JPH0322868B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention provides novel derivatives of 1-alkylamine-3[4(P-alkyloxybenzamide)phenoxy-2-propanol, pharmaceutical compositions containing the derivatives, and the above-mentioned 1-alkylamine-3
The present invention relates to a method for producing a [4(P-alkyloxybenzamido)phenoxy]-2-propanol derivative. The main object of the present invention is to provide a new group of compounds that confer sympatholytic activity and can therefore be used in the treatment of disorders caused by hyperactivity of the sympathetic nervous system. Although it is well known that many derivatives of 1-alkylamine-3-phenoxy-2-propanol confer beta-sympatholytic activity, these compounds lack cardioselectivity and have strong hepatic metabolism. It is also well known that it poses a risk of harm to the heart. For example, 1-(P-acetamido-phenoxy)-3-isopropylamine-2-propanol (AFC Crowther, R. Howe,
LHSmith, J.Med.Chem. 14 , 6, 511, 1971)
Compounds such as , which confer β ₁ -cardioselectivity and low liver metabolism, do not exhibit chronotropic selectivity for muscle contraction. In contrast, for example 1-isopropylamine-3-[(2-methylindol-4-yl)oxy]-2-propanol (Swiss 469,002), (1-tert-butylamine-ethyl)-2,5- Dimethoxybenzyl alcohol (Levy, J.Pharmacol.Exp.Ther. 151 , 413,
1966; Wilkenfels, Levy, Arco.Int.
Compounds that confer chronotropic selectivity, such as Pharmacodyn. Ther. 176 , 218, 1968), have no cardioselectivity or are more active against _β2 receptors than against _β1 receptors. According to the invention, the general formula (R ₁ in the formula is a linear or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms; R is a carbon number Novel compounds having improved beta-sympatholytic activity are provided. The new compounds of the above general formula and their salts are:
It is a drug with improved β-sympatholytic activity and associated β ₁ -cardioselectivity, inherent sympathicomimetic actireity and high biodisposability. We found that it also exhibits temporal selectivity. Examples of the compounds of the present invention represented by the general formula are shown below, but the present invention is not limited to these examples. 1) 1-isopropylamine-3-[4(P-methoxybenzamido)phenoxy]-2-propanol (in the general formula, R=CH( _CH3 ) ₂ ,
R ₁ = 4-OCH ₃ ) Melting point 174-176℃ (Hydrochloride melting point 208-210℃) IR (Nudiyol) ν (cm ^-1 ): 1640 (CO) H-NMR (DMSO) δ (ppm): 1.15 ( d,
2xCH ₃ ), 2.7-3.0 (m, CH ₂ +CH), 3.8-4.1
(m, CH ₂ + CH), 6.9-8.3 (m, 2xC ₆ H ₄ ) 2 1-t-butylamine-3-[4(P-methoxybenzamido)phenoxy]-2-propanol hydrochloride (in the general formula, R= C
(CH ₃ ) ₃・HCl, R ₁ = 4−OCH ₃ ) Melting point 210-213℃ IR (Nujiol) ν (cm ^-1 ): 1650 (CO) H-NMR (D ₂ O) δ (ppm): 1.30 (s,
3xCH ₃ ), 2.8−3.2 (m, CH ₂ +CH), 3.5 (s,
CH ₃ ), 3.7-4.4 (m, CH ₂ +CH), 6.5-7.6 (m,
2xC ₆ H ₄ ) 3 1[4(P-ethoxybenzamide)phenoxy]-3-isopropylamine-2-propanol hydrochloride (in the general formula, R=CH
(CH ₃ ) ₂・HCl, R ₁ = 4−OCH ₃ ) Melting point 215-217℃ IR (Nujiol) ν (cm ^-1 ): 1640 (CO) H-NMR (DMSO) δ (ppm): 1.15 (d ，
2xCH ₃ ), 1.25 (t, CH ₃ ), 2.8−3.6 (m, CH ₂
+CH), 3.8-4.3 (m, 2xCH ₂ +CH), 6.8-8.0
(m, 2xC ₆ H ₄ ) 10.0 (s, NH) 4 1[4(P-allyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol hydrochloride (in the general formula, R=CH
(CH ₃ ) _2.HCl , R ₁ = 4-OCH ₂ CH=CH ₂ ) Melting point 200-202°C IR (Nudiyol) ν (cm ^-1 ): 1635 (CO) 5 1-isopropylamine-3-[4 (P-propyloxy-benzamido)phenoxy]-2
-propanol hydrochloride (in the general formula R=
CH (CH ₃ ) ₂・HCl, R ₁ = 4−OC ₃ H ₇ ) Melting point 224-225°C IR (Nudiyol) ν (cm ^-1 ): 1635 (CO) H-NMR (DMSO) δ (ppm): 0.95 (t, CH ₃ )
1.25 (d, 2xCH ₃ ) 1.75 (s, CH ₂ ) 2.8−3.4
(m, CH ₂ + CH) 3.7-4.4 (m, CH ₂ + CH) 4
(t, CH ₂ ) 6.8−8.1 (m, 2xC ₆ H ₄ ) 10.1 (s,
NH) 6-isopropylamine-3-[4(P-isopropyloxybenzamide)phenoxy]-2
-propanol hydrochloride (in the general formula R=
CH (CH ₃ ) ₂・HCl, R ₁ = 4−OCH (CH ₃ ) ₂ ) Melting point 218-219℃ IR (Nujiol) ν (cm ^-1 ): 1635 (CO) H-NMR (DMSO) δ (ppm ): 1.20(d,
4xCH ₃ ) 6.8−8.0 (m, 2xC ₆ H ₄ ) 10.0 (s,
NH) 7 1[4(P-butyloxybenzamide) phenoxy-3-isopropylamine-2-propanol (in the general formula, R=CH( _CH3 ) ₂ ,
R ₁ = 4-OC ₄ H ₉ ) Melting point 152-154℃ IR (Nudiyol) ν (cm ^-1 ): 1635 (CO) H-NMR (DMSO) δ (ppm): 1.05 (t, CH ₃ )
1.10 (d, 2xCH ₃ ) 1.3−2.0 (m, 2xCH ₂ ) 2.7−
3.1 (m, CH ₂ + CH) 3.6-4.2 (m, CH ₂ + CH)
6.8-8.1 (m, 2xC ₆ H ₄ ) 10.0 (s, NH) 8 1-isopropylamine-3-[4(P-pentyloxybenzamide)phenoxy]-2-
Propanol (in the general formula R=CH
(CH ₃ ) ₂ , R ₁ = 4-OC ₅ H ₁₁ ) Melting point 157-159°C IR (Nujiol) ν (cm ^-1 ): 1635 (CO) H-NMR (DMSO) δ (ppm): 0.95 (t , _CH3 )
1.0 (d, 2xCH ₃ ) 1.2−2.0 (m, 3xCH ₂ ) 2.6−
3.0 (m, CH ₂ + CH) 3.8-4.3 (m, CH ₂ + CH)
6.9-8.05 (m, 2xC ₆ H ₄ ) 10.0 (s, NH) 9 1[4(P-hexyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol hydrochloride (in the general formula, R=CH
(CH ₃ ) ₂ HCl, R ₁ = 4-OC ₆ H ₁₃ ) Melting point 199-201°C IR (Nujiol) ν (cm ^-1 ): 1635 (CO) H-NMR (DMSO) δ (ppm): 0.8 ( t, CH ₃ )
1.10 (d, 2xCH ₃ ) 1.3−1.9 (m, 4xCH ₂ ) 2.9−
3.6 (m, CH ₂ + CH) 3.6-4.5 (m, CH ₂ + CH)
6.8−8.2 (m, 2xC ₆ H ₄ ) 10.1 (s, NH) 10 1-isopropylamine-3-[4(P-octyloxybenzamide)phenoxy]-2-
Propanol (in the general formula R=CH
(CH ₃ ) ₂ , R ₁ =4-OC ₈ H ₁₇ ) Melting point 116-118℃ IR (Nudiyol) ν (cm ^-1 ) 1645 (CO) 11 1 [4(P-benzyloxybenzamide) phenoxy]-3 -isopropylamine-2-propanol hydrochloride (in the general formula R=CH
(CH ₃ ) ₂ HCl, R ₁ = 4-OCH ₂ −C ₆ H ₅ ) Melting point 217-220°C IR (Nudiyol) ν (cm ^-1 ): 1645 (CO) H-NMR (DMSO) δ (ppm) :1.3(d,
2xCH ₃ ) 2.8-3.2 (m, CH ₂ +CH) 3.8-4.4
(m, CH ₂ + CH) 5.2 (s, CH ₂ ) 6.85−7.10
(m, 2xC ₆ H ₄ +C ₆ H ₅ ) Pharmaceutically acceptable non-toxic salts of the above compounds include hydrochloride, hydrobromide, hydroiodide, phosphate, sulfate. , tartrate, citrate, as well as methyl iodide, methyl bromide, ethyl bromide, ethyl iodide. Optical isomers of compounds of general formula are also encompassed by the present invention. Another object of the invention is to use the general formula () as an intermediate compound for preparing derivatives of the general formula R ₁ CONH position Melting point (℃) 4-CH ₃ 4 236-8 4-C ₂ H ₅ 4 235-7 4-C ₃ H ₇ 4 223-5 4-isoC ₃ H ₇ 4 213-5 4-C The object of the present invention is to provide a compound having the following formula: ₄ H ₉ 4 217-20 4-C ₅ H ₁₁ 4 216-17 4-C ₆ H ₁₃ 4 205-7 4-C ₆ H ₅ CH ₂ 4 242-44. Yet another object of the present invention is to provide a method for preparing compounds of general formula and. The compound with the general formula is the following formula (R ₁ in the above formula has the same meaning as in the general formula, and M is a hydrogen atom or an alkali metal.) A compound represented by the formula () (R in the above formula has the same meaning as in the general formula, and R ₂ is

[Formula] Group (Al is a halogen atom) ) or

It can be prepared by reacting with a compound of the formula [formula]. Preferably, the reaction is carried out in a solvent such as alcohol, dioxane, dimethylformamide, or water. A compound of general formula () can be prepared, for example, from a suitable benzoic acid chloride and an aminophenol. Compounds of general formula () are, for example, 1,3-dihalogen-2-propanol or epihalogenidrin (epihalogenidrin).
and RNH ₂ , where R has the same meaning as in the general formula. Compounds of the general formula also have the general formula (): (R ₁ in the above formula has the same meaning as in the general formula, and R ₃

[Formula] group or

It can be prepared by reacting a compound of the formula NH ₂ R with an amine having the same meaning as in the general formula. The solvent to be used in this reaction is either an excess of amine or preferably a polar solvent such as ethanol. A halogenhydrin of the general formula () can be obtained by reacting a compound of the general formula with an epihalogenhydrin such as epichlorohydrin. Epoxides of general formula () can be obtained by conventional methods, for example from the halogenhydrin and sodium hydroxide described above. The compound with the general formula is the following formula (): (R and R ₁ in the above formula have the same meanings as in the general formula) can also be obtained by reduction of a compound. Preferably, the reduction of compound () is carried out with a hydride such as sodium borohydride. The compound of the general formula is the compound of the general formula and 1,3
- the following compounds corresponding to dihalogenacetones, e.g. 1,3-dichloroacetone: by preparing and then treating with the amine RNH ₂ (R has the same meaning as in the general formula). Yet another object of the present invention is to provide a method for preparing optical isomers by classical methods used to separate the isomers from racemates. For example, the racemic compound is reacted with an optically active acid, the resulting diastereomeric mixture is then fractionally crystallized from a suitable solvent such as ethanol, and then treated with a base to liberate the optically active derivative from the salt. be able to. A further object of the present invention is to provide a process for preparing esters starting from compounds of the general formula by treatment in classical manner, for example with anhydrides or acid chlorides. Derivatives of the general formula and corresponding esters are:
It can be converted into an acid addition salt or an alkyl halide addition salt by conventional methods. Yet another object of the invention is to provide pharmaceutical compositions containing as active ingredients one or more derivatives of the general formula (or esters or addition salts) and a pharmaceutically acceptable diluent or carrier. It is to be. Suitable compositions include, for example, tablets, capsules, aqueous or oil solutions, suspensions, emulsions, dispersed powders, powders or aerosol compositions. The present invention will be illustrated by the following examples, but the present invention is not limited by these examples. Example 1 1-isopropylamine-3[4(P-methoxybenzamido)phenoxy]-2-propanol 0.02 mol of 4(P-methoxybenzamido)phenol was added to 120 ml of 0.02N aqueous potassium hydroxide solution, then 0.045 mol of epichlorohydrin and 10 ml of methanol was added and the mixture was kept stirring at room temperature for 2 days. The reaction product was separated and washed twice with water (50 ml), then the resulting crude epoxide was suspended in methanol (300 ml), to which water (0.5 ml) and isopropylamine (0.6 mol) were added. . 2 at room temperature
After stirring for days, the reaction product was separated, dried in vacuo, and added again to some water. The reaction product was recrystallized once to obtain an n-propanol derivative (melting point 174-176°C). The product was dissolved in ether and anhydrous hydrogen chloride gas was passed through it to give the hydrochloride salt (ethyl alcohol), mp 208-210°C. Example 2 1-tert-butylamine-3[4(P-methoxybenzamido)phenoxy]-2-propanol Obtained in Example 1 and methanol (300 ml)
To 0.028 mol of crude 1-[4(P-methoxybenzamido)phenoxy]2,3-epoxypropane suspended in 2,3-epoxypropane was added water (0.5 ml) and tert-butylamine (0.6 mol). After stirring at room temperature for 48 hours,
The reaction product was separated, dried in vacuo and dissolved in acetone (20ml). It was then treated with hydrogen chloride gas, and the precipitate thus obtained was separated, dissolved in water and made alkaline to give a precipitate, which was separated, washed and dried. This was dissolved again in acetone and treated with HCl gas to obtain the hydrochloride (dioxane/isopropanol (melting point 210-212°C). Example 3 1 [4(P-butyloxybenzamide)phenoxy]-3 -isopropylamine-2-propanol 0.08 moles of 4(P-butyloxybenzamide)
The phenol was heated in epichlorohydrin (0.6 mol) and piperidine (0.1 ml) at bm for 6 hours.
Excess epichlorohydrin was distilled off, then the residue was dissolved in ether and filtered. The crude product 1[4(P-
butyloxybenzamide) phenoxy]-3-
Chlorin-2-propanol was dissolved in methanol (600
ml) suspended in isopropylamine (1.8 mol)
After addition, the mixture was stirred at room temperature for 48 hours and then separated. The liquid was dried, dissolved in acetone (15 ml), filtered, and crystallized from ethanol. The melting point of the product was 152-154°C. Example 4 1[4(P-allyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol 0.08 moles of 4(P-allyloxybenzamide)
The phenol was heated in epichlorohydrin (0.64 mol) and piperidine (0.1 ml) at bm for 6 hours.
Excess epichlorohydrin was distilled off, then the residue was extracted with ether and filtered. The crude 1[4(P-allyloxybenzamido)phenoxy]-3-chloro-2-propanol thus obtained is suspended in methanol (1), in which isopropylamine (1.8 mol) is suspended.
added. After stirring at room temperature for 72 hours, the product was filtered, dried, washed with water, filtered and dried again, then the product was dissolved in acetone and treated with anhydrous hydrogen chloride gas to obtain the hydrochloride salt, which was crystallized from isopropanol. (melting point 200-202℃). Example 5 1 [4(P-ethoxybenzamido)phenoxy]-3-isopropylamine-2-propanol 0.02 mol of 4(P-ethoxybenzamido)phenol was added to 120 ml of a 0.02N aqueous solution of potassium hydroxide, then methanol ( Add epichlorohydrin (0.045 mol) in 10 ml) and then at room temperature
Stirred for 48 hours. The product was filtered and washed twice with water (50 ml) and the crude 1[4(P-ethoxybenzamido)phenoxy]-2,3-epoxypropane was suspended in methanol (200 ml) and water (0.2 ml). ) and isopropylamine (0.5 mol) were added. After stirring for 2 days at room temperature, the product was filtered and dried. The hydrochloride salt, which was dissolved in acetone and treated with anhydrous hydrogen chloride gas and crystallized from isopropanol, had a melting point of 215-217°C. Biological Activities To investigate the beta-sympatholytic activity of the compounds of the present invention, the β ₁ -chronotropic effects of isoprenaline (increase in cardiac pulse frequency) on anesthetized and reserpenized rats were investigated. ),
It was tested in vivo after oral administration as an antagonist to the _β1 -inotropic effect (increase in systolic release rate) and _β2 effect (lower diastolic blood pressure), and also the _β1- chronotropic effect of isoprenaline ( guinea pig right atrium), _β1 inotropic effect (guinea pig ventricle)
and was tested in vitro as an antagonist to the _β2 effect (guinea pig trachea). From the results of in vivo and in vitro tests, it was found that 1-alkylamine-3[4(P
-alkyloxybenzamide) phenoxy]-2
- the propanol derivative exhibits a competitive type of β-blocking activity and, in contrast to β-blocking components such as propranolol;
It was found that it exhibits cardioselectivity and intrinsic sympathomimetic activity, the latter being manifested in this context by an increase in resting heart pulse rate in animals treated with reserpine. The beta-sympatholytic activity of 1-alkylamine-3[4(P-alkyloxybenzamido)phenoxy]-2-propanol compounds is significantly greater in vivo than compounds such as propranolol; It is more active in the tract, but its in vivo activity is associated with this due to its strong hepatic metabolism. All such favorable properties, i.e. cardioselectivity, intrinsic sympathomimetic activity and no significant difference in potency between in vivo and in vitro, are present in a compound such as 1-(4-benzamidophenoxy)- 3-isopropylamine-2-propanol (Ralph Howe, Leslie, Harald Smith, U.
S.3408387; AFCrowther, R.Howe, LH
Smith, J.Med.Chem. 14 (6), 511, 1971), 1 [4
(P-chlorobenzamide) phenoxy]-3-isopropylamine-2-propanol (AF
Crowther, R. Howe, LM Smith, J. Med.
Chem. 14 , (6), 511, 1971), Practrol (Howe, Smith, US3408387; Scales,
Casgrove, J.Pharmacol.Exp.Ther. 175 , 338,
4-benzamido (or acetamido) phenoxy-3-isopropylamine-2 such as (1970)
-Also present in propanol derivatives. On the other hand, compared to these compounds, 1[4(P-alkyloxybenzamido)phenoxy]-3-isopropylamine-2-propanol derivatives exhibit novel pharmacological properties, namely the β ₁ inotropic effect of isoprenaline. gives significantly greater potency to block _β1 chronotropic effects. In in vivo tests, the compounds of the invention have shown, at certain dosage levels, to have a significant effect on cardiac pulse frequency (chronotropy) without producing a concomitant decrease in myocardial contractility (inotropy). It was found to have a beta-sympatholytic effect. The angina-blocking activity of beta-sympatholytic agents is exerted by a decrease in heart rate (BardauxA.et.Eur.J.Pharmacol. 39 , 287,
1966; Gross GJand Waltier Dc.J.Pharm.Exp.
Ther. 203 , 544, 1977), therefore, 1 [4 (P
-alkyloxybenzamide) phenoxy]-3
- Isopropylamine-2-propanol derivatives have significant anti-ischemic effects compared to beta-sympatholytic agents conventionally used for treatment, and also have a significant anti-ischemic effect on angina attacks (Kauerina NVand
Chumburidze VBPharmac.Ther. 4 , 109,
Hypocinetic myocardial function, which is thought to be a decisive factor in the development of
The risk of developing the condition is very low. 1[4(P-alkyloxybenzamide... or 1[4(m-alkyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol derivative, and 1[2(P-alkyloxybenzamide... or 1[3( P-alkyloxybenzamido)phenoxy]-3-isopropylamine-2-propanol derivatives interestingly confer competitive type β-sympatholytic activity, cardioselectivity and intrinsic sympathomimetic activity, but this It was observed that the activity was lower than that of the corresponding derivative of the invention, and in some cases it lacked chronotropic activity.From the above results, the phenoxy group was replaced with P-
It is clear that complete substitution with alkyloxybenzamide groups is of fundamental importance. Substitution of the allylkyloxy group by another group results in a clear decrease in activity or loss in selectivity, and a decrease in activity or loss in selectivity also occurs when two or more alkoxyl groups are introduced.

Claims (1)

[Claims] 1 General formula () (R ₁ in the formula is a straight chain or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms; R is a linear or branched alkyl group having 1 to 8 carbon atoms; 1-alkylamine-3-[4-(P-alkyloxybenzamide) represented by 8 straight-chain or branched alkyl groups)
Phenoxy]-2-propanol derivative. 2. The compound according to claim 1, which has an optically active form. 3. The compound according to claim 1, which is a pharmacologically acceptable non-toxic salt. 4. The compound according to claim 2, which is a pharmacologically acceptable non-toxic salt. 5 1-isopropylamine 3[4(P-methoxybenzamide)phenoxy]-2-propanol and its pharmacologically acceptable salts, 1-t-butylamine-3[4(P-methoxybenzamide)
phenoxy]-2-propanol and its pharmacologically acceptable salts, 1[4(P-ethoxybenzamide)phenoxy]-3-isopropylamine-2-propanol and its pharmacologically acceptable salts, 1[4( P-allyloxybenzamide)
phenoxy]-3-isopropylamine-2-propanol and its pharmacologically acceptable salts;
1-isopropylamine-3[4(P-propyloxybenzamide)phenoxy]-2-propanol and its pharmacologically acceptable salts, 1-isopropylamine-3[4(P-isopropyloxybenzamide)phenoxy]-2 - Propanol and its pharmacologically acceptable salts, 1[4(P
-butyloxybenzamide) phenoxy]-3
- Isopropylamine-2-propanol and its pharmacologically acceptable salts, 1-isopropylamine-3[4(P-pentyloxybenzamide)phenoxy]-2-propanol and its pharmacologically acceptable salts, 1[ 4(P-Hexyloxybenzamido)phenoxy]-3-isopropylamine-2-propanol and its pharmacologically acceptable salts, 1-isopropylamine-3
[4(P-octyloxybenzamide)phenoxy]-2-propanol and its pharmacologically acceptable salts and 1[4(P-benzyloxybenzamide)phenoxy]-3-isopropylamine-2-propanol and its pharmacology 2. A compound according to claim 1 selected from the group consisting of publicly acceptable salts. 6 (a) reacting a suitable benzamidophenol with a suitable 3-amino-2-hydroxy-1-halogenpropane or a suitable 3-amino-1,2-epoxypropane under alkaline conditions; or (b ) reacting a suitable benzamidophenol with a suitable amine; or (c) reacting a suitable benzamidophenol with a dihalogenacetone followed by treatment with a suitable amine and then the corresponding reaction. General formula characterized by reduction to alcohol (R ₁ in the formula is a straight chain or branched alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms; R is a linear or branched alkyl group having 1 to 8 carbon atoms; A method for producing a 1-alkylamine-3-[4(P-alkyloxybenzamido)phenoxy]-2-propanol derivative represented by 8 linear or branched alkyl groups. 7 General formula () (R ₁ in the formula is a linear or branched group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an arylalkyl group having 7 to 10 carbon atoms; R is a linear or branched group having 1 to 8 carbon atoms; 1-alkylamine-3-[4
(P-alkyloxybenzamide) phenoxy]
- A pharmaceutical composition containing a 2-propanol derivative as an active ingredient. 8. The composition according to claim 7, which is in a form suitable for oral, parenteral or rectal administration.