WO1980000567A1

WO1980000567A1 - Phosphorylethanolamine derivatives,process for preparing same,and medicinal composition containing same

Info

Publication number: WO1980000567A1
Application number: PCT/JP1979/000244
Authority: WO
Inventors: M Hashimoto; K Hayashi
Original assignee: Dainippon Pharmaceutical Co; M Hashimoto; K Hayashi
Priority date: 1978-09-18
Filing date: 1979-09-17
Publication date: 1980-04-03
Also published as: JPS5540651A

Abstract

3-(4-(4'-Halogenobenzyloxy) phenoxy)propylphosphoryl-ethanola mines represented by the following general formula: (FORMULA) (wherein X represents a halogen atom), physiologically acceptable salts thereof, process for preparing them, uses, and medicinal compositions containing them. The compounds of this invention represented by the above general formula and physiologically acceptable salts thereof show excellent hypotensive action and renin-inhibiting action, and are useful as hypotensives.

Description

One detail

Title of invention

Phosphorinoleethanol mono-noreamin derivatives, methods for producing them and pharmaceutical compositions containing them

Technical field

TECHNICAL FIELD The present invention relates to a novel and useful homophosphorinolenoinoremin derivative having an antihypertensive action and a renin inhibitory action.

Background art

Conventionally, various phosphorylethanolamine derivatives have been synthesized and their pharmacological properties have been studied.

See, for example, U.S. Patent No. 3,678,137 and J. Nano-Role Medicinal Chemistry.

1 ^ 111.), Vol. 14 (1971), pp. 493-499, the formula (V)

O_ [3-C2- (1-Adamantino) etoxy)) -propinole phosphine] represented by the formula Disclosed to have an effect

OMPI However, the compound of the formula (V) has almost no antihypertensive effect as is clear from the experimental results described later.

Further, the present inventors have previously described the formula (VI)

O (VI)

C CH ₂ CH ₂ NH2

2-C 4-(4'-black mouth) represented by the following formula:〕ホホホホホががががががIn addition, they found that they exhibited an excellent antihypertensive effect by renin-inhibiting action and repeated oral administration (see US Pat. No. 3,985,875). However, continuous administration of a relatively high dose of the compound of the formula (W) to animals shows suppression of weight gain, so this compound is not necessarily satisfactory in terms of safety. .

The present inventors have conducted intensive studies in order to find a more excellent phosphorylethanolamine derivative, and as a result, have found that one hydrogen atom of phosphorylethanolamine derivative can be obtained. Is the expression

(Where X represents a halogen atom)

3-Γ 4-(4'-halogenobenzene threoki

O PI

Λ WIPO When converted to a 1-propyl group, the effect of inhibiting renin is much stronger than that of the compound of the formula (VI), and the toxicity is far less. To obtain the compound of the present invention, and completed the present invention.

5 Disclosure of the invention

The present invention relates to general formula (I)

io (where X represents a halogen atom)

(4'-halogenopenpeninoleoxy) phenox) represented by the formula: [propinole] hosholinole etano monoamine and the like Physiologically acceptable salts, their production methods, their uses and pharmaceutical compositions containing them

1 5 Regarding products.

The physiologically acceptable salts according to the present invention include a compound represented by the formula (

It includes salts of the compound of the formula (I) with an organic acid or an organic acid, and phenolic metal salts of the compound of the formula (I). Salts with inorganic acids include, for example, hydrochloride, hydrobromide, sulfuric acid

20 Salts and phosphates and salts with organic acids include, for example, acetate, succinate, maleate, fumanoleate,

_ΟΜΡΙ WIPO Lactate, phosphate, tartrate, citrate, and methansulfonate are examples of alkali metal salts such as sodium The halogen atom represented by X in the formula (I), which gives a salt and a potassium salt, includes fluorine, chlorine, bromine, and iodine. And the compounds of formula (I) in which chlorine and chlorine are particularly preferred are compounds of the general formula (n)

(Wherein X represents the same as described above) and a compound represented by the general formula (I) o

II

Y-P-O CH ₂ CH ₂ Z (I)

Y

(Wherein Υ represents a halogen atom or a hydroxy group, and ζ represents a protected primary amino group), and reacted with a compound represented by the general formula (W)

OMPI _ (Where X, Y and z mean the same as above

When a compound represented by the formula is obtained and a compound in which Y is a halogen atom is obtained, the compound represented by the formula is hydrolyzed under a mild condition to obtain a compound represented by the general formula (IV ′)

OH

[Wherein, x and z mean the same as those described above), after removing the protecting group of the first amino group in the compound of the formula (If). It can be manufactured by

Specific examples of the halogen atom represented by Y in the above formulas (I) and (F) include a chlorine atom and a bromine atom. In addition, specific examples of the protected first amino group represented by z in the formulas (m), (:) V) and (W) include a phthalanolamide group and a tri-amino group. Examples include a chinoleamino group, a ββ-trichloro mouth ethoxy cannonylamino group, and a t-butoxycanoleponinamino group.

The above method is represented by the following reaction formula.

OMPI

(Wherein, x, Y and z mean the same as described above.) The reaction of the compound (IT) with the compound (亚) is carried out in an organic solvent. Hydrologenones such as dichloromethane, dichloroethane, dichlorobenzene, benzene, etc., benzene, tonolenene, etc. Hydrocarbons, tetrahydrofuran, dioxan OMPI

VA, WIPO One hundred one

And the like, such as acetone, acetonitrile and pyridine. These organic solvents are preferably in an anhydrous state. The amount of the compound of the formula (m) to be used is usually the same as that of the compound of the formula (n :) but it is a slightly excessive amount (1.1 to: I. 7 times the amount of monolayer). When a compound in which Y is a halogen atom in the formula (IT) is used, this reaction is preferably performed in the presence of an acid binder. Specific examples of acid binders include tertiary amines such as pyridin, quinoline or triethylenamine and sodium carbonate or carbonate. Carbonated lime such as potassium lime.

—On the other hand, when a compound in which γ is a hydroxy group in the formula (m) is used, it is preferable that this reaction be performed in the presence of a condensing agent. Specific examples of the condensing agent include hexinole benzoyl benzodiimide, trichloracetonitrile and triisopropynolebenze. Non-slip horns and lids. The reaction temperature varies depending on the type of the compound of the formula () and the presence or absence of an acid binding agent or a condensing agent, but is usually about 120 ° C. to about 0 ° C., preferably about 0 ° C. C or about 50. The compound of the formula (IF :) may be isolated and purified, or it can be used crude for the reaction in the next step.

O PI _ WIPO * In the formula (iy :), the hydrolysis of a compound in which γ is a halogen atom to the compound of the formula (if) is carried out by bringing the compound of the formula (w) into contact with water. Easy to do. In this reaction, the reaction solution obtained in the preceding step is usually shaken at room temperature or about 7 ° C with water containing a salt such as sodium chloride or potassium chloride. Or by injecting into a mixture of water and pyridine with vigorous stirring.

The elimination reaction of the protecting group of the first amino group in the compound of the formula (IT) is carried out by a conventional method. For example, when Z is a phthalinoimido group, the compound in a lower alcohol such as methanol, ethanol or isopropanol may be used. This is done by treating (If) with hydrazine hydrate at room temperature or about 90 ° C. When Z is a triamino group, the compound (If) is treated with a mixture of acetic acid and water at room temperature to about 100 ° C to obtain 1β, β, β-. In the case of a trichloroethoxy phenol compound, the compound (If) can be prepared by treating the compound (If) with sub-complex-acetic acid at room temperature without using the compound at about zero. When z is a t-butoxycarbinole amino group, the compound (If) is dissolved in a solvent such as chlorophore, dioxane or acetic acid. Removal of the protecting group is achieved by treatment with an acid such as hydrogen chloride or trifluoroacetic acid at a temperature that is not about zero or room temperature.

The compound of the formula (I) formed by the above reaction can be isolated and purified by a conventional method such as extraction, chromatography, recrystallization and the like.

The compounds of the formula (I) can be prepared in the customary manner, for example by means of lower phenols such as methanol, ethanol or isopropanol, or lower hydrates containing water. By treating with an equivalent amount of a physiologically acceptable inorganic or organic acid or an alkali metal compound, to form a salt or an alkali with an inorganic or organic acid. Li Can be led to metal salts. Specific examples of the inorganic acid include hydrogen chloride, hydrogen bromide, sulfuric acid, and sulfuric acid, and specific examples of the organic acid include acetic acid, succinic acid, maleic acid, and the like. Examples of fumanolic acid, lactic acid, lingic acid, tartaric acid, citric acid and methanophoric acid are specific examples of metal compounds. Hydroxylation power such as sodium hydroxide or hydration reamer and hydration force such as sodium methacrylate, etc. Be raised

The starting material represented by the formula (n) is a new material. 4-(4-ヽヽベキキフフフノフエフフ 3 ノと 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 3 Among them, the compound can be produced by performing a heat reaction in the presence of a base such as sodium hydroxide or a hydroxylating lime. Nao, 4-(4 '-ヽヽヽペペフフ)

c

Vol. (1974), H.106.69

e

You can easily get one according to the method. In formula (I), Y is a halogen atom. C

h The starting material is

Himika 4 0

A

957)), 1 9 2 8 9 c 32

a

By hydrolyzing a compound which can be easily obtained according to the method under mild conditions, it is converted into a compound in which Y is a hydroxy group in the formula (iso) be able to. In order to explain the pharmacological action of the compound of the present invention in detail, the results of pharmacological experiments on representative compounds of the present invention and known compounds are shown below. The compounds used in the experiment are as follows.

(Compound of the present invention)

A: 3-[4-(4 '-black mouth pen nose fox)

O PI drawing Nokia] propinolone-phosphorinone ethanol monoethanolamine hydrochloride

B: 3-[4-(4 '-full-year benzene oxy) phenoxy dipropanol

(Control compound)

O-3- (2- (1-adaptive) hydroxy)-1-propylphosphoryl] hetano-norane [US Patent No. 3,677 8, 1 3 7 and

Med. Chetn., Vol. 14 (1971), Vol. 4

93 3-49 9

2: 2-C4-(4: '-Chlorophenox) phenolic phenolic phosphoric acid (Disclosed in U.S. Pat. No. 3,985,875)

Test example Antihypertensive effect

For evaluation of anti-hypertensive effect, a birenal gonad platform was used.

Gol db l a t t) 60 hypertensive rats were used per group. This renal hypertension rat was prepared as follows: ft: The left renal artery of an 8-week-old male STD Wistar rat was clipped in silver under anesthesia with an anesthesia. (Internal diameter 0.20 丽)

OMPI

,: WIPO The stenosis remained, and the right kidney and renal artery remained. Tap water was provided as drinking water.

(A) 2 ~ 4 force month elapsed after the step-down effect Katajin artery stenosis in chronic phase in renal hypertension rats Bok, Te I Norre-flops of Chi M o d click ,, La notation ^tai I - pie thy smog ra A rat with a blood pressure value of about 210 ° H measured by phic me thod was used ₍ suspended in a 0.5% aqueous solution of tragant in such a rat). The test compound was orally administered once daily for 7 days at a dose of 30 ^! Z Z. Before starting continuous administration and immediately before each administration during the continuous administration period, the tinore plate was used. Blood pressure was measured without anesthesia by the Smograph method.

Blood pressure was measured on days 3 and 5

Table 1 shows the difference between this value and the blood pressure before administration (24 hours after administration) on each day based on the blood pressure before administration.

OMPI

, WIPO.

, --Table 1 Antihypertensive effect in chronic renal hypertension rat

() Hypotensive effect on acute renal hypertension in rats The test compound was administered for 4 weeks from the day of unilateral renal artery stenosis, and its antihypertensive effect could be examined.

The test compound is suspended in a 0.5% aqueous solution of

It was orally administered once daily at a dose of OOW / I ^ day. The control group was given only 0.5% aqueous solution of tragacanth <Table 2 shows the blood pressure values immediately before and at 1, 2, 3 and 4 weeks after renal artery stenosis. Show. In addition, the difference between the blood pressure values of the control group and the test compound administration group at each time point is shown in parentheses. --

2 Antihypertensive effects in acute renal hypertension rats

As is evident from Tables 1 and 2, Compounds A and B of the present invention are almost comparable to Control Compound 2 in chronic and acute renal hypertension rats. Showed an antihypertensive effect. On the other hand, control compound 1 did not show any apparent antihypertensive effect.

Test example 2. Inhibition of nin (in vivo)

Seven chronic rats with the same conditions as in Test Example 1 (a) were used per group. Test compound suspended in 0.5% aqueous tragant solution was added to 10 O W Z K

Orally once daily for 3 weeks at a daily dose of

― OMPI ^ WIPO Three weeks later, after a clear blood pressure decrease was confirmed, blood was collected under no anesthesia, and the plasma renin activity and renin concentration were measured by endocrinology. ), Vol. 90 (1972), and pages 42-430.

Plasma renin activity and renal activity in renal hypertensive rats fed only 0.5% aqueous tragarant solution and normotensive rats of the same age of the STD Wistar system. Table 3 shows the measured values of the test compound administration group, using nin concentration as a comparison control. Table 3 Inhibition of renin (in vivo)

* Indicates the concentration of produced angiotensin I

** Represents mean ± standard error

As is clear from Table 3, Compound A of the present invention and And B reduce plasma renin activity and renin concentration in renal hypertensive rats to near the level of normal rats, and their efficacy is much stronger than that of control compound 2. Test example 3. Poison

One group of 10 male S.T.D.

Test compound suspended in 10% aqueous solution of

Oral administration was performed once daily for 30 days at a dose per day, and subacute toxicity was examined.

Table 4 shows the measured body weight and weight gain on the first day of dosing and on day 30. Furthermore, the weight gain of the control group to which only the 0.5% aqueous solution of tragacanth was administered was 100, and the weight gain of each administration group was a relative value. Show

Table 4 Subacute toxicity (100 ^^ / day orally for 30 days)

* Mean value ± standard error _c

_OMPI WIPO As is apparent from Table 4, the control compound 2 suppressed the weight gain of rats, whereas the compounds A and B of the present invention did not suppress the weight gain.

Further, in the acute toxicity test was use the STD window office te male rats, LD _{5 0} during oral administration of the compounds A and B is shifted also was 1 ^ ^ or more.

As is clear from the above experimental results, the compound of formula (I) and the physiologically acceptable salts thereof have not only an excellent antihypertensive action but also an action of inhibiting renin and a toxicity. weak. Therefore, it can be used as an antihypertensive agent for the treatment of hypertension in mammals including humans and for the prevention and treatment of hypertensive cardiovascular complications. The dosage form may be oral administration, parenteral administration, or rectal administration, but oral administration is preferred. The dose of the compound of the formula (I) or a physiologically acceptable salt thereof may vary depending on the type of the compound, the method of administration and the condition of the breather. The dose is between 2 and 40 ^ body weight, preferably between 4 and 21 ^ body weight and is administered in multiple or divided doses

The compound of formula (I) and its physiologically acceptable salts usually contain an effective and non-toxic amount of the pharmaceutical composition. --It is administered to the breather in the form of an adult. This composition is prepared by mixing the compound of the formula (I) or a physiologically acceptable salt thereof with a pharmaceutical carrier. As the pharmaceutical carrier, a substance that is commonly used in the pharmaceutical field and does not react with the compound of the formula (I) or a salt thereof is used. Examples include lactose, starch, white lacquer, knot, crystal phenol, sodium phenol, sodium phenol, sodium lipodium, and 7 repo.レセLoxypropinole methyl benzoylone, polyvinylpyrrolidone, light silica anhydride, magnesium stearate, tanolec , Acid oxidized titanium, sorbitan fatty acid ester, saturated fatty acid glycerin ester, maco-glue, polypropylene glycol, and water And the like. The pharmaceutical composition may be in the form of tablets, capsules, granules, fine granules, powders, syrups, suppositories or injections. These preparations are prepared according to a conventional method. When used, liquid preparations may be in the form of being dissolved or suspended in water or another appropriate medium. Tablets may be coated by well-known methods.

These compositions usually have the formula (I)

OMPI WWIIPPOO The compound of the formula (1) or a physiologically acceptable salt thereof can be contained in an amount of 0.5% or more, preferably 10 to 70%. These compositions may also contain other therapeutically effective compounds.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples and Reference Examples will be given below to describe the present invention more specifically, but the present invention is not limited to these Examples.

Example

3 10 4-(4 '-Black mouth penguinorokishi) Fenokishi J Propinore hosu resoreta Nominami

3-[4-(4 '-Black-opening pen nose) Fenoki)-1-Prono ヽ⁰ No nose 1 4. 7 ^ (0.05) Add the dried black mouth hose 7 and 18 m of anhydrous pyridin, and stir the mixture under ice-cooling, then add 2- (N-phthalinoimido) ethyl phosphoric acid dichloride 20 9 (0.065 monol) Dry black mouth Home 10 OMi Solution is dropped slowly over 1 hour. After dropping, stir for 15 minutes while cooling with ice, return to room temperature, stir for 6 hours, and then leave overnight.

The reaction mixture was diluted with a black hole home, washed three times with saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a crude product.

OMPI

/ ,, WIPO. 3-[4-(4-chlorobenzene phenolic) phenolic] provinol 2-(-phthalocyanine imide) To 23 as an oil.

In the phthalate mid body obtained in the above,

Add ^ and 100% hydratin hydrate 3; ^, and heat to reflux for 2 hours with stirring. After cooling, the reaction mixture is concentrated under reduced pressure, and an appropriate amount of porcelain foam is added to the residue. After removing the precipitates, the filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography. The part containing the target substance is collected, concentrated under reduced pressure to an appropriate amount, and cooled. The precipitated crystals are taken out of the furnace, and recrystallized from methanol to obtain the target substance 7.9 (yield 45%). ) obtained. mp 2 0 0 ~ 2 0 4 .C elemental analysis Ci8H _{2 3} Cl N0 ₆ P

Calculated value ^): C 5 1.87, H 5.80, C 18.5 1,

N3.36, P7.43

Experimental values (¾: C5.1.37, H5.65, C18.82)

N3.34, P7.72

Example 2

3-"4-(4 '-才ペペフフフフ〕ププププププ口)

O PI 3-[4-(4 '-phenolic outlet ventilator) fenoxi]-1-prono, ⁰ nose 18 9 (0.065 nose) Add dry chloroform / rem 7 and anhydrous pyridine 2 Om to the mixture. Stir under ice-cooling and add 2- (N-phthaloamide) ethyl phosphate dichloride 3 A solution of 0.8 (0.1 mono) in a dry black mouth is slowly added dropwise over 45 minutes. Is reacted and treated in the same manner as in the first paragraph of Example 1 to obtain crude 3- [4-(^-fluorobenzene benzene) phenol. Pinore 2-(N-phthalone imido) echrehost 28 Get ^ as an oil

To the resulting phthalone mid body, add 150 ml of methanol and 100% hydratin hydrate 3. and heat to reflux with stirring for 2 hours. Let it. After cooling, the reaction solution is concentrated under reduced pressure, and an appropriate amount of clog hole home is added to the residue. After removing the precipitate, the furnace liquid is concentrated under reduced pressure, and the residue is purified by silica gel chromatography. Black mouth honolem << Elute with methanol (9 V / V), collect the part containing the target substance, concentrate under reduced pressure to an appropriate amount, and cool. The precipitated crystals were collected and recombined with methanol.

B says he obtains 7.89 (yield 30%). Melting point 2 2 0

2 2 4 ° C

REA

OMPI

W1PO Elemental analysis value C _{1 8} H _{2 3} FN0 ₆ P

Calculated value: C5 4. H5.80, F4.76

N3.5 P7.75

Found (:.. G 5 3. 8 8, H 5 8 0, F 7 8

N 3.5 7 P 7.5

Example 3

3-Γ 4 _- ^ Black mouth___________________________________________________________________________

3-C 4-(4 '-black benzene nozzle) fenoki)-1-prono, ⁰一 1 レ 2. 2.93 (0.01 ノ) Dissolve 2- (N-phthalimide) ethyl phenol phosphate 3.619 (0.01 mol) in anhydrous pyridine 60 and mix with stirring. Add 6.49 (0.03 m) to the mouth. Stir at room temperature for 7 hours and leave overnight. After removing the precipitate, the furnace liquid is concentrated under reduced pressure, and the residue is purified by silica gel chromatography. The fractions eluted with chlorophenol (9: 1 / V) are collected, concentrated under reduced pressure, and concentrated to 3-[4-(4 '-black benzene). [Fenokishi] Propinore 2-(N-Futanoreimid) Get a レレフエ 3. 3. ^ 3.1 ^

The resulting solid is the same as the one obtained with the catalyst.

O PI

Cao O-, Add--and 100% hydratin hydrate 0 and heat to reflux for 2 hours with stirring. Is the lower part of Example 1.

2 Treat in the same manner as in paragraph to obtain the desired product 0.9 da (yield 4

0%). Melting point 202 0 4 ° C

Example 4

3-[4-(^-black benzoyl) phenoxy _] propinolefos _ hollyethanol _ _ hydrochloride

3-C 4-(-Black mouth benzene) Fenoki) Propinole Dry

Dissolve in 5% methanolic hydrogen chloride 8. This solution is concentrated under reduced pressure, and the residue is recrystallized from methanol to obtain the target compound 59 (probability: 93%). Melting point 15 9 〜 16 1

° C

Elemental analysis value Ci ₈ H _{2 3} C1 N0 ₆ P .HC1

Calculated value): C47.80, H5.35, C15.69

N3.1, P6.84

Experimental values (¾: C47.24, H5.36, C1 15.9.9,

Ν3.35, Ρ6.60

The reaction and treatment were performed in the same manner as in the above example, and

4'- phenolic benzoylene) to obtain phenolic phenolic ethanomonoethanolamine hydrochloride. Melting point 146 oread

WIPO,. 4 8 ° C

Elemental analysis value Ci ₈ H ₂₃ FN 0 ₆ P * As HC1

Calculated value): C49.61, H5.55, F4.36,

N3.21, P7.10, CI8.26 experimental value): C49.51, H5.74, F4.39,

N3.47, P6.99, C18.26 Example 5

3-C 4-(4 '-black mouth penge no oki) fenoki) プロトレトナトト

3-L 4-(4 '-black mouth benzene) f eno) [propinole] 1 mol) is dissolved in 50% methanol-containing 8 containing 0.5 ^ (0.012 mol) of sodium hydroxide. This solution is concentrated under reduced pressure, and the residue is recrystallized from methanol to obtain the desired product 3.8 (yield 86%). Melting point 1 6 9 7

. C

Elemental analysis value Ci ₈ H ₂₂ ClNNaOe P

Calculated value ^: C49.38, H5.07, C18.0

N3.20, a5.25, Ρ7.007

Experimental%: 49.18, £ 15.29, 18.36

OMFI N3.2, Na5.48, P6.92

The reaction and treatment were carried out in the same manner as in the above example to give 3- [4- (4'-phenolic-opening-pentoxy) -phenoxy] propynole-phosphorylethanolー Reference example of obtaining sodium salt of Noreamin

3 100 _4 _ (_4 '-_______________________________________________________________________________________ | )

4-(4'-Black mouth vent) O / F 23.5 (0.1 mono) and 3-Black mouth-1 —Prono ヽ⁰ 3 Add 3.2 (0.35 mole) and 50% methanol (150 mole) containing sodium hydroxide (16 moles, 0.4 mole), and stir. Heat to reflux for 6 hours. The reaction solution is cooled forever. The precipitated crystals are collected by furnace and recrystallized from ethanol to obtain the desired product 34 (yield 61%). Melting point 9900. as the c elemental analysis Ci ₆ H _{1 7} C10 ₃

Calculated value): C6.5.64, H5.85, C11.2.11.1 Experimental value ^: C6.55.76, H5.61, C11.201 Reference example 2

__3 _C_4-(/---------------------------------------------- Quality)

Dissolve sodium hydroxide 1 2. 飞 9 (0.317 monol) in a mixture of acetone 10 and water 25, and then add 4- Add ginole bromide (60 C 0.317 monole) and hydroquinone 39.6 (0.36 monole) and heat to reflux for 6 hours with stirring. After cooling, remove insolubles and concentrate the solution under reduced pressure to an appropriate volume. The precipitated crystals were collected and recrystallized from isopropanol to obtain 4- (4-phenolic phenol) phenol (249% yield: 35%). obtain. Melting point 12 3 〜: L 24 ° C

Elemental analysis value C iSH uFOs

Calculated ¾:. C 7 1. 5 5 , H 5 0 8, F 8. 7 1

Experimental value ^): C 7 l. 77, H 5.22, F 9.07

The resulting phenolic mono-form 21.89 (0.1 mono-ole) and 3-black mouth-1 — prono ヽ⁰ -nore 33.2 (0.35 ) And 50% methanol (15 Om) containing sodium hydroxide (169) (0.4), and heat to reflux for 6 hours with stirring. . The reaction solution was cooled on ice, and the precipitated crystals were collected and recrystallized from 80% ethanol to obtain the desired product, 20.5 da.

(Yield 67%) 0 2 ° C

As the elemental analysis value Ci ₆ Hi ₇ F0 ₃

ΟΜΡΙ --Total value ¾: C69.55, H6.20, F6.88

Experimental value ^: C69.78, H6.35, F7.13

Example 6

3-[4-(4 in the mouth, pendinoreoxy) phenoxy] propiphosphorizoleetano-monoleamine hydrochloride per 100,000 tablets 509 Maize starch 18 9 lactose ... 4 5

Crystallized cellulose 30 Hydroxypropyl / Resinolose 5 9 Light caustic anhydride 1

Magnesium stearate 19 According to the usual method, the above ingredients are mixed, granulated, and compression-molded to make 1 tablet 150 0 ^ tablet core 1,100 tablets. Prepare. Then, use hydroxypropynolemethinolose, release, tac, titanium oxide and sonorebitan fatty acid ester, and follow the usual method. To give a film coating tablet.

Example 7

— 1,0 0 'potion

3-[4-(4 to black mouth venge / reoxy) phenoxy]

OMPI WIPO Pour pill phospholinolethanone 0 0 9 Maize starch 6 6 Lactose 5 0 9

Crystal clear mouth 30 Light anhydrous gay 29 Stearate phosphate magnesium 29

According to a conventional method, the above components are mixed, and the resulting granules are filled into 1,000 capsules to prepare 250 capsules each.

Example 8

3-[4-(4-phenolic benzoyl) phenoxy] propinole hoshorinoletaetone monozoleamine or its hydrochloride Work up as in Examples 6 and 7 to obtain tablets and capsules.

Industrial applicability

As described above, the compound of the formula (I) and a physiologically acceptable salt thereof of the present invention are useful as antihypertensives for treating hypertension and preventing hypertensive cardiovascular complications. It is also useful for treatment.

OMPI

Claims

The scope of the claims

-General formula (I)

o CI) CH ₂ CH ₂ NH ₂

(Where x represents a halogen atom)

Or a physiologically acceptable salt thereof.

2. The compound has the formula

O

C 1 ₂

OH [31] [4- (4'-chloropennoxy) phenoxy] propinole phosphinole etano normine or its physiology 2. The compound according to claim 1, which is a salt that is chemically acceptable.

3. The compound has the formula -OCH ₂ CH ₂ H ₂

3-[4-(4 '-fluorene benzene) represented by OH A) a compound according to claim 1 which is a propinole hosphorinoletanoaminoremine or a physiologically acceptable salt thereof;

4. General formula (F ')

O

-C¾) 3 -OP-OCH ₂ c¾ z ()

OH

(Where x represents a halogen atom and z represents a protected primary amino group)

Wherein the protecting group for the first amino group in the compound represented by the formula (1) is removed, and the compound obtained as desired is converted into a physiologically acceptable salt thereof. ,

—General formula (I)

(Where x means the same as above)

Or a method for producing a physiologically acceptable salt thereof.

5. General formula (H)

f _OMPI (Where x represents a halogen atom)

And a compound represented by the general formula (m)

o

II

γ-P-OCH ₂ CH Z (π)

Y

(In the formula, ハ means a halogen atom or a hydroxy group, and ζ means a protected first amino group.)

Reacting with the compound represented by the general formula (w)

O (W)

CH ₂ 0 -OCH ₂ CH ₂ Z

Y

(Where X, Y and z mean the same as above

When a compound represented by is obtained and a compound in which Y is a halogen atom is obtained, the compound is hydrolyzed under mild conditions to obtain a compound represented by the general formula (If)

X _7-0Η ₂ Ο

OH

(Wherein x and z mean the same as above), and then converted to the formula (IT)

OMPI-ノ A general formula (I) characterized in that the protecting group of the first amino group in the compound is removed, and the compound obtained as desired is converted into a physiologically acceptable salt thereof. )

(Where X means the same as above)

Or a method for producing a physiologically acceptable salt thereof.

6. General formula (I)

X CH

(Where X represents a halogen atom)

Or a physiologically acceptable salt thereof, and a pharmaceutical carrier.

7. The compound of the formula (I) is 3- [4- (4'-cyclobenzene benzoyloxy) phenoxy] propiphospholinol ethano monoamine The pharmaceutical composition according to claim 6, which is:

8. The compound of formula (I) is 3-[4-(4 '-

OMPI

wiPO 7. The pharmaceutical composition according to claim 6, which is benzyloxy) phenoxy) propylphosphonolenorenoamine.

9. General formula (I)

(Where x represents a halogen atom)

Use of the compound represented by or a physiologically acceptable salt thereof as an antihypertensive agent

ΟΜΡΙ

/ χ. WIPO <»