JPH11180958A - New amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new compound having a strong antagonistic function to CRH receptor esp. CRH2 receptor and useful for treatment for melancholia, anxiety, anorexia nervosa, Alzheimer's disease or the like. SOLUTION: This compound is shown by the formula (X is S or O; A1 and A2 are each an aryl or heteroaryl; A3 is a benzene or pyridine ring; and R1 and R2 are each e.g. a lower alkyl, lower alkenyl), e.g. N,N-dimethyl-4-(4,5- diphenylthiazole-2-yl)aniline. A compound of the formula is obtained by reacting a halogenoketone derivative with a thioamide derivative in the equal molar ratio or slightly different molar ratio in an alcohol-based solvent such as isopropanol or methanol in the presence of a basic compound (e.g. calcium carbonate or potassium hydroxide) under heating, pref., under a heating reflux and, if necessary, removing any protecting group. When the protecting group of amino group is a benzyl group, it is removed by an acid treatment using dichloroacetic acid/methanol or the like.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel amine derivative or a pharmaceutically acceptable salt thereof.

[0002]

2. Description of the Related Art Corticotropin-releasing factor (CR)
H) is deeply involved in the biological response to stress.
It has also been suggested that gastrointestinal dysfunction due to stress and gastrointestinal hypersensitivity due to stress are involved (Neurogast).
roenterol. Mot. , 8: 9-18, 199.
6 years). Two subtypes have been identified for CRH receptors. In 1993, humans, rats and mice
The structure of the RH1 receptor has been determined (Proc. Natl.
Acad. Sci. , 90: 8967-71, 1993.
Year; Endocrinology, 133: 3058-
61, 1993; FEBS Letter, 335:
1, 1993), and then the structure of the CRH2 receptor was elucidated (Proc. Natl. Acad. Sc.
i. ScL USA, 92: 836, 1995; Proc.
Natl. Acad. Sci. USA, 92: 296.
9, 1995; Endocrinology, 13
7:72, 1996; Endocrinolog.
y, 137: 1-6, 1996). Regarding the CRH2 receptor, sub-subtypes of the CRH2α receptor and CRH2β receptor have been further identified (Biochim. Bio).
phys. Acta. , 1352: 129-132, 1
997). The CRH1 receptor is distributed in the pituitary, hypothalamus, cerebral cortex, etc., whereas the CRH2 receptor is mainly distributed in the heart, blood vessels, the core of the brain, the paraventricular nucleus of the hypothalamus, and the abdominal nucleus of the hypothalamus. (Endocrinology, 136:
4139, 1995; TiPS, 17: 166, 19
1996). This site is considered to be a site related to higher brain functions such as learning and memory, autonomic nervous control function, feeding control mechanism, etc. It also plays a role in regulating classical emotional circuits and controlling emotions such as fear and aggression. Is speculated to be. Involvement in the regulation of autonomic nerves has been suggested (Goo
dman &Gilman's The Pharmac
Logical Basis of Therape
utils. 9th edition, edit
d by Joel G. Hardman and L
ee E. Limbird, Chapter 12 Ne
urotransmission and the C
central Nervs System, p26
7). CRH receptor antagonists are expected to be useful medicaments that act on central and peripheral tissues involving CRH receptors.

[0003] Conventional CRH receptor antagonists include rat
Based on the experiment for inhibiting the binding between the pituitary membrane and labeled CRH,
O94 / 13643, WO94 / 13644, WO94
/ 13661, WO94 / 13676, WO94 / 13
677, WO95 / 33727, WO95 / 33750,
WO95 / 34563, EP691128, EP729
58, EP576350, EP655747, WO95
/ 10506, WO96 / 39400, WO96 / 35
689, etc. In addition, recombinant human CRH1
Based on the experiment for inhibiting the binding between the receptor and labeled CRH, WO9
6/39400, WO97 / 00868, WO97 / 3
5539, WO97 / 35580, WO97 / 3584
It has been reported to 6 mag. On the other hand, substituted triarylthiazo
The details of the phenol derivative are described in JP-A-56-152469.
-Halogenophenyl-4,5-diphenylthiazole
Conductors are disclosed for prostaglandin synthase inhibitors, drugs
Pain, anti-inflammatory, anti-arthritic, antipyretic, antithrombotic
And that it is useful. In addition, Japanese Unexamined Patent Publication No.
No. 33186 discloses 2-pyrrolyl-4,5-diphenylthio.
Azole derivatives disclosed and useful as platelet aggregation inhibitors
Is described. However, in each case C
No disclosure or suggestion of effects on RH receptors
No. Further, 2- (4-nitrophenyl) -4,5-bi
Sphenylthiazole and triphenylthiazole are literature
No usefulness as a medicine is disclosed.
Not.

[0004]

[Problems to be solved by the invention] The object of the present invention is excellent
CRH receptor antagonists, particularly selective antagonists for CRH2 receptor
Provide anti-drugs.

[0005]

[Means for Solving the Problems] The present inventors have set forth the above object.
Intensive research to achieve a new amine derivative
Found that the body has a strong antagonistic effect on CRH2 receptor
The present invention has been completed. That is, the present invention provides the following:
The amine derivative represented by the general formula (I) or a pharmaceutically acceptable salt thereof
Regarding acceptable salts.

Embedded image (The symbols in the formula have the following meanings: X: S or O A ₁ , A ₂ : same or different aryl or heteroaryl A ₃ : benzene or pyridine ring R ₁ , R ₂ : same or different lower alkyl A lower alkenyl, a lower alkyl-O-lower alkyl group, or R ₁
And R ₂ together with an adjacent N atom may form a nitrogen-containing heterocyclic ring which may be substituted with a lower alkyl, lower alkyl-O- or benzyl group. )

[0006] The amine derivative of the present invention has a thiazole ring or
Is aminophenyl or amino at the 2-position of the oxazole ring.
The nopyridyl group is substituted, and aryl or
Having a structural feature at the point of substitution by a heteroaryl,
Has strong antagonism at RH receptor, especially CRH2 receptor
Has pharmacological characteristics. Triphenylthiazole
Although some derivatives have been reported as described above,
Amino group is substituted on the benzene ring, which is the 2-position substituent on the toluene ring
No compounds have been reported. Also known trif
Phenylthiazole derivatives on CRH receptor
No effect is suggested or disclosed.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION The following describes the compound (I) of the present invention.
I will tell. Unless otherwise specified in the definition of the general formula in this specification
As far as possible, the term "lower" refers to a straight-chain or
Represents a branched carbon chain. Therefore, "lower alkyl
The term "group" means an alkyl group having 1 to 6 carbon atoms.
For example, methyl, ethyl, propyl, butyl, pen
These structures such as tyl, hexyl or isopropyl
An isomer, preferably an alkyl group having 1 to 4 carbon atoms
It is. “Lower alkenyl group” means having 2 to 6 carbon atoms
Is a straight-chain or branched alkenyl group, specifically,
Vinyl, 1-propenyl, 1-butenyl, 1-pentenyl
, 1-hexenyl group or allyl group.
And an allyl group.

[0008] “Aryl group” refers to a group having 6 to 14 carbon atoms.
An aromatic ring group which may have a substituent.
For example, phenyl, naphthyl, anthryl, phenane
Tolyl groups and the like, preferably phenyl, naphthyl
Group. "Heteroaryl group" means N, O or S atom
A 5- or 6-membered aromatic ring group having 1 to 3 or 5 or
A 6-membered aromatic ring-fused bicyclic group having a substituent
For example, furyl, isothiazoly
, Pyridyl, naphthyridinyl, etc.
Is a pyridyl group. "Aryl group" and "heteroa"
Substituents of "reel group" are halogen atom, hydroxy,
Toro, cyano, lower alkyl groups and the like;
May have one or more substituents. "Halogen atom"
Are fluorine, chlorine, bromine or iodine
Is mentioned. "Nitrogen-containing heterocycle" includes O atom
3 to 8 membered saturated with 1 to 3 N atoms optionally
Or an unsaturated monocyclic ring, preferably pyrrolidine,
Piperidine, piperazine, morpholine, imidazole,
Pyridine.

[0009] The compound of the present invention may have a steric
Isomer (optically active substance, diastereomer, etc.) exists
You. Further, the compound of the present invention may be a compound having an amide bond.
There are also tautomers based on amide bonds. Departure
The clarification means that these isomers are separated or mixed
Things. The compound of the present invention forms a salt with an acid or a base.
You. Hydrochloric acid, hydrobromic acid, hydrogen iodide as salts with acids
Inorganic acids such as acids, sulfuric acid, nitric acid, and mineral acids with phosphoric acid, formic acid,
Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid,
Fumaric acid, maleic acid, lactic acid, malic acid, citric acid, sake
Phosphoric acid, carbonic acid, picric acid, methanesulfonic acid, ethanes
Acid addition salts with organic acids such as sulfonic acid and glutamic acid
Can be As salts with bases, sodium and potassium
Of magnesium, calcium, aluminum, etc.
Base, methylamine, ethylamine, meglumine, d
Organic bases such as tanolamine or lysine, arginine,
Salts and ammonium salts with basic amino acids such as ornithine
Is mentioned. Further, the compound of the present invention is a hydrate, ethanol
Can form solvates and polymorphs with
You.

Manufacturing method (first manufacturing method)

Embedded image(Where A₁, A_Two, A_Three, R₁, R_TwoHas the above meaning
You. Z represents a halogen atom. )  Among the compounds of the present invention, compounds represented by the general formula (Ia)
Is the same as the halogenoketone derivative represented by the general formula (II).
Reacting with a thioamide derivative represented by the general formula (III)
It can be manufactured by This reaction is performed with isopropanol,
Base in alcoholic solvents such as methanol and ethanol
Compounds of formula (II) and formula (III) in the presence of a neutral compound
The moles or one of them is made slightly excessive, and
It is desirable to carry out under heat reflux. Basic compounds used
As the substance, for example, calcium carbonate, potassium hydroxide,
Potassium carbonate, potassium bicarbonate and the like can be mentioned. protection
The elimination of the group depends on the type of protecting group, for example,
When the protecting group of the phenyl group is a substituted or unsubstituted benzyl group,
Acid treatment with dichloroacetic acid / methanol
You. When the protecting group is a benzyloxycarbonyl group, etc.
In some cases, catalytic reduction is preferred, and in some cases hydrogen bromide
Acid / acetic acid, hydrobromic acid / trifluoroacetic acid, hydrogen fluoride
An acid treatment with an acid or the like is used. tert-butoxy
Other urethane-type protecting groups such as carbonyl groups are hydrobromic acid
/ Acetic acid, trifluoroacetic acid, hydrochloric acid, hydrochloric acid / acetic acid, hydrochloric acid /
Acid treatment with dioxane or the like is advantageous.

(Second production method)

Embedded image(Where A₁, A_Two, A_Three, R₁, R_Two, Z have the above meaning
I do. ) Among the compounds of the present invention, compounds represented by the general formula (Ib)
Is obtained by reacting the compound represented by the general formula (V) in an appropriate solvent
Water, ammonium acetate, ammonium chloride, sulfuric acid
Reaction in the presence of ammonium salts such as ammonium acid
It is manufactured by In this case, use ammonia water or
The ammonium salt is at least equal to the compound of formula (V).
Mol, preferably from equimolar to 5-fold molar amount.
No. The reaction is usually carried out at room temperature to 200 ° C., preferably at room temperature.
It is completed in about 1 to 5 hours at a temperature of about 150 ° C. formula
The compound of the formula (V) is a compound of the formula (II) and a compound of the formula (IV)
The carboxylic acid derivatives shown are ethanol, propanol
Alcohol solvents such as benzene, toluene, xylene
By reacting in the solvent of aromatic hydrocarbons such as
Is done. In this reaction, the compound of the formula (IV) is converted to the compound of the formula (II)
At least equimolar, preferably equimolar to 1.
About 5 times the molar amount is good. The reaction is usually carried out at room temperature to 200
° C, preferably at room temperature to about 150 ° C for about 1 to 5 hours
To end.

[0012] The compound of the present invention thus produced
Is isolated or purified as free or as its salt.
You. Isolation and purification include extraction, concentration, evaporation, crystallization, filtration,
Normal chemical operations such as recrystallization and multiple chromatography
Done by applying. Various isomers are suitable starting compounds
Or physical properties between isomers
Can be separated using the difference between For example, optical activity
Sex is determined by selecting appropriate raw materials or
Racemic resolution of semi-compounds (eg, general optical activity
For diastereomeric salts with various bases and optical resolution
Method) can lead to stereochemically pure isomers.
Wear.

[0013]

【The invention's effect】 The compound of the present invention is a CRH receptor, particularly a CH receptor.
It has a strong antagonism at the RH2 receptor. Therefore, the present invention
Compounds include depression, anxiety, anorexia nervosa, Alzheimer's disease
-Disease, hypertension, angina, sudden cardiac death, peptic ulcer, diabetes
Disease, irritable bowel syndrome (IBS), hyperpnea syndrome, inflammatory disease
Patients and other stresses may be one of the causes
Diseases: bronchial asthma, hyperthyroidism, migraine
Pain, myotonic headache, writing spasticity, spastic torticollis, Meniere's syndrome
Group, alopecia areata, impotence, menopause, insomnia,
Useful as a prophylactic / therapeutic agent for autonomic imbalance, etc.
(J. Clin. Endocrinol. Meta
b., 74: 1325-30, 1992; Cli
n. Endocrinol. Metab. , 62: 3
19-24, 1986, Life Sci. , 53: 6
97-706, 1993, Arzneim. Forsc
h. / Drug Res. , 44: 715-26,19.
94, Proc. Natl. Acad. Sci. US
A, 93: 6096-6100, 1996, Endoc
r. J. 41: 453-459, 1994, Clin.
Endocrinol. oxf. , 32: 93-10.
0, 1990, Neuroendocrinology
y, 49: 367-386, 1989, Endocr.
Regul. , 25: 151-158, 1991). Book
The CRH receptor antagonism of the compound of the present invention was determined by the following experiment.
confirmed. Endocrinology, 116: 1
653-59, 1985 and Peptides, 10:
179-88, 1985.
Transcribes mRNA isolated from amygdala and generates it in CHO cells
Revealed recombinant human CRH2 receptor and 125I-labeled CRH
And the binding inhibitory activity of 125I-labeled souvazine was measured.
Was. Compound (I) of the present invention or a pharmaceutically acceptable compound thereof
Contains salt (one or more of them) as active ingredient
Pharmaceutical compositions are usually composed of carriers and excipients used for formulation,
Tablets, powders, fine granules, granules with other additives
Preparations, capsules, pills, solutions, injections, suppositories, ointments, patches
Orally (including sublingual administration) or parenteral
It is administered orally.

[0014] Clinical administration of compound (I) of the present invention to humans
The dosage depends on the patient's symptoms, age of administration, gender, etc.
Is determined appropriately according to the individual case in consideration of
10 mg to 500 mg per adult per day, preferably
Preferably in the range of 100mg to 500mg once a day
It is administered orally in several doses, or 1 dose per adult
1 mg to 100 mg, preferably 10 mg to 1 per day
Intravenous administration in the range of 00 mg once to several times a day
Or intravenously for 1 hour to 24 hours a day
Administered continuously. Of course, as mentioned above,
Since it fluctuates under various conditions, a smaller dose than the above
It can be confusing.

[0015] Solid composition for oral administration according to the invention
As such, tablets, powders, granules and the like are used. This
In such solid compositions, one or more actives
If the quality is at least one inert diluent, such as lactose,
Mannitol, glucose, hydroxypropyl cellulose
, Microcrystalline cellulose, starch, polyvinyl pyrrolide
And magnesium metasilicate are mixed with magnesium aluminate.
The composition shall be added according to the usual method except for an inert diluent.
Lubricants such as magnesium stearate,
Disintegrants such as calcium cellulose glycolate, lacto
Stabilizers, such as glucose, glutamic acid or asparagine
A solubilizing agent such as an acid may be contained. Tablets or
Pills can be sucrose, gelatin, hydroxyprop
Cellulose, hydroxypropyl methylcellulose
Coated with gastric or enteric film such as tarate
You may.

[0016] Liquid compositions for oral administration are
Emulsions, solutions, suspensions, syrups, d
Inactive dilution commonly used, including lyxil
Agents such as purified water and ethanol. This composition is not
In addition to the active diluent, solubilizing or solubilizing agents, wetting agents, suspending agents
Auxiliaries such as turbidity agents, sweeteners, flavors, fragrances, preservatives
May be contained. Injectable for parenteral administration
Sterile aqueous or non-aqueous solutions, suspensions, emulsions
Is included. Aqueous solutions and suspensions include, for example,
Includes distilled water for propellants and saline. Insoluble in water
Examples of solutions and suspensions include propylene glycol,
Vegetable oils such as polyethylene glycol and olive oil, d
Alcohols such as tanol, polysorbate 80
(Product name). Such compositions may be more isotonic
Agents, preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg
Lactose), solubilization or dissolution aids
It may contain an agent. These are, for example, bacterial retention
Sterilized by filtration through a filter, blending of a disinfectant or irradiation
Be transformed into They also produce and use sterile solid compositions.
Before use, dissolve in sterile water or sterile injection solvent before use.
Can also be.

[0017]

【Example】 Next, the present invention will be described in more detail by way of examples.
As will be explained, the present invention is limited to these Examples.
There is no. The starting compounds used in the examples are referred to as reference examples.
I will explain. Reference Example 1  2.0 g of sodium hydride (60% mineral oil dispersion)
2.0 g of 4-aminobenzonitrile in 40 ml of Lumamide solution
The mixture was stirred at room temperature for 20 minutes. Here, ethyl iodide 26.5
g was added dropwise and stirred at 50 ° C. for 15 hours. Add water to the reaction solution
And extracted with ethyl acetate. Wash the organic layer with saturated saline
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
did. The residue was purified by silica gel column chromatography (solvent).
(Effluent: n-hexane / ethyl acetate)
2.7 g of 4-diethylaminobenzonitrile as a white powder
I got it. Compounds of Reference Examples 2 to 6 were prepared in the same manner as Reference Example 1.
I got something. Reference Example 2 4-dipropylaminobenzonitrile Reference Example 3 4- (pyrrolidin-1-yl) benzonit
Lil Reference Example 4 4- (2-propyl) aminobenzonitrile
Reference Example 5 2-Diethylaminobenzonitrile Reference Example 6 3-Diethylaminobenzonitrile

Reference Example 7  1.0 g of 4-aminobenzonitrile dimethylformamide
2.3 g of potassium carbonate and 13.2 g of ethyl iodide were added to 30 ml of the solution.
Then, the mixture was stirred at 50 ° C for 15 hours. Water is added to the reaction solution,
Extracted with chill. The organic layer is washed with a saturated saline solution,
After drying with magnesium acid, the solvent was distilled off under reduced pressure. Get
The oily matter was separated by silica gel column chromatography.
(Eluent: n-hexane / ethyl acetate)
4-diethylaminobenzonitride as a less polar substance
Lil 190mg as a white powder and 4 as a highly polar substance
-820 mg of ethylaminobenzonitrile as a white powder
Obtained. The obtained 4-ethylaminobenzonitrile 74
Perform a conventional addition reaction using 0 mg and 3.55 g of methyl iodide.
By adding 4-ethylmethylaminobenzonitrile 540m
g was obtained as a yellow powder. In the same manner as in Reference Example 7,
The compound of Example 8 was obtained. Reference Example 8 4-ethylisopropylaminobenzonit
Lil

Reference Example 9  3.0 g of 4-fluorobenzonitrile in dimethylformamide
17 g of potassium carbonate and 6.5 g of morpholine are added to 50 ml of the solution.
Then, the mixture was stirred at 90 ° C. for 8 hours. Water is added to the reaction solution, and acetic acid is added.
Extracted with ethyl. The organic layer was washed with a saturated saline solution and dried.
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Profit
Recrystallize the obtained crude crystals (recrystallization solvent: hexane / acetic acid
Tyl) and 2.7 g of 4-morpholinobenzonitrile
Obtained as a white powder. In the same manner as in Reference Example 9, Reference Example 1
Compounds 0 to 16 were obtained. Reference Example 10 4- [bis- (2-methoxyethyl) a
Mino] benzonitrile Reference Example 11 4-piperidinobenzonitrile Reference Example 13 4- (4-methylpiperazin-1-yl)
Benzonitrile Reference Example 12 4- (4-methoxypiperidino) benzoni
Tolyl Reference Example 14 4- (4-benzylpiperazine-1-i
L) Benzonitrile Reference Example 15 4- (Imidazol-2-yl) benzoni
Tolyl Reference Example 16 2-diethylamino-5-cyanopyridine

Reference Example 17  4-diethylaminobenzonitrile 190mg 4N hydrochloric acid
/ Ethyl acetate solution with 200 mg of O, O-diethyl dithiophosphate
The mixture was stirred at room temperature for 15 hours. The solvent is distilled off under reduced pressure.
The crystals are collected by filtration and washed with ether to give 4-diethyl.
Luminobenzthioamide hydrochloride 220 mg as yellow powder
I got it. As in Reference Example 17, Reference Examples 18 to 27
Was obtained. Reference Example 18 2-diethylaminobenzthioamide hydrochloride
Salt Reference Example 19 3-diethylaminobenzthioamide hydrochloride
Salt Reference Example 20 4-dimethylaminobenzthioamide hydrochloride
Salt Reference Example 21 4-dipropylaminobenzthioamide salt
Acid salt Reference Example 22 4-ethylmethylaminobenzthioamide
Hydrochloride Reference Example 23 4-ethylisopropylaminobenzthio
Amide hydrochloride Reference Example 24 4- (Pyrrolidin-1-yl) benzthio
Amide hydrochloride Reference example 25 4-Piperidinobenzthioamide hydrochloride Reference example 26 4-morpholinobenzthioamide hydrochloride Reference example 27 4- (4-benzylpiperazine-1-i
B) Benzthioamide hydrochloride

Reference Example 28  4- [bis- (2-methoxyethyl) amino] benzoni
Dithiol was added to 20 g of 4N hydrochloric acid / ethyl acetate solution of 1.0 g of tolyl.
0.8 g of O, O-diethyl phosphate was added and stirred at room temperature for 18 hours.
Was. The solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue,
Wash with 1N aqueous sodium hydroxide solution, water and saturated saline,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure.
The obtained oil is subjected to silica gel column chromatography.
(Chloroform / methanol) to purify the desired 4-
(Bis- (2-methoxyethyl) amino) benzthioa
0.84 g of the amide was obtained as a yellow powder. Compounds of Reference Examples 29 to 32 as in Reference Example 28
I got Reference Example 29 4- (4-methoxypiperidino) benzti
Oamide Reference Example 30 4- (4-methylpiperazin-1-yl)
Benzthioamide Reference Example 31 4- (Imidazol-2-yl) benzti
Oamide Reference Example 32 6-Diethylaminothionicotinamide

Reference Example 33  1.87 g of hydroxylamine hydrochloride, 2.1 of triethylamine
g, 50 ml of 1,2-dichloroethane solution
A solution of 3.3 g of Toyl in 1,2-dichloroethane was added dropwise, and the
Stirred at warm for 4 hours. The organic layer was diluted with 1N aqueous hydrochloric acid, water, 1
Wash with normal aqueous sodium hydroxide solution and dry anhydrous magnesium sulfate.
After drying over sodium, the solvent was distilled off under reduced pressure. The oil obtained
The product was subjected to silica gel column chromatography (hexane /
(Ethyl acetate) to give the desired N-methoxy-N-
3.2 g of tyl-1-naphthamide were obtained as an orange oil.
Compounds of Reference Examples 34 to 47 in the same manner as in Reference Example 33
I got Reference Example 34 N-methoxy-N-methyl-2-naphthoa
Mido Reference Example 35 N-methoxy-N-methyl-2-biphenyl
Lcarboxamide Reference Example 36 N-methoxy-N-methyl-3-nicotine
Amide Reference Example 37 N-methoxy-N-methyl-4-nicotine
Amide Reference Example 38 N-methoxy-N-methyl-2-franca
Ruboxamide Reference Example 39 N-methoxy-N-methyl-2-thiophene
Reference Example 40 2, N-dimethyl-N-methoxybenzure
Mid Reference Example 41 3, N-dimethyl-N-methoxybenzure
Mid Reference Example 42 4, N-dimethyl-N-methoxybenzure
Mido Reference Example 43 N-methoxy-2,3, N-trimethylbe
Nsamide Reference Example 44 2, N-dimethoxy-N-methylbenzure
Mido Reference Example 45 N-methoxy-N-methyl-1-naphthale
Reference Example 46 N-methoxy-N-methyl-2-naphthale
Nacetamide

Reference Example 47  1,4-diazabicyclo [2,2,2] octane 1.1 g
N-butyl lye in 30 ml of a toluene solution of
6.3 ml of a solution of 1.6 M in hexane / hexane is dropped at room temperature
Then, the mixture was stirred at 80 ° C. for 30 minutes. The reaction was then brought to -78 ° C.
Cool and add N-methoxy-N-methyl-1-naphthamide
30 g of a solution of 1.0 g of anhydrous tetrahydrofuran was added dropwise, and -78
Stirred at C for 1 hour. After stirring at room temperature for 2 hours,
A 1N aqueous hydrochloric acid solution was added to the solution, and the mixture was extracted with ethyl acetate.
Was. The organic layer was washed with a saturated aqueous solution of sodium bicarbonate and saturated saline
After washing with water, drying over anhydrous magnesium sulfate and dissolving under reduced pressure
The medium was distilled off. The obtained oil is purified by silica gel column chromatography.
Purify by chromatography (hexane / ethyl acetate)
930 mg of the desired benzyl-1-naphthyl ketone in pale yellow crystals
As obtained. In the same manner as in Reference Example 47, Reference Examples 48 to
58 compounds were obtained. Reference Example 48 Benzyl-2-naphthyl ketone Reference Example 49 Biphen-2-ylbenzyl ketone Reference Example 50 Benzyl-3-pyridyl ketone Reference Example 51 Benzyl-4-pyridyl ketone Reference Example 52 Benzyl-2-furyl ketone Reference Example 53 Benzyl- 2-thienyl ketone Reference Example 54 Benzyl- (2-methylphenyl) ketone Reference Example 55 Benzyl- (3-methylphenyl) ketone Reference Example 56 Benzyl- (4-methylphenyl) ketone Reference Example 57 Benzyl- (2,3- Dimethylphenyl)
Ketone Reference Example 58 Benzyl- (2-methoxyphenyl) keto
N

Reference Example 59 1,4-diazabicyclo [2.2.2] octane 2.2 g
12 ml of a 1.6 M butyl lithium / hexane solution was added dropwise to 80 ml of a toluene solution of the above under an argon atmosphere, followed by stirring at 80 ° C. for 30 minutes. After cooling to −78 ° C., 1.0 g of 2-cyanopyridine was added, and the mixture was stirred at −78 ° C. for 1 hour. 50 ml of a 6N aqueous hydrochloric acid solution was added to the reaction solution, followed by stirring at room temperature for 1 hour. After neutralization with sodium hydroxide, the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogencarbonate and brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
The residue is purified by silica gel column chromatography (hexane / ethyl acetate) to give the desired benzyl-
0.85 g of 2-pyridyl ketone was obtained as a yellow oil.

Reference Example 60  N-methoxy-N-methyl-2-naphthaleneacetamido
-2.0 g of anhydrous ether solution under argon atmosphere
17% phenyllithium / cyclohexane-ether at ℃
16 ml of the mixed solution was added dropwise, and the mixture was further added at -20 ° C for 2 hours and then at room temperature.
For 2 hours. 1N aqueous hydrochloric acid and water are added to the reaction solution.
In addition, the mixture was extracted with ethyl acetate. Wash the organic layer with saturated saline
And dried over anhydrous magnesium sulfate.
I left. The obtained crude crystals were recrystallized (recrystallization solvent:
(Hexane / ethyl acetate) to give the desired 2-naphthyl.
1.7 g of methyl phenyl ketone were obtained as white crystals. three
In the same manner as in Reference Example 60, the compound of Reference Example 61 was obtained. Reference Example 61 1-naphthylmethyl phenyl ketone

Reference Example 62  To a 30 ml acetic acid solution of 0.91 g of benzyl-1-naphthyl ketone
0.59 g of bromine was added dropwise under ice cooling, and the mixture was stirred for 1 hour.
Further, after stirring at room temperature for 3 hours, the solvent was distilled off under reduced pressure.
Dilute the residue with ethyl acetate and dilute with 1 N sodium hydroxide.
Washed with an aqueous solution of water, water and saturated saline, and dried over anhydrous magnesium sulfate.
Then, the solvent was distilled off under reduced pressure. The resulting oil
To silica gel column chromatography (hexane / vinegar)
(Ethyl acetate) to give the desired α-bromobenzyl-1-
1.0 g of naphthyl ketone was obtained as a brown oil. Reference example 6
In the same manner as in 2, compounds of Reference Examples 63 to 64 were obtained. Reference Example 63 α-bromobenzyl-2-naphthyl ketone Reference Example 64 α-bromo-α- (2-naphthyl) aceto
Phenon

Reference Example 65  Benzyl-2-thienyl ketone 0.43 g of tetrahydrofuran
Tetra n-butylammonium tribro
Add 1.03 g of Mide, and stir at room temperature for 30 minutes.
Distilled off. Ethyl acetate was added to the residue for dilution.
After washing with aqueous sodium chloride solution, water and saturated saline,
After drying with magnesium acid, the solvent was distilled off under reduced pressure. Get
The oily matter was separated by silica gel column chromatography (He
Xane / ethyl acetate) to give the desired α-bromoben
0.54 g of jyl-2-thienyl ketone was obtained as a colorless oil.
Was.

Reference Example 66 To a solution of benzyl-2-furyl ketone (0.36 g) in tetrahydrofuran was added 0.73 g of phenyltrimethylammonium tribromide, and the mixture was stirred at room temperature for 30 minutes. After filtering the reaction solution, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain 0.48 g of desired α-bromobenzyl-2-furyl ketone as pale yellow crystals. In the same manner as in Reference Example 66, the compounds of Reference Examples 67 to 74 were obtained. Reference Example 67 Biphen-2-yl-α-bromobenzyl ketone Reference Example 68 α-bromobenzyl- (2-methylphenyl) ketone Reference Example 69 α-bromobenzyl- (3-methylphenyl) ketone Reference Example 70 α-bromo Benzyl- (4-methylphenyl) ketone Reference Example 71 α-bromobenzyl- (2,3-dimethylphenyl) ketone Reference Example 72 α-bromobenzyl- (2-methoxyphenyl) ketone Reference Example 73 α, 4′-dibromo Benzyl phenyl ketone Reference Example 74 α-bromo-α- (1-naphthyl) acetophenone

REFERENCE EXAMPLE 75 To a 10% solution of 0.42 g of benzyl-3-pyridyl ketone in 31% hydrobromic acid / acetic acid, 5 ml of an acetic acid solution containing 0.34 g of bromine was added dropwise.
Stirred at C for 1 hour. Further, after stirring at room temperature for 1 hour, the precipitated crystals were collected by filtration to obtain 0.68 g of desired α-bromobenzyl-3-pyridyl ketone hydrobromide. In the same manner as in Reference Example 75, the compounds of Reference Examples 76 to 77 were obtained. Reference Example 76 α-bromobenzyl-2-pyridyl ketone hydrobromide Reference Example 77 α-bromobenzyl-4-pyridyl ketone hydrobromide

Reference Example 78  Α-Bromobenzyl-1-naphthyl shown in Reference Example 62
4-Diethylamino in 40 ml of a xylene solution of 0.5 g of ketone
1.75 g of potassium benzoate was heated and refluxed for 48 hours. Reaction solution
After cooling to room temperature, water was added, and the mixture was extracted with ethyl acetate.
The organic layer is washed with a saturated saline solution and dried over anhydrous magnesium sulfate.
After drying, the solvent was distilled off under reduced pressure. Silica gel residue
Purification by column chromatography (hexane / ethyl acetate)
To give 4-diethylaminobenzoic acid 2-naphthalene-1
-1-yl-2-oxo-1-phenylethyl ester 38
0 mg was obtained as light brown crystals. As in Reference Example 78.
Thus, the compound of Reference Example 79 was obtained. REFERENCE EXAMPLE 79 4-Diethylaminobenzoic acid 2-phenyl
2-oxo-1-phenylethyl ester

Embodiment 1  Carbonic acid was added to 20 ml of a 2-propanol solution of 0.2 g of decyl chloride.
0.18 g of Lucium and 4-dimethylamino shown in Reference Example 20
Add 190 mg of benzthioamide hydrochloride and stir at 50 ° C for 18 hours.
Stirred. Water is added to the reaction solution, and n-hexane / ethyl acetate is added.
Extracted with a 20: 1 mixed solvent. Organic layer with saturated saline
After washing and drying over anhydrous magnesium sulfate, the solvent is removed under reduced pressure.
Distilled off. The crude product obtained is purified by recrystallization
(Recrystallization solvent: ethyl acetate / n-hexane)
N-dimethyl-4- [4,5-diphenylthiazole-
0.29 g of [2-yl] aniline was obtained as a green powder.

In the same manner as in Embodiment 1, Reference Examples 62 to 7
Compounds of Examples 2 to 40 were obtained using the compound shown in Example 9 and the compounds shown in Reference Examples 17 to 32. The obtained compound was treated with a mineral acid such as hydrochloric acid or sulfuric acid, or an organic acid such as fumaric acid or maleic acid as needed to obtain a corresponding salt.

Embodiment 41  1-benzyl-4- [4- (4-na) shown in Example 32
Phthalen-1-yl-5-phenylthiazol-2-i
Le) phenyl] piperazine 0.43 g of 1,2-dichloroe
Chloroformic acid 1-chloroethyl ester 0.
23 g was added, and the mixture was heated under reflux for 19 hours. Methanol 2
0 ml was added, and the mixture was further heated under reflux for 2 hours.
Was distilled off. Dilute the residue with ethyl acetate and add 1N water
Wash with aqueous sodium oxide, water and saturated saline, and dry
After drying over magnesium sulfate, the solvent was distilled off under reduced pressure. Profit
The oily product was subjected to silica gel column chromatography.
(Chloroform / methanol)
The oil was treated with hydrochloric acid in ether to give the desired 1- [4-
(4-naphthalen-1-yl-5-phenylthiazole
-2-yl) phenyl] piperazine dihydrochloride 0.21 g to white
Obtained as a colored powder.

Hereinafter, in the same manner as in the embodiment 41, the embodiment 39
Was used to obtain the compound of Example 42.

Example 43 2-Diethylaminobenzoic acid 2- as shown in Reference Example 78
Ammonium acetate was added to 20 ml of an acetic acid solution containing 0.39 g of naphthalen-1-yl-2-oxo-1-phenylethyl ester.
After adding 0.27 g and heating and refluxing for 8 hours, the solvent was distilled off under reduced pressure. Ethyl acetate was added to the residue for dilution, and the mixture was washed with a 1N aqueous solution of sodium hydroxide, water and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting oil was purified by silica gel column chromatography (hexane / ethyl acetate) and the resulting yellow oil was treated with hydrochloric acid in ether to give the desired N, N-diethyl-4-.
[4- (1-naphthyl) -5-phenyloxazole-
0.11 g of 2-yl] aniline hydrochloride was obtained.

Hereinafter, in the same manner as in Example 43, Reference Example 79
Was used to obtain the compound of Example 44. Tables 1 to 3 show the structures of the example compounds, Tables 4 to 6 show the physical properties of the reference examples, and Tables 7 to 6 show the physical properties of the example compounds.
It is shown in FIG. The symbols in the table have the following meanings. Rex: reference example number, Ex: example number, Sal: salt (1H ₂ O indicates monohydrate), DATA: physical properties, mp:
Melting point, dec: decomposition, NMR: nuclear magnetic resonance spectrum (using tetramethylsilane as internal standard, reference example uses DMSO-d6), MS: mass spectrometry (FAB is fast atom bombardment, EI is electron bombardment) , Me: methyl, Et: ethyl, Pro: propyl, i
Pro: Isopropyl, Ph: Phenyl, Naph: Naphthyl, P
yr: pyridyl, MeO: methoxy, diMe: dimethyl

[0037]

[Table 1]

[0038]

[Table 2]

[0039]

[Table 3]

[0040]

[Table 4]

[0041]

[Table 5]

[0042]

[Table 6]

[0043]

[Table 7]

[0044]

[Table 8]

[0045]

[Table 9]

[0046]

[Table 10]

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification code FI A61K 31/42 ACL A61K 31/42 ACL ADP ADP AED AED 31/425 AAK 31/425 AAK 31/44 AAE 31/44 AAE 31 / 445 AAM 31/445 AAM 31/495 ABU 31/495 ABU 31/535 ABN 31/535 ABN C07D 263/32 C07D 263/32 277/28 277/28 401/04 233 401/04 233 417/10 211 417 / 10 211 233 233 (72) Inventor Hidenobu Yuki 21 Miyukigaoka, Tsukuba, Ibaraki Pref. Yamanouchi Pharmaceutical Co., Ltd.

Claims (2)

[Claims] 1. An amine derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof. Embedded image (The symbols in the formula have the following meanings: X: S or O A ₁ , A ₂ : same or different aryl or heteroaryl A ₃ : benzene or pyridine ring R ₁ , R ₂ : same or different lower alkyl A lower alkenyl, a lower alkyl-O-lower alkyl group, or R ₁
And R ₂ together with an adjacent N atom may form a nitrogen-containing heterocyclic ring which may be substituted with a lower alkyl, lower alkyl-O- or benzyl group. ) 2. A CRH2 receptor antagonist comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.