JP2962186B2 - Piperidine derivative and serotonin antagonist containing the same - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel serotonin antagonist and an antiplatelet agent, and more particularly to a serotonin antagonist and an antiplatelet agent which potently and specifically inhibit the serotonin 2 receptor and have few side effects.

[0002]

2. Description of the Related Art Thrombosis is greatly involved in ischemic diseases such as myocardial infarction and cerebral infarction, and platelets are considered to play an important role in thrombus formation particularly in arteries. Conventional antiplatelet drugs include arachidonic acid metabolism inhibitors, platelet cyclic nucleoside-related drugs, thromboxane receptor antagonists and the like, and aspirin and ticlopidine are used clinically. However, it cannot be said that a sufficient effect has been obtained, and a more effective drug has been desired.

[0003] On the other hand, serotonin (5HT) is a component of platelet α.
It is stored in granules and released upon activation of platelets by various stimuli, and serotonin 2 (5
It is known that the concentration of intracellular calcium ions is increased via the HT ₂ ) receptor, causing platelet aggregation. In addition, 5HT ₂ receptors present on vascular smooth muscle is thought to be also involved in the constriction of blood vessels.
Therefore, since a 5HT ₂ receptor antagonist can be expected not only to inhibit platelet aggregation but also to inhibit vasoconstriction, a strong antithrombotic effect may be obtained.

[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a serotonin antagonist and an antiplatelet drug which potently and specifically inhibit the serotonin 2 receptor and have few side effects.

[0005]

Means for Solving the Problems The present invention relates to a serotonin antagonist or an antiplatelet drug which contains a piperidine derivative represented by the following general formula (I) or a salt thereof as an active ingredient.

[0006]

Embedded image Wherein A ¹ is a pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group which may have a substituent;
X represents an alkyl group having 1 to 8 carbon atoms having a substituent, a cycloalkyl group having 4 to 8 carbon atoms having a substituent, or an alkoxy group having 1 to 8 carbon atoms which may have a substituent; ¹ represents a hydrogen atom or a halogen atom, Y ¹ is any of the following organic groups, wherein n is 0 to
Represents an integer of 4,

[0007]

Embedded image Z ¹ represents any of the following organic groups.

[0008]

Embedded image In the general formula (I), the substituent of A ¹ is preferably any one of the following.

[0009]

Embedded image In the group, R ¹ represents a hydrogen atom, an alkyl or alkoxy group having 1 to 6 carbon atoms, an amino group or an acylaminoalkyl group optionally substituted with an alkyl group, and R ² and R ³ are the same. Alternatively, it represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group or an alkoxycarbonyl group, or an aminocarbonyl group which may be substituted with an alkyl group.

Specific examples of such compounds include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N, N -Dimethylcarbamoyl, N, N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β
-Alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-ethyl-N-formyl or N-ethyl-N-acetyl Is raised.

A preferred example of Y ^{1 in} the general formula (I) is a —CONH— group, and a preferred example of Z ¹ is a —CH ＝ CH— group.

Among the compounds represented by the general formula (I), the compound represented by the following general formula (II) is a novel compound which has not been described in the literature.

[0013]

Embedded image In the formula, A ² represents piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group which may have a substituent, an alkyl group having 1 to 8 carbon atoms having a substituent, carbon having a substituent. A cycloalkyl group having 4 to 8 atoms or an alkoxy group having 1 to 8 carbon atoms which may have a substituent;
When A ² has a substituent, the substituent is any of the following.

[0014]

Embedded image In the group, R ⁴ represents an alkyl group or an alkoxy group having 1 to 6 carbon atoms, an amino group or an acylaminoalkyl group optionally substituted with an alkyl group, and R ⁵ and R ⁶ are the same or different. A hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group or an alkoxycarbonyl group, or an aminocarbonyl group which may be substituted with an alkyl group. X ² , Y ² and Z ² have the same meanings as X ¹ , Y ¹ and Z ¹ , respectively.

Examples of the substituent of A ² include acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N, N-dimethylcarbamoyl, N , N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N
-Ethyl-N-formyl or N-ethyl-N-acetyl is preferable, and Y ² and Z ² are each preferably a —CONH— group and a —CH ＝ CH— group.

The piperidine derivative represented by the above general formula (I) can be produced by a known method such as the method described in JP-A-3-47168. As an example, 4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1- included in the general formula (I).
(2-t-butoxycarbonylamino) ethyl) piperidine (compound (3)) is prepared by combining Nt-butoxycarbonyl-2-bromoethylamine (compound (1)) and 4- (5H- Dibenzo [a, d] cycloheptene-5-ylidene) piperidine (compound (2)) can be easily obtained by condensation in the presence of a base such as triethylamine.

[0017]

Embedded image

1-Formyl-N- (2- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl)) which is also included in the general formula (I)
As shown in Reaction Scheme II, ethyl isonipecotinamide (Compound (6)) is obtained by removing Compound (3) from Compound (4) obtained by removing the t-butoxycarbonyl group using 4 M hydrochloric acid / dioxane or the like. It can be easily obtained by condensing isonipecotic acid (compound (5)) using a condensing agent such as 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide.

[0019]

Embedded image The reaction product obtained by such a production method is isolated and produced as a free form or a salt thereof. The isolated product is
Extraction, concentration, distillation, crystallization, various types of chromatography and the like can be performed.

Examples of the salt of the piperidine derivative include mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, formic acid, acetic acid, lactic acid, salicylic acid, mandelic acid, citric acid, and the like.
Acid addition salts with organic acids such as oxalic acid, maleic acid, fumaric acid, tartaric acid, tannic acid, malic acid, tosylic acid, methanesulfonic acid and benzenesulfonic acid can be mentioned.

The piperidine derivative represented by the general formula (I) exhibits serotonin antagonism, and ischemic disease, thrombosis, embolism, mental (depression, anxiety) disease, diabetic complication, arteriosclerosis, hypertension, It is useful as a therapeutic drug for arrhythmia, migraine, microcirculation deficiency, and the like.

Further, the present piperazine derivative is particularly useful as an antiplatelet drug, and is useful for various ischemic diseases, thrombosis, embolism, vasculitis, diabetic complications, arteriosclerosis, kidney disease, chronic arterial occlusion. It can be used as a therapeutic agent for ulcers, pain, cold sensation, etc., as a therapeutic agent for the improvement of various ischemic diseases associated with circulatory insufficiency and for the prevention of restenosis after surgical treatment of ischemic heart disease and for improvement of blood circulation. Can also be used.

When the piperidine derivative of the general formula (I) is used as a serotonin antagonist or an antiplatelet drug, the route of administration may be oral or parenteral, and the dosage may be the age, weight, condition of the patient. The daily dose to an adult is usually 0.01 to 500 mg, preferably 0.1 to 500 mg for oral administration, depending on the administration method.
50 mg, 1 μg to 100 m for parenteral administration
g, preferably 0.01 to 10 mg.

As the dosage form, it is possible to use ordinary preparations such as tablets, powders, sugar coatings, emulsifiers, capsules or solutions, and it is produced according to a conventional method using usual preparation auxiliaries. be able to.

[0025]

Next, the present invention will be described in more detail with reference to examples, but the present invention is not limited to these examples.

Production Example A 1-methoxycarbonyl-N-
Synthesis of (2- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl)) ethyl isonipecotinamide hydrochloride

Step 1 Synthesis of 2-t-butoxycarbonylaminoethyl bromide 35.77 g of 2-aminoethyl bromide hydrobromide
(174.6 mmol) and 22.80 g (104.5 mmol) of di-t-butyl dicarbonate in ether 3
After adding to a mixed solvent of 00 ml and 300 ml of water, 44.00 g (523.7 mmol) of sodium hydrogen carbonate was gradually added, and the mixture was stirred at room temperature overnight. 1N hydrochloric acid 8
The extract was washed with 0 ml and then with saturated saline (80 ml), dried over magnesium sulfate powder and evaporated to give the title compound. Yield 21.57 g (96.25 mmol) Yield 9
2%

Step 2 4- (5H-dibenzo [a, d]
Synthesis of cycloheptene-5-ylidene) -1- (2-t-butoxycarbonylamino) ethyl) piperidine 4.5 g (20.1 mmol) of 2-t-butoxycarbonylaminoethyl bromide, 4- (5H-dibenzo [a, d] Cycloheptene-5-ylidene) piperidine 2.7 g (10.0 mmol) and triethylamine 4.2 ml (30 mmol) were mixed with acetonitrile (300
ml) and stirred in a 50 ° C. oil bath for 16 hours. After returning to room temperature and distilling off the solvent, the residue was dissolved in 300 ml of ethyl acetate, the insolubles were removed by filtration, and the mixture was washed with 100 ml of 1N hydrochloric acid, 100 ml of 1N sodium hydroxide and 100 ml of saturated saline. After drying over powdery magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound. Yield 3.6 g (8.6 mmol) Yield 86%

Step 3 1- (2-aminoethyl) -4-
Synthesis of (5H-dibenzo [a, d] cycloheptene-5-ylidene) piperidine dihydrochloride 4- (5H-dibenzo [a, d] cycloheptene-5-
8.47 g of (ylidene) -1- (2-t-butoxycarbonylamino) ethyl) piperidine (20.4 mmol
l) was dissolved in 100 ml of dichloromethane and 4M
Hydrochloric acid / dioxane (100 ml) was added, and the mixture was stirred at room temperature for 1 hour. The solvent was distilled off to obtain the title compound (8.56 g).

Step 4 1-t-butoxycarbonyl-N
Synthesis of-(2- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl)) ethyl isonipecotinamide 1- (2-aminoethyl) -4- (5H 2.3 g (6.0 mmol) of -dibenzo [a, d] cycloheptene-5-ylidene) piperidine dihydrochloride, 1.6 g (7.2 mmol) of 1-t-butoxycarbonylisonipecotic acid
l), 3.0 ml of triethylamine (21.6 mmol)
l) and 1.4 g of 1-ethyl-3- (3-dimethylaminopropyl) -carbodiimide hydrochloride (7.2 mmol)
l) was mixed and stirred at room temperature overnight. After the solvent was distilled off, the residue was dissolved in 100 ml of dichloromethane, and 10 ml of 1N hydrochloric acid was added.
The mixture was washed with 0 ml, 1N sodium hydroxide (100 ml) and saturated saline (50 ml). The solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain the title compound. Yield 2.0 g (3.8 mmol) Yield 63%

Step 5 Synthesis of N- (2- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl)) ethyl isonipecotinamide dihydrochloride 1-t- Butoxycarbonyl-N- (2- (4- (5H
-Dibenzo [a, d] cycloheptene-5-ylidene)
-1-Piperidinyl)) To 0.10 g (0.185 mmol) of ethyl isonipecotinamide was added 10 ml of 4M hydrochloric acid / dioxane, and the mixture was stirred at room temperature for 1 hour, and the solvent was distilled off to obtain the title compound. Yield 0.093 g (0.186 mmol) Yield 1
00%

Step 6 1-methoxycarbonyl-N-
Synthesis of (2- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl)) ethyl isonipecotic acid amide hydrochloride N- (2- (4- (5H-dibenzo [A, d] cycloheptene-5-ylidene) -1-piperidinyl)) 0.59 g (1.18) of ethyl isonipecotinamide dihydrochloride
mmol) and 0.8 ml of triethylamine (5.70).
mmol) was dissolved in 50 ml of dichloromethane, and 0.1 ml (1.40 mmol) of methyl chloroformate was added, followed by stirring for 1 hour. After adding 100 ml of dichloromethane and washing with 70 ml of water, 70 ml of 1N sodium hydroxide and 70 ml of saturated saline, the mixture was purified by silica gel column chromatography and converted into hydrochloride to obtain the title compound. Yield 0.39 g (0.75 mmol) Yield 63%

In the same manner as in Production Example A, the compounds shown in Tables 1 to 3 were produced.

[0034]

[Table 1]

[0035]

[Table 2]

[0036]

[Table 3]

Production Example B 1- (4- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-)
Synthesis of piperidinyl) butyl) morpholine Step 1 Synthesis of 1- (4-oxo-4-morpholino-butyryl) -4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) piperidine 4- (5H-dibenzo [ a, d] cycloheptene-5-
0.27 g (1.0 mmol) of ilidene) piperidine,
After stirring 0.12 g (1.2 mmol) of succinic anhydride and 0.17 ml (1.2 mmol) of triethylamine in 50 ml of dichloromethane at room temperature overnight, 0.14 ml (1.6 mmol) of morpholine and 1-ethyl-
0.27 g (1.4 mmol) of 3- (3-dimethylaminopropyl) -carbodiimide hydrochloride was added, and the mixture was further stirred at room temperature for 8 hours. After washing with 30 ml of 1N hydrochloric acid, 30 ml of 1N sodium hydroxide and 30 ml of saturated saline,
It was dried over powdered magnesium sulfate and purified by silica gel column chromatography to obtain the title compound. Yield 0.44 g (1.0 mmol) Yield 100%

Step 2 Synthesis of 1- (4- (4- (5H-dibenzo [a, d] cycloheptene-5-ylidene) -1-piperidinyl) butyl) morpholine dihydrochloride 1- (4-oxo-4- Morpholino-butyryl) -4-
0.45 g (1.00 mmol) of (5H-dibenzo [a, d] cycloheptene-5-ylidene) piperidine was reacted at 0 ° C. with 0.38 g (10.0 mmol) of lithium aluminum hydride in tetrahydrofuran (60 ml). Thereafter, the reaction was carried out in the same manner as in a conventional manner to obtain the title compound. Yield 0.32 g (0.66 mmol) Yield 66%

The compounds shown in Table 4 were produced in the same manner as in Production Example B.

[0040]

[Table 4]

Test Example 1 The binding affinity to the serotonin 2 receptor was evaluated using a bovine cerebral cortex membrane preparation. 3 nM in 200 μl of bovine membrane specimen prepared to 50 mg (wet weight) / ml
200 μl of [ ³ H] -ketanserin and 200 μl of a test drug solution dissolved in 1.7% ethanol were added and mixed.
This was incubated at 25 ° C. for 30 minutes, then filtered through a glass filter, and the radioactivity on the filter was measured with a liquid scintillation counter. Non-specific binding is 1
0 ^-6 defined by LY53857 of M. The concentration (IC ₅₀ value) of the test drug that inhibited the specific binding by [ ³ H] -ketanserin by 50% was determined, and the Ki value was calculated from the following formula.
The results were expressed as the negative logarithm of the Ki value (pKi value).

[0042]

(Equation 1)

In the formula, K _d represents the dissociation constant of the bond, and [L] represents the concentration of [ ³ H] -ketanserin. From the results in Tables 1 to 4, it can be seen that the piperidine derivatives of the present invention show strong binding affinity to the serotonin 2 receptor.

Test Example 2 In vitro platelet aggregation inhibitory action based on serotonin antagonism was measured using SD rats (body weight: about 300 to 400).
g, male). Under diethyl ether anesthesia, platelet-rich plasma (PRP) and platelet-poor plasma (PPP) were collected from 0.38% citrated blood obtained from the abdominal aorta of the rat, and the platelet concentration of PRP was determined using PPP. It was adjusted to × 10 ⁸ cells / ml. Next, this PR
After adding a test drug dissolved in 0.4% ethanol aqueous solution to P and incubating at 37 ° C. for 3 minutes, adenosine diphosphate (ADP) is added to 0.5 μM or 0.8 μM
When added and when ADP is 0.5 μM or 0.8 μM
Aggregation of platelets caused by adding μM and 5 μM of serotonin was measured as an increase in light transmittance of PRP. The negative logarithm of the concentration of the test drug was calculated as pIC ₅₀ , which suppresses the platelet aggregation enhancement by serotonin by 50% when the test drug is not added. The results are shown in Tables 1 to 4.
These results indicate that the piperidine derivative of the present invention strongly inhibits serotonin-induced platelet aggregation.

Test Example 3 Measurement of the ex vivo platelet aggregation inhibitory action based on serotonin antagonism was performed using SD rats (body weight: about 210 to 330
g, male). The test drug was dissolved or suspended in gum arabic and orally administered at the doses shown in Table 6. Two hours after administration of the test drug, the rats were anesthetized with diethyl ether, and PRP and PPP were collected from 0.38% citrated blood obtained from the abdominal aorta. The platelet concentration of PRP was adjusted to 5 × 10 ⁸ / ml using PPP.
Next, after incubating the PRP at 37 ° C. for 3 minutes, the platelet aggregation induced when 0.7 μM of ADP was added and when 5 μM of serotonin was added simultaneously with 0.7 μM of ADP was determined by the light transmission of PRP. It was measured as an increase in degree. Aggregation and AD when ADP alone was added to each group
The maximum aggregation rate due to simultaneous addition of P and serotonin was measured, and the enhanced aggregation derived from serotonin was calculated. 100% of the cohesive enhancement derived from serotonin in the gum arabic group
The effect of the test drug was determined using the aggregation-enhancing component derived from serotonin in the test drug administration group as an index (n = 3).
Table 5 shows the results.

[0046]

[Table 5]

The results show that the piperidine derivative of the present invention strongly inhibits serotonin-induced platelet aggregation even by oral administration.

Test Example 4 Serotonin antagonism in the center was examined by its inhibitory effect on 5-hydroxytryptophan (5HTP) -induced head twitch in mice. IC fasted the day before
Using R mice (27-32 g in weight, male), test drugs 1, 3, 10, and 30 mg were dissolved in 100 ml of water, and 10 ml per kg of body weight was orally administered 90 minutes before 5HTP administration. As a control, 5% gum arabic was used. 15 minutes after subcutaneous administration of carbidopa (6 mg / kg), 5HTP (180 mg / kg) was administered intraperitoneally. Head t for 15 to 2 minutes after 5HTP administration
Count the number of witches and head t of 5% gum arabic group
The drug concentration for suppressing the witch frequency to 50% was determined. The results are shown in Table 6.

[0049]

[Table 6]

From the results shown in the table, it can be seen that the piperidine derivative of the present invention has a low central activity and is highly safe.

[0051]

INDUSTRIAL APPLICABILITY The piperidine derivative of the present invention has a specific strong affinity for serotonin 2 receptor and has a serotonin antagonism, and is clinically useful as a disease caused by serotonin, such as an antiplatelet drug. Is a potential drug.

──────────────────────────────────────────────────の Continued on the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 409/04 211 C07D 409/04 211 (72) Inventor Ryota Yoshimoto 1-1 Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa Prefecture Ajinomoto stock Investigator in the Central Research Laboratories Hidehide Hoshino (56) References JP-A-3-128354 (JP, A) JP-A-5-97808 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB Name) CA (STN) REGISTRY (STN)

Claims (6)

(57) [Claims] 1. A serotonin antagonist comprising, as an active ingredient, a piperidine derivative represented by the following general formula (I) or a salt thereof. Embedded image Wherein A ¹ is a pyridyl, piperidyl, piperidino, morpholinyl, morpholino, thiomorpholinyl, thiomorpholino or piperazinyl group which may have a substituent;
X represents an alkyl group having 1 to 8 carbon atoms having a substituent, a cycloalkyl group having 4 to 8 carbon atoms having a substituent or an alkoxy group having 1 to 8 carbon atoms which may have a substituent; ¹ represents a hydrogen atom or a halogen atom; Y ¹ represents any ^one of the following organic groups, wherein n represents an integer of 0 to 4; Z ¹ represents any of the following organic groups. Embedded image 2. The serotonin antagonist according to claim 1, wherein A ¹ has a substituent, and the substituent is any of the following. Embedded image In the group, R ¹ represents a hydrogen atom, an alkyl or alkoxy group having 1 to 6 carbon atoms, an amino group or an acylaminoalkyl group optionally substituted with an alkyl group, and R ² and R ³ are the same. Alternatively, it represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an acyl group or an alkoxycarbonyl group, or an aminocarbonyl group which may be substituted with an alkyl group. 3. The method according to claim 1, wherein the substituent is formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, carbamoyl, N-methylcarbamoyl, N-ethylcarbamoyl, N-propylcarbamoyl, N, N-dimethylcarbamoyl, N , N-diethylcarbamoyl, N-formylglycyl, N-acetylglycyl, N-formyl-β-alanyl, N-acetyl-
β-alanyl, N-methyl-N-formyl, N-methyl-N-acetyl, N-methyl-N-propionyl, N-
The serotonin antagonist according to claim 1, which is ethyl-N-formyl or N-ethyl-N-acetyl. 4. The serotonin antagonist according to claim 1, wherein Y ¹ is a —CONH— group. 5. The method according to claim 1, wherein Z ¹ is a —CH ＝ CH— group.
The serotonin antagonist according to the above. 6. An antiplatelet drug comprising a piperidine derivative represented by the above general formula (I) or a salt thereof as an active ingredient.