KR840002004B1 - Process for preparing piperazine derivatives - Google Patents

Abstract

A pharmaceutical, injectable soln. for use in reducing intracranial pressure comprises an aq. soln. of I (R = H, C1-7 alkyl, halogeno C1-4 alkyl, C1-4 alkoxycarbonyl-C1-4 alkyl, C3-6 cycloalkyl, C2-5 alkkenyl, C1-4 alkoxy; A = Ph, C1-4 alkylphenyl, halogenophenyl; n = 2-6), their salts and a compd., such as Dmannitol, that will allow adjustment of the osmotic pressure of the parental soln. to that of blood plasma. Thus, the effectiveness of an injection soln. prepd. from 1-[3-(4-acetamido-2methoxyphenoxy)-n-propyl-4-(3-fluorophenyl) piperazine in aq. 5% D-mannitol was demonstrated in rats.

Description

[Name of invention]

Process for the preparation of the pyrazine derivative

Detailed description of the invention

The present invention relates to a method for preparing a piperazine derivative.

The present invention relates to a process for preparing piperazine derivatives of the general formula (I) and pharmaceutically acceptable acid addition salts thereof.

In formula (I), R is hydrogen, (C _1-7 ) alkyl, halogeno (C _1-4 ) alkyl, (C _1-4 ) alkoxycarbonyl- (C _1-4 ) alkyl, (C _3-6 ) cycloalkyl, (C _2-5 ) alkenyl or (C _1-4 ) alkoxy, ring A is phenyl, (C _1-4 ) alkylphenyl or halogenophenyl and n is 2-6 Is an integer.

Brain edema, a known complication of various brain diseases (eg, cerebral hemorrhage, cerebral hemorrhage, cerebral thrombosis, cerebral embolism, head injury, brain tumor, encephalomyelitis), causes an increase in intracranial pressure due to compression of adjacent brain tissue.

Moreover, such intracranial pressure increases are known to cause side effects in brain metabolism, disrupting brain circulation and further worsening brain edema.

Thus, intracranial pressure increases can cause serious damage to patients or sometimes

As a result of various studies, it was found that the piperazine derivative (I) of the present invention resulted in a significant decrease in intracranial pressure. For example, test compound 1- [3- (4-acetamido-2) when a test compound solution in an aqueous solution of 5w / v% mannitol was injected at a rate of 0.2 ml / kg / min in 20 minutes through a femoral vein of a rat. It was found that intracranial pressure decreased by about 27% after 40 minutes of dosing with -methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl) piperazine (dosage 1 mg / kg).

In view of this effect of piperazine derivatives (I) on intracranial pressure, the compounds of the present invention described above can be used for brain impotence fractures, cerebral thrombosis, cerebral hemorrhage, cerebral retinal hemorrhage, head injury, brain tumors, cerebral edema and encephalitis And increased intracranial pressure resulting from various brain diseases such as the analogous disease.

Moreover, since the piperazine derivative (I) of the present invention has a strong depressurizing effect in the central nervous system, this compound is also useful as an antipsychotic, analgesic and / or antiemetic agent.

Compound (I) may be used for medicament as a free base or a pharmaceutically acceptable acid addition salt thereof. Examples of pharmaceutically acceptable acid addition salts of the compound (I) of the present invention include inorganic acid addition salts (eg, hydrochloride, bromate, sulfate, nitrate, phosphate) and organic acid addition salts (eg, vinegar salt, lactate, oxalate, citrate, tartarate, Fumarate, maleate, methanesulfonate, benzoate).

Compound (I) of the present invention may be administered orally or parenterally. The daily dosage of this compound (I) is about 0.05 to 50 mg (as free base), in particular 0.1 to 10 mg (free base) per kg of body weight

In addition, the mixture (I) may be used in the form of a pharmaceutical containing the same compound in the present invention in combination or combined with a pharmaceutical excipient suitable for enteral or parenteral administration. Suitable excipients include, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum, vegetable oils and other known excipients. The medicament may be in the form of a powder, tablet, or solid form of capsule; Or in liquid form such as solutions, suspensions or emulsions. The compound (I) may also be used in the form of injection for red injection.

Examples of piperazine derivatives of the present invention include R being (C _1-7 ) alkyl (eg methyl, ethyl, propyl, isopropyl, butyl, t-butyl, pentyl, hexyl, heptyl); Halogeno (C _1-4 ) alkyl (eg trifluoromethyl); (C _1-4 ) alkoxy-carbonyl- (C _1-4 ) alkyl (eg 2-methoxycarbonylethyl, 2-ethoxycarbonylethyl; (C _3-6 ) cycloalkyl (eg cyclopropyl , Cyclopentyl, cyclohexyl); (C _2-5 ) alkenyl (e.g. 2-methyl-1-propenyl); (C _1-4 ) alkoxy (e.g. methoxy, ethoxy, propoxy, isoprop Foxy, Butoxy, t-butoxy) and Ring A is phenyl, (C _1-4 ) alkylphenyl (e.g. 2-methylphenyl, 3-methylphenyl, 4-methylphenyl) or halogenophenyl (e.g. 2-chloro Phenyl, 3-chlorophenyl, 4-chlorophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl), and n is an integer of 2-6. have.

Examples of preferred subspecies among the piperazine derivatives of the present invention include those in which R is hydrogen, (C _1-7 ) alkyl, (C _3-6 ) cycloalkyl, (C _2-5 ) alkenyl or (C _1-4 ) alkoxy And ring A is phenyl, (C _1- ) alkylphenyl or halogenophenyl, and n is 2-4. The compound of general formula (I) is mentioned.

Examples of other preferred subgenus are R, hydrogen, (C _1-7 ) alkyl, (C _3-6 ) cycloalkyl, (C _2-5 ) alkenyl or (C _1-4 ) alkoxy, and ring A is phenyl, The compound of general formula (I) whose methylphenyl, chlorophenyl, or fluorophenyl, and n is 3 or 4 is mentioned.

Examples of other preferred subgenus include R is hydrogen, methyl, isopropyl, t-butyl, cyclopropyl, cyclohexyl, 2-methyl-1-propenyl, ethoxy or t-butoxy, ring A is phenyl, 3-methylphenyl, 2-fluorophenyl, or 3-fluorophenyl, and n is 3 or 4, The compound of general formula (I) is mentioned.

According to the present invention, compound (I) can be prepared by the method described in the following scheme.

In the above reaction, R, ring, A and n are the same as defined above.

Acylation of compound (II) can be carried out in a solvent with or without an acid acceptor. Methylene chloride, tetrahydrofuran, benzene, chloroform and the like are suitable as solvents. Examples of acid acceptors include organic bases such as triethylamine, pyridine and the like and inorganic bases such as sodium carbonate, potassium carbonate and the like.

Alkyl formate is preferably used as an acylating agent when a formyl group is introduced into compound (II). On the other hand, when introducing an alkoxycarbonyl group, an alkoxycarbonyl halide or 2- (alkoxycarbonylthio) -4,6-dimethylpyridine is used as the acylating agent. In addition, a substituted or unsubstituted alkanoyl or alkenylcarbonyl group can be introduced by using the corresponding acid halide or acid anhydride as the acylating agent.

It is preferable to advance this reaction at the temperature of -10-70 degreeC. When the reaction is carried out using ethyl formate as the acylating agent or pyridine as the acid acceptor, it is not necessary to use a solvent because ethyl formate and pyridine serve as a solvent.

Starting compound (II) in this invention can be manufactured by the method as described in the following reactivity.

In the above reaction scheme, R 'is acyl, each of Y and Z is a reactor or reaction atom, and rings A and n are the same as defined above.

The condensation reaction of compound (II) with compound (IV) and the condensation reaction of compound (V) with compound (VI) include acid acceptors (e.g., organic bases such as triethylamine or N-methylpiperidine; In a solvent at 20 to 100 ° C. (eg, alkanols such as methanol, ethanol or isopropanol, dimethylformamide, dimethylsulfoxide) in the presence of an inorganic base such as sodium bicarbonate).

On the other hand, the starting compounds (III) and (VI) of the above-described reaction may be prepared according to the method described in the following reaction diagram.

Synthesis of Compound (III)

In the above schemes R ″ is (C _1-4 ) alkyl, X is halogen and R ¹ , Y and n are as defined above.

Synthesis of Compound (VI)

R ″, rings A, Z, X and n in the above scheme are the same as defined above.

[Experiment 1]

Intravenous effect of test compound on intracranial pressure in rats

Male SD-rats (each group consisting of 5 rats) weighing 500-800 g were anesthetized with urethane. A test compound solution in an aqueous solution of 5w / v% mannitol was injected through the femoral vein at a rate of 0.2 ml / kg / min for 20 minutes (when the test compound is used in the free base form, the above-mentioned solution is treated with 0.5 N hydrochloric acid). Prepared by dissolving in 5w / v% mannitol aqueous solution with help). Intracranial pressure (ie, cerebrospinal fluid pressure in the cerebellum) is continuously

The pipe was connected to the transmitter and the records were recorded on graph paper. The effect of the test compound on intracranial pressure was measured as the increase or decrease in intracranial pressure, which was calculated according to the following equation.

The results are listed in Table 1 below.

TABLE 1

[Experiment 2]

(Inhibitory Effects of Test Compounds on the Central Nervous System in Rats)

The inhibitory effect of the test compound on the central nervous system was measured by the following method.

(1) Inhibitory effect on spontaneous motor activity:

A test compound solution or suspension added in water or aqueous carboxymethylcellulose solution was administered intraperitoneally to males of 18-20 g (each group consisting of 5 mice) body weight. Thirty minutes after administration of the test compound, the spontaneous motor activity of the rats was measured by an animex activity meter for 5 minutes. The 50% dose of the test compound (ED ₅₀ ) was calculated as the dose necessary to reduce the motor activity of the mice administered to 50% of the motor activity of the control group (ie, non-drug rats).

The results are listed in Table 2.

(2) Effect on Hexobarbital Sodium Injection Anesthesia:

50% effective dose (ED ₅₀ ) of the test compound added in water or aqueous carboxymethylcellulose solution of control rats (ie, non-drug rats) The dose required to reduce to 50% of the number was calculated.

The results are listed in Table 4.

TABLE 2

TABLE 3

TABLE 4

[Experiment 3]

18-22 g of test compound solution or suspension added in water or aqueous carboxymethylcellulose solution (each group consists of 5 mice) was administered intraperitoneally of male rats of body weight, and these mice were observed for 72 hours after test compound administration. It was. The result is 1 [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl) -piperazine and 1- [3- (4-acetamido -2-methoxyphenoxy) -n-propyl] -4- (2-fluorophenyl) -piperazine and 1- [3- (4-ethoxycarbonylamino-2-methoxyphenoxy) -n The maximum permissible dose of -propyl] -4-phenyl-piperazine methanesulfonate was at least 300 mg / kg.

Example 1

A mixture of 1 g, 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine and 30 ml of ethyl formate was refluxed for 76 hours. After the reaction, the mixture is evaporated to remove excess ethyl formate. The residue is dissolved in isopropyl alcohol and then treated with activated carbon.

This gives 750 mg of 1- [3- (4-formylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine as a pale yellow granular material. Yield: 69.4

Melting point 113-115 ℃

(cm^-1) : 3295, 1670, 1130, 1040

(cm ^-1 ): 3295, 1670, 1130, 1040

NMR (CDCl ₃ ) δ: 8.61 (s, 1H, HCO-NH-), 7.99 (wide s, 1H, HCONH-), 7.6-6.8 (m, 8H, aromatic), 4.06 (t, 2H, J = 6.7 Hz, -OCH ₂ CH _2- ), 3.81 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.25-1.7 (m, 2H)

Mass m / e: 369 (M ⁺ ), 203, 175 (reference peak)

Example 2

1 g of 1- [3- (4-amino-2-methoxyphenoxy-n-propyl] -4-phenyl-piperazine, 586 mg of a solution of 468 mg of isobutyl chloride dissolved in 3 ml of methylene chloride under ice-cooling Was added dropwise to a mixture of triethylamine and 40 ml of methylene chloride, and the mixture was stirred for 1 hour at room temperature After the reaction, methylene chloride was added to the mixture, and the mixture was washed with water and dried and then evaporated under reduced pressure. The residue is recrystallized in ethyl acetate to give 1.1 g of 1- [3- (4-isobutylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine colorless Obtained as acicular material Yield: 92%

Melting Point 171-172 ℃

(cm^-1) : 3270, 1650, 1135, 1040

(cm ^-1 ): 3270, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.6-6.7 (s, 9H, aromatic and -CO-NH-), 4.07 (t, 2H, _{2 2 3 3 2}

Mass m / e: 411 (M ⁺ ), 203, 175 (reference peak)

Example 3

1.0 g 1- [3- (4-amino-2-methoxyphenoxy-n-propyl] -4-phenyl-piperazine, 586 mg triethylamine, 529 mg t-butylcarbonyl chloride and 43 ml chloride Methylene is treated in the same manner as in Example 2.

The crude product thus obtained was recrystallized in isopropyl alcohol to give 1.09 g of 1- [3- (4-t-butylcarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-pipe Razine is obtained as a colorless needle. Yield: 87.2%

Melting point 140-142 ℃

(cm^-1) : 3320, 1645, 1140, 1040

(cm ^-1 ): 3320, 1645, 1140, 1040

NMR (CDCl ₃ ) δ: 8.40 (wide s, 1H, -NH-), 7.5-6.6 (m, 8H, aromatic), 4.05 (t, 2H, J = 6.5 Hz, -OCH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.0 (m, 2H), 1.29 (s, 9H, -C (CH ₃ ) ₃ )

Mass m / e: 425 (N ⁺ ), 203, 175

Example 4

1.0 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, 586 mg triethylamine, 459 mg cyclopropylcarbonyl chloride and 43 ml chloride Methylene was treated in the same manner as in Example 2.

The crude product thus obtained was recrystallized in ethyl acetate to give 910 mg of 1- [3- (4-cyclopropylcarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, colorless Obtained as acicular material. Yield: 75.8%

Melting Point 160.5-162.5 ℃

(cm^-1) : 3280, 3050, 1640, 1140, 1040

(cm ^-1 ): 3280, 3050, 1640, 1140, 1040

), 1.15-0.6 m, 4H, -CO-◁)NMR (CDCl ₃ ) δ: 7.9 (wide s, 1H, -NH-), 7.5-6.6 (m, 8H, aromatic), 4.05 (t, 2H, J = 6.0 Hz, -OCH ₂ CH _2- ), 3.78 (s, 3H, -OCH ₃ ), 3.35-3.0 (m, 4H), 2.75-2.3 (m, 6H), 2.0 (m, 2H), 1.50 (m, 1H, -CO

), 1.15-0.6 m, 4H, -CO- ◁)

Mass m / e: 409 (M ⁺ ), 203, 175 (reference peak)

Example 5

1.0 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, 586 mg triethylamine, 644 mg cyclohexylcarbonyl chloride and 43 ml chloride Methylene is treated in the same manner as in Example 2. The crude product thus obtained was recrystallized in ethyl acetate to yield 1.17 g of 1- [3- (4-cyclohexylcarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine. Obtained as a colorless needle. Yield:

Melting point 162-163.5 ℃

(cm^-1) : 3270, 1650, 1140, 1130, 1035

(cm ^-1 ): 3270, 1650, 1140, 1130, 1035

NMR (CDCl ₃ ) δ: 7.7-6.8 (m, 9H, aromatic -NH-), 4.08 (t, 2H, J = 6.2 Hz, -OCH ₂ CH _2- ), 3.83 (s, 3H, -OCH ₃ ) , 3.4-3.0 (m, 4H), 2.8-2.35 (m, 7H), 2.3-1.0 (m, 12H)

Mass m / e: 451 (M ⁺ ), 203, 175

Example 6

1.0 g 1- [3- (4-amino-2-methoxyphenoxy-n-propyl] -4-phenyl-piperazine, 586 mg triethylamine, 494 mg (2-methyl-1-propenyl) Carbonyl chloride and 43 ml of methylene chloride were treated in the same manner as in Example 2. The crude product thus obtained was recrystallized in ethyl acetate to give 596 mg of 1- {3- [4-((2-methyl-1- Propenyl) carbonylamino) -2-methoxyphenoxy] -n-propyl} -4-phenyl-piperazine is obtained as a colorless granular material Yield: 48%

Melting point 136-138 ℃

(cm^-1) : 3275, 1655, 1140, 1040, 800

(cm ^-1 ): 3275, 1655, 1140, 1040, 800

NMR (CDCl ₃ ) δ: 7.8-6.7 (m, 9H, aromatic and -NH-), 5.03 (wide m, 1H, -CO-CH = C <), 4.06 (t, 2H, J = 6.5 Hz,- OCH ₂ CH _2- ), 3.81 (s, 3H, -OCH ₃ ), 3.4- _{3 2}

Mass m / e: 423 (M ⁺ ), 203, 175 (reference peak)

Example 7

1 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, 439 ml triethyl amine, 479 mg methoxycarbonyl chloride and 43 ml chloride Methylene is treated in the same manner as in Example 2. The crude product thus obtained was recrystallized in isopropyl ether to give 960 mg of 1- [3- (4-ethoxycarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine as a colorless needle. Obtained as material. Yield: 79.2%

Melting Point 106.5-107.5 ℃

(cm^-1) : 3330, 1690, 1235, 1140

(cm ^-1 ): 3330, 1690, 1235, 1140

NMR (CDCl ₃ ) δ: 7.45-6.6 (m, 9H, aromatic and -NH-), 4.1 (q, 2H, J = 7.0 Hz, -CO ₂ -CH ₂ -CH ₃ ), 4.05 (t, 2H, J = 6.3 Hz, -OCH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.4-3.1 (m, 4H), 2.8-2.4 (m, 6H), 2.8-2.4 (m, 6H) , 1.29 (t, 3H, J = 7.0 Hz, -CO ₂ CH ₂ CH ₃ )

Mass m / e: 413 (M ⁺ ), 368, 203, 175 (reference peak)

Methanesulfonate:

Melting point 198-199 ° C (colorless needle, recrystallized in ethanol)

(cm^-1) : 3260, 2700-2400, 1695, 1230, 1040

(cm ^-1 ): 3260, 2700-2400, 1695, 1230, 1040

Hydrochloride:

Melting point 233-235 ° C. (decomposition) (colorless granular, recrystallized in methanol)

(cm^-1) : 3200, 2600-2300, 1705, 1230,

(cm ^-1 ): 3200, 2600-2300, 1705, 1230,

Example 8

1 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, 1.06 g 2- (t-butoxycarbonylthio) -4,6 -A mixture of dimethylpyrimidine and 15 ml of anhydrous tetrahydrofuran is refluxed for 65 hours. After the reaction, the mixture is evaporated under reduced pressure to remove tetrahydrofuran. Methylene chloride is added to this residue and the mixture is washed successively with 10% aqueous sodium hydroxide solution and water.

The mixture is dried and then evaporated under reduced pressure to remove the solvent. The residue is purified by silica gel chromatography (solvent; 1.5% methanol / chloroform) and then recrystallized from a mixture of benzene and n-hexane. Thus, 1.31 g of 1- [3- (4-t-butoxycarbonylamino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine is obtained as a colorless needle. Yield: 85%

Melting point 125-126.5 ℃

(cm^-1) : 3350, 1690, 1160, 1000

(cm ^-1 ): 3350, 1690, 1160, 1000

NMR (CDCl ₃ ) δ: 7.44-6.8 (m, 9H, aromatic and -NH-), 4.09 (t, 2H, _{2 2 3 3 3}

Mass m / e: 441 (M ⁺ ), 175 (reference peak)

Example 9

1.0 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine, 586 mg triethylamine, 529 mg n-pentane oil and 43 ml Methylene chloride is treated in the same manner as in Example 2. The crude product thus obtained was recrystallized in isopropyl alcohol to give 840 mg of 1- [3- (4-pentaneamido-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine as a colorless needle. Obtained as material. Yield: 67%

Melting point 117-118 ℃

(cm^-1) : 3300, 1650, 1140, 1040, 1020

(cm ^-1 ): 3300, 1650, 1140, 1040, 1020

NMR (CDCl ₃ ) δ: 7.65 (wide s, 1H, -NH-), 7.5-6.7 (m, 8H, aromatic), 4.03 (t, 2H, J = 6.5 Hz, -OCH ₂ CH _2- ), 3.79 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-1.0 (m, 14H), 0.91 (wide t, 3H, J = 6.5 Hz, CH ₃ CH _2- )

Mass m / e: 425 (M ⁺ ), 203, 175

Example 10

1 g of 1- [3- (4-amino-2-methoxyphenoxy-n-propyl] -4-phenyl-piperazine and 878 mg of triethylamine are dissolved in 40 ml of methylene chloride, and methylene chloride is added thereto. A solution of 1.84 g of trifluoroacetic anhydride dissolved in 3 ml is added dropwise at a temperature not higher than 10 ° C. The mixture is stirred at room temperature for 4 hours, and then methylene chloride is added to the reaction mixture, and the mixture is washed with water and dried. The resulting residue was purified by silica gel chromatography (solvent; 1% methanol / chloroform) to yield 787 mg of 1- [3- (4-trifluoroacetami). Fig. 2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine yield: 61.5%

Melting Point 144.5-145.5 ℃

(cm^-1) : 3290, 1700, 1150, 1140, 1035

(cm ^-1 ): 3290, 1700, 1150, 1140, 1035

NMR (CDCl ₃ ) δ: 8.26 (wide, 1H, -NH-), 7.6-6.8 (m, 8H, aromatic), 4.10 (t, 2H, J = 6.5 Hz, -OCH ₂ CH _2- ), 3.83 ( s, 3H, -OCH ₃ ), 3.4-3.1 (m, 4H), 2.9-2.4 (m, 6H), 2.4-1.9 (m, 2H)

Mass m / e: 437 (M ⁺ ), 203, 175 (reference peak)

Example 11

1 g of 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine 586 mg triethylamine, 714 ml n-octanyl chloride and 43 ml methylene chloride The treatment was carried out in the same manner as in Example 2. The crude product thus obtained was re-purified in ethyl acetate.

Melting point 124-126 ℃

(cm^-1) : 3280, 1650, 1135, 1040, 1020

(cm ^-1 ): 3280, 1650, 1135, 1040, 1020

NMR (CDCl ₃ ) δ: 7.7-6.7 (m, 9H, aromatic and -NH-), 4.07 (t, 2H, J = 6.3 Hz, -OCH ₂ CH _2- ), 3.83 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-1.0 (m, 2OH), 0.88 (wide t, 3H, -CO ₂ CH ₃ )

Mass m / e: 467 (M ⁺ ), 203, 175

Example 12

2.0 g 1- [3- (4-amino-2-methoxyphenoxy) -n-propyl] -4-phenyl-piperazine 800 mg triethylamine, 1.0 g 3-methoxycarbonyl-propy O'Neill and 30 ml of methylene chloride were treated in the same manner as in Example 2.

The crude product thus obtained was recrystallized in ethyl acetate to give 2.51 g of 1- {3- [4- (3-methoxycarbonyl-propionamido) -2-methoxyphenoxy] -n-propyl}- 4-phenyl-piperazine is obtained as a colorless needle.

Yield: 94%

Melting point 134-136 ℃

(cm^-1) : 3360, 1725, 1670, 1140

(cm ^-1 ): 3360, 1725, 1670, 1140

NMR (CDCl ₃ ) δ: 7.90 (wide s, 1H, -NH-), 7.6-6.65 (m, 8H, aromatic), 4.04 (t, 2H, J = 6.3 Hz, -OCH ₂ CH _2- ), 3.79 (s, 3H, -OCH ₃ ), 3.66 (s, 3H, -CO ₂ CH ₃ ), 3.45-3.0 (m, 4H), 2.9-2.3 (m, 10H), 2.3 = 1.8 (m, 2H)

Mass m / e: 455 (M ⁺ ), 203, 175 (reference peak)

[Examples 13 to 30]

The following compounds can be obtained by the same method described in Example 2.

13: 1- [3- (4-acetamido-2-methoxyphenoxy] -n-propyl] -4- (4-methylphenyl) -piperazine: colorless tree leaf material

Melting point 144-145 ° C. (purification by silica gel chromatography (solvent: 3% methanol / chloroform))

(cm^-1) : 3250, 1650, 1140, 1040

(cm ^-1 ): 3250, 1650, 1140, 1040

NMR (CDCl ₃ ) δ: 7.92 (wide s, -NH-), 7.32 (d, 1H, J = 1.5 Hz, aromatic), 7.3-6.8 (m, 2H, aromatic), 7.10 (d, 2H, J = 8.9 Hz, aromatic), 6.84 (d, 2H, J = 8.9 Hz aromatic), 4.06 (t, 2H, J = 6.0 Hz, -OCH ₂ CH _2- ), 3.80 (s, 3H, -OCH ₃ ), 3.16 (m, 4H), 2.58 (m, 6H), 2.26 (s, 3H, -Ph-CH ₃ ), 2.11 (s, 3H, CH ₃ CONH-), 2.00 (m, 2H)

Mass m / e: 397 (M ⁺ ), 189 (reference peak)

14: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (4-chloro

Melting Point 152-153 ° C (Recrystallized from Acetone)

(cm^-1) : 3320, 1650, 1055, 1045

(cm ^-1 ): 3320, 1650, 1055, 1045

NMR (CDCl ₃ ) δ: 7.75 (wide s, 1H, -NH-), 7.30 (wide s, 1H, aromatic), 7.22 (d, 2H, J = 9 Hz, aromatic), 7.1-6.8 (m, 2H, Aromatic), 6.82 (d, 2H, J = 9 Hz, aromatic), 4.07 (t, 2H, J = 5.9 Hz, -OCH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.4-3.0 ( m, 4H), 2.8-2.4 (m, 6H), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 419, 417 (M ⁺ ), 211, 209 (reference peak)

15: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (4-fluorophenyl) -piperazine: colorless prismatic material

Melting point 137-138 ° C (recrystallized in acetone)

(cm^-1) : 3250-3070, 1650, 1135, 1040

(cm ^-1 ): 3250-3070, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.92 (wide s, 1H, NH), 7.36 (d, 1H, J = 1.5 Hz, aromatic), 7.2-6.7 (m, 6H, aromatic), 4.09 (t, 2H, J = 6.6 Hz, -OCH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.4-2.9 (m, 4H), 2.9-2.4 (m, 6H), 2.13 (s, 3H, CH ₃ CONH- ), 2.1-1.8 (m, 2H)

Mass m / e: 401 (M ⁺ ), 193 (reference peak)

16: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (4-methylphenyl) -piperazine: colorless acicular material

Melting point 113-114 ° C (recrystallized in acetone)

(cm^-1) : 3250, 1650, 1135, 1040

(cm ^-1 ): 3250, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.79 (wide s, 1H, -NH-), 7.6-6.5 (m, 7H, aromatic), 4.08 (t, 2H, J = 6.5 Hz, -OCH ₂ CH _2- ), 3.83 (s, 3H, -OCH ₃ ), 3.4-3.30 (m, 4H), 2.8-2.3 (m, 6H), 2.32 (s, 3H, -Ph-CH ₃ ), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 397 (M ⁺ ), 189 (reference peak)

17: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-fluorophenyl) -piperazine: colorless acicular material

Melting Point 136-137 ° C (Recrystallized from Isopropyl Alcohol)

(cm^-1) : 3275, 1660, 1135, 1035

(cm ^-1 ): 3275, 1660, 1135, 1035

NMR (CDCl ₃ ) δ: 7.89 (wide s, 1H, -NH-), 7.5-6.2 (m, 7H, aromatic), 4.10 (t, 2H, J = 6.7 Hz, -OCH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.13 (s, 3H, CH ₃ CONH-)

Mass m / e: 401 (M ⁺ ), 193 (reference peak)

18: 1- [3- (4-acetamido-2-methoxyphenoxy] -n-propyl] -4- (2-chlorophenyl) -piperazine: colorless prismatic material

Melting Point 115-116 ° C (Recrystallized from Isopropyl Alcohol)

(cm^-1) : 3275, 1655, 1140, 1040

(cm ^-1 ): 3275, 1655, 1140, 1040

NMR (CDCl ₃ ) δ: 7.84 (wide s, 1H, -NH-), 7.6-6.8 (m, 7H, aromatic), 4.11 (t, 2H, J = 6.5 Hz, -OCH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.3-3.0 (m, 4H), 2.9-2.5 (m, 6H), 2.4-1.8 (m, 2H), 2.14 (s, 3H, CH ₃ CONH-)

Mass m / e: 419, 417 (M ⁺ ), 211, 209 (reference peak)

19: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (2-fluorophenyl) -piperazine: colorless prismatic material

Melting Point 122.5-123.5 ° C (Recrystallized from Isopropyl Alcohol)

(cm^-1) : 3270, 1655, 1140, 1040

(cm ^-1 ): 3270, 1655, 1140, 1040

NMR (CDCl ₃ ) δ: 7.91 (wide s, 1H, -NH-), 7.37 (wide s, 1H, aromatic), 7.2-6.7 (m, 6H, aromatic), 4.11 (t, 2H, J = 6.6 Hz , -OCH ₂ CH _2- ), 3.84 (s, 3H, -OCH ₃ ), 3.3-2.9 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.14 (s , 3H, CH ₃ CONH-)

Mass m / e: 401 (M ⁺ ), 193 (reference peak)

Hydrochloride:

Melting point 265-268 ° C (decomposition) (colorless needles, recrystallized in methanol)

(cm^-1) : 3240-3100, 2600-2300, 1670, 1135, 1040

(cm ^-1 ): 3240-3100, 2600-2300, 1670, 1135, 1040

Methanesulfonate:

Melting point 196-197 ° C (colorless needles, recrystallized in ethanol)

(cm^-1) : 3250-3100, 2700-2400, 1670, 1170, 1030, 1040

(cm ^-1 ): 3250-3100, 2700-2400, 1670, 1170, 1030, 1040

20: 1- [4- (4-acetamido-2-methoxyphenoxy) -n-butyl] -4- (2-fluorophenyl) -piperazine: colorless acicular material

Melting point 115-116.5 ° C. (recrystallized from isopropyl alcohol and isopropyl ether mixture)

(cm^-1) : 3270, 3150, 1655, 1130, 1030

(cm ^-1 ): 3270, 3150, 1655, 1130, 1030

NMR (CDCl ₃ ) δ: 7.89 (wide s, 1H, -NH-), 7.25-6.85 (m, 7H, aromatic), 3.98 (wide t, 2H, J = 5.5 Hz, -OCH ₂ CH _2- ), 3.79 (s, 3H, -OCH ₃ ), 3.2-2.9 (m, 4H), 2.7-2.3 (m, 6H), 2.12 (s, 3H, CH ₃ CONH-), 2.1-1.7 (m, 2H)

Mass m / e: 415 (N ⁺ ), 235 (reference peak), 193

Methanesulfonate:

Melting point 169-170 ° C (colorless platelets, recrystallized from isopropyl alcohol)

(cm^-1) : 3250, 2700-2400-2400, 1670, 1150, 1035

(cm ^-1 ): 3250, 2700-2400-2400, 1670, 1150, 1035

21: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-butyl] -4-phenyl-piperazine: colorless acicular material

Melting point 136-137 ° C (recrystallized from benzene)

(cm^-1) : 3240, 1650, 1130, 1040

(cm ^-1 ): 3240, 1650, 1130, 1040

NMR (CDCl ₃ ) δ: 7.93 (wide s, 1H, -NH-), 7.6-6.7 (m, 8H, aromatic), 4.08 (t, 2H, J = 6.4 Hz, -OCH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.5-3.1 (m, 4H), 2.8-2.4 (m, 6H), 2.35-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 383 (M ⁺ ), 175 (reference peak)

Hydrochloride:

Melting point 281-283 ° C (decomposition) (colorless needles, recrystallized in methanol)

(cm^-1) 3230, 2450, 1655, 1600, 1130, 1035

(cm ^-1 ) 3230, 2450, 1655, 1600, 1130, 1035

Methanesulfonate:

Melting point 197-199 ° C (colorless needles, recrystallized in ethanol)

(cm^-1) : 3580, 3260, 1680, 1170, 1160, 1045

(cm ^-1 ): 3580, 3260, 1680, 1170, 1160, 1045

22: 1- [3- (4-acetamido-2-methoxyphenoxy) -n-propyl] -4- (3-chloro

Melting Point 138-139 ° C (Recrystallized from Isopropyl Alcohol)

(cm^-1) : 3280, 1655, 1140, 1040

(cm ^-1 ): 3280, 1655, 1140, 1040

NMR (CDCl ₃ ) δ: 7.79 (wide s, 1H, -NH-), 7.5-6.6 (m, 7H, aromatic), 4.10 (t, 2H, J = 6.1 Hz, -OCH ₂ CH _2- ), 3.85 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.8 (m, 2H), 2.14 (s, 3H, CH ₃ CONH-)

Mass m / e: 419, 417 (M ⁺ ), 211, 209 (reference peak)

23: 1- [3- (4-acetamido-2-methoxyphenoxy-n-propyl-4- (2-methylphenyl) -piperazine: colorless prismatic material

Melting Point 109-110 ° C (Recrystallized In Acetone)

(cm^-1) : 3275, 1655, 1135, 1040

(cm ^-1 ): 3275, 1655, 1135, 1040

NMR (CDCl ₃ ) δ: 7.82 (wide s, 1H, -NH-), 7.5-6.7 (m, 6H, aromatic), 4.08 (t, 2H, J = 6.4 Hz, -OCH ₂ CH _2- ), 3.82 (s, 3H, -OCH ₃ ), 3.15-2.8 (m, 4H), 2.8-2.4 (m, 6H), 2.30 (s, 3H, -Ph-CH ₃ ), 2.3-1.8 (m, 2H), 2.12 (s, 3H, CH ₃ CONH-)

Mass m / e: 397 (N ⁺ ), 189 (reference peak)

24: 1- [4- (4-acetamido-2-methoxyphenoxy) -n-butyl] -4-phenyl-piperazine: colorless acicular material

Melting Point 128-129 ° C (Recrystallized from Benzene)

(cm^-1) : 3250, 1650, 1135, 1040

(cm ^-1 ): 3250, 1650, 1135, 1040

NMR (CDCl ₃ ) δ: 7.45 (wide s, 1H, -NH-), 7.1-6.3 (m, 8H, aromatic), 3.78 (t, 2H, J = 5.2 Hz, -OCH ₂ CH _2- ), 3.59 (s, 3H, -OCH ₃ ), 3.2-2.8 (m, 4H), 2.65-2.1 (m, 6H), 1.97 (s, 3H, CH ₃ CONH-) 1.9-1.3 (m, 4H)

Mass m / e: 397 (M ⁺ ), 217 (reference peak), 175

Methanesulfonate:

Melting point 184-185 ° C (colorless platelets, recrystallized from ethanol)

(cm^-1) : 3400, 3280, 2800-2300, 1670, 1145, 1045

(cm ^-1 ): 3400, 3280, 2800-2300, 1670, 1145, 1045

25: 1- [2- (4-acetamido-2-methoxyphenoxy) ethyl] -4- (2-fluorophenyl) -piperazine: colorless scale substance

Melting point 118-119 ° C. (recrystallized from ethyl acetate and n-hexane)

(cm^-1) : 3250, 3200, 1655, 1140

(cm ^-1 ): 3250, 3200, 1655, 1140

NMR (CDCl ₃ ) δ: 8.00 (wide s, 1H, -NH-), 7.4-6.45 (m, 7H, aromatic), 4.11 (t, 2H, J = 6.0 Hz, -OCH ₂ CH _2- ), 3.75 (s, 3H, -OCH ₃ ), 3.45-2.45 (m, 10H), ₃

Mass m / e: (M ⁺ ), 207, 193 (reference peak)

Hydrochloride:

Melting point 178.5-179.5 ° C (colorless needles, recrystallized from isopropyl alcohol and isopropyl ether mixture)

(cm^-1) : 3250, 2700-2300, 1670, 1140, 1030, 1010

(cm ^-1 ): 3250, 2700-2300, 1670, 1140, 1030, 1010

26: 1- [6- (4-acetamido-2-methoxyphenoxy) -n-hexyl] -4-phenyl-piperazine: colorless scale substance

Melting point 103-104 ° C. (recrystallized from ethyl acetate)

(cm^-1) : 3250, 3200, 1660, 1140, 1030

(cm ^-1 ): 3250, 3200, 1660, 1140, 1030

NMR (CDCl ₃ ) δ: 7.7 (wide s, 1H, -NH-), 7.45-6.5 (m, 8H, aromatic), 3.97 (wide t, 2H, J = 6 Hz, -OCH ₂ CH _2- ), 3.78 (s, 3H, -OCH ₃ ), 3.5-2.95 (m, 4H), 2.8-1.0 (m, 14H), 2.10 (s, 3H, CH ₃ CONH-)

Mass m / e: 425 (M ⁺ ), 175 (reference peak)

Hydrochloride:

Melting point 183-185 ° C. (decomposition) (colorless needles, recrystallized from a mixture of methanol and isopropyl alcohol)

(cm^-1) : 3250, 2700-2400, 1680, 1130, 1030

(cm ^-1 ): 3250, 2700-2400, 1680, 1130, 1030

27: 1- [2- (4-acetamido-2-methoxyphenoxy) ethyl] -4-phenyl-piperazine: colorless prismatic material

Melting point 134-135 ° C. (recrystallized in benzene)

(cm^-1) : 3200, 1645, 1600, 1150, 1140, 1030

(cm ^-1 ): 3200, 1645, 1600, 1150, 1140, 1030

NMR (CDCl ₃ ) δ: 7.96 (wide 1H, -NH-, quenched by D ₂ O), 7.5-6.5 (m, 8H, aromatic), 4.14 (t, 2H, J = 5.9 Hz, -OCH ₂ CH _2- ), 3.78 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 3.0-2.4 (m, 6H), 2.10 (s, 3H, CH ₃ CONH-)

Mass m / e: 369 (M ⁺ ), 189, 175 (reference peak)

Methanesulfonate:

Melting point 147-148 ° C. (colorless prismatic material, recrystallized from isopropyl alcohol)

(cm^-1) : 3300-3000, 2800-2400, 1665, 1600, 1165, 1130, 1040

(cm ^-1 ): 3300-3000, 2800-2400, 1665, 1600, 1165, 1130, 1040

28: 1- [3- (4-ethoxycarbonylamino-2-methoxyphenoxy) -n-propyl] -4- (3-methylphenyl) -piperazine: colorless acicular material

Melting point 112-113 ° C (recrystallized from isopropyl ether)

(cm^-1) : 3340, 1695, 1530, 1240, 1140

(cm ^-1 ): 3340, 1695, 1530, 1240, 1140

NMR (CDCl ₃ ) δ: 7.4-6.3 (m, 8H, aromatic and -NH-), 4.20 (q, 2H, J = 7.0 Hz, -COOCH ₂ CH ₃ ), 4.05 (t, 2H, J = 6.1 Hz , -O-CH ₂ CH _2- ), 3.85 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.4 (m, 6H), 2.30 (s, 3H, -CH ₃ ) , 2.3-1.6 (m, 2H), 1.29 (t, 3H, J = 7.0Hz, -COOCH ₂ CH ₃ )

Mass m / e: 427 (M ⁺ ), 381, 217, 189 (reference peak)

Methanesulfonate:

Melting point 182-183 ° C (colorless needles, recrystallized in ethanol)

(cm^-1) : 3250, 2800-2300, 1720, 1230, 1170, 1040

(cm ^-1 ): 3250, 2800-2300, 1720, 1230, 1170, 1040

29: 1- [3- (4-ethoxycarbonylamino-2-methoxyphenoxy) -n-propyl] -4- (3-chlorophenyl) -piperazine: colorless acicular material

Melting point 109-110 ° C. (recrystallized from isopropyl ether and benzene mixture)

(cm^-1) : 3350, 1695, 1235, 1140

(cm ^-1 ): 3350, 1695, 1235, 1140

NMR (CDCl ₃ ) δ: 7.4 (m, aromatic and 8H, -NH-), 4.22 (q, 2H, J = 7.0 Hz, -COOCH ₂ CH ₃ ), 4.07 (t, 2H, J = 6.3 Hz,- O-CH ₂ CH _2- ), 3.85 (s, 3H, -OCH ₃ ), 3.4-3.0 (m, 4H), 2.8-2.3 (m, 6H), 2.3-1.6 (m, 2H), 1.31 (t , 3H, J = 7.0 Hz, -COOCH ₂ CH ₃ )

Mass m / e: 449, 447 (M ⁺ ), 401, 239, 237, 211, 209 (reference peak)

Methanesulfonate:

Melting point 163-164 ° C (colorless granular material, recrystallized in ethanol)

(cm^-1) : 3260, 2750-2400, 1715, 1220, 1165, 1045

(cm ^-1 ): 3260, 2750-2400, 1715, 1220, 1165, 1045

30: 1- [3- (4-ethoxycarbonylamino-2-methoxyphenoxy) -n-propyl] -4- (3-chlorophenyl) -piperazine: colorless acicular material

Melting point 114-115 ° C. (recrystallized from isopropyl ether and benzene mixture);

(cm^-1) : 3340, 1695, 1240, 1140

(cm ^-1 ): 3340, 1695, 1240, 1140

NMR (CDCl ₃ ) δ: 7.4-6.3 (m, 8H, aromatic and -NH-), 4.23 (q, 2H, J = 7.0 Hz, -COOCH ₂ CH ₃ ), 4.07 (t, 2H, J = 6.3 Hz , -O-CH ₂ CH _2- ), 3.86 (s, 3H, -OCH ₃ ), 3.4-3.1 (m, 4H), 2.8-2.4 (m, 6H), 2.3-1.7 (m, 2H), 1.30 (t, 3H, J = 7.0 Hz, -COOCH ₂ CH ₃ )

Mass m / e: 431 (M ⁺ ), 385, 221, 193 (reference peak)

Methanesulfonate:

Melting point 188-189 ° C (colorless needles, recrystallized in ethanol)

(cm^-1) : 3270, 2750-2400, 1710, 1220, 1175, 1160, 1040

(cm ^-1 ): 3270, 2750-2400, 1710, 1220, 1175, 1160, 1040

Claims (1)

The following compound of formula (II) is reacted with an acylating agent capable of introducing RCO- groups such as alkyl formate, acid halide, acid anhydride and the like, and the piperazine derivative of formula (I) or a pharmaceutically acceptable acid moiety thereof. Preparation of salt.

In the formulas (I) and (II), R is hydrogen, (C _1-7 ) alkyl, halogeno (C _1-4 ) alkyl, (C _1-4 ) alkoxy-carbonyl- (C _1-4 ) Alkyl, (C _3-6 ) cycloalkyl, (C _2-5 ) alkenyl or (C _1-4 ) alkoxy, ring A is phenyl, (C _1-4 ) alkylphenyl or halogenophenyl, and n is an integer of 2-6.