JP2001122865A - Benzothiazolone derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a benzothiazolone derivative useful as an active component in medicaments for the therapy and/or prophylaxis of diseases such as hyperalimentosis in which eating adjustment, neuropeptide Y or the like is concerned, hypercholesterolemia, hyperlipidemia, etc. SOLUTION: The benzothiazolone derivative is a compound represented by formula (I) [wherein R1 is a lower alkyl; R2, R3 and R4 are each H or a halogen atom; R5 is H or a lower alkyl; L is a 1-6C alkylene; and M is an alkylsulfonyl amino group having the total carbon number of 1 to 10 or an arylsulfonyl amino group having the total carbon number of 6 to 10] or its salt.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a benzothiazolone compound useful in the field of medicine and a medicine containing the compound as an active ingredient.

[0002]

2. Description of the Related Art Neuropeptide Y (hereinafter sometimes abbreviated as "NPY" in the present specification) is a peptide consisting of 36 amino acids and was first isolated from pig brain in 1982 by Tachimoto et al. Nature, 296, 659 (198
2 years)]. NPY is a pan from its amino acid primary sequence homology.
It was revealed that it belongs to the creatic polypeptide (PP) family. As a polypeptide belonging to this family, pancreatic pol produced in endocrine cells of the pancreas
ypeptide (PP) and pep produced by endocrine cells of the digestive tract
tide YY (PYY) is known. All of these PP family peptides consist of 36 amino acids, but the amino acid sequence at the carboxy terminus (C-terminus) is well conserved. It is. For these reasons, receptors for peptides of the PP family are called Y-type receptors. The Y-type receptor has also been found to be a seven-transmembrane receptor coupled to a G protein.

[0003] NPY is widely distributed in the central nervous system and the peripheral nervous system. As one of the most abundant peptides in the nervous system, NPY plays various functions in living organisms. For example, regulation of blood pressure, regulation of eating behavior, regulation of intestinal function, regulation of circadian rhythm and inhibitory regulation of insulin secretion, prolactin, luteinizing hormone,
It is involved in the suppression of secretion of hormones such as ACTH, gonadotropin releasing hormone, and vasopressin. It is known that continuous administration of NPY into the ventricle induces obesity and insulin resistance based on these effects. It is also involved in emotional control and the function of the central autonomic nervous system.

[0004] Furthermore, NPY coexists with norepinephrine at sympathetic nerve endings and is associated with the tone of the sympathetic nervous system. Peripheral administration of NPY causes vasoconstriction,
It is known to enhance the action of other vasoconstrictors, including norepinephrine [International
Journal of Obsity (International journal)
al of obesity), 19, 517 (199); Endocrinology, 133, 1753 (1993); British Journal of Pharmacology (Bri)
tish Journal of Pharmacology), 95, 419 (1988)
Year)].

[0005] The function of NPY is expressed by binding to the Y-type receptor of NPY present in the central or peripheral nervous system. NP
To date, at least six subtypes have been identified as Y receptors, and their genes have been isolated except for Y3. Y1 is the first cloned receptor [FEBS Lett., 271: 81 (1990)],
In the periphery, it is mainly distributed in blood vessels, and is involved in the contraction of blood vessels (increase in blood pressure). In the center, it is mainly distributed in the cerebral cortex, thalamus and tonsils, and it is said that anxiety in tonsils is expressed via Y1 receptors.

[0006] The Y2 receptor has been classified as a pharmacologically different receptor from the Y1 receptor, and its gene has been isolated and its existence has been clarified [Journal of
Biological Science (J. Biol. Chem.), 270
Volume, 22661 (1995)]. The expression site of this receptor is mainly in the brain, especially in the cerebral cortex, hippocampus, amygdala, etc.
On the other hand, it was not detected in the cerebellum or spinal cord. Y3 receptor
Although classified pharmacologically, no gene has yet been isolated. The Y4 receptor has been found using the human Y1 receptor cDNA as a probe and the gene has been isolated [Journal of Biological Sciences (J. Biol. Che.
m.), 270, 26762 (1995)]. The expression site is specific to the prostate, colon, pancreas, and small intestine, and has not been detected in the brain, kidney, lung, heart, spleen, and the like.

Previously, it has been suggested that another NPY receptor subtype that has a ligand affinity close to that of the Y1 receptor and controls feeding behavior exists in the hypothalamus.
Have successfully cloned a Y5 receptor that regulates feeding from a rat hypothalamus cDNA library [Nature (Na
ture), 382, 168 (1996)]. Y5 receptor is other NP
The homology with the Y receptor is low at 35% or less, and the expression site is restricted to the hypothalamus of the brain, and is most involved in the control of eating. The Y6 receptor is found only in mice and does not function as a pseudogene in humans.

[0008] Substances which have an affinity for these Y-type receptors and act as agonists or antagonists for these receptors can regulate the expression of NPY. Substances having such properties include various diseases involving NPY, for example, cardiovascular diseases such as hypertension, kidney disease, heart disease, and vasospasm, for example, central diseases such as binge eating, depression, epilepsy, and dementia. For example, obesity, diabetes,
Hyperlipidemia, useful in the prevention or treatment of anorexia and glaucoma such as metabolic diseases such as hormonal abnormalities or cancer patients can be expected [Trends in Pharmacological Sciences (Trendsin Pharmacological Sciences), 1
5, 153 (1994)].

[0009] In particular, a substance having a selective affinity for the Y5 receptor (hereinafter, sometimes referred to as "NPY / Y5 receptor") among NPY receptors involves the NPY / Y5 receptor. It is expected to be useful for the prevention and / or treatment of diseases that occur, and that it can be used without side effects such as enhancing or antagonizing the function of other Y-type receptors. Since Y5 receptor is most involved in the control of eating, it can be used as a food intake regulator such as anorexia in bulimia and cancer patients, as well as central diseases such as depression, epilepsy, and dementia. Can be used for the prevention or treatment of metabolic diseases such as obesity, diabetes, hyperlipidemia, and hormonal abnormalities.

Regarding the gene encoding the NPY / Y5 receptor and its use, see US Pat. No. 5,602,024, WO 96/16
No. 542 and International Publication WO96 / 46250. However, these publications do not specifically disclose or suggest the compounds of the present invention.

As antagonists for the NPY / Y5 receptor, WO97 / 19682 discloses arylsulfonamide and sulfamide derivatives, WO97 / 20820, and WO
WO 97/20821, WO 97/20822, and WO 97
/ 20823, quinazoline derivatives, WO98 / 35944 and WO98 / 35957, amide derivatives, WO
WO98 / 40356 discloses aminopyridine derivatives,
/ 24768, International Publication WO98 / 25907, International Publication WO98 / 25908
No., and WO98 / 27063, pyrazole derivatives,
International Publication WO98 / 47505 and the like disclose xanthene derivatives. However, these publications do not specifically disclose or suggest the compounds of the present invention. In addition, International Publication WO99 / 27965 describes that an NPY / Y5 receptor antagonist is useful for prevention and treatment of hypercholesterolemia, hyperlipidemia, or arteriosclerosis.

The compounds structurally related to the compound of the present invention include JP-A-04-198174, JP-A-01-129046, JP-A-61-140576, and JP-A-60-126275. International Publication WO97 / 10825, International Publication WO95 / 02166, European Patent 789025, European Patent 737826, European Patent 785201
No., European Patent 202906, European Patent 321368, European Patent 51
No. 4133, German Patent No. 3809842 and the like. However, these publications do not specifically disclose or suggest the compound of the present invention and its NPY antagonistic activity.

[0013]

The problem to be solved by the present invention is that NPY
It is an object of the present invention to provide a substance having an affinity for a receptor, particularly a substance having a selective affinity for an NPY / Y5 receptor. Another object of the present invention is to provide a medicament which has an action of controlling eating and is useful as an eating control agent for, for example, anorexia in bulimia and cancer patients. Also,
Still another object of the present invention is to provide a medicament useful for preventing or treating central diseases such as depression, epilepsy and dementia, obesity, diabetes, hyperlipidemia, and metabolic diseases such as hormonal abnormalities. It is in.

The present inventors have conducted intensive studies to solve the above-mentioned problems, and as a result, a novel compound represented by the following formula (I) has an affinity for the NPY receptor. Have been found to have an action of regulating the expression of the action of these, and that these substances are useful as a medicament for controlling feeding or preventing or treating the above-mentioned diseases, and completed the present invention. .

That is, the present invention provides the following general formula (I):

Embedded image [In the formula, R ¹ represents a lower alkyl group (the lower alkyl group may have a ring structure and may have one or more substituents); R ² , R ³ , And R ⁴ each independently represent a hydrogen atom or a halogen atom; R ⁵ represents a hydrogen atom or a lower alkyl group (the alkyl group may have a ring structure and has one or more substituents. L may be an alkylene group having 1 to 6 carbon atoms (the alkylene group may have one or two hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in its main chain; 1
Alternatively, it may contain two or more unsaturated bonds. The alkylene group may have a ring structure and may have one or more substituents); M is an alkylsulfonylamino group having 1 to 10 carbon atoms, A arylsulfonylamino group having 6 to 10 carbon atoms, a heteroarylsulfonylamino group having 1 to 10 total carbon atoms, or a heterocyclic group containing one or more nitrogen atoms] or a salt thereof. Is provided.

According to a preferred embodiment of the present invention, the following general formula (II):

Embedded image (Wherein, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and M are as defined above) or a salt thereof. According to a further preferred embodiment, the above formula (I) or (I
There is provided a compound or a salt thereof, wherein M in I) is a tetrazolyl group, triazolyl group, imidazolyl group, pyridyl group, pyrazinyl group, pyrimidinyl group, or pyridazinyl group.

In another aspect, the present invention provides a compound of the formula
There is provided a medicament comprising as an active ingredient a substance selected from the group consisting of the compound represented by (I), a physiologically acceptable salt thereof, a hydrate thereof, and a solvate thereof. Preferably, there is provided a medicament comprising, as an active ingredient, a compound represented by the formula (II) and a physiologically acceptable salt thereof, and a substance selected from the group consisting of hydrates and solvates thereof. . The medicament is useful for the prevention and / or treatment of NPY-related diseases, particularly NPY / Y5 receptor-related diseases, for example, a dietary control drug or a medicament for prevention and / or treatment of diabetes, Alternatively, it is useful as a medicament for preventing and / or treating hypercholesterolemia, hyperlipidemia, or arteriosclerosis.

From still another viewpoint, the compounds represented by the above formula (I) and the physiologically acceptable salts thereof, and the hydrates and solvates thereof for the production of the above-mentioned medicament are considered. Use of a substance selected from the group consisting of: a method of regulating food intake, wherein the compound represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof are used. Administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of:
A method for treating and / or preventing a disease associated with, comprising a compound represented by the above formula (I) and a physiologically acceptable salt thereof, and a hydrate and a solvate thereof. And administering to a mammal, including a human, an effective amount of a substance selected from the group consisting of:

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION The meanings of the terms used in the present specification are as follows. An alkyl moiety in an “alkyl group” or a substituent containing an alkyl moiety (eg, an alkylsulfonylamino group) may be linear, branched, cyclic, or a combination thereof unless otherwise specified. . The cyclic alkyl group may be a polycyclic alkyl group. Unless otherwise specified, the alkyl group has 1 to 10 carbon atoms, preferably has 1 to 8 carbon atoms, and particularly preferably has 1 carbon atom.
~ 6 alkyl groups can be used.

When a substituent is referred to as "lower", the substituent has 1 carbon atom unless otherwise specified.
66, preferably 1-5, particularly preferably 1-4. For example, as a lower alkyl group,
Methyl group, ethyl group, n-propyl group, isopropyl group,
Cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropylmethyl group, n-pentyl group, neopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group And the like, but are not limited thereto. When referring to a "halogen atom", any of a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom may be used.

In the present specification, when a functional group is referred to as "may have a substituent", the functional group may have one or more optional substituents unless otherwise specified. It means that you may have it. When it has two or more substituents, they may be the same or different. The position of the substituent is not limited, and the substituent can be located at any substitutable site. Although the type of the substituent is not particularly limited, for example, a hydroxyl group, an amino group, a mercapto group, a cyano group, a carbamoyl group, a sulfamoyl group, a monoalkylamino group, a dialkylamino group, an ammonium group, an imino group, a cyano group, a nitro group, Carboxyl group, sulfo group, hydrazino group, ureido group, halogen atom, lower alkyl group, lower alkenyl group, lower alkynyl group, aryl group having 6 to 10 carbon atoms, lower alkoxy group, lower alkylthio group, lower alkylsulfonylamino group, Or a lower alkylcarbonylamino group. Further, the substituents exemplified above may be further substituted with one or more other substituents. As such an example, for example, carbon number 1-6
And an alkoxyalkyloxy group having 1 to 6 carbon atoms. However, the substituents described above are for the purpose of illustration, and the present invention is not limited to these.

In the general formula (I), R ¹ represents a lower alkyl group, and the lower alkyl group may have a ring structure.
Alternatively, it may have two or more substituents. Preferred examples of the lower alkyl group represented by R ¹ include ethyl group, n-propyl group, isopropyl group, cyclopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, cyclobutyl group, cyclopropyl Methyl group, methoxymethyl group, methoxyethyl group, methylthiomethyl group, methylthioethyl group, cyanomethyl group, cyanoethyl group, propargylmethyl group, hydroxymethyl group, hydroxyethyl group and the like, more preferably, ethyl group, Examples thereof include an n-propyl group, an n-butyl group, an isopropyl group, an isobutyl group, a cyclopropyl group, and a cyclopropylmethyl group. R ² , R ³ , and R ⁴ each independently represent a hydrogen atom or a halogen atom, and are preferably a hydrogen atom, a fluorine atom, or a chlorine atom.

A group represented by -NH-CO-N (R ⁵ ) -LM, R ² , R ³ ,
And the substitution position of R ⁴ is not particularly limited, but is -NH-CO-N (R ⁵ )
Preferably, the group represented by -LM is substituted at the 5- or 6-position of the benzothiazolone ring, and the group represented by -NH-CO-N (R ⁵ ) -LM is substituted at the 6-position of the benzothiazolone ring. Is particularly preferred. R ⁵ represents a hydrogen atom or a lower alkyl group, preferably a lower alkyl group. Further, the lower alkyl group may have a ring structure, and may have one or more substituents. When the lower alkyl group represented by R ⁵ has a substituent, preferred substituents include a lower alkoxy group.

L represents an alkylene group having 1 to 6 carbon atoms, preferably an alkylene group having 2 to 4 carbon atoms.
The alkylene group may contain one or two hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in its main chain, and may contain one or more unsaturated bonds.
The alkylene group may have a ring structure.
Alternatively, it may have two or more substituents. Examples of preferred alkylene groups include ethylene, propylene, and butylene groups.

M is an alkylsulfonylamino group having a total of 1 to 10 carbon atoms (including the carbon number of the substituent; the same applies hereinafter), an arylsulfonylamino group having a total of 6 to 10 carbon atoms, 1 to 10 heteroarylsulfonylamino groups or a heterocyclic group containing one or more nitrogen atoms. These groups may have one or more substituents. The alkylsulfonylamino group represented by M preferably has a total of 1 to 6 carbon atoms, and particularly preferred examples include a methanesulfonylamino group and an isopropylsulfonylamino group. Preferred examples of the arylsulfonylamino group represented by M include, for example, a benzenesulfonylamino group, a naphthalenesulfonylamino group and the like.When a substituent is present on the ring of these groups, the substituent is an amino group Alternatively, it is preferably a hydroxyl group or the like.

Preferred examples of the heteroarylsulfonylamino group represented by M include a pyridinesulfonylamino group, a quinolinesulfonylamino group and the like. Examples of heterocyclic groups containing one or more nitrogen atoms include:
Examples thereof include a tetrazolyl group, a triazolyl group, an imidazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, and a pyridazinyl group, and a pyridyl group is particularly preferable. The bonding position of the heterocyclic group represented by M is not particularly limited, and the heterocyclic group may be bonded at any position on the ring. For example, 3-pyridyl group, 3-isomer of pyridyl group,
Both a pyridyl group and a 4-pyridyl group are similarly preferred.

The compound represented by the formula (I) may have one or more asymmetric carbons depending on the type of the substituent, and the compound based on one or more asymmetric carbons Active form,
Stereoisomers, such as diastereoisomers based on two or more asymmetric carbons, may exist. Further, when the compound represented by the formula (I) has a functional group containing a double bond,
The arrangement may be either Z or E.

The compound represented by the formula (I) may exist as a salt. As salts, acid addition salts such as inorganic acid salts and organic acid salts; base addition salts such as metal salts, ammonium salts and organic ammonium salts; and amino acid addition salts can be used. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, nitrate, hydrobromide, sulfate, hydrogen sulfate, monohydrogen phosphate and dihydrogen phosphate, as well as aliphatic monocarboxylic acids, Organic acids such as dicarboxylic acids, hydroxyalkanoic acids, hydroxyalkane diacids, amino acids, aromatic carboxylic acids, or aliphatic or aromatic sulfonic acids can be used.

The organic acids include formate, acetate, propionate, benzoate, maleate, malonate, fumarate, phthalate, succinate, tartrate, citrate and mandel. Acid salt, oxalate, methanesulfonate, p-toluenesulfonate, benzenesulfonate,
Mention may be made of organic acid salts such as lactate, malate, glycolate, aspartate or glutamate. Examples of the metal salt include alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as magnesium salt and calcium salt, aluminum salt, zinc salt and the like. Ammonium salts include ammonium and tetramethylammonium salts, and organic ammonium salts include addition salts such as morpholine and piperidine. Further, as the amino acid addition salt, for example,
Addition salts such as glycine, phenylalanine, glutamic acid and lysine can be mentioned. Further, the compound represented by the formula (I) or a salt thereof may exist as a hydrate or a solvate. The type of the solvent that forms the solvate is not particularly limited, and examples thereof include alcohols such as methanol, ethanol, and isopropanol, and ethers such as tetrahydrafuran.

The compounds of the formula (I) in free form or any salts thereof, or hydrates or solvates thereof, are all included in the scope of the present invention. Also,
The above-mentioned isomers in pure form represented by the formula (I), arbitrary mixtures of the above-mentioned isomers, racemates and the like are all included in the scope of the present invention. The active ingredient of the medicament of the present invention is represented by the formula
The free form compound represented by (I) or a physiologically acceptable salt thereof, or a hydrate or solvate thereof can be used. Preferably, formula (II)
Or a physiologically acceptable salt thereof, or a hydrate or solvate thereof. As the active ingredient of the medicament of the present invention, the above-mentioned isomer in a pure form, an arbitrary mixture of the above-mentioned isomers, a racemate, and the like may be used. Further, the formula (I)
May be used as the active ingredient of the medicament of the present invention. For example,
Dimers or prodrugs of these compounds may be used as the active ingredient of the medicament of the present invention.

Specific examples of the compound represented by the formula (I) are shown below, but the compound of the present invention is not limited to these.

[0032]

Embedded image

Hereinafter, a preferred embodiment of the present invention is represented by formula (II)
The production method of the compound of formula (II) will be described, but the scope of the present invention is not limited to the compound of formula (II). The following equation (I
II):

Embedded image 6-nitro-2-benzothiazolone represented by the general formula: R ¹ X
¹ (wherein, R ¹ has the same meaning as described above, and X ¹ represents a leaving group)
Is reacted in an organic solvent in the presence of a base to obtain a compound represented by the general formula (IV):

Embedded image (Wherein, R ¹ has the same meaning as described above).

Examples of the leaving group X ^1, for example, a halogen atom,
A tosyl group or a mesyl group is preferred. The type of the organic solvent used in the reaction is not particularly limited as long as it is inert in the reaction, for example, acetonitrile, tetrahydrofuran, dimethylformamide, dimethylacetamide,
Common organic solvents such as dimethyl sulfoxide and acetone can be used. As the base, for example, a common base such as sodium hydride, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, triethylamine and the like can be used. The reaction temperature is
Usually, it is -20 ° C to 100 ° C, preferably 0 ° C to room temperature. The reaction time is usually 1 minute to 3 days, preferably 1 minute.
From time to one day.

Next, the nitro group of the compound represented by the general formula (IV) is reduced to obtain a compound represented by the general formula (V):

Embedded image (Wherein R ¹ has the same meaning as described above). Various general methods can be used as the reduction method, and a typical method includes reduction using iron. Preferred reaction solvents include:
Acetic acid and isopropyl alcohol can be used, and when isopropyl alcohol is used, the reaction can be performed in the presence of ammonium chloride. The reaction temperature is usually from 0 ° C to 100 ° C, preferably from room temperature to 100 ° C.
The reaction time is generally 1 minute to 3 days, preferably 1 hour to 1 day.

Next, the compound represented by the general formula (V) is reacted with phenyl chloroformate in an organic solvent in the presence of a base to obtain a compound represented by the general formula (VI):

Embedded image (Wherein, R ¹ has the same meaning as described above). For example, the condensation can be carried out in a common organic solvent such as tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, acetonitrile and the like in the presence of a common base such as potassium carbonate and triethylamine. The reaction temperature of the condensation reaction is usually from -20 ° C to 100 ° C, preferably from -20 ° C to room temperature. The reaction time is usually 10 minutes to 3 days, preferably 1 minute.
From time to one day.

The compound represented by the general formula (VI) obtained above is represented by the general formula: HN (R ⁵ ) -LM (wherein R ⁵ , L and M are as defined above). By reacting the compound with or without an organic solvent in the presence or absence of a base, the compound of the present invention represented by the general formula (II) can be obtained. When the reaction is carried out in an organic solvent, a common organic solvent such as tetrahydrofuran, dimethylformamide, dimethylacetamide, dichloromethane, acetonitrile, or a mixed solvent thereof can be used as the organic solvent. General bases such as potassium and triethylamine can be used. The reaction temperature of the condensation reaction is usually from 0 ° C to 200 ° C, preferably from room temperature to 120 ° C. Reaction time is usually 10 minutes to 3
Days, preferably 1 hour to 1 day. Further, a compound represented by the general formula (V) obtained by the above production method and a general formula: MLN (R ⁵ ) -CO-X ¹ (wherein, R ⁵ , L,
M and X ¹ have the same meanings as described above), and the compound of the general formula (II) can also be obtained.

The preparation of representative compounds of the present invention is described in detail in the Examples of the present specification. Therefore, based on the description of the general production method and the examples described above, by appropriately selecting the starting material compounds, the reaction reagents, the reaction conditions, and the like, and as necessary, the methods disclosed in the examples may be appropriately modified. By making modifications or alterations, those skilled in the art can produce any of the compounds included in the above general formula (I). For example, when R ² , R ³ , or R ⁴ is a halogen atom or when the substitution position of the group represented by -NH-CO-N (R ⁵ ) -LM is different from the above, an appropriate nitro form Can be synthesized in the same manner as described above. In performing the above reaction, the reaction yield may be increased in some cases by appropriately protecting the reactive functional group. The protecting group can be appropriately selected according to the type of the reactive functional group. For example, Protective Groups in Organic S
ynthesis, TWGreene, John Wiley & Sons, Inc., 198
The selection becomes easier by referring to 1 or the like.

The compound of the present invention has an affinity for the Y-type receptor of NPY, and is particularly characterized in that it has a selective affinity for the Y5 receptor. Therefore, the compound of the present invention has an effect of regulating the expression of the action of NPY, various diseases involving NPY, such as hypertension, kidney disease, heart disease,
Cardiovascular diseases such as vasospasm, such as bulimia, depression,
It is useful for preventing or treating central diseases such as epilepsy and dementia, for example, metabolic diseases such as obesity, diabetes, hyperlipidemia, and hormonal abnormalities, and anorexia and glaucoma in cancer patients. In particular, since the Y5 receptor is most involved in the control of eating, the above-mentioned compounds have, for example, an eating control effect such as anorexia such as bulimia and cancer patients, as well as depression, epilepsy, and dementia. It is useful for prevention and / or treatment of metabolic diseases such as central diseases, obesity, diabetes, hypercholesterolemia, hyperlipidemia, arteriosclerosis, and hormonal abnormalities.

The medicament provided by the present invention is a substance selected from the group consisting of a compound represented by the formula (I) and a physiologically acceptable salt thereof, and a hydrate or solvate thereof. As an active ingredient. As the compound represented by the formula (I), preferably a compound represented by the formula
The compound represented by (II) can be used. The medicament of the present invention can be administered orally or parenterally. Parenteral administration can include administration routes such as intra-airway, rectal, subcutaneous, intramuscular, and intravenous. As the medicament of the present invention, the above-mentioned substance which is an active ingredient may be administered as it is, but generally, a pharmaceutical composition is prepared and administered using one or more pharmaceutical additives. Is desirable. Examples of formulations suitable for oral administration include, for example,
Tablets, granules, fine granules, powders, syrups, solutions, capsules, chewables, or suspensions, and the like, examples of formulations suitable for parenteral administration include, for example, injections, Examples include drops, inhalants, sprays, suppositories, transdermal absorbers, transmucosal absorbers, eye drops, ear drops, nasal drops, patches, and the like. Liquid preparations such as injections and drops are provided as a powdered pharmaceutical composition, for example, in lyophilized form, which can be dissolved or dissolved in water or other suitable medium (eg, saline, dextrose infusion, buffer, etc.) before use. It may be used by suspending.

The additives for pharmaceutical preparations can be appropriately selected according to the form of the pharmaceutical composition, and the type thereof is not particularly limited.
For example, stabilizers, surfactants, plasticizers, lubricants, solubilizers, buffers, sweeteners, bases, adsorbents, corrigents, binders, suspending agents, brighteners, coating agents , Flavoring agents, fragrances, wetting agents, wetting regulators, fillers, defoamers, chewing agents, fresheners, coloring agents, sugar coatings, tonicity agents, pH regulators, softeners, emulsifiers, adhesives , Tackifiers, thickeners, thickeners,
Foaming agents, excipients, dispersants, propellants, disintegrants, disintegration aids, fragrances, moisturizers, preservatives, preservatives, soothing agents, solvents, solubilizers, dissolution aids, fluidizers, etc. And two or more of these may be used in combination. Specific examples of these pharmaceutical additives are described, for example, in the Pharmaceutical Excipients Dictionary (edited by the Japan Pharmaceutical Excipients Association, published by Yakuji Nippo). Pharmaceutical compositions in a desired form can be produced by selecting pharmaceutical additives and according to a method commonly used in the art. Generally, the above-mentioned pharmaceutical composition contains 1.0 to 100% (W / W), preferably 1.0 to 60% (W / W) of the above-mentioned substance as an active ingredient.
W) can be prepared.

More specifically, gelatin, lactose, sucrose,
Titanium oxide, starch, crystalline cellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, corn starch, microcrystal wax, white petrolatum, magnesium metasilicate aluminate, anhydrous calcium phosphate, citric acid, trisodium citrate, hydroxypropylcellulose, sorbitol, sorbitan fatty acid Ester, polyisobate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil,
Polyvinylpyrrolidone, magnesium stearate, light silicic anhydride, talc, vegetable oil, benzyl alcohol,
Pharmaceutical additives such as gum arabic, propylene glycol, polyalkylene glycol, cyclodextrin or hydroxypropylcyclodextrin can be used, but are not limited thereto.

The dose and the number of times of administration of the medicament of the present invention are not particularly limited, but may be appropriately determined according to various conditions such as the purpose of treatment or prevention, the type of disease, the age, weight, and symptoms of the patient. The number of doses can be determined. In the case of oral administration, the amount of active ingredient per adult per day is 0.1 to 1
It can be administered once or several times a day so as to be 00 mg / kg, and in the case of parenteral administration, 0.001 to 10 mg / kg
Is preferably administered once or divided into several times a day.

[0044]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to the following Examples. The compound numbers in the examples correspond to the compound numbers of the compounds specifically shown above.

Example 1 Synthesis of Compound 1 2 mL was added to 0.16 g of sodium hydride (60%) under a nitrogen stream.
Of dimethylacetamide, and 0.50 g of 6-
Nitro-2-benzothiazolone was added and stirred. next,
0.34 mL of ethyl iodide was added, and the mixture was stirred at room temperature for 1 hour.
Water was added, and the obtained crystals were washed with a mixed solution of hexane and ethyl acetate to obtain 0.18 g of 6-nitro-3-ethyl-2-benzothiazolone. Ammonium chloride (0.05 g) was dissolved in 1 mL of water, 4 mL of isopropyl alcohol and 0.3 g of iron powder were added, and the mixture was refluxed for 15 minutes with stirring. Subsequently, the 6-nitro-3-ethyl-2-benzothiazolone obtained above (0.18
g) was added and stirred for 1 hour. After allowing the reaction solution to cool to room temperature, insolubles were removed by filtration, and the filtrate was concentrated to give 6-amino acid.
3-Ethyl-2-benzothiazolone was obtained quantitatively.

Next, 6-amino-3-ethyl-2-benzothiazolone (2.1 g) synthesized as described above was dissolved in 40 ml of dichloromethane, and 1.7 g of phenyl chloroformate was added.
1.8 mL of triethylamine was added dropwise. After stirring at room temperature for 1 hour, water was added, and the mixture was extracted with ethyl acetate. Organic layer
10% citric acid aqueous solution, saturated sodium hydrogen carbonate aqueous solution,
Next, the extract was washed with saturated saline, dried over sodium sulfate, and concentrated under reduced pressure. The residue was recrystallized from acetonitrile, and 1.25 g of 6-phenoxycarbonylamino-3-ethyl-
2-benzothiazolone was obtained.

6-phenoxycarbonylamino-3 obtained
-Ethyl-2-benzothiazolone (0.16g), Journal
Of Pharmaceutical Science (J. Phar
m. Sci.), Vol. 66, p. 1089, 1977, isopropylsulfonylaminobutylamine was dissolved in 2 mL of acetonitrile and stirred under reflux for 10 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with a 10% aqueous citric acid solution, a saturated aqueous sodium hydrogen carbonate solution, and then with a saturated saline solution, dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (eluent, ethyl acetate) to give 0.15 g of compound 1. ¹ H NMR (300MHz, CDCl ₃ ) δ 1.10-1.03 (m, 9H), 1.45
(br, 2H), 2.50 (br, 2H), 3.00 (br, 2H), 3.08 (se
p., 1H), 3.92 (q, 2H), 6.15 (t, 1H), 6.98 (t, 1H),
8.42 (m, 2H), 7.75 (br, 1H), 8.47 (br, 1H) FAB-MS (m / e) (M + 1) ⁺

Example: Synthesis of Compound 2 Except that in Example 1 6-nitro-2-benzothiazolone was changed to 5-nitro-2-benzothiazolone which can be obtained by the method described in US Pat. No. 2,108,712. Compound 2 was synthesized in the same manner as in Example 1. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.29 (t, 3H), 1.34 (d, 6
H), 1.61 (br, 4H), 1.92 (br, 2H), 3.14 (br, 2H),
3.19 (sep., 1H), 3.27 (br, 2H), 3.96 (q, 2H), 5.08
(t, 1H), 5.50 (br, 1H), 6.84 (d, 1H), 7.22 (d, 1
H), 7.65 (br, 1H), 7.66 (d, 1H) FAB-MS (m / e) 415 (M + 1) ⁺

Example 3 Synthesis of Compound 3 Compound 3 was synthesized in the same manner as in Example 1 except that isopropylsulfonylaminobutylamine was changed to N-methyl-N- (4-pyridino) ethylamine. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.21 (t, 3H), 2.83 (t, 2
H), 2.90 (s, 3H), 3.56 (t, 2H), 3.86 (q, 2H), 6.53
(s, 1H), 6.85 (d, 1H), 7.06-7.12 (m, 3H), 7.48 (d,
2H), 8.42 (d, 2H) FAB-MS (m / e) 356 M ⁺

Example 4 Synthesis of Compound 4 The procedure of Example 1 was repeated except that ethyl iodide was changed to propyl iodide and isopropylsulfonylaminobutylamine was changed to N-methyl-N- (4-pyridino) ethylamine. Compound 4 was synthesized in the same manner as in 1. ¹ H NMR (300MHz, CDCl ₃ ) δ 0.98 (t, 3H), 1.60-1.90
(m, 2H), 2.92 (t, 2H), 2.98 (s, 3H), 3.65 (t, 2H),
3.85 (t, 2H), 6.15 (s, 1H), 6.94 (d, 1H), 7.17 (d
d, 1H), 7.18 (d, 2H), 7.56 (d, 1H), 8.54 (d, 2H) FAB-MS (m / e) 370 M ⁺

Example 5: Synthesis of Compound 5 In Example 1, ethyl iodide was changed to butyl iodide, and isopropylsulfonylaminobutylamine was changed to N-methyl-N- (4-pyridino) ethylamine. Synthesized in the same manner as in Example 1. ¹ H NMR (300MHz, CDCl ₃ ) δ 0.98 (t, 3H), 1.30-1.50
(m, 2H), 1.60-1.90 (m, 2H), 2.92 (t, 2H), 2.98 (s,
3H), 3.65 (t, 2H), 3.91 (t, 2H), 6.26 (s, 1H), 6.9
3 (d, 1H), 7.12 (dd, 1H), 7.18 (d, 2H), 7.56 (d, 1
H), 8.54 (d, 2H) FAB-MS (m / e) 385 M ⁺

Example 6: Synthesis of compound 6 In Example 1, ethyl iodide was changed to isobutyl iodide and isopropylsulfonylaminobutylamine was used.
Compound 6 was synthesized in the same manner as in Example 1 except that N-methyl-N- (4-pyridino) ethylamine was used. ¹ H NMR (300 MHz, CDCl ₃ ) δ 0.92 (t, 3H), 0.97 (d, 6
H), 2.18 (sep.1H), 2.92 (t, 2H), 2.98 (s, 3H), 3.
65 (t, 2H), 3.72 (d 2H), 6.22 (s, 1H), 6.93 (d, 1
H), 7.10 (dd, 1H), 7.19 (d, 2H), 7.56 (d, 1H), 8.5
4 (d, 2H) FAB-MS (m / e) 385 M ⁺

Example 7: Synthesis of Compound 7 In Example 1, 6-nitro-2-benzothiazolone was replaced with 6-nitro-2-benzothiazolone.
Changed to nitro-5-chloro-2-benzothiazolone, changed ethyl iodide to isobutyl iodide, and changed isopropylsulfonylaminobutylamine to N-methyl-N- (4-pyridino)
Compound 7 was synthesized in the same manner as in Example 1 except that ethylamine was used. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.01 (d, 6H), 2.21 (m, 1
H), 2.96 (t, 2H), 3.04 (s, 3H), 3.67 (t, 2H), 3.71 (d, 4
H), 6.83 (s, 1H), 7.02 (s, 1H), 7.23 (d, 2H), 8.35
(s, 1H), 8.57 (br, 2H) FAB-MS (m / e) 419 (M + 1) ⁺

Example 8: Synthesis of compound 8 Compound 8 was synthesized in the same manner as in Example 1 except that isopropylsulfonylaminobutylamine was changed to N-methyl-N- (3-pyridino) ethylamine. . ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.32 (t, 3H), 2.93 (t, 2
H), 2.98 (s, 3H), 3.63 (t, 2H), 3.97 (q, 2H), 6.24
(brs, 1H), 6.94 (d, 1H), 7.16 (dd, 1H), 7.25 (d, 1
H), 7.56 (d, 1H), 7.58 (d, 1H), 8.50 (brd, 2H) FAB-MS (m / e) 357 (M + 1) ⁺

Example 9: Synthesis of compound 9 A compound was synthesized in the same manner as in Example 1 except that isopropylsulfonylaminobutylamine was changed to N-methyl-N- (2-pyridino) ethylamine. ¹ H NMR (300 MHz, CDCl ₃ ) δ 1.33 (t, 3H), 2.99 (s, 3
H), 3.19 (t, 2H), 3.88 (t, 2H), 3.97 (q, 2H), 6.95
(d, 1H), 7.20-7.30 (m, 2H), 7.31 (dd, 1H), 7.67 (d,
1H), 7.65-7.70 (m, 1H), 8.65 (ddd, 1H), 8.82 (br,
1H) FAB-MS (m / e) 357 (M + 1) ⁺

Example 10 Preparation of Hydrochloride of Compounds 3 to 9 Compounds 3 to 9 obtained in Examples 3 to 9 were dissolved in ethyl acetate, and a 4N dioxane hydrochloride solution was added dropwise. The resulting precipitate was washed with ether, and each compound 3
-The hydrochloride of compound 9 was obtained.

Test Example 1: Y5 receptor binding inhibition test The human Y5 receptor gene was isolated by PCR based on its cDNA sequence [Nature, 382, 168 (1996)]. This was performed by amplifying the fragment and incorporating it into the expression vector pcDNA3. ABI PRISM Dye Terminatior Kit
(PERKIN ELMER) was used to analyze the sequence of the obtained human Y5 gene, and it was confirmed that the sequence was correct. Expression of the human Y5 receptor was performed using a baculovirus expression system. Baculovirus expression system kit (Life Te
Using Chnokogies, a recombinant virus containing the human Y5 gene was prepared and infected into High Five insect cells to express the human Y5 receptor in large amounts.

A membrane preparation prepared from insect cells expressing the human Y5 receptor was tested with a test compound (10 μM) and ³ H-NPY (amers
assay buffer (1 mM magnesium chloride, 2 mM calcium chloride, 0.25
The cells were incubated at 4 ° C. for 2 hours in 50 mM HEPES buffer (pH 7.4) containing mg / mL bacitracin, 10 μg / mL leupeptin, 1 μg / mL ebelactone B, and 1% bovine serum albumin.
The radioactivity bound to the membrane was recovered by a filtration method using a 96-well unifilter. Specific binding to the human Y5 receptor is
The binding was determined to be antagonized when cold NPY was excessively added. Table 1 shows the results. In the table, the inhibition rate is the inhibition rate of the test compound with respect to the Y5 specific binding amount of the solvent group of the test compound (%)
Indicated by

[0059]

[Table 1]

Test Example 2: Animal test for eating behavior induced by fasting and NPY Male SD rats (6-7 weeks old, 150-250 g) under pentobarbital anesthesia (single administration intraperitoneally at 50 mg / kg) ) Chronic guide cannula for stereotaxic fixation in left ventricle (outer diameter 0.5m)
m, inner diameter 0.4 mm, length 4 mm) and fixed with a dental resin. The tip of the guide cannula is 0.8 mm behind the bregma, 1.5 mm to the left of the midline, and 3.2 mm deep from the brain surface.When the inner needle is inserted, about 0.5 mm of the tip comes out from the tip of the guide cannula. To reach the lateral ventricle. After a recovery period of about one week, rat neuropeptide Y (rNPY, 300 pmol / head / 5 μl) was administered to the lateral ventricle. The test compound was mixed with rNPY and co-administered.
Food consumption up to time was measured. Note that rNPY and the test compound were administered after being dissolved in a 25% methanol solution containing 1% DMSO. The compound of the present invention significantly suppressed the increase in food intake by rNPY administered simultaneously.

[0061]

The compounds represented by the general formula (I) of the present invention include, for example, diseases involving NPY, particularly various diseases involving NPY / Y5 receptor, such as appetite in patients with bulimia and cancer. Eating regulators such as depression, depression, epilepsy, central illnesses such as dementia, obesity, diabetes, hypercholesterolemia,
It is useful as an active ingredient of a medicament for treating and / or preventing metabolic diseases such as hyperlipidemia, arteriosclerosis, and hormonal abnormalities.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme court ゛ (Reference) A61K 31/506 A61K 31/506 A61P 3/04 A61P 3/04 3/06 3/06 3/10 3 / 10 9/10 101 9/10 101 43/00 43/00 C07D 417/12 C07D 417/12 (72) Inventor Akihiko Ikegawa 2-12-1, Ogimachi, Odawara City, Kanagawa Prefecture Fuji Photo Film Co., Ltd. Odawara Plant (72) Inventor Minoru Nagatetsu 333 3-103 Amatsubo, Minamiashigara-shi, Kanagawa Prefecture Naomi 760, Shikaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Prefecture Inside the Pharmaceutical Research Laboratory (72) Inventor Shinichi Tsunoi 760, Shikaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa Meiji Seika Co., Ltd. (72) Inventor Jiro Tanaka Meiji, Inc., Pharmaceutical Research Laboratory, Kohoku-ku, Yokohama, Kanagawa Prefecture, Japan (72) Inventor Yuji Meiji, 760, Shioka-cho, Kohoku-ku, Yokohama, Kanagawa Prefecture Inside the Pharmaceutical Research Institute of Confectionery Co., Ltd. (72) Kenji Asai Inventor Kenji Asai 760-shi, Shiokaoka-cho, Kohoku-ku, Yokohama-shi, Kanagawa F-term in the Pharmaceutical Research Institute of Meiji Seika Co., Ltd. DD25 DD28 DD29 DD34 DD41 DD42 DD47 EE01 4C086 AA01 AA02 AA03 BC84 GA07 GA08 GA10 MA01 MA04 NA14 ZA45 ZA70 ZC33 ZC35 ZC42

Claims (8)

[Claims] 1. The following general formula (I): [In the formula, R ¹ represents a lower alkyl group (the lower alkyl group may have a ring structure and may have one or more substituents); R ² , R ³ , And R ⁴ each independently represent a hydrogen atom or a halogen atom; R ⁵ represents a hydrogen atom or a lower alkyl group (the alkyl group may have a ring structure and has one or more substituents. L may be an alkylene group having 1 to 6 carbon atoms (the alkylene group may have one or two hetero atoms selected from the group consisting of an oxygen atom and a sulfur atom in its main chain; 1
Alternatively, it may contain two or more unsaturated bonds. The alkylene group may have a ring structure and may have one or more substituents); M is an alkylsulfonylamino group having 1 to 10 carbon atoms, A arylsulfonylamino group having 6 to 10 carbon atoms, a heteroarylsulfonylamino group having 1 to 10 total carbon atoms, or a heterocyclic group containing one or more nitrogen atoms] or a salt thereof. . 2. The following general formula (II): The compound according to claim 1, wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , L and M are as defined above, or a salt thereof. 3. M is a tetrazolyl group, a triazolyl group,
The compound according to claim 1 or 2, which is an imidazolyl group, a pyridyl group, a pyrazinyl group, a pyrimidinyl group, or a pyridazinyl group, or a salt thereof. 4. A compound selected from the group consisting of the compound according to any one of claims 1 to 3, a physiologically acceptable salt thereof, a hydrate thereof, and a solvate thereof. Pharmaceutical containing as an ingredient. 5. The medicament according to claim 4, which is for controlling food intake. 6. The medicament according to claim 4, for preventing and / or treating diabetes. 7. The medicament according to claim 4, for preventing and / or treating hypercholesterolemia, hyperlipidemia, or arteriosclerosis. 8. The compound according to any one of claims 1 to 3, which is a neuropeptide Y receptor ligand, or a physiologically acceptable salt thereof.