JPS58103361A - Novel compound - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] The present invention is a novel compound having chestnut-related activity.

The present invention relates to pharmaceutical compositions containing these and their use as infants.

Butopril (Uaptyl) is a known compound with anti-hypertensive activity and is represented by the formula (2).

European Patent Publication No. 1112401) has antihypertensive activity, but captozolyl has the formula (B
) (In the formula, 1.ru is hydrogen, alkyl, i11-substituted lower alkyl, substituted or unsubstituted aryl, substituted or unsubstituted ar-lower alkyl (1t1・veralkyl), ar-lower alkenyl (ar&・w@r -alkemyl), heteroalk lower alkyl # (ketaroarlov@ra
h
and R5 is hydrogen or lower alkyl), and R is hydroxy or fulkenoxy or alkoxy,
It describes a group of compounds that differ in that they are replaced by a group represented by aryloxy or anno, each of which may be substituted.

One representative compound disclosed in this European patent publication is represented by the formula (5N-(1(8)-ethoxycarginyl-3
-722luzolopyl)-L-7RaniruL--)P ■ Called syrin.

In the present invention, it has been found that certain novel almethyleneoxy-substituted compounds also possess antihypertensive activity.

Therefore, the present invention provides compounds of formula (I) [wherein R1 is NHRs (wherein 8. is hydrogen or U
or with halogen%01-@alkyl or with 0)-1furkoxy, or with benzo moiety %01-1 alkoxy in alkyl, halogen 1j) is Cμm alkyl which may be substituted with dihydrobenzo7-2-yl which may be substituted with trifluoromethyl, R1 and R are the same or different. 9. % is agino optionally substituted with ζ droxy, 01→alpoxy% 01-, karunyl in alkyl, or o i-S alkyl, Rs is a group -NHRy (wherein at is water volume, CI.

Alkyl or []]toalkyl carni) may be substituted with 01-4 Al, 1LR4 is halogen, cμ, alkyl V,) 11 fluoromethyl may be substituted with CI-, alkyl, 4 ．． The present invention provides a compound represented by 7), which is carbon phenyl, or a salt thereof suitable as a drug.

Preferably, s R1 is Ot-S alkyl, such as methyl, ethyl, n-propyl and isozorobyl, or at, such as ethyl substituted by phenyl or methyl, or propyl substituted by dihydrobenzofuran-2-yl. -S alkyl.

Preferably, Rin! is substituted with ethyl, n-propyl, 7enethyl or dihydrobenzo7ran-2-yl
-It is propyl.

Preferred examples of - and R include hydroxy, methoxy, ethoxy and n- and inozoropoxy. Accordingly, RI is hydroxy and - is hydroxy ethoxy.

Preferred examples of R3 are unsubstituted O1-@alkyl11 such as methyl, ethyl, n- and iso-propyl, and anno-substituted alkyl groups -(OHm)nNH*, where n is 1-4, e.g. 1 .zl*F14.).

A preferred example of R4 is unsubstituted phenyl.

Pharmaceutically suitable salts of the compounds of formula include those with bases, such as alkali metal and alkaline earth metal salts, such as sodium and potassium salts and ammonia salts, and with acids, such as hydrochloric acid. salt, hydrobromide,
Contains 5 salts such as sulfates, gentates, and maleates.

Formula (I) K is a compound in which R1 is -NHR.
There are equivalent compounds which are 01-S alkyl optionally substituted by (where 几. is hydrogen or OL.alkylcar-nyl).

From the above description, the interesting compound represented by formula (I) is represented by formula (2) (wherein R- may be substituted by phenyl or di-benzofuran-2-yl). 01-alkyl, -1 is 01→alpoxy or human anV, RIal is o,-salcodF, and B
, l is hydroxy).

A compound having the same meaning as a preferable sub-concept included in formula (1) is the formula (to) (11) (in the formula, stone 3 is an alkyl group), and the remaining 9 variable groups are the same as in formula (6). There is a symbol t, which has the same meaning as °.

Preferred values for R11 are the related nine R in formula (I)
This is as described for IK. - Preferred values for enrichment are ethyl, isozorobyl and sag-butyl, most preferably ethyl and l-propyl.

Another preferred subgroup of compounds encompassed by formula (6) is the formula (transformation) (wherein R- is optionally substituted by phenyl)
1-1 alkyl, and the variable group of SO is of formula (6)
has the same meaning as in ).

R- is preferably 7-enethyl.

Another preferred subgroup of subgroups encompassed by the formula @ is Ozeki (wherein R14 is O1-s alkyl optionally substituted by hydrobenzo7ran-2-yl), and the remaining variables has the same meaning as in formula (2)).

Preferred values for 凰14 are dihydrobenzo7ran-xol-ylmethyl and dihydrobenzofuran-2-ylzolobyl.

The compound represented by formula (I) is anginotensin (am
gimo-1@main) IJ% convertase inhibitor
Therefore it has antihypertensive activity. Therefore, they can be used in the treatment of hypertrophy in mammals such as humans.

The invention therefore also provides a pharmaceutical composition comprising a compound of formula (I), or especially of formula (6), and a suitable carrier.

The composition of the present invention is most preferred K):! Although it applies to oral administration, it is also possible to apply it to other routes of administration, such as by injection.

In order to obtain consistency of administration, the compositions of the invention are preferably in unit dosage form, preferably in unit dosage form.
Ii includes anchors, capsules, and ampoules.

and powders in medicine packets. Such unit dosage forms suitably contain from 1 to 100 ■ of a compound of the invention, more usually from 2 to 75, for example from 5 to 50 ■.

Such a composition is suitable for adults weighing 70jC#.
Dosage for 5-zouaps, preferably 10-100
A defined amount, such as 81", can be administered 1 to 6 times per day, more usually 2 to 4 times per day.

The compositions of the invention can be formulated in a conventional manner, for example in a manner similar to that used in the case of known antihypertensive agents such as hydralfgin.

Such compositions may also contain NK activators, e.g.

1% compared to other antihypertensive drugs! It can contain a blocking agent and a urine clearing agent.

The present invention also provides a method for treating hyperbaric pressure in mammals, including humans, comprising administering a compound of formula (I) or a pharmaceutically suitable salt thereof.

The present invention also provides a compound represented by the formula (6) (wherein R1-81 has the same meaning as in formula (I)).
Also provided is a process for the preparation of compounds of I), the reduction being carried out in any suitable manner commonly known for such reductions. Can be used in

Alternatively, the reaction may be carried out by hydrogenation using one of the conventional catalysts, such as carbon or platinum or rhodium, in a suitable dry solvent such as ethanol.

The compounds represented by the formula (to) are novel intermediates and form a part of the present invention, and these compounds have the formula -R, -(J=0 (wherein R1 and 83 are of the formula (I) K) The compound represented by the formula - (having the same meaning as R5-
3s can be produced by reacting it with a compound of formula (I) (having the same properties as K).

Coupling reactions between compounds represented by the formulas can be carried out by mixing the reactants in a dry solvent.

The two-step conversion to convert the compound represented by the formula and - into the desired compound represented by the formula (I) or (6) is carried out by the formula (6).
↑It is preferable to carry out a single operation in which the expressed imine is generated in situ; in such a case, the by-product of the imine generation
Means for removing the water formed as a reaction, such as molecular stability, must be present; the reduction of the imine and the removal of the water allow the reaction to proceed to give the desired compound of formula (I). Here, the actual amount of ions produced at any given time is very small.

Compounds of the formulas - and vIA'''C- are known compounds or can be prepared by analogous methods to those used for known structurally similar compounds.

R, Adams and && R4adfu
mx, J, Anb υhenhdanoc, 41,
648 (1919) and H. Normant ΔS, Himiaki ± 7, 335 (1942) are suitable for the preparation of these compounds of the formula -, in which dihydrobenzofuran There are 2 parts
Y is bromine and 1 m
is 0.

And n is l. This synthesis is shown schematically below.

After the compound represented by formula (I) is prepared as described above, a specific variable group in the compound can be converted into another group in the next step. For example, the compound represented by formula (I) A compound in which R and R are both alkoxy can be esterified by a conventional method to form a corresponding compound of formula (I) in which R and R are both alkoxy. It is possible to obtain a compound.

The salts of the compounds represented by formulas (I) and (2) can be produced by a conventional method, for example, by reacting the compounds represented by formulas (I) and (2) with an appropriate acid or base.

The compounds of formulas (I) and (2) have asymmetric centers and can thus exist as multiple stereoisomers. The present invention extends to each of these stereoisomers and mixtures thereof (including racemic forms); the different stereoisomers may be separated one from the other by conventional techniques, or Any given isomer can be obtained by stereospecific synthesis.

The asymmetric center indicated by vc "•" in the partial structure has an 8-steric configuration. The asymmetric center indicated by "1" in the pyrrolidino ring in -H is in the α or β configuration mv*. However, the alpha configuration is preferred.

Abanoic acid substructure R, -roH-N)1 c OR.

The asymmetric center indicated by the "fist" symbol inside is R and/or S
It can have a configuration, preferably 8 configurations or both configurations as in a race mixture.

Furthermore, when %R1 is alkyl which may be substituted with dihydrobenzofuran-2-yl, the fifth asymmetric central force S1h is indicated by a mark "." in the iI structure.

This structure may have 8 and/or 8 configurations, preferably both configurations as in racemic mixtures.

Hereinafter, the present invention will be explained with reference to Examples.

Example 1 N-(1-calzexizolovir)=(8)-79yl-
4α-benzyl chloride (8) - Production of proline (8)
-Alanyl-4-4-4-benzyloxy-(8) -Nia"Hydroxylate a solution of lolin (α75#) and α-ketobutyric acid (LO3jl) in water (3011j)) with IJ solution.
I prepared 11g of lK. While stirring this solution under nitrogen,
Add sodium 7-anoborohydride (α389) to this and stir at room temperature for 48 hours to reduce the reaction mixture.
ax 50-W ion exchange resin (20j). Elution of water followed by aqueous pyridine (2%) and the final aqueous fraction was combined with the basic fraction and evaporated gave a gum (7509). This gummy material was purified using chroma)on (2M silica gel Pl'ss4 plate, solvent flow rate 6IIJZ minutes) and eluted with a methanol-chloroform (3:1) mixture to give the title compound as a white solid (530Q). obtained as.

NMR (D, O) J α88 (3Hebr-t)
;147 (31(, d); L82I (3H, ff1); 5L35 (1B, m) λs s (su e m): 3.80-4.85 (6H, m) 4.
45 (2H, S) near, 34 (5H, b?・3)・ff X X vector (M - H) m/i
at 377 (negative ions F, A, B,) Example 2 N-(1-carbetoquin-3-phenylpuhya-)-
Production of (S)-alanyl-4α-andyloxy-(8)-proline (S)-7ranyl-4-4-andyloxy-(8)-
Florin salt (α709) was converted into triethylamine (
dry ethanol (20:1 lJ) containing α22#)
dissolved in. 4A molecule II (?, 50 g) and ethyl 4-phenyl-2-ketobutyrate (α881I) were added to the lacquer solution, and the resulting mixture was stirred at room temperature tα for 5 hours. Shear λ
Sodium hydride (0.19#) was added portionwise over 1.5 hours and the reaction mixture was stirred overnight, then further
．． 44.9 of the ketoester was added. Stirred at room temperature for 6 days, then filtered and filtered into F-box K Dowax 5 Q-
W ion exchange resin (30#) was added under stirring.

After α5 hours, the resin suspension was applied to a chromatography column. The mixture (600
mg) were isolated. Purification of p! ! Titled gold compound colored glassy substance (
380) was obtained.

IR (thin film), 1725.1630fflNMR
(ODOIm)0.95-L45 (irregular m
, l$ H) 1.70-4.80 (a series of wide multiplets, 14N) overlapping with 416 (irregular qe2) 1) and Table 40 (8,2H) 7.22 (m, 10H) Mass suikt & (EI) M -H2O, m/x
At 464.231J5.

(Q)'," = -44, Oo, < 11 r/-r, o
=1>Example 3 N-(1-,1fluzxy-3-7enylpropyl)-
Preparation of (S)-7 ranyl-4-benzyloxy-(19)-zoroline Compound of Example 2 (3(i5m19), 10% sodium hydroxide solution (06iu) and ethanol (6jIj)
was stirred at room temperature for 16 hours. The organic phase was dried over anhydrous sodium sulfate, filtered, and evaporated to give a gummy material, which was triturated with diethyl ether to give the title compound as the white homologue (23(jQ/)). .

Mass spell) M-HxO, 436, 2UOI
K.

Goose / [α) = -27,5 (methanol sc""t)
Example 4 N-(2-(2,3-dihydro-2-benzo7tunyl)
-! -(Ethoxyruzenyl)ethyl]-(8)-alanyl-4α-benzyloxy-(8)-Production of Searin (Rjk8) (8)-7ranyl-40-benzyloxy-(8)-
f Lorin Salt M Kan (α5j) was dried in ethanol (2011
1) K was dissolved and triethylamine (0.16N) was added. Powdered 4X molecules all (3, O
2) and ethyl 2,3-dihydro-3-(2-shuohinzo7ranyl)-2-ketopropionate (α731) were added, and the resulting mixture was stirred at room temperature under nitrogen for 5 hours.
Sodium cyanoborohydride was added portionwise over 3 hours. After stirring for 3 days, the reaction was filtered and Dow@
x 50- W ion exchange tree l11 (2511) to FI
IK was added. The mixture was stirred for 1 hour, then subjected to chromatography, and sequentially dissolved with ethanol, water, and a 2% aqueous pyridine solution. mixture from the basic fraction (300
) was obtained, and this product was purified using a Yumu Madtron (2-silica gel PFmus flow rate 6111/min).

Elution with methanol-chloroform (1:10) followed by trituration with pentane gave the title compound as an off-white solid (90 mg).

NMR (ODql,) Jα95-L50 (irregular m, 6H) 1.55-5.15 (series of wide multi-1#
1゜15H) The following and rich are 4.15 (irregular En, 2H) and 4.44 (gourd, 2
H) a55-7.50 (irregular m, 41()7.27(s
, 58) Mass spectrum M - Hl Oa M/ x
49'l-2273K.

■ (α), = -51,9 (methanol, C=l) Example 5 N-(4-(213-dihydro-2--(nzo7ranyl)-1-(ethoxyca#-yl)-ethyl ]-(S)-
Preparation of 7-ranyl-4α-benzyloxy-(8)-zoroline 2.3-dihydro-5-(2-4-7-rael)2-ketopentanesone-ethyl (toy) in dry ethanol (le
The solution in dJ was converted into (8)-alanyl-40-
xy-(8)-zololine hydrochloride (!OI) triethylamine (α511j) and powdered activated 4A molecule 11 (2
24F) in dry Xfi)-# (4011J) at lukewarm temperature under nitrogen and stirring.

After 15 hours, sodium cyanoborohydride (α43I)
was added little by little over a period of 30 hours, and after a total of 48 hours, the mixture was filtered. Dow*x 5 g -Vd ion exchange resin (6 oj) was added to Pwi and stirred for Lz hours. Transfer to the fifth column and add the first ethanol.

Elution was carried out sequentially with water and 2% aqueous pyridine.

By emitting 1M of the desired piri-zine-water components, an oily substance is obtained, and this is mixed with taloma goutphy (silica,
I! by purifying 5% methanol-chloroform). The title compound (L3N) was obtained as a solid.

-rX*Spectrum) LeM -Hl O, M/m 5
2α2571, te.

Example 6 N-(4-(2,3-dihydro-2-sekunzo7ranyl)
-1-cal-dityl-(8)-7ranyl-40-benzyloxy-(8) -f Lorin-e - ○ Compound of Example fli5 (α4511) and sodium hydroxide pellets (α067JF) Q ethanol (7 g)
The mixture was stirred at room temperature 't' for 2 days. The solution was neutralized with 20% phosphoric acid and extracted with phosphoric acid. The title compound (α25I) was obtained from drying over anhydrous Na180a, filtration and evaporation as a chromatographically homogeneous solid.

ff 211
/1492L230U.

Example 7 N-(1-carbet life sea 5-i-no-zen-pentyl)
-(8)-7ranyl-40-4-ndyloxy(8)-
Production of Zoroline - The present compound was produced in a manner substantially similar to the production of the compound of Example 1, except that the terminal anno group may be protected and then deprotected prior to reduction with sodium cyanoborohydride. % were produced with different amounts.

Example 8 N-(1-carbethoxy-2-methylpropyl)-2-
(a) Production of -alanyl-4α-benzyloxy-(8)-proline (8) “Alanyl-4-benzyloxy-(8)-proline hydrochloride (α50!i) and triethylamine (α
Powdered 4-sulfur molecules 1it(3,OjF) and 3-methy#-2- in a solution of 16jl) in ethanol (3G114)
Ethyl ketobutyrate (L5jl) was added. Sodium cyanoborohydride (α111) was added to this stirred suspension over a period of 3 hours. After stirring for 4 days, it was filtered and then D
OWEX 50-W ion exchange resin 1) was added. The resin was washed sequentially with ethanol, water and an aqueous bisodine (2%) solution. (by evaporating pyridine-water mackerel liquid)
% crude gummy material was obtained.

Use this chromatotron (2
The elution rate was 6-7 minutes). Elution with methanol-chloroform (increasing concentration of methanol up to 50%) afforded the required title compound (a26).

Mass spectrum M s rn / g 420.
2262 K [α), --4116 (methanol, C
±1) Example 9 N-(1-car-xy-2-methylpropyl)-(8)
-72yl-4α-indyloxy-(8) -F■
The compound of Phosphorus Production Example 8 (80 #1 kg) was treated with an aqueous F hydrium solution (21 JA amount) for 24 hours. After P 15KII conversion with 20% citric acid solution and extraction with chloroform, D.vex solution exchange tree IN (aO#) was added to the aqueous phase and then eluted with water. By elution with an aqueous solution of pyridine (29), collecting and evaporating these fractions containing the most polar components, the title compound (40 m
g) was obtained.

Mass spectrum M”-Hl O, m/x374.1
At 838 [α]^=-46.1' (methanol, Cx
1) Implementation sl.

N-(1-carbethoxy-3-methyl-butyl)-(8
)-alanyl-4α-indyloxy-(2))-7P
lolin(8)-alanyl-4α-benzyloxy-fin>-
f loline hydrochloride C'LOI) and triethylamine (α
93 g) of 2-keto-4-
Ethyl methylpentanoate (1461) and sodium cyanophohydride (α58#) were added in small portions.
The reaction mixture was stirred for 4 days.

Then P was removed and evaporated. The residue was deposited in chloroform, washed with sodium hydrocarbon solution and 1 ml of sulfuric acid! Gune 7
It was dried in a vacuum and evaporated. The crude product thus obtained was transferred to a chromatotron (2■v1 Kagel P F @@@
The title compound was chromatographed as a chromatographically homogeneous solid (α3
3JF) was obtained.

Mass spectrum M-H2O,s/14i6(I
I) at K, + and MHm/z43s (ammonia Or) (Q):' = -718° (methanol μ = 1) Example 11 N-(1-calcexy-3-methylbutyl)-(8)-
Ding ff-4α-benzyloxy-(8)-F II
The compound of Example 10 (291151) and sodium hydroxide pellets (55I) were stirred in ethanol (811j) at room temperature for 16 hours. The solution was neutralized with a 20% aqueous taenoic acid solution and extracted with chloroform.

The title compound was obtained as a white powder (17Q111) by drying the organic phase over MII 804, evaporation and trituration of the resulting gummy material with ether.

Mass Spectro M-)110. m/m3B&
(8) − Manufacture of Sorolin (
1001t tlooH (8)-alanyl-40-(ndyloxy-(8)-zololine hydrochloride (1,0#) and triethylamine (03
Powdered into a solution of 2 C) in ethanol (20117) 4
A molecular sieve (5g) and 2-ke)lsal ethyl (17,
9) was added. Sodium cyanoborohydride (α2j
1) was added to the above suspended IFK under stirring for 3 hours, and then stirring was continued for 4 ts, followed by filtration.

Dewex 50-V' ion exchange resin (20j
F) is added to the reaction mixture and the resin is mixed with ethanol, water and.

Pyriline (2%) was eluted with aqueous il''1' and these basic fractions containing the product were combined, evaporated and transferred to a chromatotron (2-silica gel P Fu4m, solvent flow rate 6 WL).
1 min). Methanol-chloroform (2:
3) The title compound (0,33
#) was obtained as a solid.

Mass Spectrum M H,0,m/Expletive 3B8.2
At 006 [α), = -70,2 (methanol, c
=1) Example 13 N-(1-car-xybutyl)-(8)-7 ranyl 4
Preparation of α-benzyloxy-(8)-proline The title compound was prepared in a similar manner to the compound of Example 1, but using α-ketopentanoic acid in place of α-ketobutyric acid.

wx*xvec) le(M -HzO) * -/ z
j74. i 85 Sec”J: [α) =-
37,99° (methanol, (zl) Pharmacological data 1 Compound of in vitro test example for angio°tensin converting enzyme inhibition, N-(1-caldZ*sibtetravir)-(8)-7ranyl-4α -benzyloxy- (8)
-Proline was found to cause 50% inhibition (■0..) of rat lung angiotencin converting enzyme preparations at a concentration of λ3×10−M.

2 In Vivo Test on Aniotensin Converting Enzyme Inhibition The compounds of Examples 1.2.4 and 5 were tested for their ability to reduce the pressor response to angiotensin IK without reducing the pressor response to aniotensin ■. Tested in anesthetized rats. The dose of angiotensin ■ is 3UOwIg/*t 1. V
) The dose was 10011I910 (1,v).

Results are the average of those obtained from a given number of rats.

rIJ is the increase in diastolic blood pressure (mH,) to angiotensin I (control response).

"%R" is the control aniotensin after time (minutes) has passed since administration! is the rate of decline in response.

Examples 1, 2.4 and 5 contain slightly angiotensin I
increased the pressor response.

From the above results, the compounds of Examples 1, 2.4, and 5 reduce the pressor response of aniotensin Ⅰ, but do not reduce the pressor response to aniotensin MK, and therefore are capable of inhibiting aniotensin convertase. It was concluded.

λ antihypertensive activity I M, 01axtoa, M, (L Palfr
Eymam, &H.

Poyser and Rh k Whitmg
, guropeta +Jsurn -al
of Pharmacology, 3 7,
Systolic blood pressure was recorded by a modification of the nine-tailed lock method described by 179 (1976).

Pulse rate was displayed using a Wasp recorder, model 8005.

Before every #j test, rats were placed in a heated environment (:jL5±0
．． 5° C.) and then transferred to a restraining machine. Each blood pressure determination was the average of at least 6 readings (as 17 L)
Spontaneous hypertensive rats with systolic blood pressure in the intestines) (
(12 to 18 weeks of age) were considered hypertensive.

The compound of Example 2, N-(1-carbethoxy-3-2enylpropyl)-(8)-acnyl-4a-benzyloxy-(8)-proline, was administered orally to rats at a dose of 1(l/Ilf#). and the compound of Example 5.

N-(4-(2,3-dihydro-2-benzofuranyl)
-1-(engineering)
It was administered orally to rats at a dose of 0 jl/h. The is arterial pressure and the 6-stroke frequency were determined and distributed along with the rate of change copper that occurred at subsequent time points.

Progress after administration Systolic blood pressure jc4f hours (hours)
Rate of change % i-type actual meal example 2 1 -5±3 -7±
3 6 rats 2 -1O±3 -
2±3 Initial blood pressure: 4 -22±
3 -5±4223±'ImHI 6 -
22±4 1±4 dormitory example 5 1
-10±3 -2±2 6 rats 2
-7±2 0±4 Initial blood pressure:
4 -23±1 45±3210±6
-Hg Toxicity No toxic effects were observed in the above tests.

Agent Patent attorney Masamitsu Akizawa and one other personContinued from page 1Priority claim @January 15, 1982 [Sir] United Kingdom (
GB) [Yes] 1100 @March 8, 1982 [Phase] United Kingdom (GB)■6752 1.Indication of the incident/F10 Ganshota 2-No. I14 Seven Meetings 3. Relationship with the case of the person making the amendments Address: Taiyo Building 8, 12-1 Nihonbashi Kabuto-cho, Chuo-ku, Tokyo
, the content of the correction is as per the attached sheet”tp#eritl->p
IaυIl? t (Internal Strife) JP-A-58-1033
61 (15)

Claims (1)

[Claims] Formula (I) [In the formula, R1 is NOR・(In the formula, B6 is hydrogen or 0 μ
S alkyl car-nyl), or halogen, 0117 is substituted with a ,-,7#dP le,mouth l=I ah-
0-, alkyl, which may be substituted with -1 or trifluoromethyl or trifluoromethyl; h, and R, are the same or different, and s6* is hydroxybull alcohol, carnyl,
or U)-1 is an amino optionally substituted with alkyl, R, is a group -NIiRy (wherein R is hydrogen, 0-alkyl, and is C3-.alkylcar-nyl); or-i alkyl which may be substituted.几4 is a halogen %01-s alcohol, trif is substituted with 0, 1, and 1) and is suitable as a metal compound or medicine. Naso salt. (2) The compound according to claim (1), wherein at is 01-almonyl which may be substituted with MilB6. (3) Formula (2) (in the formula, -9-7yl or dihydrobenzo7ran-2-yl may be substituted (・μS alkyl), and -1 is O,, alkoxyl or hydroxyl, R41 is 018 alkyl), and R41 is hydroxyl).
Compound described in section 1). (4) Formula (to) (wherein mR1'' is 0 i alkyl, and the remaining radicals are represented by the claims @I Jll (having the same meaning as in Section 31) The compound according to claim 1, paragraph (2) or (3). !J
N-(1-caru-Φdibutyl)-1)-alanyl-
4-benzyloxy-(S)-zololine or N-(1
-carbethoxy-2-methylpropyl) -2-(II
-Alanyl-4-benzyloxy-(8)-zoroline! II! (Compound according to item 11. 7) N-(1-carbeto-3-phenylpropyl)-(8)-7ff-40- Benzyloxy-(S
)-zoroline or N-(2-(2,3-dihydro O-2
-Benzofuranyl)-1-(ethoxycarzenyl)-ethyl)-(8)-79yl-4α-benzyloxy-(8)-purine. (8) Formula (to) (wherein B14 is C1-3 alkyl substituted by dihydrobenzo7ran-2-yl), and the remaining flexible groups are defined by claim (3). The compound according to claim 5(3), which has the same meaning as in claim 5(3). (9) N-(2-(2,3-dihydro-2-benzfuranyl)-1-(ethoxycarzenyl)-ethyl)-(
8)-7 Raniru 4α-penziluo*j/-(19)-
purin, N-(2'(2,3-dihydro-2-benzofuranyl)-1-(ethyl)-ethyl)-(8)-alanyl-4α-benzyloxy-(19
)-Zololine, N-(4-(2,3-dihydro-2-4
nzofuranyl)-1-(ethoxy6 di nyl)-
Zoti#) -(8)-Arax#-4a-benzyloxy-(8)-Zololine or N-(4-(2,3
-dihydro-2-benzofuranyl)-dibutyl-(81-alanyl-4α-4-benzyloxy(S
)-zoroline according to claim (1). Claim 1, characterized in that the compound represented by a* t, (to) (in the formula, %R1 to R5 have the same meanings as in claim 8 (1)) is reduced. A method for producing a compound described in JIJK according to any one of items (1) to 48). 9141#IF A vM pharmaceutical composition comprising a compound or medicament according to any one of claims (1) to (9) and a suitable extemporaneous and pharmaceutically suitable carrier. (6) Claims for use in treating high pressure in mammalian VlJK! 15 Ng (1) to (9)
Li Kk of any one of the terms! Compounds listed.