JP2009040769A - 3-amino-propoxyphenyl derivative (i) - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an effective β1-specific β-adrenergic receptor blocker having a short action time. <P>SOLUTION: A concrete example of the β1-specific β-adrenergic receptor blocker is 1-(2-cyano-4-(2-(2-methylpropoxy)ethoxy)phenoxy)-2-hydroxy-3-(2-(4-methoxyphenoxy)ethylamino)propane. S(-)-1-(4-(2-ethoxyethoxy)phenoxy)-2-hydroxy-3-(2-(3,4-dimethoxyphenyl)ethylamino)propane and physiologically acceptable hydrolysable derivatives thereof having a hydroxy group in the 2-position of the 3-aminopropoxy side chain in an esterified form are provided in a racemic or optically active form of the compound or derivatives thereof, and their pharmaceutically acceptable acid addition salts are also provided. <P>COPYRIGHT: (C)2009,JPO&INPIT

Description

  The present invention relates to a β1-specific β-adrenergic receptor blocker having a short action time and a β1-specific β-adrenergic receptor blocker having a short action time in the systemic circulation. It relates to a method for the treatment and / or prevention of symptoms which are particularly advantageous.

  A class of drugs known as β-blockers are well known in the art for the treatment of heart disease and especially ophthalmic conditions. However, the optimal combination of such drug properties varies significantly depending on the condition being treated. Therefore, in the long-term treatment of cardiovascular diseases such as hypertension and cardiac arrhythmia, β1-selective compounds have a low incidence of side effects associated with blockade of β2-receptors such as asthma, and the remaining characteristics usually The combination of β1-selectivity with high potency, good oral availability, and long plasma half-life and duration of action is usually optimal because it can be treated by oral administration once a day It is considered to be.

  In other conditions where β1-selectivity is preferred, some of these properties are not optimal. Administration to the eye for the treatment of glaucoma can cause undesirable systemic side effects due to oral availability and prolonged plasma half-life. Treatment of cardiac arrhythmias that can occur during induction of anesthesia or in the care of critically ill patients can be treated quickly without the risk of inducing long-acting beta blockade if the systemic half-life is short . Treatment of glaucoma requires drugs that are well absorbed by the eye. However, since it passes through the eye or is administered via the nasolacrimal tubule, it becomes an inactive metabolite by metabolism and is quickly removed from the systemic circulation, so treatment is limited to the eye and side effects are very small. For short-term systemic administration, a combination of β1-selectivity and a short half-life is ideal. For both conditions, there is a limit to the practical concentration that can be prescribed for eye drops, so high efficacy is required, but high efficacy reduces the dose required for systemic administration. Tends to be greater for compounds with shorter half-lives than other β-blockers.

  Therefore, there is a need to develop β1-specific blockers with high efficacy and short action times in the systemic circulation.

  Short acting beta blockers are described in US Pat. No. 4,966,914, US Pat. No. 4,455,317, US Pat. No. 4,810,717, US Pat. No. 4,593,119, US Pat. No. 5,013,734, and It is described in EP 041491. The short-acting β-blockers described in these patent specifications all have ester functional groups in their structure that are easily hydrolyzed.

  However, it is difficult to say that the compounds of the invention are perfectly suitable for the optimal combination of properties required. These can be summarized as (1) an appropriate blocking action on the receptor, (2) specificity for the β1 receptor, and (3) a short action time of systemic circulation.

  Therefore, it is necessary to develop a β-blocker having sufficient characteristics (1) to (3).

（前記式中、
Ｒはフェニル、又は１〜４個の炭素原子を有するアルキル、１〜４個の炭素原子を有するアルコキシ、又は原子番号が９〜３５のハロゲンによって一置換、独立して二置換又は独立して三置換されたフェニルであり、
Ｒ_１は、水素、１〜４個の炭素原子を有するアルキル、１〜４個の炭素原子を有するアルコキシ、１〜４個の炭素原子を有するアルキルチオ、３〜７個の炭素原子を有するシクロアルキル、原子番号が９〜３５のハロゲン、トリフルオロメチル、１−ピロリル、シアノ、カルバモイル、２〜５個の炭素原子を有するアルケニル、３〜５個の炭素原子を有するアルケニルオキシであって、二重結合が酸素原子に隣接する炭素原子に結合しているもの、又は１〜５個の炭素原子を有するアルカノイルであり、
Ｒ_２は、１〜４個の炭素原子を有するアルキル、５〜７個の炭素原子を有するシクロアルキル、シクロアルキル残基中に３〜７個の炭素原子を有しかつアルキル残基中に１〜４個の炭素原子を有するシクロアルキルアルキル、フェニル、７〜１０個の炭素原子を有するフェニルアルキル、又はフェニル、又はフェニル環において１〜４個の炭素原子を有するアルキル、１〜４個の炭素原子を有するアルコキシ又は原子番号が９〜３５のハロゲンによって一置換、独立して二置換又は独立して三置換された７〜１０個の炭素原子を有するフェニルアルキルであり、
Ａは、２〜５個の炭素原子を有するアルキレンであり、
Ｘは、結合、酸素、又は硫黄原子であり、
Ｙは、酸素又は硫黄原子であり、
Ｚは、酸素原子であり、かつｎは２又は３であるか、又は
Ｚは、結合であり、かつ１、２又は３であり、
ただし、
（ａ） Ｒ_２がアルキルであるときには、Ｚは酸素原子であり、基−ＮＨ−Ａ−Ｘ−Ｒは、式
−ＮＨＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_２Ｐｈ、
−ＮＨＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_２ＯＰｈ、
−ＮＨＣＨ（ＣＨ_３）ＣＨ_２ＣＨ_２ＣＨ_２ＯＰｈ、又は
−ＮＨＣＨ（ＣＨ_３）ＣＨ_２ＣＨ（ＣＨ_３）ＯＰｈ、
の残基以外のものであり、
（ｂ） Ｒ_２がアルキルであり、Ｘが結合又は酸素原子であるときには、Ｙは酸素原子であり、
（ｃ） Ｒ_２が未置換又は一置換フェニルであるときには、
Ｘは結合であり、
Ｚは酸素原子であり、又は
Ｒ_２がシクロアルキル又はシクロアルキルアルキルであり、Ｘが結合であるときには、
Ｒ_１は水素以外のものである）の化合物、及びエステル化形態の３−アミノプロポキシ側鎖の２位にヒドロキシ基を有する生理学的に許容される加水分解性誘導体、又はその薬学上許容される酸付加塩の群が記載されている。
米国特許第４９６６９１４号 米国特許第４４５５３１７号 米国特許第４８１０７１７号 米国特許第４５９３１１９号 米国特許第５０１３７３４号 欧州特許第０４１４９１号 米国特許第４８１６６０４号 US Pat. No. 4,816,604 describes formula (I) as a β1-selective β-blocker.

(In the above formula,
R is phenyl, mono-substituted, independently di-substituted or independently tri-substituted by phenyl, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, or halogen having an atomic number of 9 to 35. Substituted phenyl,
R ₁ is hydrogen, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, cycloalkyl having 3 to 7 carbon atoms Halogen having an atomic number of 9 to 35, trifluoromethyl, 1-pyrrolyl, cyano, carbamoyl, alkenyl having 2 to 5 carbon atoms, alkenyloxy having 3 to 5 carbon atoms, The bond is bonded to the carbon atom adjacent to the oxygen atom, or alkanoyl having 1 to 5 carbon atoms,
R ₂ is alkyl having 1 to 4 carbon atoms, cycloalkyl having 5 to 7 carbon atoms, 3 to 7 carbon atoms in the cycloalkyl residue and 1 in the alkyl residue. Cycloalkylalkyl having -4 carbon atoms, phenyl, phenylalkyl having 7-10 carbon atoms, or phenyl, or alkyl having 1-4 carbon atoms in the phenyl ring, 1-4 carbons Alkoxy having an atom or phenylalkyl having 7 to 10 carbon atoms monosubstituted, independently disubstituted or independently trisubstituted by halogen having an atomic number of 9 to 35;
A is alkylene having 2 to 5 carbon atoms,
X is a bond, oxygen, or sulfur atom;
Y is an oxygen or sulfur atom,
Z is an oxygen atom and n is 2 or 3, or Z is a bond and is 1, 2 or 3.
However,
(A) When R ₂ is alkyl, Z is an oxygen atom, and the group —NH—A—X—R has the formula —NHCH (CH ₃ ) CH ₂ CH ₂ Ph,
_{-NHCH (CH 3) CH 2 CH} 2 OPh,
_{-NHCH (CH 3) CH 2 CH} 2 CH 2 OPh, or _{-NHCH (CH 3) CH 2 CH} (CH 3) OPh,
Other than the residues of
(B) when R ₂ is alkyl and X is a bond or an oxygen atom, Y is an oxygen atom;
(C) when R ₂ is unsubstituted or monosubstituted phenyl
X is a bond,
When Z is an oxygen atom, or R ₂ is cycloalkyl or cycloalkylalkyl and X is a bond,
R ₁ is other than hydrogen) and physiologically acceptable hydrolyzable derivatives having a hydroxy group at the 2-position of the esterified form of the 3-aminopropoxy side chain, or a pharmaceutically acceptable salt thereof A group of acid addition salts is described.
U.S. Pat. No. 4,966,914 U.S. Pat. No. 4,455,317 U.S. Pat. No. 4,810,717 U.S. Pat. No. 4,593,119 US Pat. No. 5,013,734 European Patent No. 041491 U.S. Pat. No. 4,816,604

  The inventors have found that a subgroup of compounds selected from the class generally described in US Pat. No. 4,816,604 has the desired combination of features (1)-(3) above. I found it unexpectedly. They are particularly active, β1-specific and have a short action time in the systemic circulation. Since the compounds of the present invention are not altered by readily hydrolyzed ester groups coupled with prior art β-blockers that have a short plasma half-life, it is not expected to have such a short duration of action in the systemic circulation. And I could not predict.

で表される化合物（ただし、Ｒは３’，４’−ジメトキシフェニル基であり、Ｒ^１は水素であり、そしてＲ^２はメチル基、エチル基、プロピル基、イソブチル基、及びイソプロピル基から選択されるか；又は、
Ｒは３’，４’−ジメトキシフェニル基であり、Ｒ^１はフッ素、塩素、及び臭素から選択され、そしてＲ^２はメチル基、エチル基、プロピル基、イソプロピル基、イソブチル基、及びシクロプロピルメチル基から選択されるか；又は、
Ｒは４’−メトキシフェノキシ基であり、Ｒ^１は水素、フッ素、塩素、及び臭素から選択され、そしてＲ^２はメチル基、エチル基、プロピル基、イソプロピル基、イソブチル基、及びシクロプロピルメチル基から選択されるか；又は、
Ｒは３’，４’−ジメトキシフェニル基であり、Ｒ^１はシアノ基であり、そしてＲ^２はシクロプロピルメチル基又はイソブチル基であるか；又は、
Ｒは４’−メトキシフェノキシ基であり、Ｒ^１はシアノ基であり、そしてＲ^２はイソブチル基である。）、及び、エステル化された形態において水酸基を３−アミノプロポキシ側鎖の２位に有する、生理学的に許容されかつ加水分解できるその誘導体を、当該化合物若しくは誘導体のラセミ体又は光学活性体の形態で、並びに製薬上許容されるそれらの酸付加塩を提供する。 That is, the present invention provides formula (Ia) as a potent β ₁ -specific β-receptor blocker with a short duration of action in the systemic circulation.

Wherein R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is hydrogen, and R ² is selected from a methyl group, an ethyl group, a propyl group, an isobutyl group, and an isopropyl group Or
R 3 'is 4'-dimethoxyphenyl group, R ¹ is fluorine, chlorine, and is selected from bromine, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and cyclopropylmethyl Selected from the group; or
R is a 4′-methoxyphenoxy group, R ¹ is selected from hydrogen, fluorine, chlorine, and bromine, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and a cyclopropylmethyl group Or selected from
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is a cyano group, and R ² is a cyclopropylmethyl group or an isobutyl group; or
R is a 4′-methoxyphenoxy group, R ¹ is a cyano group, and R ² is an isobutyl group. And a physiologically acceptable and hydrolyzable derivative thereof having a hydroxyl group at the 2-position of the 3-aminopropoxy side chain in the esterified form, the racemic or optically active form of the compound or derivative As well as pharmaceutically acceptable acid addition salts thereof.

As a preferred aspect, the present invention provides a compound represented by the above formula (Ia), wherein R is a 3′-4′-dimethoxyphenyl group, R ¹ is hydrogen, and R ² is a methyl group or an ethyl group. , A propyl group, an isobutyl group, and an isopropyl group; or
R is 4'-methoxyphenoxy group, R ¹ is hydrogen and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and is selected from cyclopropylmethyl group; or,
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is a cyano group, and R ² is a cyclopropylmethyl group; or
R is a 4′-methoxyphenoxy group, R ¹ is a cyano group, and R ² is an isobutyl group; or
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is bromine, and R ² is a methyl group. And a physiologically acceptable and hydrolyzable derivative having a hydroxyl group at the 2-position of the 3-aminopropoxy side chain in the esterified form in the form of a racemic or optically active form of the compound or derivative. As well as their pharmaceutically acceptable acid addition salts.

A further aspect of the present invention is a method for the treatment and / or prevention of conditions in which potent β ₁ -specific β-receptor blockers with a short duration of action in the systemic circulation are particularly effective, such as There is provided a method as described above comprising administering to a patient in need of proper treatment and / or prevention an effective amount of a compound of formula (Ia).

The present invention also provides a formula (in the manufacture of a medicament for the treatment and / or prevention of a condition in which a potent β ₁ -specific β-receptor blocker is particularly effective with a short duration of action in the systemic circulation. There is provided the use of a compound represented by Ia).

Preferred compounds according to the present invention include
1- (4- (2-methoxyethoxy) phenoxy) -2-hydroxy-3- (2- (4-methoxyphenoxy) ethylamino) propane; 1- (2-cyano-4- (2- (2-methyl) Propoxy) ethoxy) phenoxy) -2-hydroxy-3- (2- (4-methoxyphenoxy) ethylamino) propane; S (-)-1- (4- (2-ethoxyethoxy) phenoxy) -2-hydroxy- 3- (2- (3,4-dimethoxyphenyl) ethylamino) propane; 1- (2-cyano-4- (2-cyclopropylmethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3, 4-dimethoxyphenyl) ethylamino) propane; and 1- (4- (2-ethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxy) Eniru) is ethylamino) propane.

Particularly preferred compounds are:
1- (4- (2-Ethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane and S (-)-1- (4- (2-ethoxy And ethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane.

Preferable symptoms for which an effective β ₁ -specific β-receptor blocker with a short period of action in the systemic circulation is particularly effective include eye treatment for glaucoma and parenteral treatment for cardiac arrhythmia and acute myocardial infarction. When, further sustained beta ₁ - there is a parenteral treatment for other heart disease blocking undesirable adrenergic receptor.

  A physiologically acceptable and hydrolyzable derivative is a derivative that acts as a prodrug and cleaves under physiological conditions to the corresponding compound having a hydroxyl group at the 2-position of the 3-aminopropoxy side chain.

で表される化合物（ただし、Ｒ、Ｒ_１及びＲ_２は、前記の通りであり、Ｒｅは炭素原子数１〜１２のアルキル基、炭素原子数３〜７のシクロアルキル基、フェニル基、炭素原子数７〜１２のフェニルアルキル基、又はフェニル基若しくは炭素原子数７〜１２のフェニルアルキル基であって、炭素原子数１〜４のアルキル基によりフェニル環上で１置換されたもの、又は原子番号が９〜３５のハロゲンによりフェニル環上で１置換若しくは独立して２置換若しくは独立して３置換されたもの、又は、炭素原子数１〜４のアルコキシル基によりフェニル環上で１置換若しくは独立して２置換若しくは独立して３置換されたものである。）である。 A group of prodrug derivatives that are esterified products of the compound represented by the formula (Ia) is, for example, the formula (E)

Wherein R, R ₁ and R ₂ are as described above, and Re is an alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms, a phenyl group, carbon A phenylalkyl group having 7 to 12 atoms, or a phenyl group or a phenylalkyl group having 7 to 12 carbon atoms, which is monosubstituted on the phenyl ring by an alkyl group having 1 to 4 carbon atoms, or an atom 1-substituted or independently 2-substituted or independently 3-substituted on the phenyl ring with a halogen number 9 to 35, or 1-substituted or independently on the phenyl ring with an alkoxyl group having 1 to 4 carbon atoms 2 or independently 3 substituted).

  A compound in which the hydroxyl group at the 2-position of the 3-aminopropoxy group side chain is not esterified is preferred.

で表される対応する化合物（ただし、Ｒ_１及びＲ_２は前述の通りであり、Ｒｘは、１級アミンと反応することができ、２−アミノ−１−ヒドロキシエチル基を与える基である）と、式（ＩＩＩ）

で表される適当な化合物（ただし、Ｒは上記の通りである）との反応、そして、必要な場合は、式（Ｉａ）で表される得られた化合物中の３−アミノプロポキシ基側鎖の２位の適当なエステル化を含む。 The compounds of the present invention are obtained by the method described in US Pat. No. 4,816,604, which has the chemical formula (II)

In the corresponding compound represented (wherein, R ₁ and R ₂ are as defined above, Rx may be reacted with a primary amine, a group which gives a 2-amino-1-hydroxyethyl) And the formula (III)

Reaction with a suitable compound represented by the formula (where R is as defined above), and, if necessary, the side chain of the 3-aminopropoxy group in the resulting compound represented by formula (Ia) A suitable esterification of the 2-position.

で表される基、又は、当該基の誘導体、例えば、式−ＣＨ（ＯＨ）−ＣＨ_２Ｌで表される基（ただし、Ｌが塩素、臭素、又はＲｙがフェニル基、トリル基若しくは低級アルキル基であるＲｙ−ＳＯ_２−Ｏ−の基）である。Ｌは特に塩素である。当該反応は、エタノール中又はジオキサンのような適当なエーテル中で行われるのが好ましい。任意に、過剰のアミンを溶媒として用いることができる。代替的に、反応は融合融解液中で行うこともできる。反応温度は、約２０°Ｃから約２００°Ｃまでが適しており、溶媒の存在下では反応化合物の環流温度が都合よい。 The amination method can be carried out by a conventional method for producing a similar 3-amino-2-hydroxypropoxyaryl compound. For example, Rx is the formula

Or a derivative of the group, for example, a group represented by the formula —CH (OH) —CH ₂ L (where L is chlorine, bromine, or Ry is a phenyl group, a tolyl group or a lower alkyl group) Ry—SO ₂ —O— group). L is especially chlorine. The reaction is preferably carried out in ethanol or in a suitable ether such as dioxane. Optionally, an excess of amine can be used as a solvent. Alternatively, the reaction can be performed in a fusion melt. The reaction temperature is suitably from about 20 ° C. to about 200 ° C., and the reflux temperature of the reaction compound is convenient in the presence of a solvent.

Although esterification of the hydroxyl group at the 2-position of the side chain is optional, it can be carried out by a method known as a method for producing a 3-amino-2-hydroxypropoxyaryl compound, which is a similar ester compound. For example, when other reactive groups are present, an esterification reaction is selectively performed.
The free base forms of the compounds of the invention can be converted to pharmaceutically acceptable acid addition salts by conventional methods and vice versa. Suitable acids for the production of acid addition salts include, for example, hydrochloric acid, hydrobromic acid, malonic acid or fumaric acid.

  In the compound of the present invention, the carbon atom at the 2-position of the side chain of the 3-aminopropoxy group is asymmetrically substituted. Thus, the compound may exist as a mixture of two optical isomers, for example as a racemate or the respective optical isomer. The preferred optical isomer is the S form at this asymmetrically substituted carbon atom of the 3-aminopropoxy side chain. Each optical isomer can be obtained by a conventional method, for example, by using an optically active starting material or by fractional crystallization of a racemic salt using an optically active acid.

で表される化合物（ただし、Ｒ_１及びＲ_２は前記の通りである。）に、Ｏ−アルキル化を通じて、−ＯＣＨ_２−Ｒｘ基を導入することにより得られる。式（ＩＶ）で表される化合物は好ましくはアニオン化された状態で反応に付される方が好ましい。 The compounds used as starting materials can be obtained by conventional methods.
In particular, the compound represented by the formula (II) is represented by the formula (IV)

Is obtained by introducing an —OCH ₂ —Rx group into the compound represented by (wherein R ₁ and R ₂ are as defined above) through O-alkylation. The compound represented by formula (IV) is preferably subjected to the reaction in an anionized state.

で表される対応する化合物（ただし、Ｒ_２は前記の通りであり、Ｂｚはベンジル基、又はテトラヒドロピラニル基等の保護基であり、チャコール上のパラジウム又は酸性加水分解等の、適当な条件下で保護するものである。）の脱保護により得られる。 The compound represented by the formula (IV) in which R ₁ is hydrogen can be obtained by selectively etherifying one of the hydroxyl groups of 1,4-dihydroxybenzene. This reaction is, for example, a reaction with 1 molar equivalent of a compound represented by the formula L—CH ₂ CH ₂ O—R ₂ (where L and R ₂ are as described above), and a base (eg, It is preferably carried out in an inert solvent (eg acetone) in the presence of potassium carbonate). Alternatively, the compound represented by the formula (IV) in which R ₁ is a hydrogen atom is represented by the formula (V)

(Wherein R ₂ is as described above, Bz is a protecting group such as benzyl group or tetrahydropyranyl group, and is subjected to appropriate conditions such as palladium on charcoal or acidic hydrolysis) It is obtained by deprotection of the following.

Compounds of formula (V) are, for example, 4-benzyloxy phenol is, for example, derivative _{L-CH 2 CH 2 O-} R 2 ( where, L and _{R 2} are as defined above) with It can be obtained by appropriate etherification. L is preferably 4′-toluenesulfonate.

The compound represented by formula (IV) (wherein R ₁ is bromine) is obtained by monobromination of the corresponding compound represented by formula (IV) (where R ₁ is hydrogen). The obtained bromide is converted into a compound represented by the formula (IV) in which R ₁ is a cyano group, for example, by treatment with copper cyanide in dimethylformamide.

  Unless a specific starting material preparation is specifically stated, the preparation can be carried out in a conventional manner.

  In the following examples, all temperatures are in centimeter grades and are not corrected.

S (-)-1- (4- (2-ethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane

  Sodium hydride (9.6 g, no oil) is suspended in anhydrous dimethylformamide (200 ml) and 4-ethoxyethoxyphenol (70.5 g) is added slowly over 30 minutes. The reaction mixture is then cooled to 5 ° C. and S (+)-glycidyl-3-nitrobenzenesulfonate (100 g) dissolved in dimethylformamide (200 ml) is added over 1 hour. The mixture is allowed to reach room temperature and stirred for an additional 1.5 hours. The excess sodium hydride is then destroyed by the slow addition of water, the mixture is diluted with 2 liters of water and the intermediate epoxide is extracted three times with 800 ml of ethyl acetate. The extract is dried, redissolved in dioxane (200 ml) and 3,4-dimethoxyphenylethylamine (70.2 g) dissolved in dioxane (200 ml) is added. After the mixture is heated to reflux for 6 hours, the solvent is evaporated and the residue is redissolved in diethyl ether. A saturated solution of hydrogen chloride in diethyl ether (500 ml) is added to precipitate the hydrochloride salt of the title compound. The product is filtered, dried and recrystallized from isopropanol (750 ml). Yield 103-106 g, mp 147-149 ° C.

  4- (2-Ethoxyethoxy) phenol is obtained as follows.

  2-Toluenesulfonic acid 2'-ethoxyethyl is prepared by reacting 4-toluenesulfonyl chloride with 2-ethoxyethanol in the presence of sodium hydroxide. The product is reacted with 4-benzyloxyphenol and sodium hydroxide without isolation. The crude product precipitates upon cooling, can be filtered off and washed with 5% sodium hydroxide and water. This material is then suspended in ethanol and debenzylated with hydrogen and 10% palladium / charcoal at atmospheric pressure. The catalyst is filtered off over Celite and the solvent is distilled off under reduced pressure. The residue is dissolved in toluene, filtered and phenol is extracted with 5% sodium hydroxide. The extract is acidified with hydrochloric acid and the phenol is extracted into diethyl ether. After drying, the crude product can be distilled under reduced pressure to obtain a colorless liquid product, which gradually crystallizes. Melting point: 39.5-40.5 ° C.

である）の適当な化合物と、式ＩＩＩの適当な化合物から、下記の式Ｉａの表１の化合物を例１と同様な方法で得ることができる。 Formula II where Rx is

Can be obtained in the same manner as in Example 1 from the appropriate compound of formula III and the appropriate compound of formula III.

  These compounds are more prominent than expected for compounds having this type of structure and have a wide range of beneficial pharmacological properties. They are particularly active, β1-specific and have a short action time in the systemic circulation. Since the compounds of the present invention are not altered by readily hydrolyzed ester groups coupled with prior art β-blockers that have a short plasma half-life, it is not expected to have such a short duration of action in the systemic circulation. And I could not predict.

  The β1-specificity and β-adrenergic receptor blocking action of compounds of formula Ia can be demonstrated in vitro using guinea pig isolated tissue according to standard procedures.

Tissue preparation:
The animal is quickly killed by cervical dislocation after striking the head. Open chest, remove heart and trachea and place in carbonated Krebs-Ringer-bicarbonate solution (Krebs). Carefully pump blood out of the ventricle (LH Tung, GP Jackman, B. Champbell, S. Louis, D. Iakovidis & WJ Louis, J. Cardiovasc. Pharmacol., 21, (2), 484-488, 1993. See).

Atrium:
Carefully detach all foreign tissue from the heart and the atrium from the ventricle. A suture with a loop is tied to each atrium and used to suspend the tissue from the organ bath rod. The other loop is attached to a force transducer with 1 g force applied. The atrium is then held in a bath containing oxygenated (5% Carbogen) Krebs at 37 ° C. and Krebs are replaced for 50 minutes at 10 minute intervals. The isoprenaline dose-response curve is then measured by adding isoprenaline until a plateau is seen in the response at increasing doses from 10 ⁻¹¹ M (about 10 ^−5.5 M). The dose is increased at 2 minute intervals and the maximum contractile force and heart rate are recorded. At the end of the dose-response curve, the organ bath is replaced with fresh Krebs and washed 3 times every 10 minutes for 50 minutes. The dose of test drug is then added to the organ bath and allowed to equilibrate for 10 minutes. The isoprenaline dose-response curve is then repeated. After washing the atria for an additional 50 minutes with Krebs as before, the control dose-response curve is repeated in the absence of drug.

Trachea All exogenous tissue is cut off and five rings 1 to 2 mm wide are cut from the trachea and placed in order on a loose loop. The ring is suspended from an isometric transducer set with a resting force of 1.0 g. The rings are then incubated in oxygenated (5% Carbogen) Krebs in an organ bath at 37 ° C. and replaced with Krebs three times for 50 minutes at 10 minute intervals. Next, Carbachol 10 ⁻⁶ M is added to the bath to induce contraction. Once the contractile force has stabilized, an increasing amount of isoprenaline (10 ⁻⁸ to 10 ⁻⁵ M) is added to generate a control dose-response curve. The tissue is then washed every 10 minutes with 3 changes of Krebs for 50 minutes before adding the drug. After 10 minutes incubation, carbachol is added again and a new dose-response to isoprenaline is measured. After another 50 minutes wash, repeat the control curve.

Using these data, calculating the pA ₂ values for atrial and tracheal (Mackay, J. Pharm. Pharmacol. , 30, 312-313, see 1978). These are logarithmic values, and the higher this value, the stronger the compound. The ratio of these values indicates the selectivity of each compound.

  The β1-specificity of the compounds is shown in Table 2 below.

It was shown in the following experiment that the action time of the compound of the present invention in the systemic circulation was short.
Healthy male Sprague-Dawley rats with intrinsic catheters in the carotid artery and jugular vein were prepared under anesthesia and allowed to recover for at least 24 hours. On the first day of the experiment, the arterial catheter was attached to a flexible swivel and then attached to a pressure transducer for continuous recording of heart rate and blood pressure. An intravenous catheter was attached to an infusion pump for drug administration or a syringe for bolus administration of isoprenaline (0.1 μg / kg). The catheter was suspended out of the way of the animal and the rat was moved freely in a small covered enclosure isolated from external disturbances. When BP and HR became stable, isoprenaline bolus was administered at 10 minute intervals until the maximum response of HR was reproducible (± 10%). The dose was repeated for at least 40 minutes and the last 5 readings were considered to constitute a baseline response. This dose was continued at the same interval for a further 150 minute study period. Approximately 3.5 minutes before the next dose of isoprenaline, infusion of the test compound was started and the dead volume of the infusion line was observed and continued for an additional 33.5 minutes.

  Rats were used for one or more experiments when the catheter remained effective for daily replacement with heparinized saline, with each experiment spaced at least 24 hours apart.

  Thus, rats with cannulas inserted into the left carotid artery and left jugular vein can be studied in the awake state. Thereby, the heart rate and blood pressure can be continuously recorded before and after intravenous infusion of a β-blocker at a selected dose. Determine the time of β-blocking after cessation of an intravenous infusion of β-blocker by examining the time required to increase the heart rate caused by the standard dose of isoprenaline and controlling the value after cessation of β-blocker infusion Can do. A record of the maximum inhibition of heart rate response to isoprenaline in the test drug infusion is assessed, and the pharmacodynamic half-life is the time required to reduce this inhibition by 50% after cessation of the drug infusion.

  These studies have a very short half-life of action for the compounds of the invention in plasma in vivo compared to standard drugs such as atenolol and betaxolol, which is unexpected and predictable from the prior art I couldn't. This characteristic is extremely important in that the β-blocker can be used safely and in a controlled manner when required as a short-acting intravenous drug in the field of treatment such as anesthesia or intensive care. This property is useful for diseases such as glaucoma because when drugs are administered by the ocular route, drugs that enter the circulation are rapidly degraded and therefore are much less likely to produce side effects with systemic beta blockade. It is also important for treatment.

  Table 3 shows the half-lives of the action of the compounds in the systemic circulation measured in vivo by the above method in rats.

  It has been observed that when standard β-blockers are administered by the ocular route, some of the drugs can enter the systemic circulation and cause systemic side effects such as death (UK Safety of Medicines Report, “Recently (Current Problems), No. 28, 1990). Β-blockers with this level of β1 specificity with a short period of systemic activity are expected to significantly reduce this risk. Drugs described in recent applications surprisingly combine the properties of potent β1-specificity and short half-life in the systemic circulation, with a level of safety not previously available for the treatment of glaucoma. It is special in that it provides a foundation.

  The compound in free form or in the form of a pharmaceutically acceptable acid addition salt thereof can be administered alone or in a suitable dosage form.

  The invention also provides a pharmaceutical composition comprising a compound of the invention in free form or in the form of an acid addition salt in combination with a pharmaceutical carrier or diluent. Such a form, for example, a solution, can be produced by a known method.

  When the compounds of the invention are used in the field of therapy such as anesthesia and intensive care for the treatment of heart disease, they are advantageously administered parenterally, for example by intravenous injection or intravenous infusion. Formulations for intravenous injection preferably include the active compounds as soluble acid addition salts in appropriately buffered isotonic solutions.

  The dosage and time of infusion administered to a patient will vary depending on the patient's needs and the particular compound used. A dosage of about 0.0001 to about 100 mg per kg body weight per hour is generally used, with a preferred dosage ranging from about 0.01 to about 10 mg per kg body weight per hour.

  When the compounds of the present invention are used for the treatment of glaucoma eyes, they are advantageously administered topically to the eye in the form of solutions, ointments or solid inserts as described in US Pat. No. 4,195,085. Formulations may contain the active compound, preferably in the form of a soluble acid addition salt, in an amount ranging from about 0.01 to about 5% by weight, preferably from about 0.2 to about 2% by weight. . Unit dosages of active compound can range from about 0.01 to about 2.0 mg, preferably from about 0.1 to about 0.5 mg. The dosage administered to a patient will vary depending on the patient's needs and the particular compound used.

  The carriers used in the formulations of the present invention are preferably non-toxic such as water, water and water miscible solvents such as mixtures of lower alcohols, inorganic oils, petroleum jelly, ethyl cellulose, polyvinylpyrrolidone, and other conventional carriers. A pharmaceutical organic or inorganic composition. Pharmaceutical formulations can also contain additional ingredients such as emulsifiers, preservatives, wetting agents, and bactericides. These are known to have polyethylene glycol 200, 300, 400 and 600, carbowax 1,000, 1,500, 4,000, 6,000 and 10,000, quaternary ammonium compounds, pasteurization properties. Bactericidal ingredients such as phenylmercury salts, thimerosal, methyl and propylparaben, benzyl alcohol, phenylethanol, and buffer ingredients such as sodium chloride, sodium borate, sodium acetate, gluconate buffer Sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitylate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediaminetetraacetic acid Such normal component thereof. Appropriate ophthalmic vehicles such as normal phosphate buffer vehicles, isotonic borate vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles, etc. should be used as carrier media for this purpose. Can do.

  Advantageously, the method of treating glaucoma of the present invention involves the topical administration of eye drops containing the active compound. Formulations for eye drops include the active compounds as soluble acid addition salts, preferably in suitably buffered sterile isotonic aqueous solutions.

Claims (25)

A method for treating and / or preventing a condition in which an effective β ₁ -specific β-receptor blocker with a short duration of action in the systemic circulation is particularly effective, such treatment and / or prevention For patients in need of formula (Ia)

Wherein R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is hydrogen, and R ² is derived from a methyl group, an ethyl group, a propyl group, an isobutyl group, and an isopropyl group. Selected; or
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is selected from fluorine, chlorine, and bromine, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and cyclopropylmethyl. Selected from the group; or
R is a 4′-methoxyphenoxy group, R ¹ is selected from hydrogen, fluorine, chlorine, and bromine, and R ² is a methyl group, an ethyl group, a propyl group, an isopropyl group, an isobutyl group, and a cyclopropylmethyl group Selected from; or
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is a cyano group, and R ² is a cyclopropylmethyl group or an isobutyl group; or
R is a 4′-methoxyphenoxy group, R ¹ is a cyano group, and R ² is an isobutyl group. And a physiologically acceptable and hydrolyzable derivative thereof having a hydroxyl group at the 2-position of the 3-aminopropoxy side chain in the esterified form in the form of a racemic or optically active form of the compound or derivative. And administering an effective amount of a pharmaceutically acceptable acid addition salt thereof. In the manufacture of a medicament for the treatment and / or prevention of conditions in which an effective β ₁ -specific β-receptor blocker with a short duration of action in the systemic circulation is particularly effective, Use of a compound of formula (Ia) as defined. Treat one or more conditions in the group consisting of glaucoma, parenteral treatment for cardiac arrhythmias and acute myocardial infarction, and other heart diseases where blockade of persistent β ₁ -adrenergic receptors is undesirable The method according to claim 1, wherein: When R is a 3 ′, 4′-dimethoxyphenyl group and R ¹ is a hydrogen atom, R ² is not a methyl group; furthermore, R is a 4′-methoxyphenoxy group and R ¹ is a hydrogen atom. The compound represented by the formula (Ia) as defined and defined in claim 1, wherein when it is an atom, the condition that R ² is not a methyl group or a cyclopropylmethyl group is satisfied. In racemic and optically active forms, R is 3 ′, 4′-dimethoxyphenyl group, R ¹ is hydrogen and R ² is selected from ethyl, propyl, isobutyl, and isopropyl; ,
R is a 4′-methoxyphenoxy group, R ¹ is hydrogen, and R ² is selected from an ethyl group, a propyl group, an isobutyl group, an isopropyl group; or
R is a 3 ′, 4′-dimethoxyphenyl group, R ¹ is a cyano group, and R ² is a cyclopropylmethyl group; or
R is a 4′-methoxyphenoxy group, R ¹ is a cyano group, and R ² is an isobutyl group; or
In the esterified form of claim 4, wherein R is a 3 ', 4'-dimethoxyphenyl group, R ¹ is bromine, and R ² is a methyl group. Physiologically acceptable and hydrolyzable derivatives having a hydroxyl group at the 2-position of the 3-aminopropoxy side chain, and their pharmaceutically acceptable acid addition salts.   1- (2-Cyano-4- (2- (2-methylpropoxy) ethoxy) phenoxy) -2-hydroxy-3- (2- (4-methoxyphenoxy) ethylamino) propane.   S (-)-1- (4- (2-ethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane.   1- (2-Cyano-4- (2-cyclopropylmethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane.   1- (4- (2-Ethoxyethoxy) phenoxy) -2-hydroxy-3- (2- (3,4-dimethoxyphenyl) ethylamino) propane.   10. A compound according to any one of claims 4 to 9, characterized in that it acts as a prodrug and, under physiological conditions, cleaves the hydroxyl group into the corresponding compound at the 2-position of the 3-aminopropoxy side chain. A physiologically acceptable and hydrolysable derivative. Ester (e.g. a compound of formula (Ia), R, is as described _{R 1,} and _{R 2} in claim 1, Re is an alkyl group having 1 to 12 carbon atoms, the carbon atoms 3-7 A cycloalkyl group, a phenyl group, a phenylalkyl group having 7 to 12 carbon atoms, or a phenyl group or a phenylalkyl group having 7 to 12 carbon atoms, which is 1 on the phenyl ring by an alkyl group having 1 to 4 carbon atoms. A substituted group, or a monocyclic or independently bisubstituted or independently trisubstituted group on the phenyl ring by a halogen having an atomic number of 9 to 35, or an alkoxyl group having 1 to 4 carbon atoms Which is monosubstituted or independently disubstituted or independently trisubstituted on the phenyl ring by the formula (E)

10. A physiologically acceptable and hydrolyzable derivative of a compound according to any one of claims 4 to 9, characterized in that it is a compound represented by A potent β ₁ -specific β comprising at least one compound of formula (Ia) according to claim 1 together with a pharmaceutically acceptable carrier or diluent and having a short period of action in the systemic circulation. A pharmaceutical compound characterized in that it is suitable for the treatment and / or prevention of conditions in which the receptor blocker is particularly effective.   14. A pharmaceutical compound according to claim 13, comprising at least one of the compounds according to claims 4-9.   The compound represented by the formula (Ia) is a compound selected from the compounds described in any one of claims 4 to 9, and is used for treatment and / or prevention according to claim 1 or 3. Method.   The compound of formula (Ia) according to claim 1 in the manufacture of a medicament, characterized in that the compound of formula (Ia) is a compound selected from the compounds described in claims 4 to 9. The use according to claim 2 of a compound represented by Wherein R ₁ and R ₂ are as defined in claim 4 and Rx is a group capable of reacting with a primary amine to give a 2-amino-1-hydroxyethyl group;

A corresponding compound represented by formula (III)

(Wherein R is as defined in claim 4) and, if necessary, 3-amino in the resulting compound represented by formula (Ia) The compound represented by the formula (Ia) as defined in claim 1, wherein the hydroxyl group at the 2-position of the propoxy group side chain is appropriately esterified, or The manufacturing method of the compound represented by the formula (E) of description. Rx is the formula

The method according to claim 17, wherein the group is a group or a derivative of the group. Rx is a group represented by the formula —CH (OH) —CH ₂ L (where L is chlorine, bromine, or a group of the formula Ry—SO ₂ —O— (where Ry is a phenyl group, a tolyl group or a lower group) The method according to claim 17, which is an alkyl group)). The compound represented by formula (II) is represented by formula (IV)

It is obtained by introducing —OCH ₂ —Rx group (wherein R ₁ and R ₂ are as defined in claim 4) through O-alkylation into the compound represented by 20. A method according to any of claims 17 to 19, wherein 21. The compound represented by formula (IV), wherein R ₁ is hydrogen, is obtained by selectively etherifying one of the hydroxyl groups of 1,4-dihydroxybenzene. The method described. The compound represented by the formula (IV) in which R ₁ is hydrogen is represented by the formula (V)

Claim in the corresponding compound represented (wherein, R ₂ is as defined in claim 17, Bz is the a protecting group), characterized in that it is obtained by deprotecting the under appropriate conditions 20. The method according to 20.   The compound represented by the formula (V) is obtained by appropriately etherifying an unprotected hydroxyl group in a derivative containing one protecting group of 1,4-dihydroxybenzene. 23. The method according to 22. Compound R ₁ is represented by the formula (IV) is a bromine, to claim 20 wherein R ₁ is characterized in that it is obtained by monobromination of the corresponding compounds of formula (IV) is hydrogen The method described. 21. The compound of formula (IV), wherein R ₁ is a cyano group, is obtained by converting the compound wherein R ₁ is bromine to the corresponding cyan compound, the method of.   A compound of formula (Ia), prepared and defined by any of claims 4 to 9, produced by a method according to any of claims 17 to 25.