JPH05155884A - Condensed pirazine derivative - Google Patents

Abstract

PURPOSE:To obtain the subject new derivative, having a specific condensed pyrazine structure containing tetrazolebiphenyl group, capable of exhibiting antagonistic action on angiotensin II receptors and useful for treating hypertension, congestive cardiac insufficiency, renal insufficiency and glaucoma, etc. CONSTITUTION:The objective condensed pyrazine derivative expressed by formula III (R<1> is H, lower alkyl or cycloalkyl; R<2> is H, benzyl, benzhydryl or trityl; R<3> and R<4> are H or lower alkyl; Z is CH or N) is obtained by dissolving a condensed pyrazine compound expressed by formula I (R<1>, R<3>, R<4> and Z are same as those described above) in dimethylformamide, adding sodium hydride to the solution, stirring the resultant mixture for 10min while cooling the mixture with ice, adding a solution of biphenyl-2-yl-1H-tetrazole compound expressed by formula II (Hal is halogen; R<2a> is benzyl, benzhydryl or trityl) in dimethylformamide to the mixture, carrying out reaction at ambient temperature for 10hr, then adding an aqueous solution of ammonium chloride, collecting the formed crystal by filtration and purifying the collected crystal according to silica gel chromatography. This derivative has antagonistic action on angiotensin II receptors.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to angiotensin II.
The present invention relates to a fused pyrazine derivative which exhibits a receptor antagonistic action (hereinafter referred to as AII) and is useful for treating hypertension, congestive heart failure, renal failure, glaucoma and the like.

[0002]

2. Description of the Related Art A which is a kind of peptide-type pressor hormone
As a receptor antagonist of II, a condensed heterocyclic compound containing a biphenylmethane derivative in its structure is known. A condensed heterocyclic compound obtained by condensing a 6-membered nitrogen-containing heterocyclic ring such as pyridine or pyrimidine and an aromatic ring such as phenyl or thienyl is disclosed in JP-A-3-44377, JP-A-3-115271, EP-443568A and EP. -445811A
Are disclosed as AII receptor antagonists. However, in the context of the present invention, a compound containing a biphenylmethane derivative in the structure and a 6-membered nitrogen-containing heterocycle condensed with an aromatic ring by pyrazine is not known.

[0003]

DISCLOSURE OF THE INVENTION The object of the present invention is to
It is intended to provide a novel condensed pyrazine derivative having an I receptor antagonistic action.

[0004]

The present invention provides a compound of formula (I)

[0005]

[Chemical 2]

(Wherein R ¹ represents hydrogen, lower alkyl or cycloalkyl, R ² represents hydrogen, benzyl, benzhydryl or trityl, R ³ and R ⁴ are the same or different and represent hydrogen or lower alkyl, Z is C
A condensed pyrazine derivative represented by H or N) [hereinafter referred to as compound (I). The same applies to compounds of other formula numbers] or a pharmaceutically acceptable salt thereof.

In the definition of each group of the formula (I), lower alkyl is linear or branched and has 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl. , Pentyl, isopentyl, hexyl and the like, and cycloalkyl includes, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl and the like having 3 to 8 carbon atoms.

The pharmacologically acceptable salts of compound (I) are inorganic acid salts such as hydrochloride, sulfate, nitrate and phosphate,
Examples thereof include organic acid salts such as acetate, maleate, fumarate and citrate, metal salts such as sodium salt, potassium salt and calcium salt, addition salts such as ammonium salt, tetramethylammonium salt and morpholine. Next, the method for producing the compound (I) will be described.

The compound (I) can be obtained according to the following reaction steps.

[0010]

[Chemical 3]

(Where R^2aIs R other than hydrogen²Same as
Hal represents halogen and R ¹, R², R³,
R^FourAnd Z are as defined above)

Halogen in the definition of Hal represents each atom of chlorine, bromine and iodine. R ² in the compound (I)
The compound (Ia) in which is a group other than hydrogen is a known method [Heterocyclic compounds, "condensed pyrazines" G.
Edited by WHCheeseman, RFCookson p78 (197)
9)] or a compound (II) which can be obtained in accordance therewith, is prepared by previously preparing a metal hydride such as sodium hydride or potassium hydride or sodium methoxide,
In the presence of lower metal alkoxides such as sodium ethoxide and potassium tert-butoxide, ethers such as dioxane and tetrahydrofuran, lower alcohols such as methanol and ethanol, solvents such as dimethylformamide and dimethylsulfoxide at 0 ° C or the boiling point of the solvent. To prepare a metal salt and, if desired, the solvent is exchanged with the other solvent described above by a known method (for example,
JP-A-3-95181 and JP-A-3-148279.
No. JP-A-2003-13826) or a compound (III) which can be obtained according to the method, at room temperature to the boiling point of the solvent used.

The compound (Ib) in which R ² is hydrogen in the compound (I) can be subjected to a conventional method capable of removing the imino protecting group from the compound (Ia), for example, elimination reaction such as hydrolysis or reduction. It can be obtained by attaching.

In the case of hydrolysis, a base such as sodium hydroxide, potassium hydroxide, sodium carbonate or potassium carbonate,
It is carried out in the presence of an inorganic acid such as hydrochloric acid or sulfuric acid, or an organic acid such as acetic acid or propionic acid in the same organic solvent as described above, water or a mixture thereof at room temperature to the boiling point of the solvent. The reduction reaction is usually carried out at room temperature to the boiling point of the solvent in the same organic solvent, water or a mixture thereof as described above by the catalytic reduction method using Raney nickel, palladium carbon, platinum oxide or the like as a catalyst under normal pressure. Be seen.

The intermediate and target compound in the above-mentioned production method are isolated and purified by purification methods commonly used in synthetic organic chemistry, such as filtration, extraction, washing, drying, concentration, recrystallization and various chromatographies. be able to. Also,
The intermediate may 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, it may be purified as it is, and when it is obtained in a free form, compound (I) may be purified in a suitable solvent, It may be isolated and purified by adding an acid or a base.

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

[0017]

[Table 1]

[0018]

[Table 2]

Next, the pharmacological action of the representative compound (I) will be specifically described with reference to experimental examples.

Experimental Example 1 Receptor antagonistic test using bovine adrenal cortex After slicing the tissue of bovine adrenal cortex, 0.25M sucrose solution [NaHCO ₃ , ethylenediaminetetraacetic acid (EDT
A), leupepsin, pepstatin A, containing phenylmethanesulfonyl fluoride] and homogenized. The homogenate was centrifuged at 3,000 rpm for 10 minutes,
The supernatant was centrifuged at 9,000 rpm. Add 30 more supernatant
After centrifuging at 000 rpm for 60 minutes, the precipitate was washed with NaHCO ₃
-Suspended with EDTA solution and centrifuged at 30,000 rpm for 60 minutes. The obtained precipitate was suspended in phosphate buffer, and this was suspended in A
It was used in the competition test as a source of II receptor.

The test compound or solvent was added to A prepared above.
250 μl of II receptor liquid, Tris 50 mM buffer [containing 0.2% bovine serum albumin (BSA)] 250 μl
^{l, 12 5 I-AII (} 2.5 × 10 -10 M) 20μl was added and the mixture was left for 2 hours at room temperature. The mixture was then filtered through a glass fiber filter (GF / B Whatman), the filter was placed in a test tube and the radioactivity was measured using a γ-counter. The inhibitory concentration of the test compound (IC showing 50% inhibition of the total specific binding of ¹²⁵ I-AII
₅₀ ) was calculated and the results are shown in Table 2.

[0022]

[Table 3]

Experimental Example 2 Inhibition test of pressor response to AII Male Wistar rats were anesthetized with pentobarbital, and then a blood pressure measuring cannula was inserted from the right femoral artery into the abdominal aorta and an AII infusion cannula was inserted into the right femoral vein. did. The cannula was subcutaneously placed on the dorsal surface and fixed, and blood pressure was recorded on the polygraph from the arterial cannula using a pressure transducer.

The day after surgery, the rat was placed in a cage and
The change in mean arterial blood pressure in response to an intravenous injection of 0.3 μg / kg of II was shown as the inhibition rate against pressor before oral administration of the test compound. Compound 2 is 1 according to this test
72% 1 hour after administration by oral administration of mg / kg
The inhibition rate of

The compound (I) or a pharmaceutically acceptable salt thereof is orally prepared by preparing it into a commonly applied dosage form such as tablets, capsules, injections, drops, suppositories, etc. Alternatively, it can be administered by parenteral administration such as intramuscular injection, intravenous injection, intraarterial injection, infusion or rectal administration. Conventionally known methods are applied to formulate such dosage forms for oral or parenteral administration.
It may contain various excipients, lubricants, binders, disintegrating agents, suspending agents, isotonic agents, emulsifying agents and the like.

The carrier for the formulation used is, for example,
Water, distilled water for injection, physiological saline, glucose, sucrose, mannitol, lactose, starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, alginic acid, talc, sodium citrate, calcium carbonate, calcium hydrogen phosphate, stearin. Examples thereof include magnesium acid salt, urea, silicone resin, sorbitan fatty acid ester, and glyceric acid ester.

Dosage depends on the dosage form, age and weight of the patient,
It depends on the symptom etc., but usually 0.05 orally
5 g / 60 kg / day is suitable.
It is preferable that the range of 01-5 mg / kg / min does not exceed the daily oral dose limit. Hereinafter, embodiments of the present invention will be described with reference to Examples and Reference Examples.

[0028]

【Example】

Example 1 2-Ethyl-3,4-dihydro-6,8-dimethyl-3
-Oxo-4- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] pyrazine (Compound 1) of the compound a obtained in Reference Example 1 Dissolve 406 mg in 10 ml of dimethylformamide, and sodium hydride 88 m
g was added, and the mixture was stirred under ice cooling for 10 minutes. Then 5-
(4'-Bromomethylbiphenyl-2-yl) -1-trityl-1H-tetrazole (described in JP-A-3-95181) 1.11 g of dimethylformamide solution was added, and the mixture was stirred at room temperature for 10 hours. Aqueous ammonium chloride solution was added thereto, and the obtained crystals were collected by filtration. The crude crystals were purified by silica gel column chromatography (n-hexane-ethyl acetate 1: 1) to obtain 928 mg (yield 68%) of compound 1 as white crystals.

Melting point: 141-143 ° C IR (KBr) cm ^-1 : 1612,1447,791,728 NMR (CDCl ₃ ) δ (ppm): 7.87 (1H, m) 7.5-6.8 (23H, m) 5.37 (2
H, s) 2.68 (2H, q, J = 7.5Hz) 2.63 (3H, s) 2.57 (3H, s) 1.23
(3H, t, J = 7.5Hz)

Example 2 2-Ethyl-3,4-dihydro-6,8-dimethyl-3
-Oxo-4- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-
b] Pyrazine (Compound 2) 920 mg of the compound 1 obtained in Example 1 was dissolved in 10 ml of dioxane, 2 ml of 1N-hydrochloric acid was added, and the mixture was heated at 50 ° C for 3 hours. The solvent was evaporated, water was added to the residue, and the mixture was neutralized with an aqueous sodium hydroxide solution. The precipitated crystals were collected by filtration, dried and then recrystallized from a mixed solvent of ether and ethanol to give compound 2 as white crystals (378 mg, yield 60).
%)Obtained.

Melting point: 150-152 ° C IR (KBr) cm ^-1 : 1645,1426,770 NMR (DMSO-d ₆ ) δ (ppm): 7.64-7.48 (4H, m) 7.03 (4H, s) 6.9
2 (1H, s) 5.43 (2H, s) 2.73 (2H, q, J = 7.5Hz) 2.49 (6H, s) 1.
19 (3H, t, J = 7.5Hz)

Example 3 3,4-Dihydro-6,8-dimethyl-3-oxo-2
-Propyl-4- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] pyrazine (Compound 3) of the compound b obtained in Reference Example 2 226 mg of compound 3 as white crystals according to the method of Example 1 using 100 mg.
(Yield 69%) was obtained.

Melting point: 150-152 ° C IR (KBr) cm ^-1 : 1618,1461,750,702 NMR (CDCl ₃ ) δ (ppm): 7.90 (1H, m) 7.5-6.8 (23H, m) 5.38 (2
H, s) 2.70 (2H, t, J = 7.5Hz) 2.63 (3H, s) 2.55 (3H, s) 1.70
(2H, m) 0.90 (3H, t, J = 7.5Hz)

Example 4 3,4-Dihydro-6,8-dimethyl-3-oxo-2
-Propyl-4- [2 '-(1H-tetrazole-5-
Il) biphenyl-4-yl] methylpyrido [2,3-
b] Pyrazine (Compound 4) Using 145 mg of the compound 3 obtained in Example 3, 81 mg of the compound 4 as white crystals was prepared according to the method of Example 2.
(Yield 90%) was obtained.

Melting point: 133-134 ° C. IR (KBr) cm ⁻¹ : 1655,1432,775 NMR (CD ₃ OD) δ (ppm): 7.65-7.5 (4H, m) 7.08 (4H, s) 7.04 (1
H, s) 5.56 (2H, s) 2.81 (2H, t, J = 7.5Hz) 2.60 (3H, s) 2.57
(3H, s) 1.66 (2H, m) 0.94 (3H, t, J = 7.5Hz)

Example 5 2-Cyclopropyl-3,4-dihydro-6,8-dimethyl-3-oxo-4- [2 '-(1-trityl-1H
-Tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] pyrazine (Compound 5) Using 100 mg of the compound c obtained in Reference Example 3, compound 5 was white according to the method of Example 1. 163mg as crystals
(Yield 46%) was obtained.

Melting point: 148-151 ° C IR (KBr) cm ^-1 : 1625,1460,765,711 NMR (CDCl ₃ ) δ (ppm): 7.86 (1H, m) 7.5-6.8 (23H, m) 5.46 (2
H, s) 2.56 (3H, s) 2.53 (3H, s) 1.68 (1H, m) 1.1-0.83 (4H,
m)

Example 6 2-Cyclopropyl-3,4-dihydro-6,8-dimethyl-3-oxo-4- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [ 2,3-b] Pyrazine (Compound 6) 133 mg of the compound 5 obtained in Example 5 was used and 38 mg of the compound 6 as white crystals was prepared according to the method of Example 2.
(Yield 42%) was obtained.

Melting point: 128-130 ° C IR (KBr) cm ^-1 : 1650,1488,774 NMR (CD ₃ OD) δ (ppm): 7.65-7.50 (4H, m) 7.11 (4H, m) 6.98
(1H, m) 5.64 (2H, s) 2.56 (3H, s) 2.55 (3H, s) 2.05 (1H, m)
1.05 (4H, m)

Example 7 3,4-Dihydro-2-isopropyl-6,8-dimethyl-3-oxo-4- [2 '-(1-trityl-1H-
Tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] pyrazine (Compound 7) 122 mg of the compound d obtained in Reference Example 4 was used, and Compound 7 was white crystal according to the method of Example 1. As 242 mg
(Yield 62%) was obtained.

Melting point: 137-138 ° C IR (KBr) cm ^-1 : 1642,1476,768,714 NMR (CDCl ₃ ) δ (ppm): 7.76 (1H, m) 7.5-6.8 (23H, m) 5.37 (2
H, s) 2.77 (1H, m) 2.63 (3H, s) 2.53 (3H, s) 1.25 (6H, d, J =
6Hz)

Example 8 3,4-Dihydro-2-isopropyl-6,8-dimethyl-3-oxo-4- [2 '-(1H-tetrazole-
5-yl) biphenyl-4-yl] methylpyrido [2,2
3-b] Pyrazine (Compound 8) Using 203 mg of the compound 7 obtained in Example 7, 44 mg of the compound 8 as white crystals was prepared according to the method of Example 2.
(Yield 33%) was obtained.

Melting point: 144-145 ° C. IR (KBr) cm ⁻¹ : 1663,1418,775 NMR (CD ₃ OD) δ (ppm): 7.65-7.51 (4H, m) 7.11 (5H, m) 5.63
(2H, s) 2.63 (1H, m) 2.63 (3H, s) 2.60 (3H, s) 1.29 (6H, d,
(J = 6Hz)

Example 9 2-Butyl-3,4-dihydro-6,8-dimethyl-3
-Oxo-4- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] pyrazine (Compound 9) of the compound e obtained in Reference Example 5 Using 240 mg, 400 mg of compound 9 as white crystals according to the method of Example 1
(Yield 54%) was obtained.

Melting point: 144-146 ° C. IR (KBr) cm ⁻¹ : 1637,1477,766,714 NMR (CDCl ₃ ) δ (ppm): 7.86 (1H, m) 7.5-6.8 (23H, m) 5.33 (2
H, s) 2.65 (2H, t, J = 7.5Hz) 2.65 (3H, s) 2.56 (3H, s) 1.7-
1.2 (4H, m) 0.83 (3H, t, J = 7.5Hz)

Example 10 2-Butyl-3,4-dihydro-6,8-dimethyl-3
-Oxo-4- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-
b] Pyrazine (Compound 10) Using 350 mg of the compound 9 obtained in Example 9, 154 m of the compound 10 as white crystals was prepared according to the method of Example 2.
g (yield 66%) was obtained.

Melting point: 160-162 ° C IR (KBr) cm ^-1 : 1651,1415,770 NMR (CD ₃ OD) δ (ppm): 7.65-7.52 (4H, m) 7.11 (5H, m) 5.66
(2H, s) 2.92 (2H, t, J = 7.5Hz) 2.62 (3H, s) 2.61 (3H, s) 1.
67 (2H, m) 1.38 (2H, m) 0.90 (3H, t, J = 7.5Hz)

Example 11 3,4-Dihydro-2,6,8-trimethyl-3-oxo-4- [2 '-(1-trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3-b] Pyrazine (Compound 11) According to the method of Example 1, 100 mg of the compound f obtained in Reference Example 6 was used, and Compound 11 was obtained as white crystals in an amount of 160 m.
g (yield 45%) was obtained.

Melting point: 113-116 ° C. IR (KBr) cm ⁻¹ : 1599,1415,740,691 NMR (CDCl ₃ ) δ (ppm): 7.93 (1H, m) 7.5-6.8 (23H, m) 5.47 (2
H, s) 2.71 (3H, s) 2.69 (3H, s) 2.58 (3H, s)

Example 12 3,4-Dihydro-2,6,8-trimethyl-3-oxo-4- [2 '-(1H-tetrazol-5-yl) biphenyl-4-yl] methylpyrido [2,3 -B] Pyrazine (Compound 12) Using 157 mg of the compound 11 obtained in Example 11,
According to the method of Example 2, Compound 12 was obtained as white crystals.
mg (yield 71%) was obtained.

Melting point: 274-275 ° C. IR (KBr) cm ⁻¹ : 1597,1415,773 NMR (DMSO-d ₆ ) δ (ppm): 7.68-7.46 (7H, m) 7.15-7.12 (2H,
m) 5.56 (2H, s) 2.61 (6H, s) 2.50 (3H, s)

Example 13 2-Ethyl-1,2-dihydro-2-oxo-1-
[2 '-(1-Trityl-1H-tetrazol-5-yl) biphenyl-4-yl] methylquinoxaline (Compound 13) 3-Ethyl-1,2-dihydro-2-oxoquinoxaline [Chem. Absts., 68 , 49499n (1968)] 87mg
According to the method of Example 1, 160 mg of compound 13 was obtained as white crystals (yield 49%).

Melting point: 130-131 ° C IR (KBr) cm ^-1 : 1668,1614,755,705 NMR (CDCl ₃ ) δ (ppm): 7.82 (2H, m) 7.5-6.75 (25H, m) 5.32
(2H, s) 3.00 (2H, q, J = 7.5Hz) 1.38 (3H, t, J = 7.5Hz)

Example 14 2-Ethyl-1,2-dihydro-2-oxo-1-
[2 ′-(1H-tetrazol-5-yl) biphenyl-4-yl] methylquinoxaline (Compound 14) Using 160 mg of the compound 13 obtained in Example 13,
According to the method of Example 2, Compound 14 was obtained as white crystals.
mg (yield 42%) was obtained.

Melting point: 98-100 ° C IR (KBr) cm ^-1 : 1644,1604,758 NMR (DMSO-d ₆ ) δ (ppm): 7.81 (1H, d, J = 7.5Hz) 7.64-7.31 (7
H, m) 7.19 (2H, d, J = 7.5Hz) 7.03 (2H, d, J = 7.5Hz) 5.49 (2
H, s) 2.91 (2H, q, J = 7.5Hz) 1.27 (3H, t, J = 7.5Hz)

Reference Example 1 2-Ethyl-3,4-dihydro-6,8-dimethyl-3
-Oxopyrido [2,3-b] pyrazine (compound a) 4.0 g of 2,3-diamino-4,6-dimethylpyridine (described in JP-A-3-95181) was dissolved in 63 ml of ethanol to give 2- Oxobutanoic acid (4.0 g) was added, and the mixture was heated under reflux for 48 hours. After the solvent was distilled off and water was added to separate the precipitated crystals by filtration, the filtrate was concentrated and then subjected to silica gel column chromatography (chloroform-methanol 5
0: 1) and white crystals of compound a 2.24 g
(Yield 28%) was obtained. NMR (CDCl ₃ ) δ (ppm): 6.85 (1H, s) 3.00 (2H, q, J = 7.5Hz) 2.
65 (3H, s) 2.61 (3H, s) 1.42 (3H, t, J = 7.5Hz)

Reference Example 2 3,4-dihydro-6,8-dimethyl-3-oxo-2
-Propylpyrido [2,3-b] pyrazine (Compound b) 2,3-diamino-4,6-dimethylpyridine 1.37
g was dissolved in 20 ml of ethanol, 1.38 g of sodium 2-oxopentanoate and 0.8 ml of hydrochloric acid were added, and the mixture was heated under reflux for 2 hours. The solvent was distilled off, water was added, the mixture was extracted with chloroform, washed with water, and then the organic layer was dried and concentrated. The obtained residue was purified by silica gel column chromatography (chloroform-methanol 50: 1) to give compound b.
1.21 g (yield 63%) of pale yellow crystals were obtained. NMR (DMSO-d ₆ ) δ (ppm): 6.80 (1H, s) 2.77 (2H, q, J = 7.5Hz)
2.45 (6H, s) 1.77 (2H, m) 0.92 (3H, t, J = 7.5Hz)

Reference Example 3 2-Cyclopropyl-3,4-dihydro-6,8-dimethyl-3-oxopyrido [2,3-b] pyrazine (Compound c) Cyclopropyl glyoxylate potassium [Coll. Czech.
Chem. Commun., 40 , 1038 (1975)] using 1.27 g and following the method of Reference Example 2 for pale yellow crystals of compound c.
00 mg (yield 31%) was obtained. NMR (CDCl ₃ ) δ (ppm): 6.78 (1H, s) 2.63 (3H, s) 2.55 (3H, s)
2.15 (1H, m) 1.13 (4H, m)

Reference Example 4 3,4-Dihydro-2-isopropyl-6,8-dimethyl-3-oxopyrido [2,3-b] pyrazine (Compound d) Sodium 3-methyl-2-oxobutanoate 454 mg
Was used according to the method of Reference Example 2 to obtain 386 mg (yield 54%) of pale yellow crystals of Compound d. NMR (CDCl ₃ ) δ (ppm): 6.85 (1H, s) 3.25 (1H, m) 2.65 (6H, s)
1.43 (6H, d, J = 6Hz)

Reference Example 5 2-Butyl-3,4-dihydro-6,8-dimethyl-3
-Oxopyrido [2,3-b] pyrazine (Compound e) 500 mg of sodium 2-oxohexanoate was used and 243 mg of pale yellow crystals of Compound e were prepared according to the method of Reference Example 2.
(Yield 32%) was obtained. NMR (CDCl ₃ ) δ (ppm): 6.95 (1H, s) 3.00 (2H, bt) 2.66 (3H,
s) 2.65 (3H, s) 2.0-1.3 (4H, m) 0.97 (3H, bt)

Reference Example 6 3,4-Dihydro-2,6,8-trimethyl-3-oxopyrido [2,3-b] pyrazine (Compound f) 400 mg of methyl pyruvate was used according to the method of Reference Example 2. 134 mg of pale yellow crystals of compound f (18% yield)
Got NMR (CDCl ₃ ) δ (ppm): 7.22 (1H, s) 2.47 (3H, s) 2.44 (3H, s)
2.42 (3H, s)

[0062]

INDUSTRIAL APPLICABILITY According to the present invention, the fused pyrazine derivative represented by the formula (I) and a pharmacologically acceptable salt thereof exhibit an AII receptor antagonistic action and are induced or deteriorated by AII. It is useful for treating hypertension, congestive heart failure, renal failure and glaucoma.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Internal reference number FI Technical display location C07D 471/04 120 8415-4C (72) Inventor Koji Yamada 1309-3 Sano, Susono, Shizuoka Prefecture

Claims (1)

[Claims] 1. The formula: (Wherein R ¹ represents hydrogen, lower alkyl or cycloalkyl, R ² represents hydrogen, benzyl, benzhydryl or trityl, R ³ and R ⁴ are the same or different and represent hydrogen or lower alkyl, and Z is CH. Or a condensed pyrazine derivative represented by N) or a pharmaceutically acceptable salt thereof.