JPS6183154A - Phenethanolamine derivative - Google Patents

Abstract

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

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to phenethanolamine derivatives with inotropic and vasodilatory activity, processes for their preparation, pharmaceutical compositions containing them and their use in medicaments, especially for the treatment of heart failure.

Heart failure is characterized by the inability of the heart to pump blood in sufficient quantities to meet the demands of the body. the result,
Sympathetic action on the heart and vasculature increases reflexively, resulting in a high t9 of cardiac inversion and contractile force, and increases vascular resistance. The increased resistance further impedes the already compromised heart and an interaction is established whereby the increased resistance (caused to maintain cerebral blood ai't) progressively worsens the symptoms.

Ya therapy for heart failure generally involves increasing the contractility of the heart or decreasing resistance in the peripheral vasculature.

To date, the most commonly used drugs for the treatment of heart failure are digitalis glycosides, which increase the force of contraction of the heart, ie, they improve the pumping action of the heart. However, these cardiotonic agents have the considerable disadvantage of toxicity. Dopamine and dobutamine (d
Other drugs such as obutamine), like imprenaline, adrenaline and noradrenaline, have a short duration of action and are inactive or produce undesirable side effects when administered orally. It has the following drawback.

More recently for reducing peripheral vascular resistance (i.e.
The use of vasodilators (to reduce the resistance of blood vessels to the pumping action of the heart) has been found to be of value in the treatment of heart failure.

However, a common side effect of vasodilators such as nitroprusid and hydralazine is that they cause undesirable side effects such as headache and reflex tachycardia.

Combinations of inotropes and vasodilators are of particular value in the treatment of heart failure. When administering such combinations of drugs, it is desirable that they have similar pharmacodynamic profiles such that both drugs are active over a similar period of time.

This is often very difficult to achieve in compounds with different structures.

Therefore, a low toxicity compound that increases cardiac contractility and decreases peripheral vascular resistance without significantly affecting heart rate and has a long duration of action would be of great value in the treatment of heart failure. Activity by oral administration is also desirable.

Phenethanolamines having a wide range of substituents on the phenyl ring and on the amine 7 group are known. A number of different activities have been attributed to such compounds, such as β-adrenoreceptor blockade, vasodilation, bronchodilation and local anesthetic activity.

Many of these drugs have been used to treat conditions such as hypertension, cardiac arrhythmias, cardiac dysfunction, angina, asthma, and glaucoma.

A small group of phenethanolamines with a specific combination of Kg1 substituents in the phenyl ring and on the amino group have now been found that increase cardiac contractility and decrease peripheral vascular resistance. This particular group of phenethanolamines has not previously been described in the literature and it has been found that these compounds are cardiotonic agents and act as vasodilators and can be used in the treatment of heart failure.

Therefore, the present invention provides compounds having the general formula (I) OH (wherein R represents a hydrogen atom or a linear 01-3 alkyl group and n is 1 or 2) and their physiologically acceptable The present invention provides acid addition salts, solvates and metabolically unstable esters that can be used.

If the compound according to the invention has a free carbon atom, i.e. -OH(
It will be appreciated that there are optically active sharp lower isomers of the 2fii class which have an OH)- group and therefore have the general formula (1). The present invention relates to the individual isomeric forms of the compound of formula (1) and to such mirrors ia! It is to be understood that all mixtures of tetramers are included.

Physiologically acceptable acid addition salts of compounds of formula (1) may be derived from inorganic or organic acids. Examples of such salts include hydrochloride, hydrobromide, sulfate, phosphate, benzoate, p
-) luenesulfonate, methanesulfo/acid, sulfaminate, ascorbate, tartrate, citrate, maleate, salicylate, hepmalate, succinate, lactate, glutarate, Included are glutaconate, acetate or tricarballylate. Preferred acid addition salts are hydrochloride, heptadium salt and phosphate.

Physiologically acceptable metabolically labile ester derivatives can be formed by acylation of any hydroxyl group of an acute compound having general formula (1).

Examples of such esters include lower alkanoic esters such as acetate or pivalate. In addition to the above-mentioned ester derivatives, the present invention includes within its scope compounds of general formula (1) in any other physiologically acceptable form, i.e., metabolically unstable esters as well as in vivo. Also included are physiologically acceptable compounds which are converted back into compounds of general formula (1). The present invention also includes within its scope solvates, particularly hydrates, of the compound of general formula (1).

Studies in animals have shown that compounds of general formula (1) increase myocardial contractility and reduce total peripheral resistance at low doses. The compounds according to the invention are effective stimulators of myocardial function and act as vasodilators.

Furthermore, the compounds according to the invention are similar to imprenaline and dobutamine in that they have a longer duration of action and, in addition, they are absorbed from the gastrointestinal tract, as evidenced by their activity following oral administration. It has particular advantages compared to known cardiotonic agents. It has been found that metal compounds having the general formula <L) selectively block vascular C1-adreno receptors and stimulate myocardial β1-adreno receptors. These compounds do not show any signs of toxicity at the highest doses tested.

In one aspect of the invention, compounds of formula (1), wherein R is a hydrogen atom, a methyl group or an ethyl group, and n is 1 or 2, and physiologically acceptable acid addition salts thereof , solvates and metabolically labile esters are provided.

A preferred group of compounds of formula (I) are those where n is 1.

Another preferred group of compounds of formula (1) are compounds in which R is a hydrogen atom.

Particularly preferred compounds are 2-[: 2-1:C2-3,
5-dihydroxyphenyl)-2-hydroxyethyl]
Amino]ethoxy]benzene-acetamide and its physiologically acceptable acid addition salts.

For example, the 7-malate salt or phosphate salt is conveniently in the form of a racemic mixture of its (6) and (8) isomers.

Compounds according to the invention may be used in the treatment of heart failure, cardiac shock or ischemic heart disease.

The invention therefore further provides compounds having the general formula (I) fc and their physiologically acceptable acid addition salts and metabolically unstable esters for use in the treatment or prevention of heart failure in human or animal patients. It is something to do.

The compounds having formula 0) and their physiologically acceptable acid addition salts and metabolically labile esters can be formulated for administration in any convenient manner, and therefore the invention also provides for human or animal administration. The scope also includes pharmaceutical compositions comprising at least one compound of formula (1) or a physiologically acceptable salt, solvate or metabolically unstable ester thereof adapted for use in medicine. It is included within. Such compositions may be provided for use in conventional manner in admixture with one or more physiologically acceptable carriers or excipients.

Therefore, the compounds according to the invention can be administered orally within one dose.

They may be formulated for parenteral or rectal administration, or in a form suitable for administration by inhalation or insufflation. Oral administration is preferred.

Tablets and capsules for oral administration may contain binders such as syrup, acacia, gelatin, nlubitol, tragacanth, starch mucilage or polyvinylpyrrolidone,
Fillers such as lactose, sugar, microcrystalline cellulose, cornstarch, calcium phosphate or norbitol, lubricants such as magnesium stearate, stearic acid.

It may contain conventional excipients such as Merck, polyethylene glycol or silica, disintegrants such as potato starch or sodium starch glycolate, or wetting agents such as diuryl sodium sulfate. The tablets may be coated by methods well known in the art. Oral liquid formulations include, for example:
It may be in the form of an aqueous or oily suspension, solution, emulsion, syrup or elixir, or it may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations contain B clouding agents such as nrubitol syrup, methylcellulose, glucose/
sugar syrup, gelatin, hydroxyethylcellulose, calhodic methylcellulose, aluminum stearate gel or hydrogenated edible fats, emulsifiers such as lecithin, nrubitan monooleate or gum arabic, non-aqueous vehicles (including edible oils). sell)
For example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol,
and customary additives such as preservatives such as methyl or propyl p-hydroxybenzoate or nruby/acids. The compounds or their salts or esters may also be formulated as herbal medicines containing conventional herbal bases such as cocoa butter or other glycerides.

For buccal administration, the compositions may take the form of tablets or abrasives formulated in conventional manner.

The compounds of formula (1) and their physiologically acceptable acid addition salts and metabolically labile esters can also be formulated for parenteral administration by continuous infusion. Formulations for injection may be presented in unit dosage form in ampoules or vials with an added preservative. The compositions can take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles;
It may also contain formulation agents such as suspending agents, stabilizing agents and/or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile, pyrogen-free water, before use.

For administration by inhalation, one metal compound according to the invention may be pressurized using a suitable propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichloronatodifluoroethane, carbon dioxide or other suitable gas. Conveniently, the package is delivered in the form of an aerosol spray offering, i.e., from a nebulizer.

In the case of pressurized aerosols, the dosage unit can be measured by providing a valve to inject a metered i''.

Alternatively, for administration by inhalation, the compounds according to the invention may take the form of a dry powder composition, eg a powder mixture of the compound and a suitable powder base such as lactose or starch. The powder composition may be presented in unit dosage form, for example in capsules or cartridges made of gelatin, or in blister packs from which the powder may be administered by means of an inhaler or insufflator.

When the composition consists of dosage units, each unit preferably contains 5
Ng to so xy, when the compound is administered orally it will conveniently contain 25 my to 40019 active compounds. The daily dose used for the treatment of adults is preferably between 5 and 32. Most preferably 6D in the range of 2519 to 11, these amounts may be administered 1 to 4 times a day depending on the route of administration and the condition of the patient.

Compounds of formula (1) and their physiologically acceptable acid addition salts and metabolically labile esters may be administered in combination with other therapeutic agents.

Compounds of the invention can be made by a number of methods described below.

According to one of the general methods (1), the general formula (1) t-
Yes (in the formula -NA is a group -NHR5, -NR5CH2CH2
X , -w''J is also a hydrogen atom or a protecting group and/or is an easily substituted atom or group) and the compound having the formula @) (CH2)nCONRRl ' [wherein R and n are K as defined
R1 is a hydrogen atom or a protective group, and when present, represents hydrogen, or Y represents a group CH2CH2X (wherein X is as defined above) when -NA is replaced by -NHR5] It can be produced by carrying out an alkylation reaction with a compound having the following formula, followed by removing any protecting groups, if present, as described below.

Examples of X include halogen atoms such as chlorine, bromine or iodine atoms, or methanesulfonyloxy
Hydrocarbylsulfonyloxy groups such as -toluenesulfonyloxy are included. When X is chlorine or bromine, the reaction may be accelerated by the addition of iodite such as sodium iodide.

In one particular embodiment of this method, general formula (1)
Compounds having formula GV) are prepared by alkylating an amine having R5 with an alkylating agent having formula (V), followed by removal of any protecting groups, if present, as described below. It can be done.

This reaction is preferably carried out in the presence of a base such as an alkali metal bicarbonate or carbonate such as sodium bicarbonate or potassium carbonate, or an amine such as diisopropylethylamine or silver oxide, and in solution from -20C to +1
It is carried out at any temperature in the range of 00°C. Suitable reaction solvents include ethers such as dioxane, acetonitrile.

Included are substituted amides such as N,N-dimethylformamide and hydrocarbons such as benzene.

In another embodiment of this method, the compound of 20) is prepared by alkylating a phenol having the formula (M) (CH2)nCONRR1 with an alkylating agent having the formula (~■), followed by It can be produced by removing any protecting groups if present.

Alternatively, the compound of formula (■) may be in the form of an aziridine or aziridinium salt, in which the - represents an anion such as a halide ion.

This reaction is preferably carried out in the presence of a base. Suitable bases include inorganic bases such as sodium hydroxide, sodium hydride, potassium carbonate or potassium tert-butoxide, organic bases such as diimpropylethylamine, and basic ion exchange resins such as Amberlite. Alternatively, the compound of formula (Vl) may be used in the form of a phenolate salt, such as a phenolate salt. The reaction is carried out in a medium such as water, acetonitrile, an alcohol such as methanol, or a ketone such as acetone or methylimbutylketone from -20'C to +150°C.
It is conveniently carried out at a temperature of preferably +20°C to +1000°C.

According to another general method (2), the metal compound of formula (1) has the formula (■) [wherein R2 and R5 are as defined in the general method (1) above]. R6 represents a group (wherein R4 and X are as defined in general method (1) above)]. General method (1)
(as defined in ) and subsequent removal of any protecting groups, if present, as described below.

This reaction is carried out in the presence or absence of a solvent (/cO~15
It may be carried out at 0°C, preferably 20'C to 100°C. Suitable solvents include alcohols such as methanol or ethanol, halogenated hydrocarbons such as hachloroform or dichloromethane, substituted amides such as N,N-dimethylformamide, esters such as diethyl ether or tetrahydrofuran, acetonitrile, esters such as ethyl acetate and Mixtures of water and such solvents may be carried out in the presence of inorganic bases such as sodium carbonate, potassium carbonate, sodium hydroxide or organic bases such as viridis. Alternatively, it is also possible to use an excess of amine having formula (■).

According to another general method (3), compounds of formula (1) can also be prepared by reductive alkylation. Therefore, formula (X)? R4 (wherein R7 is a group -COCHOt or -CHCH2NHR
and R2, R5, H4 and R5 are as defined in the above method (1), and a compound having a roun is represented by the formula (to) (CH2)ncONRR' (i) R4 [wherein Z is R7] -CHCH2NHR5 represents the group Cl1O or 2 represents the group CE (2NHR5'i and R1, R
and n is as defined in general method (1) above] in the presence of a reducing agent, followed by removal of any protecting groups, if present, as described below. I can do it.

In one particular embodiment of general method (3), a compound having the formula (XI) (wherein Z Fi is CHO) is converted into a compound having the formula (XI) (wherein Z Fi is CHO). The compound is reacted with the compound in the presence of a reducing agent.

Examples of suitable reducing agents include alkali metal or alkaline earth metal borohydrides, such as sodium borohydride or cyanosodium borohydride, using alcohols such as ethanol or protonol as solvents. cyanoborohydrides, or Raney nickel, using alcohols such as alcohols, ethers such as dioxane or esters such as ethyl acetate as reaction solvents;
Included is hydrogen in the presence of a catalyst such as platinum, platinum oxide, palladium or rhodium. The catalyst may be supported, for example, on charcoal or a homogeneous catalyst such as tristriphenylphosphine rhodium chloride may be used.

The reduction is conveniently carried out at any temperature between -20°C and +100°C,
Preferably, it can be carried out at 0°C to 50°C.

This reaction can proceed via an imine (where R, R1, R2, R5, R4 and n are as defined in general method (1) above) and this intermediate can be isolated. It may also be possible to do so. Reduction of the imine using the conditions described above, followed by removal of any protecting groups if necessary, provides a compound having general formula (1).

In another embodiment of the general method (3), the formula 00 (
A compound having the formula (M) in which R7 is C'0C) (O) is reacted with a compound having the formula (M) in which Z is CH2NHR5 in the presence of a reducing agent. Suitable reducing agents are those described above in the first embodiment of the reductive alkylation step.

This reaction can proceed via an imine of formula (Xli) in which R, R1, R2, R5 and n are as defined in general method (1) above and this intermediate can be simply It is possible and exciting. This compound can also be prepared by reduction using the reagents previously described in the first embodiment of the reductive alkylation step, followed by removal of any protecting groups if necessary.
1) can be produced.

According to another general method (4), the compound of formula (1) is prepared by formula It can be manufactured by returning a compound with a certain), or removing any protection group as described below. Reduction may be accomplished using an alkali metal or alkaline earth metal borohydride such as sodium borohydride or using hydrogen in the presence of a catalyst such as palladium or platinum, which may be supported on charcoal.

Stereoselective reduction of alpine-borane (9-(2,6
,6-trimethylbicyclo[3,1,1]hept-3-
This can be achieved using an optically active borane such as (I)-9-borabicyclo[3,3,1)nonane).

This reaction is conveniently carried out in an organic solvent such as an ether, such as tetrahydrofuran, or an alcohol, such as methanol or ethanol, at a temperature of, for example, 20°C to 80°C.

Another general method (according to the group 1
) and R8 is an acid anhydride formed with a carboxyl group or a salt or reactive derivative thereof, e.g. an acid halide such as an acid chloride, an acid chloride such as piparoyl chloride or a chloroformate ester. substances or esters such as 01-C5
represents an alkyl ester] is aminated.

Subsequently, if present, it may be prepared by removing any protecting groups as described below. Reactive derivatives can also be generated in situ by treating the acid or its salt with a condensing agent such as N,N'-dicyclohexylcarbodiimide or N,N'-carbonyldiimidazole.

This amination is generally accomplished using the amine RNH2, where R is as defined in Formula I above.

The reaction is conveniently carried out in an organic solvent such as an alcohol such as methanol or ethanol, an ether such as tetrahydrofuran, an amide such as N-dimethylformamide, or a halogenated hydrocarbon such as methylene chloride, optionally such as psisilica or rhodium trichloride. For example, 0 to 150C, preferably 50C in the presence of a catalyst.
It is carried out at a temperature of ~100°C.

When ammonia is used in the reaction (ie when R is hydrogen), it may be desirable to carry out the reaction at elevated pressure, preferably using water or an alcohol such as methanol or ethanol as solvent.

Formula (XI/) (wherein R8 is a carboxyl group or 7O
Compounds containing salts or esters such as 01-C5 alkyl esters are valuable intermediates and constitute another feature of the invention.

Interesting classes of compounds of formula (xV) are R2, R5, R4
and a compound in which R5 is a hydrogen atom.

Particularly interesting group a of compounds of formula (XV) is R2-RζR
4 and R5 are hydrogen atoms, and R8 is a carboxyl group or a 01-C5 alkyl ester thereof (for example, methyl or isopropyl ester).

Of particular interest are compounds having the formula (XV) in which R2, R5, R4 and R5 are hydrogen atoms and R8 represents a carboxyl group, more particularly those where n is 1.

According to another general method (6)K, the compound of the present invention in which R is hydrogen has the formula (XM) (wherein R2, R5, R4, R5 and n are
) can be prepared by hydrolyzing a compound with ) as defined in ) followed by removal of any protecting groups, if present, as described below. Hydrolysis is carried out at 0-100°C under acidic or basic conditions using aqueous acids such as polyphosphoric acid, hydrochloric acid or sulfuric acid, or using bases such as alkaline total hydroxides such as potassium hydroxide. sell. This reaction is conveniently carried out using alcohols such as tert-butanol or methanol,
The ketone may be carried out in a water-miscible solvent such as acetone or preferably using acetic acid in the presence of water.

Another general method (according to the force) is that compounds of formula (1) can be prepared using the formula or R4 and R5 together represent a protecting group, provided that at least one of R1, R2, R5, R4 and R5 represents a protecting group). They can be produced by deprotecting the compound.

If R1, R2, R5, R4 or R5 are protecting groups, this may be the case, for example, as described by Protective Groups in Organic Chemistry.
oops in Organic Chemistry
) JJ spring F 11 double 21-7 comey (J,F
, W., McOmie) IJA.

Published by Plenum Press (
(1973). Examples of suitable hydroxyl protecting groups represented by R2, R5 and R4 are alkyl groups such as tert-butyl or methoxymethyl, aralyl groups such as benzyl, diphenylene/L/meth# or triphenylmethyl, Heterocyclic groups such as tetrahydropyranyl and acyl groups such as acetyl. Examples of suitable amino protecting groups represented by R5 are aralkyl groups such as benzyl,
diphenylmethyl or triphenylmethyl and acyl groups such as dichloroacetyl.

Examples of suitable amide protecting groups R1 are tert-butoxycarbonyl and 2,2,2-trichloroethoxy7carbonyl groups.

Protecting groups R1, R2, R5, R4 and/or R5 may be removed using conventional techniques to produce compounds of formula (1). Thus, for example, an aralkyl group such as benzyl can be cleaved by hydrogenolysis in the presence of a noble metal catalyst (eg palladium on charcoal or palladium oxide).

Acyl groups such as dichloroacetyl can be removed by reduction with, for example, zinc and acetic acid. Alkyl or heterocyclic groups protecting hydroxy groups can be cleaved by hydrolysis under acidic conditions. Amide binding groups, such as tert-butoxycarbonyl groups, can be removed by acid hydrolysis.

In a particular embodiment of this method, the groups R4 and R5 are combined to form the formula (X), where R, R1, R2, R5 and n are as defined in general method (1) above and Yl can represent a protecting group as in compounds having a carbonyl or thiocarbonyl group or a divalent group formed from an aldehyde or a broad ketone such as acetaldehyde or acetone. ) can be prepared by hydrolysis under acidic or basic conditions using, for example, aqueous hydrochloric or sulfuric acid or aqueous sodium hydroxide and, if necessary, removing any other protecting groups present using the methods described above. It can be converted into a compound of formula (1).

Alternatively, the substituent on the amino group is of formula (XIX) (C
H2) as an internal protecting group for the hydroxyl group in the ethylene moiety as in the compound having nCONRRl where R, R1, R2, R5, R5 and n are as defined in general method (1) above. can also work. Compounds of formula (C) can be prepared by reduction using the reagents described in general method (3) above and, if necessary, removing any other protecting groups present using the methods described above. (1)
can be converted into a compound of

If it is desired to prepare an acid addition salt of a compound of formula (1), the product of any of the above-described processes can be converted into a salt by treating the resulting free base with a suitable acid in a conventional manner. can be converted.

Physiologically acceptable salts of compounds of general formula (I) can be prepared by combining compounds of general formula (1) in free base form with acetonitrile, acetone, chloroform, ethyl acetate or alcohols such as methanol, ethanol or isopropanol. It can be prepared by reacting K with a suitable acid in the presence of a suitable solvent.

Physiologically acceptable salts can also be prepared by conventional methods from other salts, including other physiologically acceptable salts, of compounds having general formula (I).

Optically active enantiomers of the compounds of the invention can be obtained from intermediates having the required chirality. Such enantiomers may also be obtained by resolving the corresponding racemates using conventional means such as optically active resolving acids. For example, "Stereochemistry of Carbon Compounds"
Mistry of Carbon Compounds
) J.E. L. Eliel
), published by McGraw-Hill (1962) and Tables of Resilping Agents.
ving Agents) J Nis H Willen (S.

H. Wilen).

Examples of optically active resolving acids that can be used to form salts with racemates include organic carboxylic acids and sulfonic acids, such as mineral acid, di-rutoluoyl, +1 sulfonic acid, and lactic acid. (6) and (S) forms are included. The resulting mixture of isomeric salts can be separated into diastereoisomers, for example by fractional crystallization, and if desired the required optically active isomer can be converted to the free base.

In another method, optically active enantiomers of the invention may be obtained by separation of optically active derivatives of the compounds. Therefore, 1, for example, 1 formula (in the compound of Shu, the group R1,
Derivatives of compounds of the invention may be prepared in which one of R2, R3, R4 and R5 represents a chiral protecting group. R2, R
5t or R4 may represent, for example, an optically active sugar residue such as a β-D-glucopyranosidyl group. An example of a suitable optically active amine protecting group R5 is the α-methylbenzyl group. After separating the enantiomers, these optically active retention groups can be removed using the method described in general method (7) above.

The methods just described for the preparation of the compounds of the invention can each be used as the last major step in the preparation sequence. It will be appreciated that the same general methods can be used to introduce the desired group at intermediate steps in the stepwise formation of the required compound, and that these general methods may be combined in various ways in such multi-step processes. .

A compound having the formula (■) (in which R6 represents a group) is obtained by hydrogenation, for example, from a compound having the formula (XX) (in which R2 and R5 are as defined above and Xl is a halogen atom). It may be prepared by treatment with sodium boron to form a halohydrin followed by treatment with a base such as potassium carbonate or sodium hydroxide. This reaction is conveniently carried out under
It is carried out in a solvent such as chloroformamide, an alcohol such as methanol or ethanol or water at a temperature from room temperature to reflux temperature.

A compound having the formula (■) (wherein R6 represents a group -CH(OR')CH2Xt, where R4 and or by treatment with a suitable reagent such as p-)luenesulfonic acid, followed by introduction of a protecting group if desired.

A compound of formula (X) (wherein R7 is C0CHO) is prepared from a compound of formula (XM) (wherein R2, R5 and Xl are as defined above) such as sodium methoxide in methanol. It can be prepared by reaction with an alkoxide followed by treatment with an acid such as hydrochloric acid.

The compound of formula (XX) is a known compound. 1 set (X
XI) O compound has the formula (XXII) (wherein R2 and R
5 is as defined above), for example, by halogenating the compound with halogen (e.g., halogen) or N-herosuccinimide (e.g., N-bouwamosuccinimide).

Compounds of formula (X) in which R7 is C0CHO can also be prepared directly from K by oxidation with a suitable oxidizing agent such as selenium dioxide from compounds of formula (XX[).

The compound of formula (2) can be produced by reacting a compound of formula <XX> with an amine of formula (■) using the reaction conditions described in general method (2) above.

Compounds of formula (formula) may be prepared using any of Methods 1 to 4 above.

Formula (the latest compound is the compound of formula (■)) INCH20
H2X (wherein R5 and It can be produced by reacting with an amine having the conditions described in General Method (1), where R5 is as defined above.

The compound of formula (IK) is produced from the compound of formula (V) by reacting it with an amine having 215NH4 (wherein R5 is υ and δ as defined above) according to the reaction conditions of general method (1). It can be done.

The compound of formula (V) is converted from the compound of formula (Vl) to compound XC
It can be produced by reacting with H20H2X (in the formula or as defined above).

2〇1) (In the formula, 2 is CHO) A compound having the phenolic metal formula HCOCH2X (in the formula
is as defined above) or, in particular, a protected derivative thereof, such as an acetal such as diethyl acetal.

A compound of formula (punishment) is a compound of formula (Xx) which is a compound of formula (XXI[
) in which R5 and n are as defined above, followed by treatment with a reducing agent such as sodium borohydride.

A compound having the formula (XV) (wherein R8 is a carboxyl group or a salt or ester thereof) is a compound having the formula 4 (%) (wherein R5, R8 and n are as defined above)
is prepared by reacting a compound of formula (XX) with a compound of formula (XX) followed by treatment with a reducing agent such as sodium borohydride, followed by removal of any protecting groups as described above, if necessary. sell.

Compounds having the formula (XV) in which R8 is a carboxyl group can be prepared by hydrolyzing the corresponding ester and subsequently removing any protecting groups, if present, as described below. can be manufactured. Hydrolysis may be carried out using aqueous acids such as polyphosphoric acid, hydrochloric acid or sulfuric acid, or bases such as alkali metal hydroxides such as sodium hydroxide under acidic or basic conditions at 0-100C. This reaction may conveniently be carried out in a water-miscible solvent such as an alcohol such as methanol.

Compounds of formula (XV) in which R8 is a reactive derivative of a carboxylic acid, such as an acid chloride or an acid anhydride, may be prepared in a conventional manner, for example by forming the acid chloride or acid anhydride. .

A compound having the formula (XV) (wherein R8 is a carboxyl group or a salt or ester thereof and 69 and n is 2) can be prepared by subjecting the corresponding α,β-ethylene carboxylic acid or salt or ester thereof to the appropriate hydrogenation process described above. It can be produced by reduction using a method. The unsaturated precursors may be prepared in a similar manner to the methods described herein for the preparation of the compounds of the invention, e.g. by alkylation as described in General Method (1) and illustrated in the Examples. .

Compounds having the formula (XXIl[) and (XXIV) are of the formula (short (CH2)nR', where n is as defined above and R9 is the group c=
aN, C02H or R8 represents a carboxylic acid ester as defined above) tN is a compound of formula XC
H2CH2Br (in the formula, X is as defined above)
and subsequent amination with a compound having t-R5NH,2 (wherein R5 is 9 as defined above).

The compound of the formula (Shu) is the formula (shu) (where R, R1, R2, R5
and n are as defined in general method (1) above, and R4 and R5 are water atoms. It can be produced by reacting with imidazole.

A compound having the formula (XDO) is a compound having the formula (IV) and a compound having the formula (
M) (in the formula 2 represents a group CHO'i).

The invention is illustrated by the following examples. Temperature depends on C. "Dried" refers to drying with magnesium sulfate unless otherwise specified. Thin layer chronidography (tlc)
) was carried out on silica plates. FCC-fludge column chromatography is performed using silica (Merck).
ck) 9385).

The following abbreviations are used:

EA-acetic acid x te/l/, ER-diethyl ether, PE-petroleum ether, ME-methanol, MC
-methylene chloride, T-toluene, IT-ethanol.

A-0,88 ammonia solution, H-hexane, DMF
-dimethylformamide, THF'-tetrahydro7
Ran', q-BBN-9-borabicyclo (3:3:1)
nonane, Pd-0-palladium on carbon, pao-c
- Palladium oxide on carbon.

Intermediate 1 Methyl 2-(2-bromoethoxy)benzene acetate Methyl 2- and droxybenzene acetate in dry ME (2 L) c50.09), anhydrous potassium carbonate (84.0
jl) and dibromoethane (500 ml of mixture to 1
It was refluxed for 11 hours. The resulting mixture was evaporated and the residue was dissolved in chloroform (500 mQ).
of water (2X 25 Qml) and brine (250
The mixture was washed with filtrate, dried (over Na2SO4) and evaporated. Tf using the resulting oil (829) as an eluent,
The title compound was purified by FCO as a yellow oil.
32.59).

Elemental analysis (as C11H15Br05) C-N% Theoretical value: 48.4 4.8 Actual value: 48.5 4.8 Intermediate 2 Methyl 2-(2-((phenylmethyl)amino)ethoxy]benzene acetate dry nitrile Intermediate 1 (159) in (40Qml),
A mixture of benzylamine (5B, 7jl) and sodium iodide (16,4jl) was heated under reflux for 4 hours.

The inorganic solids were removed and the F solution was evaporated. A solution of the residue in EA (200 ml) was dissolved in water (5Q+nl).
and brine (50ml).

It dried and evaporated. Using the residue as an eluent, K
The title compound was obtained as an orange oil (<15.29).

Elemental analysis (as c18H2tNo5) Cchi N%
N% Theoretical value 772.2 7.1 4.7 Actual value near 2.
4 7.2 4.8 Intermediate 3 2-(2-Bromoethoxy)kbenzeneacetamide 2-Hydroxybenzeneacetamide (1,065')-, potassium carbonate (t) in dosifuromoethane (50 mA)
A solution of tris(2-(2-methoxy)ethyl)amine (Q, 11jl) was refluxed for 21 hours and then evaporated. The resulting solid was
m), washed with water, dried and evaporated. The residue was subjected to FC using ER and then KA as eluent.
The title compound was purified by C as a white solid (0.9jl).
obtained as. Melting point 84-86°C.

Intermediate 4 A solution of intermediate 2 (5,0ji) in 2-(2-((phenylmethyl)7mi/)tech)oxy]benzeneacetamide)IE (111 male) was added to liquid ammonia (151
111) at 75° for 45 hours. Evaporate the solvent.

The residue was purified by ME by FCC using KA-ME (9:1) as eluent to give the title compound as an off-white solid (<2.609). Melting point: 89-90°C.

Intermediate 4 (alternative method) Intermediate 3 <s2p> in acetonitrile, benzylamine (218 min and sodium iodide (60 p)
) solution was refluxed for 18 hours, filtered and evaporated.

The residue was dissolved in KA (300m).

Wash with sodium carbonate water bath solution (2M) and water.

Dry and evaporate. The resulting brown oil was purified 92 times by FCC using ER then KA as eluent to give the title compound as a white solid (129). Melting point: 85-87°C.

Intermediate 5 Methyl 2- (2-CC2-C5,5-bis(phenylmethoxy)phenyl]-2-hydroxyethyl](phenylmethyl)amine]ethoxy]benzene acetate 1- (3, 5-bis(
Phenylmethoxy)phenyl)-2-bromoethanone (
1) Dry the solution of (1,379) in DMF (25rnQ
) was added over 5 minutes to a stirred solution of intermediate 2 (1, Gjl) and diimpropylethylamine (0,4322). The mixture was stirred at room temperature under nitrogen for 6.5 hours and then evaporated. Anhydrous ET of residue (130rni)
Sodium borohydride (0,59) in medium fc & chlorine solution
was added for 10 minutes. The mixture was stirred at room temperature for 18 hours and then concentrated in vacuo.

Add water (5 ml and 100 mg) to this,
The solution was evaporated. A solution of the residue in EiA (50ml) was washed with water (25ml) and brine (25ml), dried and evaporated to give the title compound as a yellow oil (2,139). .c(JnA)
Rfo, 7゜('>S, N, Mr. Quegsy and Tori,
, R. Will Sat. [Auat, J., Ohem, 52]
.

1317 (1979).

Intermediate 6 2-(2-Amine Ethoxine Benzene Acetamide Anhydrous xT (Intermediate 4C2,51 in 25ml) was hydrogenated over 10T of Pd0-C until absorption ceased.

The catalyst was removed by t-p filtration, and the P solution was evaporated under reduced pressure to obtain a pale yellow oil, which was dichloromethane-EiT-A.
Purification by FCC using 100:8:1 as eluent gave the title compound as a colorless oil (1,3F) which crystallized on standing. Melting point 92-94°C.

Intermediate 7 α-(ahatumethyl) -3,5-bis(phenylmethoxy)benzene 3,5-bis(
Phenylmethoxy)benzaldehyde (31,8jl)
.

A mixture of trimethylsilyl cyanide C9,921)S, - and zinc iodide (0,4jl) was stirred under nitrogen for 4 hours. The resulting solution was added to an ice-cold solution of lithium aluminum hydride (7,6P) in dry THF (500 μl) and the mixture was stirred at room temperature for 18 hours. The reaction mixture was cooled in a water bath.

Add water (7,6mff1) to this and 2N sodium hydroxide solution (15,2rnIt). and water (22.81g
) was added dropwise.

The inorganic solids were removed and the P solution was evaporated to obtain a colorless gummy material, which was then processed by FCC using EA-ME 7:1 as an eluent to obtain the title compound as a colorless solid. thing(
21.8flf). Melting point 89-90 °C0 Intermediate 8 2-(2-7' lomoethoxy)henzeneacetonitrile dibromoethane (2-hydroxybenzeneacetonitrile (1,6p) in 15,5ml and potassium carbonate <
The mixture of 5.39) was heated at 120°C for 2 days. The solvent was evaporated, EA was added to the residue, the inorganic solids were removed and F tracheal evaporated to give a brown gummy material. This was purified by FCC using ER-PFi (1:1) as eluent to give the title compound as an orange oil (2.2jl). T, 1. c, (Ki-PI3:1)RfO,4
゜Intermediate 9 2-(2-((phenylmethoxyamino)ethoxy)
Intermediate 8 (in benzene acetonitrile acetonitrile CI Q 01111)
A mixture of 5, Op), benzylamine (11F), potassium carbonate (5,81) and sodium iodide <4.79) was heated under reflux for 3 hours. Removes inorganic solids.

The P solution was evaporated. F using the residue as eluent
Purification by OE gave the title compound as a yellow oil (4,89
) was obtained. 'I', Lc, (臥)Rf O, 25゜Intermediate 10 2- (2-([2-[3,5-bis(phenylmethoxy)phenylcou-2-hydroxymethyl]amine]ethoxy]benzeneacetonitrile 1-(5,5-bis(
phenylmethquine) phenyl)-2-bromoethanone C
5,969), intermediate 9 (4,0 Clp and 2,61 ml of diimpropylethylamine) at room temperature.
．． Stirred for 5 hours then evaporated. The remaining gummy material was dissolved in ME (30 tat) and treated with sodium borohydride (1,9P) for 16 hours at room temperature. The reaction mixture was evaporated, treated with Mz (50 m), evaporated again and treated with chloroform (2 x 100 ml) and water (10
0 ml). The organic phase was dried and evaporated to give a yellow gum.

This was purified by FCC using T-ER (19:1) as an eluent to obtain the title compound (5,60).
) was obtained as a yellow gum-like substance. T, 1. c, (T-I
R19:1) RfO, 24° Intermediate 11 A bath of 1-methylethyl 2-hydroxybenzene acetate in propanol (20 mA) (C5,049) was heated with sulfuric acid (18 M, The mixture was treated with 0.1 Amogen, refluxed for 3 hours and evaporated. The residue was partitioned between EA (50 mffi) and aqueous sodium bicarbonate (IM, 2 x 20 mg). The organic phase was dried and evaporated. The title compound 1
．． 45jl) was obtained as a yellow oil which later solidified.

T, 1. c, (ER)Ry 0.52゜Intermediate 12 1-methylethyl 2-(2-'lomoetquin)benzene acetate intermediate 11 (1,94 non, potassium carbonate (2,831
).

A mixture consisting of dibu p moethane (20111Q) and Impropatool (50 mffi) was refluxed for 16 hours.

F and evaporation to give a pale yellow oil (<5.0 DI). T, 1. c, (PJI knee 20%J!:R)Rf
o, 26゜ Intermediate 13 1-Methyl ether 2-(2-((phenylmethyl)amine) ethoxy) benzene acetate acetonitrile (1
b) Nakatsukudai 12 (802), indylamine (30
A mixture of 0111ffi), potassium carbonate (74jl) and sodium iodide (80F) was heated under reflux for 20 hours. The inorganic solids were removed and the F solution was evaporated. The residue was purified by YCA using ER as eluent to obtain the title compound (70F) as a pale yellow oil.
, 1. c, (ball) Rfα4゜intermediate 14 1-methylethyl 2- C2-C(2-(3,5-bis(phenylmethoxy)phenyl)-2-hydroxyethyl](phenylmethyl)amino]ethoxy]benzene acetate A solution of 1-(5,5-bis(phenylmethoxyphenyl)-2-bromoethanone C5,Open) in dry DMF (-15) was prepared as intermediate 1 in DMF (50).
3(4,0jl)′J? and diimpropylethylamine (4.5ml), and the solution was stirred at room temperature for 30 minutes.
Stir for hours. The solvent t - evaporated and the remaining "m" was ET (8
0 Makoto) and then redissolved in sodium borohydride (2,
5). The mixture was stirred for 2 hours, water (201+11) was added to it, and the mixture was further stirred for 0.5 hours.
Stir for hours. ETt-evaporated, the residue was acidified with 2N hydrochloric acid and the mixed vIJ was heated on a steam bath for 20 minutes. The solution was then neutralized with 8 volumes of sodium bicarbonate and extracted three times (5 x 80 mQ) with 80 mJ of KA. The combined extracts were washed with brine (50aui), dried and evaporated.

ER-PjC (1:1) as residue t-1 eluent
The title compound (5,6F) was purified by pca using
was obtained as a pale yellow oil. 'I',”L,O,CHR
-PHj: 1-Rf O, 35° intermediate 15 2- (2-((2-(s, s-bis(phenylmet1'
Intermediate 14 (56,1jl) in ME (400 kg)
and a solution of 2N sodium hydroxide (223ml)
Heated under reflux for 6 hours. 1 and the aqueous phase was acidified to pH 6 with glacial acetic acid (20 mg) and 100 ml of
Extracted three times with each EA. The combined extracts were washed with water and brine, dried and evaporated and the fc0 residue was purified with pccKj using KA-PK (7:3) as eluent.
D-purification afforded the title compound *(32,8jl) as a white 7-ohm substance. T, 1. c, CIA-PK 7
:5) RfO, 25° intermediate 16 2- (2-((2-(5,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetic acid xT (50 lines) and Mx (50mM) Intermediate 15 (2,OF) oge, in the mixed hit of 10%P
Hydrogenated over dC(0,2p). When the absorption has stopped, remove the catalyst and evaporate the F solution to obtain the title compound (0,9
69) was obtained as a colorless solid. Melting point: 225°C. T, 1
．． C, (dichloromethane-ffiT-water monoacetic acid.

5:5:1 21) RfO, 74゜Elemental analysis (016H21kK) as 6.H2O) 0%
N% N% Theoretical value: 60.7 6.2 3.9 Actual value: 60.
5 6.5 3.8 Example 1 (1) 2- (2-((2-(3,5-bis(phenylmethoxy)phenylcou-2-hydroxyethyl)
phenylmethyl)amino]ethoxy]inzeneacetamide MJ! l! (25ml) and liquid ammonia (25mli)
A solution of intermediate 5 (2,02F) in mffi) was heated in an autoclave at 65-75° for 65 hours. The solvent was evaporated and the residue was used as an eluent.
The title compound rW (1,23jl) was purified by FOE using 2(3:2) t- as an off-white solid. Melting point 123-125°C.

(iil 2- (2-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl)amine]ethoxy]benzeneacetamide hydrochloride formed from step (1) in anhydrous 1!iT (150 ml) * 1.08jl) was hydrogenated on Pa-c (550■).The catalyst was removed and the P solution was evaporated.The residue was used as an eluent to hydrogenate T-ET-A (78:20:2
and 6B:50:2). Treatment of the product with ethereal hydrogen chloride afforded the title compound (190'll9) as a pure yellow hygroscopic solid.

Melting point 86-88°C (decomposition).

Elemental analysis (016H22N205 ・HOIl O,3
3CH5CO2C2H50,5H20) 0% N% N% Theoretical value: 55.1 +5.4 6.65 Actual value:
55.2 6.6 6.5τ (D4 methanol-k)
2.66=2.77(2H,m), 2.92-3
．． 06 (2H.

m), 3.60 (2H, d), &77 (IH, t)
, 5.04 (IH, m), 5.60 (2H, t),
6.38 (2H, s), 6.44 (2H, t),
6.60-6.90 (2H.

noon).

Example 2 (i) 2-[2-((2-(3,5-bis(7enylmethoxy)phenylcou-2-hydroxyethyl))
phenylmethyl)amine]ethoxy]benzeneacetamide 1-(5,5-
A solution of bis(phenylmethoxy)phenylcou-2-bromoethanone (7,239) was added to a solution of intermediate 4 (5,0jl) and diimpropylethylamine (2,27F) in dry DMF (80ml) and its The mixture was stirred at room temperature for 23 hours. Evaporate the solvent.

A solution of the residue in anhydrous ET (400 jlt) was treated with sodium borohydride (2,64 jl) and the mixture was stirred at room temperature for 18 hours. Add water (4
Qml) and ME (20Qml) were added and the mixture was concentrated. Add water to this and make 1oomt of the suspension.
I extracted it three times. The combined extract was mixed with water (50j
Washed with water and brine (50m), dried and evaporated. The residue was crystallized from EA-PK to give the title compound (8,3751) as a white solid. Melting point 121
~123℃.

(il 2- (2-(C2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]penseneacetamidohemifumarate anhydrous gT (850jlt) product from step (1) (8,11') was hydrogenated over Pd-C(2,OP). The catalyst was removed and the P-oxide was evaporated. The residue C4,0
9) was dissolved in anhydrous gT (30mffi) and to this was added a solution of the 7-malic acid C670M9) in anhydrous ET (30jl). The precipitated solid was removed and crystallized from ET and then again from MF, /KA to give an off-white solid (2,39F). Melting point 110-11
At 5°C (decomposition), a portion <19% was slurried in anhydrous ET, stripped of P and dried under vacuum at 70°C to give the title compound (
65011P) was obtained as an off-white solid.

Melting point 212-213°C (decomposed).

Elemental analysis (as (01aHz2N205)2C4H404) Cchi H N% Theoretical value: 59.4 6CI 6.9 Actual measurement:
59.1 5.9 6.6 Example 6 2-(2-C(2-(3,5-bis(phenylmeth)
c)phenyl)-2-hydroxyethyl](phenylmethyl)amino]ethoxy]benzeneacetamide Intermediate 10(
0.1p) is dissolved with stirring into pulverized potassium hydroxide (0.1p).
The mixture was stirred at reflux for 50 minutes. This mixture was dissolved in saturated sodium chloride (15mM).
The mixture was diluted with KA and extracted 3 times with 5 strips of KA. The combined extracts were dried and evaporated under reduced pressure to give a pale yellow gum, which was used as eluent 4j T-ET-A 79:
Purification by FCC using 19:2 gave a pale yellow glass, which was ground under ER to give the title compound (201q).
was obtained as a white powder. Melting point: 120-121°C. T, 1
．． c, (T-胛-A79:20:1NRfO,5゜Example 4 R(→2- (2-((2-(3,5-dihydroxy
Enylune-2-hydroxyethyl amine ethoxy
Kanzeneacetamide hemi-7 malate fi) RHα
-(bromomethyl)-1-(5,5-bis(7enylmethoxy)phenyl)-2-7'lomoethanone (8
Freshly prepared alpine borane (9-BBN (4,99) and (-1-
)-α-pinene (from 7jl). The solution was stirred overnight and then kept at room temperature over the weekend. To this was added acetaldehyde (4 mffi) and the solvent was evaporated. Dissolve the residue in FR (50!IQ),
To this was added ethanolamine (2,6111 g).

The mixture was stirred at 0° C. for 15 minutes and the solids were removed. Solution F was washed with brine, dried and evaporated to give a pale yellow gum C109). This was purified by FCC using T as the eluent, crystallized from ER, and recrystallized from ER-H to obtain the title compound* (3,4p).
was obtained as colorless needle-like crystals. Melting point: 81°C.

(it) R (→ [3,5-bis(phenylmethoxy)phenylmethoxy2 product from step (1) <5.59), potassium carbonate (
1,5jl), MJlu (40g) and water (30g)
The mixture was stirred and refluxed for 1 hour. ME was evaporated, leaving t-40 ml of residue! Extracted twice with KR. The extracts were washed with brine, dried and evaporated to give the title compound C2,61) as a colorless gum.

(+ii) Step ( 11))
,54) and intermediate 4C1,89) HK were refluxed overnight.

Another amount of intermediate 4 (0.4jl) was added and the solution was refluxed for 24 hours. The solvent was removed and the residue was triturated with a mixture of ER and KA to give a white solid (1,9jl)
I got it. Part F was evaporated and the residue was purified by FCC using ER as eluent to give a colorless gum at- which was triturated with ER to give a white solid (t09). Each of the above 7 lactations was prepared by the same means in separate experiments.
This was combined with 0g9 of a white solid and recrystallized from t-1ulR to give 1.0J1)t-colorless crystals. Melting point 94
~95℃.

OVI R(-)2- (2--((2-(3,5-
(dihydroxyphenyl)-2-hydroxyethyl)7
10% Pd-C! (
0,39). Removal of the catalyst and solvent gave the free base of the title compound (1,69) as a white solid. The free base was dissolved in hot ET (20 mt) and 7 maric acid (2701R9) in hot ET (10 mt).
treated with a solution of The oil was completely separated on cooling and the mixture was evaporated to dryness to give a white glass.

This was dissolved in ME (15 ml) and inoculated into this solution to obtain the title compound <1.3j> as colorless microcrystals.

Melting point: 199-200°C.

Elemental analysis ([018H22N205] as 2C4H4o4) Cchi Hchi ■ Theoretical value: 59.4 6.0 6.9 Actual value: 59.
5 6.0 6.8 Example 5 S(+12-(2-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy)
Benzeneacetamide (DS(+α-(bromomethyl)-3,5-bis(phenylmethoxine) Benzene-methanol 1- in dry tetrahydrofuran (15 ml) under nitrogen
(3,5-his(phenylmethoxy)phenylcou2-
A solution of bromoethanone (20jI from freshly prepared alpine-borane (9-BBN (12,25j1) and H-α-pinene (17,5)) was added to 65
Heated at ℃ for 5 hours. The mixture was stirred under nitrogen at 60° overnight and the solution was cooled in an ice-bath.

To this was added acetaldehyde (101111) and the solution was stirred at 20°C for O,S hours and evaporated in vacuo. The residue was dissolved in solution (125!d) and ethanolamine (&5!) was added. This mixture was heated to 0
．． The mixture was stirred for 25 hours, and the resulting solids were filtered off. The solution was washed with brine (100 Ed), dried and evaporated to give a pale yellow semi-solid. This was purified by FCC using T as eluent and recrystallized twice from PR to give the title compound (1,77JI) as white fluffy crystals. Melting point 78-80°C.

(4i) S(±[315-bis(phenylmethoxy)phenylmethoxylane MJC (21 mQ) and water (16 mQ) in raw rfcm <1.7 yp> and potassium carbonate (805 ml) from step (1). The mixture was heated to reflux with stirring for 1 hour.The mixture was allowed to cool and the solvent was evaporated.

The residue was extracted in the ER with three 25 ml portions. The combined extracts were dried and evaporated to give the title compound (1,
39F) was obtained as a clear oil.

Elemental analysis (as 022H2oOs) 0% H% Theoretical value near 9.49 6.06 Actual value near 9.56 6.26 (iio Sf+)2- (2-((2-(3,5-
Bis(phenylmethoxy)phenyl)-2-hydroxyethyl](phenylmethyl)amino]ethoxy]benzeneacetamide ME(!10111) Product from step (11) during reaction (
A mixture of intermediate 4 (1,32jl) and intermediate 4 (1,16p) was heated to reflux under nitrogen for 24 hours. The solution was condensed in vacuo and the residue was purified by FCC using ERt- as eluent to give the title compound (1,2jl)- as a white crystalline solid. Melting point 96-96.5°C.

(iV) 5(-1-)2-1"2-((2-(3,
5-dihydroxyphenyl)-2-hydroxyethyl]
□Amine]Ethoxy]BenzeneacetamideProduct from step (iii) in ethanol (50ml)
A solution of t-10% Pd-0 catalyst (1,29) was hydrogenated at 120 m (169 m), at which hydrogen absorption stops.

The perfuming medium was removed by filtration through hydrochloride and evaporated in vacuo to give a pale yellow oil which was triturated under ER (20 mm) to give the title compound (580 mm).
was obtained as a white crystalline solid.

Melting point 154-155°C.

Elemental analysis (G1aH22N20s・0.2KtOH as CLsH% Nch Theoretical value: 62.16 6.53 7.88 Actual value: 61
．． 84 6.33 7.88 Example 6 2- (2-((2-(3,5-dihydroxy7enyl)-2-hydroxyethyl)amine]ethoxy]benzeneacetamide gT (15oILt) C2-([2-(3,
A suspension of 5-his(phenylmethoxy)phenyl)-2-hydroxyethyl)(phenylmethyl)amine]ethoxy]benzeneacetamide (18,2II) was added to 101
Hydrogenation was carried out over Pd-C (1,8F). Once hydrogen uptake had ceased, the mixture was diluted with a pot to redissolve the precipitated product and the resulting mixture was filtered. Upon standing, a colorless solid formed from the p-liquid. The solid was removed and dried to give the title compound (4,2F) as a crystalline solid, melting point 106-107°C.

Elemental analysis (as Cl8H22N205.C2H50H) Cchi N% N% Theoretical value, 5t2 72 7. f actual value 61
．． 5 7.5 7.0 Example 7 2- (2-CC2-C3,5-bis(phenylmethoxy)phenyl]-2-hydroxyethyl]amino]ethoxy]benzeneacetamide under nitrogen, dry edge at 90°) Intermediate 7 (5,241i and N,N-diisopropylethylamine ('5.88Ii) in (40m)
) in dry DMF (10+j) to a stirred solution of intermediate 5
A solution of (2,581I) was added over 10 minutes. Stirring was continued for 1 hour, after which the solution was evaporated and purified by FCC' using ■-ET-A (150:8:1) as eluent to give the title compound (3,3i) as a white solid. Obtained. Melting point: 105.5-107°C.

Elemental analysis (as C32H54N205.0.5H20) Cchi Hchi Nchi Theoretical value 72.2 6.6 5.3 Actual value 7
t7 6.3 5.1 Example 8 2- C2-CC2-Cs, s-bis(phenylmethoxy)phenyl]-2-hydroxyethyl]amino]ethoxy]benzeneacetamide ET (15M) intermediate 6(0 , 9511) (solution D in 5.5 m in ET (15 m).
Gradually add to the solution of 5-C bis(phenylmethoxy)]-]α-oxobenzeneacetaldehyde 17F),
The mixture was heated at reflux for 2 hours. Sodium borohydride (a, s71) was added to the cooled solution, and the mixture was stirred for 18 hours. To this was added ME (25M) and the solution was warmed to 40°C for 10 minutes.

The solvent was evaporated and the residue was eluted with MC-ET-A (
200:8:1) using silica gel (Merck 7747
) to give the title compound (IC1+y, ) identical to the product of Example 7.

Example 9 (i) 2- (2-((2-(5,5-bis(7enylmethoxy)phenyl)-2-hydroxyethyl)
Phenylmethyl)amino]ethoxy]-N-ethylbenzeneacetamide Intermediate 1 in dry THF (50 iu)
Pivaloyl chloride (Q, 5'l) was added to a solution of 5 and triethylamine (4,261) and then heated at 0° under nitrogen.
It was stirred with 5 minute diameter ethylamine hydrochloride (0,6+5.
! i+) was added, the reaction vessel was sealed and the solution was stirred at room temperature for 16 hours. The solution was evaporated and partitioned between water (80M) and EA (3xaom). The organic portions were combined, dried and evaporated to give an orange oil. F using ER as eluent
Purification was carried out by CC to obtain the title compound (0,581i'
) was obtained as a colorless gummy substance. T,j,c,(RA)
Rf1153゜(i+) 2- (2-((2-(
The product from step (1) (o,
Dry a solution of 101Pd-C catalyst (0,101
51) Hydrogenation was continued until hydrogen absorption stopped (650-).

The catalyst was removed by filtration through via 0 and washed with warm MIIC (50M). Add P solution to ME (5
Treatment with a solution of 7 malic acid (1105II) in au) and evaporation gave a colorless gum. The residue was triturated under ER (20 m) for 4 hours and removed to give the title compound (ct3oII) as a cream colored solid. (
MC-FiT-A 25:8:1) Rf=0.31
゜Elemental analysis ((C20H26N205)2C4H404-
0-BH20" 18C2H50H) 0% N% N% Theoretical value 59.4 7.2 5.8 Actual value 5
9.4 49 5.5 Example 10 2-C2-((2-(3,5-dihydroxy7enyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetamide phphosphate hand hydrate 2 - (2-(C2-
(5,5-dihydroxy7enyl)-2-hydroxyethyl]7mino]ethoxy]benzeneacetamide hemi 7
Malate salts (1&IF) were suspended in water (40aJ) and
A solution was obtained by treatment with 5tisicic acid (2.64 vLt) and warming to 60°. The solution was stirred and cooled to 0.degree. C. for 1 hour. The 7-maric acid was removed and the F solution was evaporated in vacuo to a total volume of 30 rILt. After warming to dissolve the solid, ET (80 nl) was added and the solution was stirred and cooled to 0°C. Remove the crystalline solids, E
The title compound (1&8N') was obtained by washing with T (20Kt) and vacuum drying at 50°. Melting point 168-140
℃.

Elemental analysis (C20H26N205.H3PO4,0,5
H20÷0.402H50H) 0% N% N% P% Theoretical value 4&1 6.1 5.9 6.5 Actual value 47.8 6.15 5,85 6.4 Example 11 (1) 2-C2 -C3-C3,5-bis(phenylmethoxy)7enyl]-2-oquino6-oxazolidinyl]ethoxy]benzeneacetamide 2-C2-((( To a stirred solution of 2-Cs,s-bis(phenylmethoxy)phenylcou2-hydroxyethyl[amine]ethoxy]benzeneacetamide (1,0 g) was added 1,1'-carbonyldiimidazole (1,1'-carbonyldiimidazole (51 Lt) in dry THF' A solution of α68I) was added. Stirring was continued for 18 hours and the solution was evaporated. The residue was dissolved in g people (5 om) and added twice with 2 SjtJ each in water (2
X25μ) and brine (25M), dried and evaporated to give a white solid. MC-BT-A was used as eluent first (150:8:1) and then (
Purification by FCC using a ratio of 1oo:a:i) afforded the title compound (ct, sog) as a white solid.

Melting point 145-146℃0 (ii) 2-C2-(C2-(3,5-bis(7
enylmethoxy)phenyl 2-hydroxyethyl]
amine]ethoxy]benzeneacetamide 2N sodium hydroxide solution (0.8M) and ET (t
Product of step (1) (401 g) in 61Lt)
The suspension was stirred at 60°C for 8 hours. After ET was evaporated, the remaining solution was extracted with EA in six 5 mL portions.

The organic portions were combined, dried and evaporated to give a white solid. MC-ET-A (1o a : s : j
) as eluent to give the title compound (5Q) as a white solid, which was identical to the product of Example 7.

Example 12 2-(2-((2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy)-U-
Propylbenzeneacetamide (1) 2- (2-
((2-(3,5-bis(phenylmethoxy)phenyl-2-hydroxyethyl)(phenylmethyl)amine)ethoxy-N-propylbenzeneacetamide DMF (40g) and 11,1-carbonyldiimidazole A solution of intermediate 15 (50I) in (0,871) was stirred at room temperature under nitrogen for 25 hours.

Add n-propylamine (0,31611) to this,
The reaction mixture was stirred at room temperature for 21 hours. The solution was evaporated and the residue dissolved in EACpK. This solution is 8%
Washed with sodium bicarbonate, water and brine, dried and evaporated. EA-PE 1 using the residue as eluent
: 1 was purified by FCC to obtain the title compound (in
) was obtained as a colorless oil. T, J, c, (FA-P
E) 1: I Rfα25゜(ii) 2゜-C
2-CC2-(5,5-dihydroxyphenyl)-2-
Product (1) from step (1) in hydroxyethyl[amine]ethoxy)-N-propylbenzeneacetamide anhydrous ET (5017)
A solution of 241) was hydrogenated over 10% Pd-C (400 g). The ethanolic F solution was evaporated by passing the catalyst through I-IFLO and leaving the door. EA with residue as eluent
The title compound (187#) was prepared using a short path column Chromadog 2F on silica gel (Merck 7747) using isopropyl 7:3.
Obtained as an ohmic substance. T, 1. c, (EA-isopropanol 7:3) R1-; α55°δ (D4 methanol) α88 (5H, t, CH2CH
2CH,).

t51 (2H, m, CH2CH2CH3), 2.
75-2.90 (2H-super part ABX, CH(O
H)CH2N), 5.13 (2H,t.

CH2CH2CH3), 122 (2L m, NH
CH2CH2), 14B(2H,a, ArCH2C
0), 4.11 (2H3, NHCH2CH20).

4.67 (2H, dd, NHCH2CH2H),
(5-1~7.3 (7H, m.

aromatics).

Example 13 2- [2-(” (2-(3,5-(dihydroxy)
Phenyl2-hydroxyethylamineethoxybenzenepropanamide (1) Methyl 2-hydroxybenzenepropane acid (16,421) and sulfuric acid (18M50. 1M)
The solution of ' was refluxed for 70 hours, cooled and filtered to give a pale brown solid (1119g). The P liquid was evaporated, the residue was partitioned between dichloromethane (2X 50m/) and aqueous sodium bicarbonate (IM, 50m) and the insoluble material (4.7g) was collected. The organic phase was dried and evaporated to give a light brown solid (2.90 g). The three batches of product were combined to give a total yield of 18.5F of the title compound. Melting point: 133-137°C.

(Ii) Methyl 2-(2-bromoethoxylic)benzenepropenoate dibromoethane (1) in dibromoethane (100117)
(IQ, 69II), potassium carbonate (96
61) and TrisC2-<2-methoxyethoxy)ethyl]amine (1 g) was refluxed for 72 hours, filtered, evaporated, dissolved in T and silica (Merck 9585
) and evaporation to give the title compound (13,2
2Ii) was obtained as a white solid. Melting point 57-59°C.

(110 Methyl 2-(2-((2-(3,5-dihydroxy7enyl)-2-hydroxyethyl)amino]ethoxy)benzenepro is a A solution of -(aminomethyl)-3,5-dihydroxybenzene metamer (aslI), sodium iodide (5 og) and diisopropylethylamine (3,5 m) was dissolved in DMF (
Products (5,7,9) from step (11) in 2Qd)
solution for 1 hour and then evaporated. The resulting gummy substance is absorbed onto the sand and then coated with silica (Merck 9385).
The title compound (1) was purified twice by the above chromatography.
4! M') was obtained as a friable off-white solid. T, l, c, (T-ET-A79:2
0:1) RfCL13゜(IV) Methyl 2- (2-([: 2- (3,
Step (product from 11D (2
, 29) and 10% Pd0-c (Yi) was hydrogenated until absorption ceased. The catalyst was removed by filtration and the liquid was evaporated under reduced pressure. The residue was purified with F using dichloromethane-ET-A (100:8:1) as eluent.
Purification by CC gave the title compound (1,6F) as a light brown oil. T, 1. C, dichloromethane-ET-
A (100:8:1) Rfo, 35° (V) 2-(
2-C(2-[3,5-(dihydroxy)phenyl-2-hydroxyethyl]amino]ethoxy]benzenepropanamide product from the process (ts,p), ME (!lO
A mixture consisting of d) and liquid ammonia (20 m) was heated in an autoclave (som) at 80 °C for 16 h. The solution was evaporated under reduced pressure and the residue was eluted with dichloromethane-ET-A (50:8:1
) was purified by FCC to obtain the title compound (α41).
was obtained as a pale yellow foam. τ, l, c,
Dichloromethane-ET-A (50:8:1) Rfo, 1
5° elemental analysis (019H24N205.0.75H20,0
,5 as EtOH)C H%N theoretical value 6Q, 5 7.2 7.1 Actual value 6
0.1 6.9 7.2 Example 14 2- (2-((3,5-(dihydroxy7e)-2
-Hydroxyethyl]amino]ethoxy]-N-methylbenzeneacetamide (+) 2- (2-(C2-(3,5-bis(7enylmethoxy)phenyl)-2- and droxyethyl)(
phenylmethyl)aminefetoxy)-N-methylbenzeneacetamide intermediate 5 (1,5 g), ET (201
j) and 33% ethanolic methylamine (201j
) was heated in an autoclave at 95° C. for 16 hours. Evaporate the solvent to form a gum-like substance (tS
y) was purified by FCC using ER as an eluent to obtain the title compound (1,11) as a colorless gum-like substance.

(ii) 2-C2-((3,5-(dihydroxy7
enyl)-2-hydroxyethyl]amino]ethoxy)
-N-Methylbenzeneacetamide product (t) from step (() in anhydrous ET (70m).

The solution was hydrogenated over 10% Pd-C (300+9). The catalyst was removed and the liquid was evaporated. The residue was purified by FCC using RA-ME (8:2) as eluent to give the title compound (387IIg) as an off-white solid. Melting point 82-85°C.

Elemental analysis (as C19H24N205-0-5H20) Uni] Wang Shi Engineering value 618 6.8 7.6 Actual value 61
．． 9 6.2 7.7 Example 15 2-C2-CC2-(3,5-dihydroxy7enyl)-2-hydroxyethyl]amine]ethoxy]benzeneacetamide ET (20M) (2-C3,5-bis(phenylmethoxy)phenyl)-2-hydroxyethyl]amine]ethoxy]benzeneacetamide (o
, 6y) was hydrogenated over 10 T of Pd-C (α069) until hydrogen absorption ceased (58 Wl). The catalyst was removed from the furnace through via 0 and washed with ET (20t7). The title compound (α231) crystallized as a white solid by reducing the volume of ET to 1017 under reduced pressure. Melting point 105-107°C. This product was identical to the sample prepared in Example 6.

Examples of suitable formulations for the compounds of the present invention are shown below.

Example A Tablets - Direct Squeeze It is then pressed using an 8.5 tmyc opener. Tablets of other strengths can be prepared by varying the crush weight and using a suitable punch.

Example B Tablet - Wet Granule Wings g/tablet Active Ingredients 50.02 Cutose B,P, 119.0 Starch B,P
, 20.0 pre-gelatinized corn 1°,
.

Starch B, P.

Magnesium stearate B, P, t O
Pressed weight 20α0 The active ingredient was sieved through a 250 μm sieve and the lactose,
Blend with starch and pre-gelatinized starch. These mixed powders are moistened with purified water, granules are prepared, dried, sieved and blended with magnesium stearate. These attenuated granules are compressed into tablets as described in the Examples.

These tablets may be film-coated with a suitable film-forming material, such as methylcellulose or hydroxypropylmethylcellulose, using standard techniques.

Alternatively, these tablets may be coated with sugar or an enteric coating.

Example C capsule wing g/capsule active ingredient 50.0 smoke starch powder
1500 149.0 Magnesium stearate 1.0 Preparation weight 2
0α0 Bitter Orpington, Kent, England
A form of directly compressible starch manufactured by Colorcon, Inc.

The active ingredient is passed through a 250 μm sieve and then mixed with the other substances. This mixture is placed into Murahard gelatin capsules using a suitable filling machine.

Other dosages may be prepared by varying the dosage weight and, if necessary, changing the capsule size to the appropriate size.

Actual example D Sucrose syrup Tomoe 4v (g) Hikil Active ingredient 5α0 sql:l
-su B, P, 275CLO Glycerin B, P, 500.0 Purified Water B, P,
Add 5. Make it Od.

The active ingredients, buffers, flavors, colors and preservatives are dissolved in some water and to this the glycerin is added. The remaining water is heated to dissolve the sucrose and then cooled. The two solutions are combined, adjusted to constant volume, and mixed. The syrup produced is clarified by filtration.

Example E Syrup jig lees tuna l containing no sucrose Active ingredient 50.0 Purified water B, P
, Add 5. Let it be Od.

The hydroxypropyl methylcellulose is dispersed in hot water, cooled and mixed with the aqueous solution containing the active ingredient and other ingredients of the formulation. The resulting solution is adjusted to a constant volume and mixed. The syrup produced is clarified by passing.

Example F Herbal medicine active ingredient 50.011! F*Witepsol Add H2S and t
It shall be OI.

1% Adeps 5olidus Ph, Eur,
grade owned by.

Ingredient Witepzo A/ (Witepgol) H2
A suspension of the active ingredient in S is prepared and filled into 11 size herbal starry sky using a suitable machine.

Example G Injection Active Ingredients for Intravenous Administration 100 Water for Injection B
, P, to make it 100.00.

Sodium chloride may be added to adjust the tonicity of the solution, which may be set to the level of maximum solubility of the active ingredient using dilute acids or alkalis or by addition of suitable buffer salts. and/or may be adjusted to promote solution conditions. Antioxidants and metal chelate salts may also be included.

The above solution is prepared, clarified and filled into appropriately sized ampoules which are sealed by glass melting. The injection is sterilized by heating in an autoclave using an acceptable cycle of 1 m. Or again,
This solution can be sterilized by Pi and then filled into sterile ampoules under aseptic conditions. This solution can be packed under an inert atmosphere of nitrogen.

The β1-adrenoceptor stimulating effect of the compounds of the invention was determined by their ability to increase the 6-beat frequency in anesthetized cats. In this test, Example 6.9.1
Each compound of 3 and 14 had a potency of 50-600 (expressed as an isopotent concentration, imprenaline =
1).

The antagonistic action of the compounds of the invention at the α1-adrenoceptor was determined by the ability of these compounds to antagonize the contractile response to noradrenaline in isolated rabbit aorta. A series of concentration-effect curves is obtained, and this
) PA2 value is Mr. Arunlakshana and 5c
By Mr. h11d [British, G.I., 7 Armacol J (Br, J.

Pharmacol, ), 1959.14.48. In this test, each of the compounds of Examples 6.9.13 and 14 had a pA of 62 to 10.
It had two values.

Generally, compounds according to the invention are non-toxic at therapeutically useful doses. Furthermore, the compound of Example 6 did not produce any adverse effects when administered intravenously to catatonic cats and rats at doses up to 4 in 30 q/d.

Patent applicant: 2 people outside of Gracs Group Limited

Claims (1)

[Claims] 1) General formula (I) ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R represents a hydrogen atom or a linear C_1_-_3 alkyl group, and n is 1 or 2 ) and their physiologically acceptable acid addition salts, solvates and metabolically unstable esters. 2) The compound according to claim 1, wherein n is 1. 3) The compound according to claim 1 or 2, wherein R is a hydrogen atom. 4) 2-[2-[[2-3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]benzene-acetamide and its physiologically acceptable acid addition salts. 5) The compound according to claim 1, wherein R is a hydrogen atom, a methyl group or an ethyl group, and n is 1 or 2. 6) (1) Formula (II) ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) (In the formula, -NA is the group -NHR^5, -NR^5CH_2C
H_2X, ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or ▲
There are mathematical formulas, chemical formulas, tables, etc. ▼, R^2, R^
3, R^4 and R^5 are each a hydrogen atom or a protecting group, and X is an atom or group that can be easily substituted) and formula (III) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (III) [wherein R and n are as defined in formula (I), R^1 is a hydrogen atom or a protecting group, and Y is -NA is -NR^5CH_2CH_2X, ▲ mathematical formula, chemical formula, There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ means hydrogen or Y is -NA
is -NHR^5, the group CH_2CH_2X (wherein X is an easily substituted atom or group)], followed by an alkylation reaction if necessary. remove any protecting groups present, or (2) Formula (VIII) ▲ Numerical formula, chemical formula, table, etc. ▼ (VIII) [wherein R^2 and R^3 are defined in method (1) and R^6 is a group ▲ has a mathematical formula, chemical formula, table, etc. ▼ or ▲ has a mathematical formula, chemical formula, table, etc. ▼ (wherein R^4 and X are as defined in method (1) ) represents a compound having the formula (IX) ▲ formula,
Chemical formulas, tables, etc.▼(IX) (CH_2)nCONRR^1 (wherein R and n are as defined in formula (I) and R^1 and R^5 are defined in method (1) above as described above),
Subsequently, if necessary, remove any protecting groups present, or (3) Formula (X) ▲ Numerical formula, chemical formula, table, etc. ▼ (X) (In the formula, R^7 is a group -COCHO or - CHCH_2N
HR^5 and R^2, R^3, R^4 and R
＾5 is as defined in method (1) above) A compound having the formula (X I ) ▲There are mathematical formulas, chemical formulas, tables, etc. ▼(X I) [In the formula, Z is R^7 is -CHCH_2NHR If ^5 represents the group CHO, or Z represents R^7 is -COC
HO represents the group CH_2NHR^5, R and n are as defined in formula (I) and R
^1 and R^5 are as defined in method (1) above] in the presence of a reducing agent, followed by removal of any protective groups present if necessary. or (4) Formula (XIV) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (XIV) (wherein R and n are as defined in formula (I), and R^1, R^2, R^3 and R^5 are as defined in method (1) above) followed by removal of any protecting groups present if necessary, or formula (5) (XV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XV) [In the formula, n is as defined in formula (I), and R^
2, R^3, R^4 and R^5 are as defined in method (1) above and R^8 represents a carboxylic acid group or a salt or reactive derivative thereof] as the amine RNH_2 (where R is as defined in formula (I)) followed by removal, if necessary, of any protecting groups present, or (6) formula (I) (in which In order to produce a compound of formula (XVI) ▲ mathematical formulas, chemical formulas, tables etc. ▼ (XVI) where n is as defined in formula (I) and R 2. R^3, R^4 and R^5 are the above method (1)
or (7) formula (XVII) ▲ mathematical formula, chemical formula, table, etc. ▼(XVII) where R and n are as defined in formula (I) and R^1, R^2, R^3, R^4 and R^5
is as defined in method (1) above, provided that at least one of R^1, R^2, R^3, R^4 and R^5 represents a protecting group) and optionally converting the compound of formula (1) or a salt thereof into a physiologically acceptable acid addition salt, solvate or metabolically labile ester. A method for producing a compound described in any one of Ranges 1 to 5. 7) a compound of formula (I) or a physiologically acceptable acid addition salt, solvate or metabolically labile ester thereof together with at least one physiologically acceptable carrier or excipient; A pharmaceutical composition comprising: 8) General formula (XV) ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (XV) (In the formula, n is 1 or 2, R^2, R^3, R^4
and R^5 each represent a hydrogen atom or a protective group, and R^8 is a carboxyl group, or a salt thereof, or a C
_1_-_5 represents an alkyl ester). 9) The above claims, wherein n is 1 or 2, R2^, R^3,^R4 and R^5 each represent a hydrogen atom, and R^8 is a carboxyl group or a C_1_-_3 alkyl ester thereof Compound according to item 8. 10) 2-[2-[[2-(3,5-dihydroxyphenyl)-2-hydroxyethyl]amino]ethoxy]benzeneacetic acid.