JPH03223284A - Xanthine derivative - Google Patents

Abstract

NEW MATERIAL:A compound expressed by formula I [R<1> hydrocarbon which may be bound through a hetero-atom or substituted; R<2> and R<3> are H or (substituted) hydrocarbon; R<4> is H, halogen or nitro; R<5> is a group capable of forming anion or a group convertible thereinto; A indicates that phenylene and phenylene are bound directly or through a spacer having <=2 atomic chains; (n) is 1 or 2; Y and Z are O or S]. EXAMPLE:8-n-Butyl-7-[2'-[(1H-tetrazol-5-yl)biphenyl-4-yl]methyl]-1,3- dimethylxanthine. USE:Useful as a therapeutic agent for circulatory diseases such as hypertension, cardiopathy or cerebral apoplexy having angiotensin II antagonistic action and hypotensive action. PREPARATION:One mol compound expressed by formula II is allowed to react with 1-3mol alkylating agent expressed by formula III in the presence of 1-3mol base normally in a solvent such as DMF.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel xanthine derivatives having excellent pharmacological effects and synthetic intermediates thereof.

More specifically, the present invention has a strong angiotenoid antagonistic effect and antihypertensive effect, and is effective against hypertension, heart disease,
General formula useful as a therapeutic agent for cardiovascular diseases such as stroke [wherein R1 represents a hydrocarbon residue which may be bonded via a heteroatom or may be substituted, R'' and R3 may be the same or different, each represents hydrogen or an optionally substituted hydrocarbon residue, and R4
represents hydrogen, halogen, or nitro group, R5 represents a group that can form an anion or a group that can be converted into an anion, and A represents a phenylene group and a phenyl group bonded directly or through a spacer having 2 or less atomic chains. , n represents an integer of 1 or 2, and Y and Z may be the same or different (representing an oxygen atom or a sulfur atom, respectively) or a salt thereof.

Prior art and inventions or problems to be solved
The angiotensin system, together with the aldosterone system, is involved in homeostatic regulation functions such as systemic blood pressure, body fluid volume, and electrolyte balance. Furthermore, the relationship between the renin-angiotensin system and hypertension has been clarified through the development of inhibitors (anti-ACE drugs) of angiotensin-converting enzyme, which generates angiotensin-containing angiotensin, which has a strong vasoconstrictive effect.

Angiotensin receptors on cell membranes increase blood pressure, so its antagonist is anti-A
Like CE drugs, it can be used to treat hypertension caused by angiotensin. Until now, many angiotensin
Analogs such as Saralasin.

It has been reported that [Sar', lie''] AU and the like have a strong angiotensin antagonistic effect.

However, it has been reported that peptide antagonists have a short action time when administered parenterally and are ineffective when administered orally [M, ^, Ondetti and D, W,
Cushman.

Annual Reports in Medicine
al Chemistry, 13°82, -91(+
978)].

Non-peptide angiotensin antagonist is JP-A-56
-71073. JP-A-56-71074° JP-A-57-
92270. JP-A-58-157768, JP-A-62
-240683. JP-A-6323868, EP-032
3841 and Japanese Unexamined Patent Publication No. 1-11787, and A. T. Chiu eLal, Eur, J.
Phara+, 157.13 (198g), P
,C.

long eL al,, J, Pharmcol,
Exp, Ther, 247°1 (1988) and P, C,ong et al, Hyper
Imidazole derivatives having angiotensin Il antagonistic activity are disclosed in Tens+on13, 489 (1989) and the like.

However, it is completely unknown that bovine santhin derivatives have angiotensin antagonistic effects (no).

Means for Solving the Problems The present inventors have diligently searched for compounds that have an angiotensin antagonist action and are useful as therapeutic agents for cardiovascular diseases such as hypertension, heart disease, and stroke. As a result, they have discovered an excellent angiotensin We succeeded in producing a xanthine derivative with antagonistic effects, and after further research, we completed the present invention.

That is, the present invention provides compounds of the formula [wherein R1 represents a hydrocarbon residue which may be bonded via a heteroatom and which may be substituted, and either R'' or R3 is substituted. and the other is hydrogen or a hydrocarbon residue that may be substituted, R4 represents hydrogen, norogen, or a nitro group, and R5 is a group capable of forming an anion or a group convertible thereto. , A indicates that a phenylene group and a phenyl group are bonded directly or through a spacer having an atomic chain of 2 or less, n indicates an integer of 1 or 2, and Y and Z
may be the same or different and each represents an oxygen atom or a sulfur atom] or a salt thereof.

Regarding formula (1) above, the hydrocarbon residue for R is, for example, a lower alkyl group having about 1 to 8 carbon atoms (e.g., methyl, ethyl, propyl, isopropyl butyl, isobutyl, 5ec-butyl, t-butyl). , pentyl, i-
pentyl, hexyl, heptyl, octyl, etc.), lower alkenyl having about 1 to 8 carbon atoms (L vinyl, allyl (
allyl), isopropenyl.

2-butenyl, I,3-butadienyl, 2-pentenyl, 2-hexenyl 1 2-octenyl, etc.).

Lower alkynyl groups having about 1 to 8 carbon atoms (e.g., ethynyl,
2-propynyl, 2-butynyl, 2-bentinyl, 2-
octynyl, etc.) or alicyclic hydrocarbon residues having about 3 to 8 carbon atoms (eg, 7-clopropyl, cyclopentyl/chlorohexyl, 2-fuclohexen-1-yl).

cyclooctyl, etc.), aromatic hydrocarbon residues having about 6 to 12 carbon atoms (eg, phenyl, naphthyl, etc.) and cyclic hydrocarbon residues.

The hydrocarbon residue as R1 may be bonded to the imidazole skeleton via a heteroatom, and the heteroatom may be S, O or NR (R represents hydrogen or an optionally substituted hydrocarbon residue). ), etc. Also R
1 is a hydroxyl group, a lower (C4) alkokino group (e.g., methoxy/
, ethoxy).

Lower (C,,)alkyl group (e.g., methyl, ethyl, etc.)
Halogen (e.g., F, Ci2,13r, etc.), nitro, optionally substituted ami7 group (e.g., ami7, etc.), a/
Ruoki/(eg, lower (C,-,)alkamyloxy).

(hendiyloxy, etc.), phenyl (phenyl, etc., which may have a substituent such as halogen, nitro, lower (C4) alkoxy, lower (C,,) alkyl, etc. at any position on the benzene ring) It may have substituents such as.

Among the hydrocarbon residues as R1 described above, carbon number 1 may be bonded to the bovine santhin skeleton via a sulfur atom.
~8 lower alkyl group, phenyl which may have a substituent such as halogen, nitro, lower (C, -,) alkoxy, lower (C, -,) alkyl at any position on the benzene ring A substituted lower alkyl group having about 1 to 4 carbon atoms (e.g., phenyl-lower (C,-,) alkyl such as benzyl, phenethyl, phenylpropyl, etc.), and a halogen, nitro, Preferred is phenyl which may have a substituent such as lower (C4) alkoxy or lower (C, -,) alkyl.

Examples of the hydrocarbon residues as R1 and R3 include lower alkyl groups having about 1 to 4 carbon atoms (eg, methylethylpropyl, isopropyl, butyl).

isobutyl, 5ec-butyl, t-butyl, etc.), lower alkenyl groups having about 1 to 4 carbon atoms (eg, vinyl).

allyl, isopropenyl, 2-butenyl.

1,3-butadienyl, etc.), lower alkynyl groups having about 1 to 4 carbon atoms ((L ethynyl, 2-7'rohynyl, 2
-butynyl) or alicyclic hydrocarbon residues having about 3 to 6 carbon atoms (e.g. /chloropropyl, cyclopentyl, cyclohexyl, 2-7 clohexen-1-ylnato) , aromatic hydrocarbon residues having about 6 carbon atoms (eg, phenyl, etc.), and cyclic hydrocarbon residues.

Hydrocarbon residues as R2 and R3 are hydroxyl groups.

Lower (C1,,4) alkoxy groups (e.g., methoxy, 7.ethkin, etc.), lower (C, -,) alkyl groups (e.g., methylethyl, etc.), halogens (e.g., F, C(, Br, etc.) Nitro, optionally substituted amino group (e.g., amine, etc.), acyloxy (e.g., lower (C, , ) alkamyloxy, hendyloxy, etc.), phenyl (e.g., halogen nitro at any position on the Hensen ring) , low grade (CI-,
) may have a substituent such as phenyl, which may have a substituent such as alkoxy or lower (C,-,)alkyl.

Among the hydrocarbon residues as R2 and R3 described above, 1 to 4 carbon atoms may be substituted with a hydroxyl group, a lower (C, -,) alkoxy group, an optionally substituted amide group, an acyloxy group, etc. lower alkyl group, nitro, lower (C,
) C1-4 substituted with phenyl which may have a substituent such as alkoxy1 lower (C1゜4) alkyl
lower alkyl groups (phenyl-lower (CI-4) alkyl nato such as L benzyl, phenethyl, phenylpropyl), and at any position on the benzene ring, nitro, lower (C, -,) alkoxy, Low grade (C,
-,) Phenyl which may have a substituent such as alkyl is preferable, and a lower alkyl group having about 1 to 4 carbon atoms is more preferable.

R4 is hydrogen or halogen (eg, chloro, bromine, etc.).

Alternatively, it represents a nitro group, which may be substituted at either the ortho or meta position, and hydrogen is particularly preferred as R4.

An example of a group capable of forming an anion or a group convertible thereto as R5 is carboxyl.

Lower (CI-4) alkoxocarbonyl, cyanide, tetrazolyl, trifluoromethanesulfonic acid amide (-N
H5O, CF3), phosphoric acid, sulfonic acid, etc., and these groups may be protected with an optionally substituted lower alkyl group or anru group as shown in R6 and R7 below, and biological under physiological conditions,
Alternatively, any group that can chemically form an anion or a group that changes thereto may be used, and R5 may be substituted at any of the ortho, meta, and para positions, but especially R
5 is preferably carpoquine or tetrazolyl, R
The preferred substitution position for 5 is the ortho position.

Compounds in which R5 is a group that can chemically form an anion or a group that can be converted into an anion (for example, n-ano) are useful as synthetic intermediates.

Δ indicates that an adjacent phenylene group and a phenyl group are bonded directly or via a spacer with a chain of 2 or less atoms, and the spacer with a chain of 2 or less atoms is either 1 or 2, depending on the number of atoms constituting the linear part. Any divalent chain may be used as long as it is, and it may have a side chain. Specifically, lower (C, , ) al and the like can be mentioned.

Y and Z each represent an oxygen atom or a sulfur atom,
Although these may be the same or different, it is preferable that Y and 2 are the same, and it is further preferable that Y and Z are oxygen atoms.

Among the compounds represented by the above formula (1), formula 2 [wherein is a lower (C, -,) which may be bonded via a sulfur or oxygen atom (preferably a sulfur atom)]
Alkyl group, optionally substituted phenyl-lower (C
, -4) alkyl or optionally substituted phenyl, R2 and R3 each represent a lower (C4) alkyl group, and R5 represents carboxyl or tetrazolyl] or a salt thereof is preferred.

Production method The compound of formula (1) above can be produced, for example, by the method shown below.

reaction (a) [In the formula, , Rt, R3, R', Rs, ZY, A and n has the same meaning as above.

X represents halogen.

] reaction (b) 2 1 ■ b c. [In the formula, R1, R1 R3, R', Z, Y, A and n are Same meaning as .

] Reaction (c) 2 t [In the formula, R', Rt, R3, R', Re, Z, YA
and n have the same meanings as above.

] Reaction (d) R” 2 f 1g [In the formula, R', R', R3, R', R7, Z, Y A
and n has the same meaning as above. 1. In the reaction (a), alkylation is carried out by using an alkylating agent in the presence of a base. 1 to 3 mol of base and 1 to 3 mol of alkylating agent per 1 mol of compound (II)
The reaction is carried out in a solvent such as methylformamide, dimethylacetamide, 7methylsulfoxide, triacetonitrile, acetone, and ethylmethylketone using a molar amount.

Such bases include sodium 2L-butoquinocassium hydride, sodium carbonate, and sodium carbonate.

As such an alkylating agent, substituted halides (eg, chloride, bromide, iodide, etc.), substituted sulfonic acid esters (eg, methyl ha, p-)luenesulfonate, etc. are used.

Although the reaction conditions vary depending on the combination of base and alkylating agent used, it is usually preferable to conduct the reaction under water cooling to about room temperature for about 1 to 10 hours.

In reaction (b), a cyanide group substituted on a benzene ring is reacted with various azides to convert it into a tetrazole compound (r c).

And compound 1 to 3 per mol of compound (lb)
Usually used in molar quantities, dimethylformamide.

It is carried out in a solvent such as dimethylacetamide, toluene, or benzene.

Examples of such and compounds include trialkyltin or triphenyltin and hydrazoic acid.

When using an organic tin azide compound, the reaction is carried out in toluene or benzene for about 10 to 30 hours while heating under reflux.

When reacting hydroacetic acid, sodium and ammonium chloride are used in about twice the mole of compound (Ib), and the reaction is carried out in dimethylformamide at about 100-+30°C for about 1 to 3 days. During this time, it is preferable to add appropriate amounts of sodium azide and ammonium chloride to accelerate the reaction.

Reaction (c) is carried out using a suitably protected tetrazole derivative (l
Compound (Ie) is obtained by removing (V-protection) d).

In this reaction, the deprotection conditions differ depending on the protecting group (Ro) used. For example, R' or triphenylmethyl, 2
-Tetrahydropyranyl When using methquin methyl or ethquin methyl, incubate for 1 to 10 hours in a water-containing alcohol containing about 0.5N to 2N hydrochloric acid or acetic acid (e.g., methanol, ethanol, etc.) at room temperature for about 1 to 10 hours. It is better.

Reaction (d) consists of a suitably protected carbonic acid derivative (I
Compound (Ig) is obtained by deprotecting ").

In this reaction, the deprotection conditions differ depending on the protecting group (R7) used. For example, when R7 is a tert-butyl group, it is preferable to react with excess trifluoroacetic acid in an appropriate organic solution (IUI, chloroform, methylene chloride, acetonide, etc.) at room temperature for 1 to 5 hours. .

Compound (1) thus produced from reaction (a) to reaction (d) can be separated and purified from the reaction solution by conventional separation and purification methods such as distillation of the reaction solvent, extraction with water or an organic solvent, IA condensation, neutralization, recrystallization, It can be easily isolated as a crystal or oil by distillation, column chromatography, etc.

In addition, these compounds (1) can be prepared by conventional methods into salts with physiologically acceptable acids or bases, such as salts with inorganic acids such as hydrochloride, sulfate, and nitrate; It can be converted into salts with organic acids such as acid salts and maleates, salts with alkali metals such as sodium salts and potassium salts, and salts with alkaline earth metals such as calcium salts.

Among these compounds, starting compound (II) is, for example, (1)
D, S, Bariana, Can,
J. Chem., 46. 3413 (1968
).

(2) A, J, Dietz, JR, an
d R, M, Burgison J Med;
Chem,, 9. 500 (1966).

(3) K, A, Jacobson, L, Ki
riasis, S. Barone.

B. J., Bradbury, U. Ka.
mi+ula, J, &l.

Caa+pagne, S, 5ecunda,
J, If, Daly, J, LNeu
Meyer, and W. Pfleider
er, J, MedChcv 32. 18
73 (1989).

(4) F, F, B11cke and It,
C, GodL, Jr., J. AmChem.
Soc, 76, 2799 (1954).

(5) K, R, H, Wooldridge a.
nd R, 5lack, J.

Chem, Soc, 1962. 1863゜(6) A, J, Dietz, Jr.
and R.M., Burgison, J.M.
ed, Chem, 9. 160 (1966)
.

(7) It can be synthesized by the method described in JP-A No. 2-247180 or a method similar thereto.

Moreover, among the raw material compounds (III), the compound (IIIa) in which n is 1 is disclosed in JP-A No. 63-23868. Compound (IV) obtained by the method described in JP-A-II 17876 and EP-0323841, but which is commercially available or synthesized by a method known in the literature, is prepared according to reaction (e), for example, A, ^, Vansheidt et al.
t,, Khim, Nauka i Prom,,
It can also be easily obtained by halogenomethylation according to the method described in, for example, 2.799 (1957).

Reaction (e) ■IIIa In formula 1, each symbol has the same meaning as above. ] Furthermore, among the raw material compounds (1), a compound (Illb) in which n is 2 can be obtained by reacting the compound (nla) according to reaction (f).

Reaction (f) a ■ ■ ■ lb [In the formula, each symbol has the same meaning as above. ] Compound (1) and its salts produced in this way have low toxicity and strongly suppress the vasoconstriction and blood pressure increasing effects caused by angiotensin H, and are useful in animals, especially mammals (e.g.
It exhibits a blood pressure lowering effect on humans, dogs, rabbits, rats, etc.) and is useful not only as a therapeutic agent for hypertension but also for cardiovascular diseases such as heart disease and stroke.

When used as such pharmaceuticals, compound (1) and its salts may be used by themselves or mixed with appropriate pharmacologically acceptable carriers, excipients, and diluents to form powders, granules, tablets, capsules, and injections. It can be administered orally or parenterally in the following dosage forms.

The dosage varies depending on the target disease, symptoms, subject, administration method, etc., but when administered as a treatment for adult essential hypertension, the daily dose is 10 to 100 mg for oral administration, and 5 to 100 mg per day for intravenous injection. It is preferable to administer 50 mg in 2 to 3 divided doses.

The present invention will be explained in more detail below using Examples, Experimental Examples, and Reference Examples, but it goes without saying that these do not limit the present invention.

Reference Example 1 5.6-Diami2-1,3-dimethyluracil hydrate (17.02 g, O, 1iol) was mixed with pyridine (100-
) and stirred. Add to this valeryl chloride (1
After stirring at room temperature for 20 hours, water was added to the reaction mixture and extracted with ethyl acetate. After washing the ethyl acetate layer with water and drying (MgSQ), the solvent was distilled off under reduced pressure. The obtained solid was powdered by adding ethyl acetate, and filtered to obtain crystals of the title compound.
g (44.9%) was obtained.

rR(Nujol)cm-': 3320.317
0.1710.1665.164ONMR(DMSO-
d,) δ: 0.87 (3) 1. t, J・7.2H
z).

1, 17-4.60 (4H, m), 2.23 (2H,
t, J=7.211z), 3.10 (311°s)
, 6.48 (211, brs), 8.25 (IH,
brs) B: 3-n-butyl-1,3-dimethylxanthine 6-amino-5-valerylamino-1,3-dimethyluracil (2,54 g) obtained in Reference Example 1-A.

10 mmol) with 1N hydroxide) l) Rum water solution 1
It was dissolved in a mixture of ffl(40-) and ethanol (10d) and stirred under heating under reflux for 15 hours. Acetic acid was added to the reaction solution, and the precipitated crystals were collected by filtration and washed with water and then petroleum ether to obtain 2.54 g of crystals. This was recrystallized from ethanol to obtain the title compound (2.27 g) as a colorless prism.
, 96N%) was obtained.

Melting point 240-241°C IR (Nujol) cm-': 3150.1715
NMR (CD CI23) δ: 0.96 (3H,
L, J・7.4Hz), 1.331, 54 (211
, l11), 1.74-1.93 (211, m),
1.7g (Ill, brs) 2.91 (211,t,
J=7.4Hz), 3.48(3H,s), 3.
64 (311,s) Elemental analysis values: C,, H,, N, O
.

Calculated value: C, 55,92; H, 6,83; Actual value: C, 55,84; H, 6,95; Reference example 2 N, 23.71 N, 23.56 5.6-Diami2 1. 3-dimethyluracil (4,5
6 g, 30 ml of acetic acid (3-) and methanol (15
Stir the mixture of d) and add benzaldehyde (3
, 18g + 30maol) in methanol solution (l
Od) was added. After stirring at room temperature for 3 hours, the precipitate precipitated was collected by filtration and dried to give the title compound (5.75 g, 7
4.2%). When 0.57 g of Honjima was recrystallized from a mixed solvent of dimethylformamide (DMF) and methanol, 0.36 g of pure product was obtained.

Melting point: 229-230°C IR(Nujol)ca+-': 3420.33
00.1695.160ONMR(DMSO-dB)δ
: 3.18 (3H, s), 3.41 (3) I, s
), 7.29 (5H, o+), 7.89 (211,
dd, J=8.01lz, 1.811z), 9.
73 (1B, S) Elemental analysis values: C,,H,4N,0.

Calculated value: C, 60, 45; H, 5, 46; N
, 21.69 Actual value: C, 60, 46; H, 5,
45: N, 21.71B: l, 3-dimethyl-8-
Phenylxanthine 6-amino-1,3-dimethylamine-5-pensyridinouracil (5,17g, 20
iron trichloride (FeC123) (3.in+ol) in ethanol solution (401n1).

25 g, 20 a+mol) was added thereto, and the mixture was stirred under heating under reflux for 4 hours. After the reaction solution was left at room temperature for 2 days, the precipitate was collected by filtration and washed with ethanol to obtain yellow crystals (3.59 g, 70.0%) of the title compound.

r R(Nujol)ca+-': 3160.16
90.165ON M R (DM S Ods) δ:
3.29 (3H, s), 3.52 (311°s),
7.28-7.59 (511, i+), 7.8B (
lit, brd, J:4.211z) Elemental analysis value:
C,3H,,N40.

Calculated value: C, 60,93, H, 4,72; N, 2
1.86 Actual value: C, 59,50; H, 4,69
; N, 22.08 The compounds listed in Table 1 were prepared by the same methods as in Reference Examples 1 and 2 or by the same methods as those described in References (1) to (7) or in accordance therewith.

(Left below) Reference example 34 Sodium hydride (oil-based, 60%) (0.22g5,
5 mmol) in N,N-dimethylformamide (DM
(abbreviated as F) (15d) and stirred under water cooling.

This was added to 8-n-butyl-1,3-dimethylxanthine (
1.18g, 5.0mmol) dissolved in DMF (15
Add the solution of (Kura) and stir for 30 minutes under water cooling f:L4-
(2-cyanophenyl)benzyl bromide (1,50
A solution of DMF (10 Ml) containing 5.5 mmol) was added dropwise. After stirring for 1 hour under water cooling, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried (MgSO, ), and the solvent was distilled off under reduced pressure. The obtained residue was subjected to silica gel column chromatography,
Elution was carried out with n-hexaethyl acetate (1:4 v/v), and the fraction containing the target product was concentrated under reduced pressure. The residue was recrystallized from a mixture of dichloromethane and ethyl acetate to give the title compound (1.68 g, 78.6%) as white crystals.

Melting point: 165i66℃ IR (Nujol) cm-': 2250.1710
．． 166ONMR(CDCf23)δ: 0.91(3
H, t, J=7.2Hz), 1.29-1, 48(
2t(,m), 1.61-1.78(211,m),
2.73 (2H, t, J4.2Hz), 3.42
(3tL s), 3.62 (311,s), 5.6
3(2H,s), 7.29(2II, d, J =
1.0Hz), 7.40-7.81 (611, m) Elemental analysis values: C, 5H,, N50.

Calculated value: C, 70, 24 H, 5, 89; N, 1
6.38 Actual value: C, 70, 23; H, 5, f3
7. N, 16.18 Reference Example 35 Sodium hydride (oil-based, 60%) (90 mg, 2
mmol) was suspended in DMF (8d) and stirred under water cooling. DM in which 8-n-butyl-1,3-dimethylxanthine (0.43g + 1.8mmol) was dissolved
After adding a solution of F (8d) and stirring for 20 minutes under water cooling, a solution of DMF (6 rotations) containing L-butyl 4'-bromomethylbiphenyl-2-carboxylate (0.95 g, 2.7 mmol) was added. dripped. After stirring at room temperature for 1 hour, the reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO,). The curved material obtained by distilling off the solvent under reduced pressure was subjected to column chromatography on silica gel, and eluted with a mixed solvent of n-hexane and ethyl acetate (1:4. v/v), which contained the target object. Fracuncone was concentrated under reduced pressure to obtain crystals. This was recrystallized from ethyl acetate-ether to obtain 0.72 g (78.7%) of the title compound as a colorless prism.

Melting point +55156°C I R (Nujol) cm-': 1710.1700
．． 166ONMR(CDCf!3)δ: 0.94(3
11,t, J=7.211z), 1.22(911
,s) 1.31-1.52(2H,m), 1.64
-1.81 (2ft, m).

2, 73 (211, t, J・7.211z), 3.
41 (3H, s), 3.61 (3tl, s).

5, 60 (211, s), 7.17-7, 53 (71
1, m), 7.75-7.87 (lit, m) Elemental analysis value: C,, H3, N40.

Calculated value: C, 69,30; H, 6,82; N
, 11.15 Actual value: C, 6g, 91; H, 6,
93; N, 10.94 Reference Example 36 8-ethoxy-1,3-dimethylxanthine (0,90
g) was dissolved in dimethylformamide (15d), sodium hydride (60% oily, 0.23 g) was added, and the mixture was stirred at room temperature for 15 minutes. A solution of [2'-(N triphenylmethyltetrazol-5-yl)biphenyl-4-ylcomethylbromide (2.51 g) in DMF (17) was added and stirred at room temperature for 3 hours. After the reaction, water was added and extracted with chloroform. The extract was washed with water and dried (MgSO,
) After that, the solvent was distilled off. The obtained residue was purified by silica gel column chromatography to obtain colorless silica. Crystallization from ethyl acetate-ether gave colorless crystals (1.29 g, 41%).

Melting point 168-169℃ Elemental analysis value C4tH3sN so s (%)
H (%) N (%) Calculated value 71.98;
5.18° 15.99 Actual value: 71.98
5.27 15.72 The compounds shown in Table 2 were prepared in the same manner as in Reference Examples 34, 35 and 36.

(Left below) Example 1 8-n-butyl-7-(2'-cyanobiphenyl-4-yl)methyl-1,3-dimethylxanthine (1,26 g
, 2.9 mmol) in DMF (50d), sodium azide (1.98 g + 30 mmol) and ammonium chloride (1.63 g, 30 mmol) were added and stirred at +15°C for 7 days. The reaction solution was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgS
The solvent was distilled off under reduced pressure. The obtained Uraaki product was subjected to silica gel column chromatography and eluted with ethyl acetate. The fractions containing the desired product were concentrated, and the residue was recrystallized from isopropyl ether to obtain the title compound (0.83 g, 59.8%) as white crystals.

Melting point: 194-195°C IR (Nujol) cm-': 1700.1655
NMR (CDC & 3) δ ゛ 0190 (3H, l, J
=7.01lz), 1.28-1, 48(2tl, m
), 1.60-1.79 (2) 1. m), 2.7
0(2H,t, J=7.2tlz), 3.28(3
11,s), 3.53(3H,s), 5.49(2
11s), 7.09(41(, dd, J4.211
z, 13)1z), 7.37-7, 84(3)1.
s), 7.96(I)I.

dd, , bl, 0) 1z, 6.2) 1z) Elemental analysis value: Calculated value of Ct5H26N 80: C, 63,
82; t+ 5.57・N 23.81 Actual value:
C, 63,69; H, 5.6g, N, 23.
69 Example 2 8-di+cy 1,3-dimethyl-7-[[2'(N-
triphenylmethyltetrazol-5yl)biphenyl-4-yl]methyl]xanthine (118 g) IN
In addition to a mixture of hydrochloric acid (5 volumes) and methanol (20 volumes),
The reaction was allowed to proceed at room temperature for 6 hours. The reaction solution was extracted with chloroform, and the organic layer was washed with water and dried (MgSO,). After distilling off the solvent, the obtained silica was purified by 7 silica gel column chromatography. The obtained silica was crystallized from ethyl acetate to obtain colorless crystals (0.69 g, 89%).

Melting point: 224-225°C Elemental analysis: C, H,, N, 0. as C (%) 11
(%) N (%) Calculated value: 60.25; 4.84- 2444
Actual value: 59.98; 4.95; 23
．． 8ON MR(t)MSO-d,)δ: 1.34
(3H, t), 3.22 (31L s).

3, 39 (3H, s), 4.50 (211, Q),
5.23 (2fL s), 7.07<211. d)
7, 23 (2H, d), 7.49-7.73 (4)!
, m)l R(Nujol)am-': 1710
．． 1660.1620 Example 3 Chin 7-(2'-t-butoxycarbonylbiphenyl-4-yl)methyl-8-n-butyl-1,3-dimethylxanthine (0.40 g, 0.8 mIRol) and trifluoroacetic acid ( The mixture was stirred for 1 hour under water cooling.

The reaction solution was concentrated under reduced pressure, and the resulting residue was recrystallized from ether to obtain 0.31 g of the title compound as a colorless prism (
87.2%) was obtained.

Melting point: 181-182°C IR(Nujol)am-': 1700.165O
NMR (DMS 0-d8) δ: 0.82 (3H, t
, J.7.211z).

1, 19-1.42 (2H, m), 1.49-1.6
7 (2H, l1l), 2.70 (2H, t.

J=7.211z), 3.23(3)1. s),
3.43 (3H, s), 5.60 (2t1.s).

7, 1L7.59 (711, m), 7.71 (III
, dd, J=1.4f (z, 7.6Hz) Elemental analysis value: CtsHt-N -0-・0.21-1.0 Calculated value: C, 66,71; H, 5,91; N,
12.45 Actual value: C, 66,79; H, 5,8
7; N, 12.25 Example 4 The compound 8-
Prepared from n-pentyl-1,3-dimesanthine.

Melting point: 142-143°C IR (Nujol) cm-1: 1700,16
Chilled beef NMR (DMS 0-do) δ: 0.75-0.90
(3H, m), 1.12-1.36 (411, m),
1.50-1.70 (2H, m), 2.71 (2H
,t, J=7,6Hz), 3.25(3tl, s
), 3.34 (3H, brs), 3.45 (38
,s).

5, 62 (211, s), 7.22 (211, d,
J=8.411z), 7.30(2H,d, J=
8,411z), 7.31-7.61(31(,m)
, 7.72 (IH, dd, J=1.4) Iz.

7.611z) Elemental analysis value: C,,H,,N,0°calculated value・C,6
7,81; H, 6,13; N, 12.17 Actual value: C, 67,66; H, 6,14; N, 12
．． 07 The compounds shown in Table 3 were prepared in the same manner as in Examples 1 to 4 or in accordance therewith.

Formulation Example The compound (1) of the present invention is used to treat, for example, hypertension, heart disease,
When used as a therapeutic agent for circulatory system diseases such as stroke,
For example, it can be used according to the following formulation.

1 Capsule (1) 8-n-butyl-7-r2'-(Il+-tetrazol-5-yl)biphenyl-4-yl 1 methyl-1
,3-dimethylxanthine IOmg (2) Lactose 90mg (3) Microcrystalline cellulose 70mg (4) Magnesium stearate 10mg 1 capsule 19
After mixing 172 of 0 mg (1), (2), (3) and (4), granulate it. The remaining (4) is added to this and the whole is encapsulated in a Seratin capsule.

2 Tablets (1) 8-n-butyl-7-[2'-(IH-tetrazol-5-yl)biphenyl-4-yl"methyl-1,
3-Dimethylxanthine IOmg (2) Lactose 35mg (3) Corn starch 150mg (4) Microcrystalline cellulose 30mg (5) Magnesium stearate 5mg 1 tablet 230mg (1), (2), (3), (4) 273 and ( After mixing 1/2 of 5), granulate it. The remaining (4) and (5) are added to the granules and compressed into tablets.

3. Injection (1) 8-n-butyl-7-[2'-(IH-tetrazol-5-yl)biphenyl-4-yl]methyl-1,
3-dimethylxanthine sodium salt
10mg (2) 100
n+g(3)henrualcohol 20
mg1 ampoule Dissolve 130 mg (1), (2), and (3) in distilled water for injection until the total volume is completely diluted, and seal it in an ampoule. The entire process is performed under aseptic conditions.

Experimental Example 1 Inhibitory effect on angiotensin-■ binding to angiotenone receptor [Experimental method] Douglas et al.'s method [εndocrinologL
] 02+685-696 (1978)] was modified to conduct an angiotensin II (A-n)-receptor binding inhibition experiment. An An receptor membrane fraction was prepared from the cortex of bovine adrenal glands.

Compound of the present invention (10--3X 10-'M) and +1
51-Angiotensin U ("I-A II) (1
, 85 kBq/50 μm) to the receptor membrane fraction,
Incubated for 1 hour at room temperature. “1” of binding and free
-Filter A-11 (Whatman GF/B
r1lLer) and bound to the receptor
The radioactivity of 1A-11 was measured.

Experimental results] Experimental results regarding the compounds of the present invention are shown in Table 4.

Table 4

Claims (1)

[Claims] Formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, R^1 represents a hydrocarbon residue which may be bonded through a hetero atom or may be substituted, R^2
and R^3 may be the same or different and each represents hydrogen or a hydrocarbon residue which may be substituted, R^4 represents hydrogen, halogen or a nitro group, and R^
5 indicates a group that can form an anion or a group that can be converted into an anion, A indicates that a phenylene group and a phenyl group are bonded directly or through a spacer with an atomic chain of 2 or less, and n is 1 or 2. an integer, Y and Z may be the same or different and each represents an oxygen atom or a sulfur atom] or a salt thereof.