homologous substances) to the mouse NPY Y5 receptor. That is, this compound showed affinity for the mouse NPY Y5 receptor.
The results are shown below.
Compound I-014: 0.86 nM
Compound I-020: 0.37 nM
Compound I-021: 1.46 nM
Compound I-022: 0.98 nM
Compound I-025: 3.65 nM
Compound I-029: 4.9 nM
Compound I-038: 2.2 nM

Test Example 2 Affinity for human NPY Y5 receptor A cDNA sequence encoding human NPY Y5 receptor (see WO96 / 16542) was expressed in expression vector pME18S (Takebe et al. Mol. Cell. Biol. 8, 466-472). Cloned into. The obtained expression vector was transfected into a host cell CHO using LipofectAMINE reagent (trademark, Invitrogen) according to the instruction manual, and NPY Y5 receptor stably expressing cells were obtained.
Membrane preparation prepared from CHO cells expressing human NPY Y5 receptor was assay buffer together with the compound of the present invention and 30,000 cpm [ ¹²⁵ I] peptide YY (final concentration 60 pM: manufactured by GE Healthcare). Incubation was performed in a liquid (20 mM HEPES-Hanks buffer containing 0.1% bovine serum albumin, pH 7.4) at 25 ° C. for 2 hours, and then filtered through a glass filter GF / C treated with 1% polyethyleneimine. . After washing with 50 mM Tris-HCl buffer, pH 7.4, the radioactivity on the glass filter was determined with a gamma counter. Non-specific binding was measured in the presence of 200 nM peptide YY, and the 50% inhibitory concentration (IC ₅₀ value) of the test compound for specific peptide YY binding was determined [Inui, A. et al. et al. Endocrinology 131, 2090-2096 (1992)].

Test Example 3 Rat Brain Migration Evaluation Intravenous to rats (Crl; CD (SD), ♂, 8weeks) using the cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) From the plasma and brain concentration 30 minutes after administration (0.5 mg / mL / kg), brain transferability (brain / plasma partition coefficient; Kp) was evaluated.

Test Example 4 Evaluation of transferability to mouse brain Oral administration to mice (Jcl; C57BL / 6J, ♂, 8weeks) using a cassette dosing method (Drug. Metab. Dispos. (2001); see 29, 957-966) Brain transferability (brain / plasma partition coefficient; Kp) can be evaluated from plasma and brain concentrations after 3 or 5 hours at 2 mg / 10 mL / kg).

Test Example 5 Pharmacokinetic Evaluation in Rats Using the cassette dosing method, the half-life was determined from the change in plasma concentration after intravenous administration (0.5 mg / mL / kg) in rats (Crl; CD (SD), ♂, 8 weeks). (T1 / 2) and systemic clearance (CLtot) were evaluated. As a result, the compound of the present invention showed good pharmacokinetics such as high bioavailability and appropriate clearance.

Test Example 6 Inhibition of cAMP production in CHO cells CHO cells expressing human NPY Y5 receptor were incubated at 37 ° C. for 20 minutes in the presence of 2.5 mM isobutylmethylxanthine (SIGMA), and then the compound according to the present invention Was added and incubated for 5 minutes, and then 50 nMNPY and 10 μM forskolin (Sigma) were added and incubated for 30 minutes. After stopping the reaction by adding 1N HCl, the amount of cAMP in the supernatant was measured using EIA kit (manufactured by Amersham LIFE SIENCE). The inhibitory action of NPY on cAMP production by forskolin stimulation was taken as 100%, and the 50% inhibitory concentration (IC ₅₀ value) of the compound according to the present invention for this NPY action was determined.
The results are shown below.
Compound I-021: 13 nM
Compound I-025: 93 nM
Compound I-030: 2.9 nM

Test Example 7 NPY Y5 Receptor Selectivity Similar to Test Example 2 using a Y1-expressing cell (human neuroblastoma, SK-N-MC) membrane sample and a Y2-expressing cell (human neuroblastoma, SMS-KAN) membrane sample The method is tested to determine the affinity of the compounds of the invention for the NPY Y1 and NPY Y2 receptors. As a result, it can be confirmed that the compound according to the present invention has NPY Y5 receptor selectivity.

Test Example 8 Feeding Inhibitory Action Under ether anesthesia, skin was incised along the midline from the external occipital crest to the back of the nose of male C57BL / 6J mice (12-14 weeks old, 28-35 g) to expose the upper skull . A hole having a diameter of about 1 mm was formed using an electric drill at a position about 1 mm rearward from the exposed part bregma toward lamda, about 1 mm from the midline to the left side. A 0.5% hydroxypropylmethylcellulose aqueous solution (manufactured by Shin-Etsu Chemical Co., Ltd.) or a test substance suspended in this aqueous solution is forcibly orally administered to mice after waking up from anesthesia, and received physiological saline or NPY Y5 one hour after administration. Body-specific agonist ([cPP ^1-7 , NPY ^19-23 , Ala ³¹ , Aib ³² , Gln ³⁴ ] -h Pancreatic Polypeptide: manufactured by Tocris) 0.1 nmol using a cannula from the head opening previously provided Injected. The food intake of mice was measured 2 hours and 4 hours after the injection, and the difference in food intake between the group administered with 0.5% hydroxypropylmethylcellulose solution and the group administered with the test substance was investigated.

Test Example 9 CYP Inhibition Test O-deethylation of 7-ethoxyresorufin as a typical substrate metabolic reaction of major human CYP5 molecular species (CYP1A2, 2C9, 2C19, 2D6, 3A4) using commercially available pooled human liver microsomes CYP1A2), methyl-hydroxylation of tolbutamide (CYP2C9), 4′-hydroxylation of mephenytoin (CYP2C19), O-demethylation of dextromethorphan (CYP2D6), and hydroxylation of terfenadine (CYP3A4) The degree to which the metabolite production was inhibited by the test compound was evaluated.

The reaction conditions are as follows: substrate, 0.5 μmol / L ethoxyresorufin (CYP1A2), 100 μmol / L tolbutamide (CYP2C9), 50 μmol / L S-mephenytoin (CYP2C19), 5 μmol / L dextromethorphan ( CYP2D6), 1 μmol / L terfenadine (CYP3A4); reaction time, 15 minutes; reaction temperature, 37 ° C .; enzyme, pooled human liver microsomes 0.2 mg protein / mL; test drug concentration 1, 5, 10, 20 μmol / L (4 points).

As a reaction solution in a 96-well plate, 5 kinds of each substrate, human liver microsome, and test drug are added in the above composition in 50 mM Hepes buffer solution, and NADPH as a coenzyme is added to start a metabolic reaction as an index. The mixture was reacted at 37 ° C. for 15 minutes, and then the reaction was stopped by adding a methanol / acetonitrile = 1/1 (v / v) solution. After centrifuging at 3000 rpm for 15 minutes, resorufin (CYP1A2 metabolite) in the supernatant of the centrifugation was analyzed with a fluorescent multi-label counter, tolbutamide hydroxide (CYP2C9 metabolite), mephenytoin 4 ′ hydroxide (CYP2C19 metabolite), Dextrorphan (CYP2D6 metabolite) and terfenadine alcohol (CYP3A4 metabolite) were quantified by LC / MS / MS.

The control (100%) was obtained by adding DMSO, which is a solvent in which the drug was dissolved, to the reaction system, and the residual activity (%) at each concentration with the test drug solution added was calculated. The IC ₅₀ was calculated by inverse estimation using a logistic model.

Test Example 10 Metabolic stability Metabolic stability evaluation by human liver microsomes: NADPH (final concentration 1 mM, in the case of oxidative metabolism), liver microsomes (final concentration 0.5 mg protein / in) in Tris-HCl buffer (pH 7.4) ml) and each compound (final concentration 2 μM) were added and reacted at 37 ° C. for 0 and 30 minutes. In the case of glucuronidation, UDPGA (final concentration 5 mM) was added instead of NADPH. After the reaction was stopped by adding acetonitrile / methanol = 1/1 (v / v) twice the amount of the reaction solution, the compound in the centrifugal supernatant was measured by HPLC. The amount of disappearance due to metabolic reaction was calculated from the comparison of the values of 0 minute and 30 minutes, and the metabolic stability of the compound of the present invention was confirmed.

Test Example 11 Powder Solubility Test An appropriate amount of a specimen is placed in an appropriate container, and JP-1 solution (2.0 g of sodium chloride, 7.0 mL of hydrochloric acid is added to make 1000 mL), JP-2 solution (pH 6.8 of phosphorus) 200 mL of water was added to 500 mL of an acid buffer, and 20 mmol / L TCA (sodium taurocholate) / JP-2 solution (1.08 g of TCA was added with water to make 100 mL). When dissolved after adding the test solution, a bulk powder was added as appropriate. Sealed and shaken at 37 ° C. for 1 hour. After filtration, 100 μL of methanol was added to 100 μL of each filtrate to perform 2-fold dilution. The dilution factor was changed as necessary. After confirming that there were no bubbles and precipitates, the mixture was sealed and shaken. Quantification was performed using HPLC by the absolute calibration curve method.

Formulation Examples Formulation examples shown below are merely illustrative and are not intended to limit the scope of the invention.
Formulation Example 1 Tablet 15 mg of the present compound
Starch 15mg
Lactose 15mg
Crystalline cellulose 19mg
Polyvinyl alcohol 3mg
30ml distilled water
Calcium stearate 3mg
Ingredients other than calcium stearate are uniformly mixed, crushed and granulated, and dried to obtain granules of an appropriate size. Next, calcium stearate is added and compressed to form tablets.

Formulation Example 2 Capsule Compound of the present invention 10 mg
Magnesium stearate 10mg
Lactose 80mg
Are mixed uniformly to make a powder as a fine powder or powder. It is filled into a capsule container to form a capsule.

Formulation Example 3 Granules Compound of the present invention 30 g
Lactose 265g
Magnesium stearate 5g
After mixing well, compression molding, pulverizing, sizing, and sieving to make granules of appropriate size.

Claims

Formula (I):

(Where
R 1 is substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted cycloalkenyl, or substituted amino;
p and q are each independently 0 or 1, provided that p and q are not 1 at the same time,
L is an oxygen atom or a sulfur atom,
R 2 , R 3 , R 4 and R 5 are each independently a hydrogen atom, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkyloxy, substituted or Unsubstituted alkylsulfonyl, substituted or unsubstituted amino, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, hydroxy, carboxy, halogen or cyano. Or a pharmaceutically acceptable salt thereof.
R 2, R 3, R 4 and R 5 are each independently hydrogen atoms, alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkoxy or cyano, the compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein.
The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is an oxygen atom.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein q is 0.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein p and q are 0.
The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 1 is substituted or unsubstituted alkyl.
The compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein R 3 is alkyl, alkylsulfonyl, halogen, haloalkyl, haloalkyloxy or cyano.
A pharmaceutical composition comprising the compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.
The pharmaceutical composition according to claim 8, which has an NPY Y5 receptor antagonistic action.
The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prevention of a disease involving NPY Y5 receptor.
A method for treating and / or preventing a disease involving NPY Y5 receptor, which comprises administering the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.