JP3229693B2 - Piperazine derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia by inhibiting nucleoside transport across the membrane and increasing extracellular adenosine concentration. A piperazine derivative or a pharmaceutically acceptable salt thereof useful for

[0002]

2. Description of the Related Art Compounds having an adenosine uptake inhibitory activity are known to exhibit a cardioprotective activity [Circul., Vol. 80, 1400-14.
11 (1989); American Journal of Physiology (Am. J. Physiol.), H1570-
1577 (1991); Journal of Cardiovascular Pharmacology (J. Cardiovasc.
Pharmacol.), 20, 173-178 (1992).
Year)]. Further, in connection with the present invention, R75231, a nucleoside transport inhibitor (JP-A-63-290869), is a compound having an action of protecting the heart from myocardial damage caused by ischemia, anoxia or hypoxia. Gazette) is known.

[0003]

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[0004]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel piperazine derivative having a nucleoside transport inhibitory activity, which is useful for cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia. It is to provide a pharmaceutically acceptable salt thereof.

[0005]

According to the present invention, there is provided a compound of the formula (I)

[0006]

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(Wherein R ¹ , R ² and R ³ are the same or different and each represents hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy,
Carbamoyl, mono- or di-lower alkylaminocarbonyl, trifluoromethyl, hydroxy, halogen, nitro, amino, mono- or di-lower alkylamino or cyano, R ⁴ represents hydrogen or halogen, X is hydrogen, carbamoyl, mono or Di-lower alkylaminocarbonyl, lower alkoxycarbonyl or carboxy
And n represents an integer of 1 to 3, and Ar represents a substituted or unsubstituted aryl or a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof. .

Hereinafter, the compound represented by the formula (I) is referred to as compound (I). The same applies to compounds of other formula numbers. In the definition of each group of the formula (I), the lower alkyl moiety of lower alkyl and lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, mono- or di-lower alkylaminocarbonyl, mono- or di-lower alkylamino may be straight-chain or branched. C1-C6, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, etc., and halogen is fluorine, chlorine, It means each atom of bromine and iodine. Examples of the aryl include phenyl and naphthyl, and examples of the heterocyclic group include pyridyl, pyrazolyl, quinolyl, and quinazolyl.

The substituents of the substituted aryl and the substituted heterocyclic groups may be the same or different, and may have 1 to 3 halogen atoms, nitro, amino, cyano, hydroxy, trifluoromethyl, lower alkyl, lower alkoxy, lower alkanoyl, Lower alkoxycarbonyl, mono- or di-lower alkylamino and the like. In the definition of the substituent, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl and mono- or di-lower alkylamino have the same meanings as described above.

The pharmaceutically acceptable salts of compound (I) include inorganic salts such as hydrochloride, sulfate and phosphate, acetate, maleate, fumarate, tartrate and citrate. And amino acid addition salts such as lysine, glycine and phenylalanine. Next, a method for producing the compound (I) will be described.

In the production methods described below, if the defined groups change under the conditions of the practice method or are unsuitable for carrying out the method, a method commonly used in organic synthetic chemistry, for example, It can be easily carried out by applying means such as protection and deprotection of the group. Production method 1: Compound (I) can be produced according to the following reaction steps.

[0012]

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(Wherein L represents a halogen atom such as chlorine, bromine or iodine, or a leaving group such as methanesulfonyloxy, toluenesulfonyloxy or benzenesulfonyloxy, and R ¹ , R ² , R ³ , R ⁴ , X, n and Ar have the same meanings as above.) The starting compound (II) can be obtained according to the method described in South Africa Patent 670512 (1968). The starting compound (III) is disclosed in
It can be obtained according to the method described in JP-A-3-290869.

Compound (I) is obtained by converting compound (II) and compound (III) into organic bases such as triethylamine, diisopropylethylamine, diazabicycloundecene, potassium carbonate, sodium carbonate, sodium hydroxide, sodium hydrogencarbonate and the like. In the presence of a base such as a metal salt of a suitable inert solvent, for example, tetrahydrofuran, dioxane
Alcohols such as ether , methanol, and ethanol; aromatic hydrocarbons such as benzene, toluene, and xylene; aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, and nitrobenzene; water, and the like; 5 to 2 minutes at the boiling point of the solvent
It can be obtained by reacting for 4 hours. Production Method 2: Compound (I) can also be produced according to the following reaction steps.

[0015]

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(Wherein, P represents an amino-protecting group such as ethoxycarbonyl, allyloxycarbonyl, benzyl, etc., L ′ represents a halogen atom such as chlorine, bromine, iodine, etc. Represents a leaving group such as oxy, and R ¹ ,
R ² , R ³ , R ⁴ , X, n and Ar have the same meanings as described above).
No. 8,544 , U.S. Pat. No. 3,267,104 or JP-A-63-290869.

The compound (VI) is obtained by using the compound (IV) in place of the compound (III) to obtain a compound (V) according to the method of Production Method 1, and then obtaining the compound described in JP-A-63-290869. It can be obtained by deprotecting the amino-protecting group of compound (V) according to the method. Next, compound (I) is obtained by converting compound (VI) and compound (VII) into organic bases such as triethylamine, diisopropylethylamine, diazabicycloundecene, sodium hydride, potassium hydride, butyllithium, potassium tert-butoxide. In the presence of a base such as a metal salt such as potassium carbonate, sodium carbonate, sodium hydroxide, and sodium hydrogen carbonate, a suitable inert solvent, for example, a halogenated hydrocarbon such as dichloromethane or chlorohom, an ether such as tetrahydrofuran or dioxane, or methanol , Alcohols such as ethanol, aromatic hydrocarbons such as benzene, toluene and xylene, aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide and nitrobenzene, water and the like, and the boiling point of the solvent used from 0 ° C. in a mixed solvent thereof And 5
It can be obtained by reacting for minutes to 24 hours.

The intermediates and the target compound in the above production method are subjected to purification methods commonly used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography and the like. It can be isolated and purified.
In addition, the intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of compound (I), when compound (I) is obtained in the form of a salt,
The salt may be purified as it is, or when it is obtained in a free form, dissolved or suspended in an appropriate organic solvent and a salt may be formed by adding an acid.

The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention. Table 1 shows specific examples of the compound (I) obtained by the above production method.

[0020]

[Table 1]

Next, the pharmacological action of the representative compound (I) will be described with reference to test examples. Test Example 1 [ ³ H] -Adenosine uptake inhibitory action Blood was collected from the brachial vein of a healthy adult male (age less than 40 years) by citrate-Na, and washed erythrocytes were obtained by centrifugation. 100 μl of erythrocyte suspension (2.5 × 10 ⁹ / ml) is added with 10 μl of a 21% dimethyl sulfoxide (DMSO) solution of the test compound.
After adding 1 l, the mixture was left at room temperature for 1 hour, and 10 μl of [ ³ H] -adenosine solution was added. 10 seconds later, dirazep solution
The reaction was stopped by adding 200 μl (1 mg / ml). Triton
After red blood cells were lysed with X-100, the amount of ³ H taken in by a liquid scintillation counter was measured. [ ³ H] −
The adenosine uptake inhibitory action was represented by the inhibition rate at 10 μM. The results are shown in Table 2.

[0022]

[Table 2]

Test Example 2. [ ³ H] -Nitrobenzylthioinosine (NBI) binding inhibitory activity (an indicator of adenosine binding inhibitory activity) A 25-fold amount (w) in the cerebral cortex of Hartley male guinea pigs
(V) ice-cold 50 mM Tris-HCl buffer pH 7.4 was added and homogenized. Centrifuge the homogenate (30
000 × g, 4 ° C., 20 minutes), the supernatant was discarded, and the same amount of buffer was added to the remaining precipitate. It was homogenized again and centrifuged similarly. The remaining precipitate was suspended by adding 20 volumes of buffer.
This was used for the test.

[ ³ H] -N was added to a DMSO solution of the test compound.
1.5 nM BI and 5 mg (wet weight) tissue homogenate were added and the mixture was left at 25 ° C. for 30 minutes. Then, 4 ml of ice-cold buffer was added, and a glass filter (GF / C) was added.
The reaction was stopped by rapid suction filtration on Whatman) or a ready filter (Beckman). The filter was transferred to a scintillation vial. After drying, scintillator EX-H was added, and radioactivity was measured with a liquid scintillation counter. [ ³ H] -NBI binding inhibitory activity was represented by the inhibition rate at 10 μM. The results are shown in Table 3.

[0025]

[Table 3]

The compound (I) or a pharmaceutically acceptable salt thereof is orally prepared, for example, in the form of tablets, capsules, syrups and the like, orally or intramuscularly or intravenously. Parenteral administration, such as injection, intraarterial injection, infusion, rectal administration with suppositories and the like, can be used. For the preparation of a dosage form for oral or parenteral administration, generally known methods are applied, for example, in the preparation of a composition in oral dosage form, any useful pharmacologically acceptable Carrier can be used. For example, oral liquid preparations such as suspensions and syrups can be prepared in water, for example, saccharides such as sucrose, sorbitol, and fructose; glycols such as polyethylene glycol and propylene glycol; For example, preservatives such as p-hydroxybenzoic acid esters, and flavors such as strawberry flavor and peppermint. Powders, pills, capsules and tablets include, for example, lactose,
Excipients such as glucose, sucrose, mannitol, and the like, disintegrants such as starch, sodium alginate, and the like, lubricants such as magnesium stearate, talc, and the like, binders such as polyvinyl alcohol, hydroxypropyl cellulose, gelatin, and the like, fatty acids It can be produced using a surfactant such as an ester and a plasticizer such as glycerin. Tablets and capsules are the most useful unit oral dosage forms because of their ease of administration. In producing tablets and capsules, solid pharmaceutical carriers are used.

The solution for injection may be distilled water, salt solution,
It can be prepared using a carrier comprising a glucose solution or a mixture of saline and glucose solution. The effective dose and the number of administrations of the compound (I) or a pharmaceutically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms and the like, but are usually 1 to 1,000 per day. mg / person 1
It is preferable to administer in 4 to 4 divided doses.

[0028]

【Example】

Example 1 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide (Compound 1) 4-chloro-6,7-dimethoxyquinazoline (0.45
g), N- (4-amino-2,6-dichlorophenyl)
-2-carbamoyl-1-piperazine acetamide (0.
A mixture of 69 g) and triethylamine (0.28 ml) was stirred in methanol (20 ml) under reflux for 5 hours. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography to give the title compound (0.85
g, 80%). 0.40 g of this was crystallized from diethyl ether containing a small amount of chloroform. This was collected by filtration and dried to give the title compound (0.3
3 g) was obtained.

Melting point: 178.2-183.5 ° C. Elemental analysis: C ₂₃ H ₂₅ N ₇ O ₄ Cl ₂ .2H ₂ O Theoretical value (%); C 48.43, H 5.12, N 17.19 Actual value (%); C 48.51, H 5.02, N 17.15 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.58 (s, 1H), 8.59 (s, 1H),
7.94 (s, 1H), 7.58 (s, 1H), 7.50 (s, 1H), 7.24 (s, 1H), 6.
67 (s, 2H), 5.71 (br s, 2H), 3.97 (s, 3H), 3.94 (s, 3H),
3.0-4.1 (m, 8H), 2.77 (m, 1H) .IR (KBr): 1675, 1658, 1505, 1427, 1242, 1210, 113
3, 991.

Example 2 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (4-quinazolinyl) -1-piperazine acetamide (Compound 2) Except that 4-chloroquinazoline (0.24 g) is used instead of 4-chloro-6,7-dimethoxyquinazoline
According to the method of Example 1, the title compound (0.35 g,
61%).

Melting point: 186.3-187.0 ° C. Elemental analysis: C ₂₁ H ₂₁ N ₇ O ₂ Cl ₂ .H ₂ O Theoretical value (%); C 51.23, H 4.71, N 19.91 Actual value (%); C 51.52, H 4.74, N 19.21 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.57 (s, 1H), 8.65 (s, 1H),
8.15 (d, 1H, J = 8.2Hz), 7.78-7.88 (m, 3H), 7.56 (m, 1H),
7.40 (s, 1H), 6.67 (s, 2H), 5.69 (s, 2H), 3.95-4.18 (m, 2
H), 3.64 (m, 1H), 3.05-3.45 (m, 5H), 2.68 (m, 1H) .IR (KBr): 1673, 1571, 1501, 1421, 799, 770.

Example 3 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,7,8-trimethoxy-4-
(Quinazolinyl) -1-piperazine acetamide (compound 3) Except for using 4-chloro-6,7,8-trimethoxyquinazoline (0.35 g) instead of 4-chloro-6,7-dimethoxyquinazoline. According to the method of Example 1, the title compound (0.49 g, 72%) was obtained.

Melting point: 150.1-150.9 ° C. Elemental analysis: C ₂₄ H ₂₇ N ₇ O ₅ Cl ₂ .H ₂ O Theoretical value (%); C 49.49, H 5.01, N 16.83 Actual value (%); C 49.35, H 4.87, N 16.17 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.57 (s, 1H), 8.61 (s, 1H),
7.91 (s, 1H), 7.48 (s, 1H), 7.39 (s, 1H), 6.67 (s, 2H), 5.
69 (s, 2H), 4.01 (s, 3H), 3.98 (s, 3H), 3.92 (s, 3H), 3.68
-3.88 (m, 3H), 3.15-3.55 (m, 5H), 2.75 (m, 1H) .IR (KBr): 1683, 1670, 1602, 1478, 1422, 1236, 112
6, 1022, 982, 803.

Example 4 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (6,8-dimethyl-4-quinazolinyl) -1-piperazine acetamide (Compound 4) Instead of 4-chloro-6,7-dimethoxyquinazoline, 4-chloro-6,8-dimethylquinazoline ( 0.28
The title compound (0.52 g, 72%) was obtained according to the method of Example 1 except for using g).

Melting point: 169.3-171.6 ° C. Elemental analysis: C ₂₃ H ₂₅ N ₇ O ₂ Cl ₂ .1.5H ₂ O Theoretical value (%); C 52.18, H 5.33, N 18.52 Actual value (%); C 52.13, H 4.95, N 17.98 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.56 (s, 1H), 8.66 (s, 1H),
7.83 (s, 1H), 7.76 (s, 1H), 7.54 (s, 1H), 7.42 (s, 1H), 6.
67 (s, 2H), 5.70 (s, 2H), 3.85-4.06 (m, 2H), 3.69 (m, 1H),
3.56 (m, 1H), 3.17-3.44 (m, 3H), 3.11 (m, 1H), 2.68 (m, 1
H), 2.59 (s, 3H), 2.46 (s, 3H) .IR (KBr): 3333, 1683, 1672, 1576, 1500, 1428, 133
6, 1244, 1131, 1076, 1014, 982, 955, 840, 801.

Example 5 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (7-chloro-4-quinazolinyl)
-1-Piperazine acetamide (Compound 5) The title was obtained according to the method of Example 1 except that 4,7-dichloroquinazoline (0.40 g) was used instead of 4-chloro-6,7-dimethoxyquinazoline. Compound (0.7
1 g, 70%).

Melting point: 184.6-185.2 ° C. Elemental analysis: C ₂₁ H ₂₀ N ₇ O ₂ Cl ₃ .H ₂ O Theoretical value (%); C 47.88, H 4.21, N 18.61 Actual value (%); C 48.15, H 4.33, N 17.30 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.56 (s, 1H), 8.64 (s, 1H),
8.20 (d, 1H, J = 9.1Hz), 7.85 (s, 1H), 7.84 (s, 1H), 7.56
(d, 1H, J = 9.1Hz), 7.40 (s, 1H), 6.67 (s, 2H), 4.12 (m, 1
H), 4.01 (m, 1H), 3.81 (m, 1H), 3.71 (m, 1H), 3.20-3.45
(m, 2H), 3.18 (s, 2H), 2.69 (m, 1H) .IR (KBr): 3300, 1680, 1598, 1560, 1504, 1440, 133
8, 1324, 1280, 1241, 1181, 1144, 1077, 1050, 958,
937, 883, 844, 803, 761, 661, 580.

Example 6 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl-4- (2-chloro-6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide
(Compound 6) 2,4-dichloro-6,7-dimethoxyquinazoline (0.56 g), N- (4-amino-2,6-dichlorophenyl) -2-carbamoyl-1-piperazineacetamide (0.69 g) ) And triethylamine (0.28 m
l) in methanol (20 ml) at room temperature for 4 hours.
The mixture was stirred for 0 minute and further for 30 minutes under reflux condition. The precipitated crystals were collected by filtration, washed with water and methanol, and dried to give the title compound (0.92 g, 81%).

Melting point:> 300 ° C. Elemental analysis: C ₂₃ H ₂₄ N ₇ O ₄ Cl ₃ .1.5H ₂ O Theoretical value (%); C 46.36, H 4.56, N 16.45 Actual value (%); C 46.95, H 4.24, N 16.14 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.58 (s, 1H), 7.96 (s, 1H),
7.62 (s, 1H), 7.52 (s, 1H), 7.20 (s, 1H), 6.67 (s, 2H), 5.
70 (s, 2H), 3.97 (s, 3H), 3.93 (s, 3H), 3.0-4.2 (m, 8H),
2.82 (m, 1H). IR (KBr): 1684, 1573, 1510, 1501, 1432, 1336, 124
5, 1220, 1148, 1135, 998, 962, 803.

Example 7 N- (4-amino-2,6-dichlorophenyl) -3-
Carbamoyl-4- (4-quinazolinyl) -1-piperazine acetamide (Compound 7) 4-chloroquinazoline (0.20 g), N- (4-amino-2,6-dichlorophenyl) -3-carbamoyl-
A mixture of 1-piperazine acetamide (0.42 g) and triethylamine (0.17 ml) was added to methanol (1
5 ml) and stirred for 1 hour under reflux conditions. After evaporating the solvent under reduced pressure, the residue was partitioned with chloroform-methanol-water,
The organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diethyl ether. This was collected by filtration and dried to give the title compound (0.15 g, 39%).

Melting point: 186.7-187.1 ° C. ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.34 (s, 1H), 8.63 (s, 1H),
8.22 (s, 1H), 8.09 (d, 1H, J = 8.4Hz), 7.7-8.0 (m, 3H), 7.5
6 (m, 1H), 6.65 (s, 2H), 5.69 (s, 2H), 5.03 (m, 1H), 4.21
(m, 1H), 2.85-3.80 (m, 6H), 2.55 (m, 1H) .IR (KBr): 1679, 1566, 1496, 800, 767.

Example 8 N- (4-amino-2,6-dichlorophenyl) -3-
Carbamoyl-4- (2-chloro-6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide
(Compound 8) Instead of 4-chloroquinazoline , 2,4-dichloro-
Except that 6,7-dimethoxyquinazoline (0.35 g) was used, the title compound (0.
11 g, 15%).

Melting point:> 300 ° C. Elemental analysis: C ₂₃ H ₂₄ N ₇ O ₄ Cl ₃ .H ₂ O Theoretical value (%); C 47.07, H 4.47, N 16.71 Actual value (%); C 47.21, H 4.08 , N 15.99 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.33 (s, 1H), 7.93 (s, 1H),
7.53 (s, 1H), 7.40 (s, 1H), 7.20 (s, 1H), 6.64 (s, 2H), 5.
69 (s, 2H), 4.94 (m, 1H), 4.21 (m, 1H), 3.93 (s, 3H), 3.89
(s, 3H), 2.85-3.65 (m, 6H), 2.56 (m, 1H). IR (KBr): 1685, 1625, 1600, 1573, 1510, 1475, 141
8, 1246, 1212, 1153, 1141, 997, 952, 805, 749.

Example 9 2-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazineacetamide (Compound 9) 4 -Chloro-6,7-dimethoxyquinazoline (0.31
g), 2-carbamoyl-N- (2,6-dichloro-4)
-Nitrophenyl) -1-piperazine acetamide (0.
45 g) and triethylamine (0.17 ml) in methanol (15 ml) under reflux for 4 hours.
Stirred for 0 minutes. After evaporating the solvent under reduced pressure, the residue was partitioned with chloroform-methanol-water, and the organic layer was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and crystallized from diethyl ether. This was collected by filtration and dried to give the title compound (0.48 g, 71%).

Melting point: 247.2-247.4 ° C. Elemental analysis: C ₂₃ H ₂₃ N ₇ O ₆ Cl ₂ .H ₂ O Theoretical value (%); C 47.43, H 4.32, N 16.83 Actual value (%); C 47.70, H 3.97, N 16.96 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.26 (s, 1H), 8.59 (s, 1H),
8.44 (s, 2H), 7.91 (s, 1H), 7.57 (s, 1H), 7.54 (s, 1H),
3.97 (s, 3H), 3.94 (s, 3H), 3.2-4.0 (m, 8H), 2.84 (m, 1H) .IR (KBr): 1690, 1572, 1534, 1506, 1428, 1346, 124
3, 1214, 1137, 994, 808.

Example 10 2-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (4-quinazolinyl) -1-piperazineacetamide (compound 10) 4-chloro-6,7 -Except that 4-chloroquinazoline (0.30 g) is used instead of dimethoxyquinazoline
According to the method of Example 9, the title compound (0.61 g,
52%).

Melting point: 142.1-144.2 ° C. Elemental analysis: C ₂₁ H ₁₉ N ₇ O ₄ Cl ₂ .H ₂ O Theoretical value (%); C 48.29, H 4.05, N 18.77 Actual value (%); C 48.40, H 3.96, N 19.05 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.26 (s, 1H), 8.66 (s, 1H),
8.43 (s, 2H), 8.16 (d, 1H, J = 8.4Hz), 7.65-8.00 (m, 3H),
7.57 (m, 1H), 7.43 (s, 1H), 3.85-4.25 (m, 2H), 3.0-3.9
(m, 6H), 2.77 (m, 1H) .IR (KBr): 1698, 1675, 1575, 1536, 1500, 1345, 115
0, 1035, 947, 814, 775.

Example 11 2-carbamoyl- 4- (7-chloro-4-quinazolini
Ru) -N- (2,6-dichloro-4-nitrophenyl)
- 1-piperazine acetamide (compound 11) 4-chloro-6,7-dimethoxyquinazoline instead 4,7
The title compound (0.78 g, 7) was prepared according to the method of Example 9 except that dichloroquinazoline (0.40 g) was used.
2%).

Melting point: 159.5-161.4 ° C. Elemental analysis: C ₂₁ H ₁₈ N ₇ O ₄ Cl ₃ .H ₂ O Theoretical value (%); C 45.30, H 3.62, N 17.61 Actual value (%); C 45.79, H 3.61, N 16.19 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.25 (s, 1H), 8.65 (s, 1H),
8.42 (s, 2H), 8.20 (d, 1H, J = 8.9Hz), 7.86 (d, 1H, J = 2.0H
z), 7.81 (s, 1H), 7.56 (dd, 1H, J = 8.9,2.0Hz), 7.42 (s, 1H
H), 3.93-4.19 (m, 2H), 3.85 (m, 1H), 3.74 (m, 1H), 3.51
(m, 1H), 3.22-3.42 (m, 1H), 3.18 (s, 2H), 3.16 (s, 2H),
2.77 (m, 1H) .IR (KBr): 3455, 3200, 1700, 1689, 1605, 1566, 153
1, 1485, 1438, 1390, 1347, 1273, 1187, 1151, 1090,
1037, 957, 886, 813, 784, 758, 744, 682.

Example 12 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (4-quinazolinyl) -1-piperazineacetamide (Compound 12) 4-chloroquinazoline (0.1%) 25 g), 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl)-
A mixture of 1-piperazine acetamide (0.56 g) and triethylamine (0.21 ml) was mixed in a mixed solvent of water (8 ml) and dioxane (8 ml) at room temperature for 25 minutes, at 50 ° C. for 3 hours and 35 minutes, and further. 3 hours under reflux condition 2
Stir for 5 minutes. After cooling to room temperature, the mixture was extracted with chloroform, and the organic layer was dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was purified by silica gel column chromatography and crystallized from chloroform / diethyl ether. This was collected by filtration and dried to give the title compound (0.23 g, 42%).

Melting point: 209.6-210.5 ° C. Elemental analysis: C ₂₁ H ₁₉ N ₇ O ₄ Cl ₂ Theoretical value (%); C 50.01, H 3.80, N 19.44 Actual value (%); C 50.26, H 3.71, N 19.06 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.24 (s, 1H), 8.64 (s, 1H),
8.41 (s, 2H), 8.08 (d, 1H, J = 9.4Hz), 8.70-8.95 (m, 3H),
7.57 (m, 1H), 7.49 (m, 1H), 5.05 (m, 1H), 4.22 (m, 1H), 3.
70 (m, 1H), 3.15-3.60 (m, 4H), 2.59 (m, 2H) .IR (KBr): 1700, 1680, 1610, 1563, 1532, 1490, 141
7, 1344, 1226, 1143, 1048, 999, 926, 814, 776.

Example 13 3-carbamoyl- 4- (7-chloro-4-quinazolini
Ru) -N- (2,6-dichloro-4-nitrophenyl)
- but using 1-piperazine acetamide (compound 13) 4-chloroquinazoline Instead 4,7 dichloroquinazoline of (0.26 g), according to the method of Example 12, the title compound (0.063 g , 4%).

Melting point: 215.7-217.5 ° C. Elemental analysis: C ₂₁ H ₁₈ N ₇ O ₄ Cl ₃ .0.5H ₂ O Theoretical value (%); C 46.05, H 3.50, N 17.90 Actual value (%); C 46.15, H 3.22, N 17.60 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.22 (s, 1H), 8.64 (s, 1H),
8.41 (s, 2H), 8.12 (d, 1H, J = 7.1Hz), 7.87 (s, 1H), 7.81
(s, 1H), 7.58 (d, 1H, J = 7.1Hz), 7.49 (s, 1H), 5.10 (m, 1
H), 4.24 (m, 1H), 3.70 (m, 1H), 3.53 (m, 1H), 3.32 (m, 2
H), 2.97 (m, 1H), 2.59 (m, 2H) .IR (KBr): 3434, 3200, 1681, 1604, 1560, 1535, 148
4, 1423, 1388, 1345, 1312, 1178, 1144, 1103, 1072,
1046, 1002, 930, 882, 810, 741, 632.

Example 14 3-carbamoyl-N- (2,6-dichloro-4-nitrophenyl) -4- (6,8-dimethyl-4-quinazolinyl) -1-piperazineacetamide (Compound 14) 4 -4-chloro-6,8- in place of chloroquinazoline
Except that dimethylquinazoline (0.26 g) was used, the title compound (0.13 g,
18%).

Melting point: 225.4-225.6 ° C. Elemental analysis: C ₂₃ H ₂₃ N ₇ O ₄ Cl ₂ .0.5H ₂ O Theoretical value (%); C 51.03, H 4.47, N 18.11 Actual value (%); C 51.35, H 4.23, N 17.61 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.24 (s, 1H), 8.65 (s, 1H),
8.41 (s, 2H), 7.75 (s, 1H), 7.68 (s, 1H), 7.55 (s, 1H),
7.44 (s, 1H), 4.95 (m, 1H), 4.08 (m, 1H), 3.69 (m, 1H), 3.
45 (m, 1H), 3.1-3.4 (m, 3H), 2.94 (m, 1H), 2.63 (m, 1H),
2.59 (s, 3H), 2.45 (s, 3H) .IR (KBr): 3432, 3200, 1699, 1680, 1573, 1533, 149
0, 1422, 1387, 1348, 1315, 1287, 1225, 1147, 1096,
1045, 996, 971, 947, 895, 882, 870, 814, 757, 741.

Example 15 N- (2,6-dichloro-4-nitrophenyl) -4-
(6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide (Compound 15) 4-chloro-6,7-dimethoxyquinazoline (0.34
g), N- (2,6-dichloro-4-nitrophenyl)
A mixture of -1-piperazine acetamide (0.50 g) and triethylamine (0.21 ml) was stirred in methanol (20 ml) for 1 hour under reflux. The precipitated crystals were collected by filtration, washed with water and methanol, and dried to give the title compound (0.47 g, 78%).

Melting point: 205.7-206.1 ° C. Elemental analysis: C ₂₂ H ₂₂ N ₆ O ₅ Cl ₂ Theoretical value (%); C 50.68, H 4.25, N 16.11 Actual value (%); C 50.48, H 4.24, N 15.80 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.10 (br s, 1H), 8.57 (s, 1
H), 8.41 (s, 2H), 7.23 (s, 1H), 7.14 (s, 1H), 3.94 (s, 3
H), 3.93 (s, 3H), 3.71 (m, 4H), 2.84 (m, 4H) .IR (KBr): 1723, 1619, 1577, 1532, 1503, 1474, 142
8, 1335, 1228, 1209, 1132, 996, 939, 847, 804, 79
2.

Example 16 N- (2,6-dichloro-4-nitrophenyl) -4-
(4-quinazolinyl) -1-piperazine acetamide
(Compound 16) Except for using 4-chloroquinazoline (0.25 g) instead of 4-chloro-6,7-dimethoxyquinazoline,
According to the method of Example 15, the title compound (0.62
g, 69%).

Melting point: 175.4-176.5 ° C. Elemental analysis: C ₂₀ H ₁₈ N ₆ O ₃ Cl ₂ Theoretical value (%); C 52.07, H 3.93, N 18.22 Actual value (%); C 51.98, H 3.86, N 18.05 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.27 (s, 1H), 8.79 (s, 1H),
8.29 (s, 2H), 7.94 (d, 1H, J = 8.4Hz), 7.91 (d, 1H, J = 8.9H
z), 7.78 (m, 1H), 7.51 (m, 1H), 3.87 (m, 4H), 3.38 (s, 2
H), 2.98 (m, 4H) .IR (KBr): 3300, 1703, 1614, 1570, 1532, 1503, 148
1, 1445, 1346, 1331, 1260, 1146, 1088, 1012, 941,
839, 808, 758, 687.

Example 17 N- (4-amino-2,6-dichlorophenyl) -4-
(6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide (Compound 17) 4-chloro-6,7-dimethoxyquinazoline (0.34
g), N- (4-amino-2,6-dichlorophenyl)
A mixture of -1-piperazine acetamide (0.46 g) and triethylamine (0.21 ml) was stirred in methanol (20 ml) for 1 hour under reflux. The solvent was distilled off under reduced pressure, and the precipitated crystals were collected by filtration, washed with methanol, and dried to give the title compound (0.39).
g, 51%).

Melting point: 174.5-176.5 ° C. Elemental analysis: C ₂₂ H ₂₄ N ₆ O ₃ Cl ₂ .1.5H ₂ O Theoretical value (%); C 50.97, H 5.25, N 16.21 Actual value (%); C 51.01, H 5.17, N 15.99 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.31 (s, 1H), 8.56 (s, 1H),
7.22 (s, 1H), 7.13 (s, 1H), 6.65 (s, 2H), 5.68 (s, 2H), 3.
93 (s, 3H), 3.92 (s, 3H), 3.69 (m, 4H), 2.79 (m, 4H) .IR (KBr): 1683, 1618, 1582, 1504, 1480, 1428, 133
5, 1241, 1212, 1136, 1000, 848, 797.

Example 18 N- (4-amino-2,6-dichlorophenyl) -4-
(4-quinazolinyl) -1-piperazine acetamide
(Compound 18) Except for using 4-chloroquinazoline (0.27 g) instead of 4-chloro-6,7-dimethoxyquinazoline,
According to the method of Example 17, the title compound (0.37
g, 52%).

Melting point: 208.5-209.4 ° C. Elemental analysis: C ₂₀ H ₂₀ N ₆ OCl ₂ .0.5H ₂ O Theoretical value (%); C 54.55, H 4.81, N 19.09 Actual value (%); C 54.99, H 4.61 , N 19.14 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.32 (s, 1H), 8.63 (s, 1H),
8.02 (d, 1H, J = 8.4Hz), 7.74-7.90 (s, 2H), 7.55 (m, 1H),
6.65 (s, 2H), 5.67 (s, 2H), 3.82 (m, 4H), 3.19 (s, 2H), 2.
78 (m, 4H) .IR (KBr): 3200, 1670, 1612, 1568, 1506, 1434, 132
1, 1134, 1010, 941, 830,802, 770, 682.

Example 19 N- (4-amino-2,6-dichlorophenyl) -4-
(7-Chloro-4-quinazolinyl) -1-piperazine acetamide (Compound 19) Except that 4,7-dichloroquinazoline (0.33 g) was used instead of 4-chloro-6,7-dimethoxyquinazoline. According to the method of Example 17, the title compound (0.
15 g, 19%).

Melting point: 236.4-237.4 ° C. Elemental analysis: C ₂₀ H ₁₉ N ₆ OCl ₃ .H ₂ O Theoretical value (%); C 49.65, H 4.38, N 17.37 Actual value (%); C 50.32, H 4.55, N 16.31 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 9.32 (s, 1H), 8.62 (s, 1H),
8.04 (d, 1H, J = 8.9Hz), 7.84 (d, 1H, J = 2.2Hz), 7.54 (dd, 1
H, J = 8.9,2.2Hz), 6.65 (s, 2H), 5.67 (s, 2H), 3.86 (m, 4
H), 3.17 (s, 2H), 2.76 (m, 4H) .IR (KBr): 3435, 3225, 1680, 1607, 1564, 1540, 145
5, 1335, 1326, 1264, 1177, 1146, 1093, 1075, 1032,
1013, 948, 881, 794, 783.

Example 20 N- (4-amino-2,6-dichlorophenyl) -2-
Carbamoyl- 4- (6,7-dimethoxy-4-quinazolinyl) -1-piperazine acetamide trihydrochloride (trihydrochloride of compound 1) The compound (0.45 g) obtained in Example 1 was subjected to chloroform and methanol. And a hydrochloric acid-saturated ethyl acetate solution was added thereto. This mixture was added to diethyl ether, and the precipitated crystals were collected by filtration and dried to give the title compound (0.44 g, 65%).

Melting point: 183.7-196.8 ° C. Elemental analysis: C ₂₃ H ₂₅ N ₇ O ₄ Cl ₂ .3HCl.2.5H ₂ O Theoretical value (%); C 40.10, H 4.82, N 14.23 Actual value (%); C 40.29, H 5.01, N 14.35 ¹ H-NMR (d ₆ -DMSO) δ (ppm): 10.09 (s, 1H), 8.89 (s, 1H),
8.26 (s, 1H), 7.73 (s, 1H), 7.56 (s, 1H), 7.53 (s, 1H),
6.80 (s, 2H), 5.36 (br s, 2H), 4.00 (s, 3H), 3.99 (s, 3H),
3.20-4.75 (m, 9H). IR (KBr): 1698, 1691, 1620, 1500, 1372, 1286, 121
8, 987, 799.

Formulation Example 1 Tablet A tablet having the following composition is prepared by a conventional method. Compound 3 50mg Lactose 150mg Potato starch 75mg Polyvinyl alcohol 7.5mg Magnesium stearate 2.5mg

Formulation Example 2 Powder A powder having the following composition is prepared by a conventional method. Compound 3 50mg Lactose 750mg

Formulation Example 3 Capsules A capsule having the following composition is prepared by a conventional method. Compound 3 50 mg Lactose 500 mg Magnesium stearate 12.5 mg Mix this and fill into gelatin capsules.

Formulation Example 4 Syrup A syrup having the following composition is prepared by a conventional method. Compound 3 50 mg Purified sucrose 75 mg p-hydroxybenzoic acid ethyl ester 100 mg p-hydroxybenzoic acid propyl ester 25 mg strawberry flavor 0.25 ml To this is added water to make a total volume of 100 ml.

Formulation Example 5 Injection An injection having the following composition is prepared by an ordinary method. Compound 3 20 mg Sodium chloride 45 mg To this is added water to make a total volume of 5 ml (for one ampoule). The water was distilled beforehand and sterilized in an autoclave.

[0073]

Industrial Applicability According to the present invention, a novel piperazine derivative or a pharmacologically acceptable derivative thereof having a nucleoside transport inhibitory activity and useful for cardioprotection from myocardial damage caused by ischemia, anoxia or hypoxia. Salt is provided.

──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiroshi Kase 3-35-18 Maeharacho, Koganei-shi, Tokyo (72) Inventor Fumio Suzuki 18-4 Fujimidai, Mishima-shi, Shizuoka Pref. Field (Int. Cl. ⁷ , DB name) C07D 239/94 A61K 31/505 CA (STN) REGISTRY (STN)

Claims (2)

(57) [Claims] 1. A compound of the formula (I) (Wherein R ¹ , R ² and R ³ are the same or different and are hydrogen, lower alkyl, lower alkoxy, lower alkanoyl, lower alkoxycarbonyl, carboxy, carbamoyl, mono- or di-lower alkylaminocarbonyl, trifluoromethyl, hydroxy Represents halogen, nitro, amino, mono- or di-lower alkylamino or cyano, R ⁴ represents hydrogen or halogen, X represents hydrogen, carbamoyl, mono- or di-lower alkylaminocarbonyl, lower alkoxycarbonyl or carboxy, n Represents an integer of 1 to 3, and Ar represents a substituted or unsubstituted heterocyclic group) or a pharmaceutically acceptable salt thereof. 2. An adenosine uptake inhibitor comprising the piperazine derivative according to claim 1 or a pharmaceutically acceptable salt thereof.