JPH0226628B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to novel compounds with therapeutic activity, processes for their preparation and pharmaceutical formulations containing them. In particular, the compounds of the invention have a bronchospaspasmolytic effect and are effective in the treatment of reversible obstructive pulmonary disorders of various origins, especially asthmatic conditions.
These compounds exhibit long-lasting therapeutic effects and low side effects, especially reduced cardiostimulatory effects. It would be desirable to find bronchodilators with longer lasting activity than those available commercially. Structural formula known by the common name "terbutaline" is one of the preferred long-acting bronchodilators currently available on the market. It is described inter alia in US Pat. No. 4,011,258 and has a duration of therapeutic activity of about 6 to 8 hours. This persistence has been confirmed by many years of clinical experience, and can be quantified by the finding that terbutaline serum concentrations of at least about 2 ng/ml are required to obtain the desired therapeutic activity. "Europ.J.clin Pharmacol."
Vol. 10, pp. 9-18 (1976)]. Structural formulas of other commercially available long-acting bronchospasmolytic active compounds "Salbutamol" has a sustained bronchospasm-relaxing activity roughly equivalent to that of terbutaline. Attempts to obtain bronchospasmodically active compounds with long-lasting activity have been reported in the literature. 32, pages 276-92 (1964) discloses, inter alia, certain esters of ethanolamine derivatives known at that time. “Journal of Pharmacology and
Experimental Therapeutics” Volume 206 No. 3
Pages 515-527 are formulas Discusses the pharmacological properties of the compound known as "bitolterol". This compound (bitolterol), which is also disclosed in Belgian Patent No. 748178, has been shown to have a duration of activity comparable to salbutamol. The problems to be solved by the present invention are at least
The objective was to find an orally active bronchospasm reliever with a clinically useful duration of activity of 12 hours. The present invention provides novel compounds that have bronchospasmolytic activity upon oral administration and exhibit a duration of activity of 12 hours or more. The compounds of the invention also exhibit less undesirable cardiovascular side effects. That is, they exhibit smaller chronotropic and inotropic effects than terbutaline. The invention also relates to processes for the preparation of these compounds, pharmaceutical compositions containing these compounds as active ingredients and the use of these compounds for therapeutic purposes;
In particular, it relates to use in producing bronchodilation in mammals, including humans. The present invention further describes the use of these compounds to produce relaxation of the human uterus, and includes compounds of the present invention in combination with commonly used bronchodilator drugs, as described in more detail below. Concerning pharmaceutical preparations. The present invention is based on the formula {In the formula, R is -C(CH ₃ ) ₃ ,

【formula】 and

is selected from the group consisting of [Formula], R ¹ is selected from the group consisting of H and R ² , and R ² is

[Formula] [In the formula, R ³ is (a) hydrogen, (b) an alkyl group containing 1 to 3 carbon atoms, (c)

[Formula] (wherein R ⁵ is selected from the group consisting of (a) OH, (b) an alkoxy group containing 1 to 3 carbon atoms), and R ⁴ is (a) Hydrogen, (b)1
an alkyl group containing ~3 carbon atoms, provided that R ³ and R ⁴ are as follows: If R 3 is hydrogen, R ⁴ is hydrogen; ^{R 3 is} an alkyl group containing 1 to 3 carbon atoms; R ⁴ in the case of alkyl groups containing atoms
is hydrogen or an alkyl group containing 1 to 3 carbon atoms and R ³ is

The ^invention relates to novel compounds and therapeutically acceptable salts thereof. The formula encompasses compounds in which one of the hydroxyl substituents at the 3- or 5-position of the phenyl group is substituted and the other hydroxyl substituent is unsubstituted, and compounds in which both hydroxyl groups are substituted with a basic structure. ing. Illustrative examples of groups R ¹ and R ² are as follows. Specific examples of the compounds of the present invention are as follows. A preferred group of compounds of formula are: 1 A compound in which R is -C(CH ₃ ) ₃ . 2 formulas A compound of the formula wherein R ³ and R ⁴ are hydrogen or an alkyl group containing 1 to 3 carbon atoms. 3 formulas A compound of the formula wherein R ³ and R ⁴ are hydrogen or an alkyl group containing 1 to 3 carbon atoms. 4 A compound of the formula and wherein R ³ and R ⁴ are CH ₃ or CH ₃ CH ₂ —. Preferred compounds of the invention have the formula It is a compound of Since the compounds of the present invention of the formula contain at least one asymmetric carbon atom, the present invention encompasses all possible optically active forms and racemic mixtures of the compounds. This racemic mixture can be resolved in the usual manner, for example by salt formation with a photoactive acid followed by fractional crystallization. The invention also relates to solvates of compounds of formula with water or alcohols such as 1/2 per mole of compound,
Includes solvates with 1 or 2 moles of water and solvates with 1 mole of aliphatic alcohol per mole of compound. In clinical practice, the compound usually contains the active ingredient, either in the form of the raw compound or in the form of a pharmaceutically acceptable salt thereof, in a pharmaceutical composition which may be a solid, semi-solid or liquid diluent or an ingestible capsule. It is administered orally by injection or by inhalation in the form of a pharmaceutical preparation in combination with a carrier acceptable to the patient.
Such formulations then constitute another aspect of the invention. The compounds can also be used without carrier materials. Examples of pharmaceutical formulations include tablets, drops, aerosols for inhalation, and the like. Usually the active substance is 0.05-99% by weight of the preparation, or 0.1-99% by weight, e.g. 0.5-20% by weight for preparations intended for injection and for preparations intended for oral administration. is 0.1~50
Makes up % by weight. The novel compounds of the invention can be administered in the form of salts with physiologically acceptable acids. Suitable acids that can be used are, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, fumaric acid, citric acid, tartaric acid, maleic acid or succinic acid. The invention further provides pharmaceutical compositions comprising at least one compound of the invention as an active ingredient in combination with a pharmaceutical carrier. Such compositions can be used for oral, bronchial, rectal or parenteral administration. For the preparation of pharmaceutical preparations in the form of dosage units for oral administration containing a compound of the invention in the form of the free base or a pharmaceutically acceptable salt thereof, the active ingredient may be combined with a solid, powdered carrier such as lactose, sucrose, etc. , sorbitol, mannitol, starches such as potato starch, corn starch, maize starch or amylopectin, cellulose derivatives or gelatin. It can also include lubricants such as magnesium or calcium stearate or carbo waxes or other polyethylene glycol waxes and be compressed to form tablets or dragee cores. If dragee-coated tablets are desired, the core is dissolved in a concentrated sugar solution which may contain, for example, gum arabic, talc and/or titanium dioxide, or in a lacquer dissolved in a readily volatile organic solvent or organic solvent mixture. Can be coated.
Dyes can be added to these coatings. For the production of soft gelatin capsules (pearl-shaped sealed capsules) or similar sealed capsules of gelatin and, for example, glycerol, the active substance can be mixed with carbo wax.
Hard gelatin capsules may contain granules of the active ingredient together with solid powder carriers such as lactose, sucrose, sorbitol, mannitol, starches (eg potato starch, corn starch or amylopectin), cellulose derivatives or gelatin. And it may also contain magnesium stearate or stearic acid. Dosage units for rectal application may be in the form of suppositories containing the active ingredient in a mixture with carbo waxes or other polyethylene glycol waxes. Each dosage unit preferably ranges from 1 to
Contains 50mg of active ingredient. Liquid preparations for oral administration may contain, for example, about 0.1 to 20% by weight.
The composition may be in the form of a syrup, suspension or emulsion containing the active ingredient and optionally also additives such as stabilizing agents, suspending agents, dispersing agents, flavoring agents and/or sweetening agents. Liquid preparations for rectal administration may be in the form of aqueous solutions containing about 0.1 to 2% by weight of active substance and also, if desired, stabilizers and/or buffer substances. For parenteral injection applications, the carrier is a sterile parenterally acceptable liquid such as pyrogen-free water or an aqueous polyvinylpyrrolidone liquid or a parenterally acceptable liquid. eg peanut oil and optionally stabilizers and/or buffer substances. The dosage units of this solution can advantageously be enclosed in ampoules and each dosage unit is preferably
Contains 0.1-10 mg of active substance. For bronchial administration, the composition is advantageously in the form of a spray solution or suspension. The solution or suspension preferably contains 0.1 to 10% by weight of active ingredient. The dosage of the active ingredient administered can vary within wide limits and depends on various factors, such as the individual requirements of each patient. A suitable oral dosage range may be 5-200 mg per day. In dosage aerosol treatment, a suitable dosage unit may contain from 0.1 to 10 mg of active ingredient.
One or two such dosage units may be administered in each treatment. Pharmaceutical compositions containing the active ingredients may suitably be formulated so that they provide dosages within these ranges in single dosage units or in multiple dosage units. The test results in Table 1 below show that the compounds of the invention have a later onset of bronchodilator effect than that of the reference substance terbutaline. This activity profile makes the compounds of the invention suitable not only for use on their own in continuous therapy, but also in combination with bronchodilators with a more rapid onset of action in acute therapy. Close. Examples of known bronchospasmolytic active compounds suitable for use in combination with the compounds of the invention include terbutaline, buterol, orciprenaline, salbutamol, epinephrine, isoprenaline and efuedrine. These compounds have the following structural formulas. The following active compounds as bronchospasmolytic agents can also be used in combination with the compounds of the invention. Combination formulations containing the compounds of the invention together with other bronchospasmolytic actives with a more rapid onset of action constitute another aspect of the invention. In pharmaceutical compositions containing a combination of a commonly used bronchospasmolytic agent and a compound of the formula as described above, the weight ratio of the known compound to the compound of the formula of the present invention is suitably from 1:2 to 1:
5, and preferably 1:3 to 1:4. The compounds of the present invention can be produced by known methods such as those described below. A formula (wherein R, R ¹ and R ² are as defined above, but when R ¹ or R ² is hydrogen, the hydroxy substituent may be protected with a hydroxy-protecting group, and R ⁶ is hydrogen or an N-protecting group) and then optionally replaces the remaining protecting group with hydrogen. Examples of groups which can be used for the protection of the hydroxy substituents of the groups R ¹ and R ² are, for example, alkyl groups or acyl groups having not more than 5 carbon atoms or 11 groups such as benzyl or naphthylmethyl.
Mention may be made of the customary hydroxy-protecting groups which can easily be replaced by hydrogen, such as mono- or bicyclic aralkyl groups having not more than 3 carbon atoms. Examples of groups that can be used to protect said amino nitrogen atoms include conventional protecting groups such as mono- or bicyclic aralkyl groups containing not more than 11 carbon atoms such as benzyl and naphthylmethyl. can be given. Said reduction can be carried out by known methods using, for example, Pd/C or NaBH ₄ . B formula (wherein R ¹ and R ² are as described for method A) above, and X is a halogen or a functionally equivalent group capable of reacting with the amine HNR ⁶ R described below). formula (wherein R and R ⁶ are as described for method A) above) to form a compound of the formula (In the formula, R, R ¹ , R ² and R ⁶ are the above method A)
(as described for) and then optionally replacing the protecting groups with hydrogen. Examples of said groups X include F, Cl, Br, I, or leaving groups such as OSO ₂ R ⁸ , where R ⁸ is an alkyl, aralkyl or aryl group. C formula (wherein R ¹ and R ² are as described for method A) above) (wherein R and R ⁶ are as described for method A) above) to form a compound of the formula (In the formula, R, R ¹ , R ² and R ⁶ are the above method A)
(as described for) and then optionally replacing the protecting groups with hydrogen. D formula (wherein R ⁷ is hydrogen or the above method A)
a hydroxy-protecting group as exemplified for, but with the proviso that at least one group R ⁷ is hydrogen) a compound of the formula (In the formula, R ³ and R ⁴ are as described above.)
or a reactive derivative thereof, followed by optionally replacing the protecting group with hydrogen. formula Examples of reactive derivatives include acid halides such as acid chlorides, alkyl esters, acid anhydrides or formate esters or mixed anhydrides or compounds with carboxylic acids, sulfonic acids or inorganic acid esters. and derivatives obtained by reaction with carbodiimide or similarly acting compounds such as N,N'-carbonyldiimidazole or N-ethyl-5-phenylisoxazolium-3'-sulfonate, Commonly used reactive carboxyl groups -
You can give CO-Y. Other reactive derivatives that can be used to prepare compounds in which one of R ³ and R ⁴ is hydrogen and the other is an alkyl group or a phenyl group substituted as described above are those of the formula R ⁴ -N=C=O isocyanate. E formula (wherein R, R ¹ and R ² are as defined above) is reduced, and then, if necessary, the protecting group is replaced with hydrogen. The above reduction can be carried out in known manner, for example using NaBH ₄ . In order to prepare compounds of the formula in which R ¹ is hydrogen, in the aforementioned methods A to E, the starting materials are the groups --OR ¹ or the corresponding substituent-protected hydroxy group --OR ⁷ (but The group R ⁷ is a customary hydroxy-protecting group, as exemplified for method A) above, which is optionally replaced by hydrogen in the step in which the remaining protecting groups are replaced by hydrogen. Said methods A to E
It will be understood that 3,5-disubstituted compounds as described for. Benzyl is a preferred hydroxy-protecting group.
Benzyl is also a suitable protecting group for the amino nitrogen. The compounds of the formula thus obtained are, if desired, separated into their optical isomers. The compounds can also be converted into pharmaceutically acceptable salts, if desired. The intermediates used in the above methods A-E are in some cases novel compounds. Examples of the production of intermediates are given below. All illustrative reactions are known. For the sake of clarity, the various possible routes for producing the intermediates are illustrated by specific examples. It will be readily understood how these specific examples may be applied to the production of other intermediates that may be required in the production of other target compounds. In the reaction formula below, the benzyl group is represented by Bz. Manufacturing route route A1 for intermediates used in method A: Route A2: Manufacturing route for intermediates used in method B Production route for intermediates used in method C The intermediate used in method D is the known compound terbutaline, which can be prepared, for example, as described in US Pat. No. 4,011,258. Manufacturing route for intermediates used in method E formula The starting materials (wherein R, R ¹ , R ² and R ⁶ are as described for Process A above) are novel and as such constitute yet another feature of the invention. Starting materials used in method E above (where R, R ¹ and R ² are as described with respect to Method A above) is also novel and constitutes a feature of the invention. Methods B, C and D above, wherein the target compound of the formula has a hydroxy protecting group or a nitrogen protecting group.
The intermediates of are also novel and constitute yet another feature of the invention. The present invention will be specifically explained with reference to the following examples. Example 1 Production of 1-[bis-(3′,5′-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride Bis-3′,5 in 300 ml of ethanol '-(N,N
-dimethylcarbamoyloxy)-2-(N-benzyl-tertiary butyl)-aminoacetophenone
78 g of the solution was hydrogenated in the presence of 25 ml of benzyl chloride and 3.5 g of 10% Pd/C in a Parr apparatus. Hydrogenation time is 345KPa
(50 psig) and a temperature of 50° C. for 24 hours. The catalyst was separated and the liquid was evaporated to dryness. The residue was dissolved in isopropanol, filtered, and diethyl ether was added to the solution to precipitate the title compound. The identity of the title compound thus obtained was confirmed by NMR. Yield: 46.5g NMRδppm: 1.3 9H (s), 3.0 12H (d), 3.2 2H
(m), 4.6 (DOH), 5.0 1H (q), 7.0 3H
(m) (D ₂ O) GCMS: 99.8% Cl - Calculated value: 8.8% Cl - Actual value: 8.8% HPLC: 100.0% The above bis-3′5′- used as a starting material
(N,N-dimethylcarbamoyloxy)-2-
(N-benzyl-tertiary butyl)aminoacetophenone was produced as follows. 1a Bis-3,5-(N,N-dimethylcarbamoyloxy)-acetophenone To a solution of 152 g of 3,5-dihydroxyacetophenone in 700 ml of dry pyridine was added 280 ml of N,N-dimethylcarbamoyl chloride. This mixture was stirred at 60-70°C for 18 hours. After evaporation in vacuo, the residue was treated with a mixture of diethyl ether and water. The aqueous phase was extracted with diethyl ether, then the combined diethyl ether phases were washed with water and dried over _MgSO4 . After evaporation, the residue was dissolved in isopropyl alcohol/petroleum ether (bp40
~60°C). The identity of the product is
Confirmed by NMR. Yield: 180.4g NMRδppm: 2.6 3H (s), 3.1 12H (s), 7.4
3H (m) (CDCl ₃ , TMS) 1b Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromo-acetophenone Bis-3,5-(N,N-dimethylcarbamoyloxy) obtained in the above step 1a) in 700 ml of dioxane. )-A solution of 31 ml of bromine in 200 ml of dioxane was added dropwise to a solution of 180 g of acetophenone.
This mixture was stirred at 35°C for 1 hour. The residue obtained after vacuum evaporation was recrystallized from isopropyl alcohol/petroleum ether (bp 40-60°C). Product identity was confirmed by NMR. Yield: 174g NMRδppm: 3.1 12H (s), 4.5 2H (s), 7.4
3H (m) (CDCl ₃ , TMS) 1c Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)aminoacetophenone Bromo-acetophenone obtained in step 1b) above in 75 ml of acetone A solution of 4.9 g of N-benzyl-tertiary butylamine in 30 ml of acetophenone was added to the 5.6 g solution. The mixture was refluxed under stirring for 18 hours, filtered and evaporated in vacuo. The residue was dissolved in diethyl ether, petroleum ether (bp 61-70°C) was added and the yellow precipitate formed was separated. After washing with water and subsequently with a 1:1 mixture of isopropyl alcohol/petroleum ether, white crystals were obtained. Product identity was confirmed by NMR. Yield: 4.6g NMRδppm: 1.2 9H (s), 3.1 12H (s), 3.9
2H (s), 4.0 2H (s), 7.3 8H (m)
( _CDCl3 , TMS) Example 2 1-[3-(N,N-dimethylcarbamoyloxy)-5-hydroxy]-phenyl-2-tertiary butylamino-ethanol hydrochloride a 3'-benzyloxy-5'-(N,N -dimethylcarbamoyloxy)-2-N-benzyl-
Tertiary butylamino-acetophenone hydrochloride 3-benzyloxy-5- in 150 ml of acetone
(N,N-dimethylcarbamoyloxy)-N- in a solution of 9.1 g of acetophenone in 50 ml of acetone.
7.5 g of benzyl-tert-butylamine was added.
The mixture was stirred under reflux for 4 days and then evaporated. The residue was dissolved in diethyl ether and the precipitated N-benzyl-tert-butylamine hydrobromide (5.5 g) was separated. 2NHCl was added to the solution and the ether phase was discarded. The aqueous phase was neutralized with 10% sodium carbonate solution and extracted with diethyl ether. The ether phase was dried over _MgSO4 ,
and then acidified with ethereal hydrogen chloride.
Separate the precipitated brown oil and add ethanol (25ml)
dissolved in it. When diethyl ether was added to this ethanol solution, the title compound crystallized. The identity of this product was confirmed by NMR. Yield: 5.3g NMRδppm: 2.05 9H (s), 3.25 6H (d), 5.15
2H (s), 5.45 2H (s), 7.75 13H (m),
( _CDCl3 , TMS) b 1-[3-(N,N-dimethylcarbamoyloxy)-5-hydroxy]-phenyl-2-
Tertiary butylamino-ethanol hydrochloride 3'-benzyloxy-5'-N,N-dimethylcarbamoyloxy-2-N-benzyl-tertiary butylamino- obtained in step a) in 75 ml of ethanol. 10% solution of acetophenone hydrochloride
Ambient temperature and 380KPa in the presence of %Pd/C1g
(55 psig) for 18 hours. The catalyst was separated and the liquid was evaporated to dryness. The residue was recrystallized from isopropyl alcohol/diethyl ether. The identity of the title compound was confirmed by NMR. Yield: 1.6g GCMS: (di-TMS-derivative) 99% HPLC: 99% NMRδppm: 1.40 9H (s), 3.05 6H (d), 3.12
2H (m), DOH 4.70, 4.95 1H (q), 6.70
3H (m) ( _D2O ) The 3-benzyloxy-5-(N,N-dimethylcarbamoyloxy)-acetophenone used as a starting material was produced as follows. 2a 3-benzyloxy-5-(N,N-dimethylcarbamoyloxy)-acetophenone 3-benzyloxy-5- in 200 ml of pyridine
5.5 ml of dimethylcarbamoyl chloride was added to a solution of 9.7 g of hydroxy-acetophenone.
The mixture was stirred at 60-70°C for 18 hours, then evaporated to dryness and the residue was dissolved in diethyl ether.
Partitioned into _H2O . Evaporation of the ether phase gave a yellow oil. This was transferred onto silica gel 60 using CHCl ₃ /petroleum ether (bp 40-60°C) as eluent.
Purified by column chromatography using (8:2). Yield: 11.3g NMRδppm: 2.55 3H (s), 3.10 6H (s), 5.10
2H (s), 7.30 8H (m) (CDCl ₃ , TMS) 2b 3'-benzyloxy-5'-(N,N-dimethylcarbamoyloxy)-2-bromo-acetophenone 3-benzyloxy-5-(N,N-dimethyl) obtained in step 2a) in 150 ml of dioxane. carbamoyloxy)-acetophenone 11.3
1.8 ml of bromine in 50 ml of dioxane were added dropwise to the solution of g. The mixture was stirred for 1 hour at ambient temperature and then evaporated. The residue was dissolved in diethyl ether and treated with activated charcoal. After filtration, the liquid was evaporated and the residue was recrystallized from isopropanol. Product identity was confirmed by NMR. Yield: 7.9g NMRδppm: 3.10 6H (s), 4.40 2H (s), 5.10
2H (s), 7.2 8H (m) (CDCl ₃ , TMS) Example 3 Production of 1-[3',5'-bis-(N-ethylcarbamoyloxy)-phenyl]-2-tertiary butylaminoethanol hydrochloride a 3',5'-bis-(N-ethyl carbamoyloxy)-2-N-benzyl-tertiary-butylaminoacetophenone hydrochloride A solution of 8.0 g of 3',5'-bis-(N-ethylcarbamoyloxy)-2-bromo-acetophenone in 100 ml of acetone 7.0 g of N-benzyl-tertiary butylamine was added. This mixture was refluxed for 18 hours. The N- formed and precipitated during the reaction
Benzyl-tertiary butylamine hydrobromide 4.1
g was separated and the solution was acidified with concentrated HCl. The liquid was evaporated to dryness. The title compound was purified on silica gel 60 with 1) CHCl ₃ /ethanol (2:1) as eluent;
2) Isolated by column chromatography using ethanol. Product identity determined by NMR
It was confirmed. Yield: 0.3g NMRδppm: 1.2 6H (t), 1.6 9H (s), 3.3 6H
(m), 4.2 2H (m), 4.9 2H (s), 7.4 8H
(m) (CD ₃ OD, TMS) b 1-[3',5'-bis-(N-ethylcarbamoyloxy)-phenyl]-2-tertiary butylaminoethanol hydrochloride Aminoacetophenone 0.3 in 50 ml of methanol
g solution in the presence of 0.1 g Pd/C at ambient temperature and
Hydrogenation was carried out at 345 KPa (50 psig) for 18 hours.
The catalyst was separated and the liquid was evaporated to dryness. The residue was dissolved in isopropanol and diethyl ether was added to precipitate the title compound. The identity of the title product obtained was confirmed by NMR. Yield: 0.18g GCMS: TMS derivative NMRδppm: 1.2 6H (t), 1.5 9H (s), 3.3 6H
(m), 5.3 1H (m), 6.1 2H (t), 6.9 3H
(m), CDCl ₃ , TMS) HPLC: 98.4% The above 3',5'-bis used as a starting material
(N-Ethylcarbamoyloxy)-2-bromo-acetophenone was produced as follows. 3a 3,5-bis-(N-ethylcarbamoyloxy)-acetophenone Ethyl isocyanate is added to a solution of 15 g of 3,5-dihydroxy-acetophenone in 200 ml of pyridine.
18.8ml was added. This mixture was heated at 70℃ for 18
After stirring for an hour, it was evaporated. The residue was partitioned between chloroform/water, the chloroform phase was washed with dilute hydrochloric acid and then evaporated. The crystalline residue was recrystallized from isopropanol. The identity of the product is
Confirmed by NMR. Yield: 19.4g NMRδppm: 1.2 6H (t), 2.6 3H (s), 3.35
4H(p), 5.45 2H(t), 7.3 1H(q), 7.6
2H(d) (CDCl ₃ , TMS) 3b 3',5'-bis-(N-ethylcarbamoyloxy)-2-bromo-acetophenone A solution of 19.4 g of acetophenone obtained in step 3a) above in 300 ml of dioxane
3.7ml of bromine in 100ml was added. The mixture was stirred for 1 hour at ambient temperature and then evaporated and the residue was crystallized from isopropanol. Product identity was confirmed by NMR. Yield: 16.7g NMRδppm: 1.2 6H (t), 3.3 4H (p), 4.45
2H(s), 5.35 2H(t), 7.3 1H(q), 7.6
2H(d), (CDCl ₃ , TMS) Example 4 Production of 1-[bis-(3′,5′-(N,N-dimethylcarbamoyloxy)phenyl]-2-cyclobutylaminoethanol sulfate) Bis-3′,5′-( N, N-
A solution of 2.9 g of dimethylcarbamoyloxy)-2-(N-benzyl-cyclobutyl)-amino-acetophenone hydrochloride was hydrogenated in the presence of 0.5 g of 10% Pd/C at a pressure of 345 KPa (50 psig) and 45° C. for 18 h. did. The oil obtained after separating off the catalyst and evaporating the liquid was dissolved in water made alkaline with 1M sodium carbonate solution and then extracted with diethyl ether. The residue after evaporation was dissolved in ethanol and ethanolic sulfuric acid was added to pH 5.5. After evaporation a crystalline residue was obtained. This was recrystallized from isopropanol. The identity of this product was confirmed by NMR. Yield: 1 g CIMS (NH ₃ ): Calculated molecular weight observed. SO ₄ ^2- : 98.7% NMR (D ₂ O) δppm: 2.05 6H (m), 3.00 14H
(m), 3.65 1H (m), 4.60 (DOH), 4.95
1H (m), 6.95 3H (m). The above bis-3′,5′- used as a starting material
(N,N-dimethylcarbamoyloxy)-2-
(N-benzylcyclobutyl)-amino-acetophenone hydrochloride was produced as follows. 4a Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-cyclobutyl)-amino-acetophenone hydrochloride Bis-3',5'-(N,
4.9 g (0.013 mol) of N-dimethylcarbamoyloxy)-2-bromo-acetophenone and N-
A solution of 4.4 g (0.0027 mol) of benzyl-cyclobutylamine was refluxed with stirring for 18 hours. After filtration and evaporation to dryness, the residue was dissolved in dry ethyl ether. Ethanolic hydrogen chloride was then added to the ether solution until pH 2. After evaporation of the ether solution, a brown oil was obtained, which was crystallized from acetone/ethyl ether. Yield: 5.5g. The product was dissolved in chloroform and CHCl ₃ /
Purified by _{chromatography using C2H5OH (} 10:1). The crystalline material is then obtained by evaporating the fraction containing the title compound.
2.9g was obtained. The identity of this product was confirmed by NMR. NMR (CDCl ₃ ) δppm: 2.0 4H (m), 2.8 2H
(m), 3.05 12H (d), 4.4 5H (m), 7.5
8H (m). Example 5 Production of 1-[bis-(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-(1-methyl)-cyclobutylaminoethanol hydrochloride Bis-3 in 100 ml of ethanol) ′,5′-(N,N
A solution of 6 g of dimethylcarbamoyloxy-2-N-benzyl(1-methyl)-cyclobutylamino-acetophenone hydrochloride in the presence of 0.5 g of 10% Pd/C at a pressure of 380 KPa (55 psig) and 45° C. for 18 hours. Hydrogenated. After separating the catalyst,
The liquid was evaporated to dryness and the residue was crystallized from isopropanol/diethyl ether. The identity of this compound was confirmed by NMR. Yield: 4.3g HPLC: Purity 98.9% Cl - Calculated value: 8.5% Cl - Actual value: 8.4% NMR: (D ₂ O) δppm: 1.50 3H (s), 2.10 6H
(m), 3.08 14H (m), 4.70 (DOH), 5.08
1H (m), 7.08 3H (m). The above bis-3', 5'- used as a starting material
(N,N-dimethylcarbamoyloxy)-2-
N-benzyl-(1-methyl)-cyclobutylamino-acetophenone hydrochloride was produced as follows. 5a Bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-N-benzyl-(1-methyl)-cyclobutylamino-acetophenone hydrochloride Bis-3',5' in 100 ml of dry acetone -(N,
6.7 g (0.018 mol) of N-dimethylcarbamoyloxy)-2-bromoacetophenone and 6.9 g of N-benzyl-1-methylcyclobutylamine
(0.039 mol) was boiled under reflux for 18 hours.
The reaction mixture was filtered and the liquid was evaporated to dryness. The residue was dissolved in diethyl ether and ethanolic hydrogen chloride was added to it until PH2. After evaporation, the residue was recrystallized from ethanol/diethyl ether. Product identity was confirmed by NMR. Yield: 6g NMR (CDCl ₃ ) δppm: 1.75 3H (s), 2.0 4H
(m), 3.15 14H (m), 4.67 4H (m), 7.68
8H (m). Example 6 (Method A) Production of 1-[bis-(3′,5′-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride a 1-bis-(3 Preparation of ',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-benzyl-N-tert-butylaminoethanol 0.066 mol (30.1
Add 25 ml of g) to the solution of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)aminoacetophenone.
A solution of 0.07M (2.7g) _NaBH4 dissolved in _H2O was added. The mixture was stirred at ambient temperature for 3 hours and then evaporated to dryness. Convert the residue into Et ₂ O/H ₂ O
The combined ethereal extracts were acidified with isopropanolic hydrogen chloride. The resulting precipitate was recrystallized from isopropanol/diethyl ether. Yield: 26.3g (81%) NMR: δppm: 1.40 9H (s), 2.83 12H (d),
3.05~4.70 5H (m), 4.50 (DOH), 6.25
2H (d), 6.60 1H (m), 7.43 5H (m)
( _D2O ). b Hydrogenation of the product obtained in step a) above as described in Example 1 yields 80-90% of the title compound.
It was obtained in a yield of . Example 7 Production of 1-[bis-(3′,5′-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride Bis-3′,5′-(N, N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)
Hydrogenation of aminoacetophenone as a catalyst
It was carried out as described in Example 1 using _PtO2 .
A product identical to that of Example 1 was obtained in a similar yield. Example 8 Production of 1-[bis-(3′,5′-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride Bis-3′,5′-(N, N-dimethylcarbamoyloxy)-2-(N-benzyl-tert-butyl)
Hydrogenation of aminoacetophenone was carried out as described in Example 1 using Raney nickel as catalyst. A product identical to that of Example 1 was obtained in a similar yield. Example 9 (Method B) Production of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride a 1-bromo-2- Production of (3,5-N,N-dimethylcarbamoyloxyphenyl)ethanol 0.02 mol of 3, dissolved in 100 ml of dioxane
To the solution of 5-N,N-dimethylcarbamoyloxy-bromoacetophenone was added 10 ml of an aqueous solution of _0.02M NaBH4. The reaction mixture was stirred at ambient temperature for 3 hours and then evaporated in vacuo. The residue was dissolved in diethyl ether and washed with water. The ether phase was then dried over _MgSO4 , filtered and the liquid evaporated to give a pale yellow oil, which
According to NMR analysis, it consisted mainly of the title compound. Yield: 4.5g. b Preparation of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 0.012 mol of 1- dissolved in 100 ml of ethanol
Bromo-2-(3,5-N,N-dimethylcarbamoyloxyphenyl) 0.02 in a solution of ethanol
A mole of tert-butylamine was added. The reaction mixture was stirred under reflux for 18 hours and then evaporated in vacuo. The residue was dissolved in isopropanol, acidified with ethereal hydrogen chloride and then evaporated in vacuo. The residue was crystallized from isopropanol/diethyl ether. Yield: 1.9g. This was consistent with a reference sample of the hydrochloride salt of the title compound. Example 10 (Method B) Production of 1-[bis-(3′,5′-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride a 1-[bis-( Preparation of 3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-bromoethanol 0.02 mol (7.4
g) 0.03 mol (1.2 g) dissolved in 20 ml H ₂ O in a solution of bis-3′,5′-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone
A solution of NaBH ₄ was added. The reaction mixture was stirred for 3 hours at ambient temperature and then the solvent was evaporated. The residue was partitioned between diethyl ether and water and the ether phase was then evaporated to give 3.5 g of a yellow oil. NMR: δppm: 3.05 (d, 12H), 3.70 (m, 2H),
4.95 (m, 1T), 6.97 (m, 3H), (CDCl ₃ ,
TMS). b Production of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-benzyl-N-tert-butylaminoethanol hydrochloride 0.01 mol ( 3.8g)
of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-bromoethanol in 60 ml of ethanol.
0.015 mole (2.4 g) benzyl-tert-butylamine was added. The mixture was stirred under reflux for 18 hours, then the solvent was evaporated. The residual oil was dissolved in isopropyl alcohol and acidified with isopropanolic hydrogen chloride. Addition of diethyl ether precipitates 3.6 g of impure title compound;
It was further purified by column chromatography on silica 60 (CHCl ₃ /EtOH; 10/1) to 1.3
g of pure title compound was obtained. NMR: δppm: 1.63 (s, 9H), 3.00 (m, 1H),
3.02 (s, 12H), 3.80 (m, 1H), 4.20 (m,
1H), 4.85 (m, 1H), 5.65 (m, 1H), 6.25
(d, 2H), 6.80 (t, 1H), 7.50 (m,
3H), 7.95 (m, 2H), ( _CDCl3 , TMS). This compound is 3′,5′-bis-(N,N-dimethylcarbamoyloxy)-2-N-benzyl-
It was consistent with a reference sample prepared by reducing tert-butylaminoacetophenone with _NaBH4 . c Production of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 0.01 mol (4.9 g) of the compound obtained in b) 120ml
The solution in EtOH was hydrogenated in the presence of 0.2 g of 10% Pd/C at atmospheric pressure and ambient temperature. After the calculated amount of hydrogen had been used, the catalyst was removed and the liquid was evaporated in vacuo. The crystalline residue was recrystallized from propanol/diethyl ether. Yield: 3.8g Cl ^-calculated value: 8.8% Cl ^-measured value: 8.8 HPLC: 99.8% Example 11 (Method C) 1-[Bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl] -2-N-Tertiary butylaminoethanol hydrochloride production a Production of bis-(3',5'-N,N-dimethylcarbamoyloxy)styrene oxide 0.02 mol (7.4
g) of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone, 0.04 mol (1.6 g) dissolved in 20 ml _H2O .
A solution of NaBH ₄ was added. The mixture was stirred at ambient temperature for 3 hours and then evaporated. The residue was partitioned between diethyl ether and water and the ether phase was evaporated to give 3.8 g of a colorless oil. NMR: δppm: 2.75 (q) + 3.10 (q) (1H), 3.05
(d, 12H), 3.52 (m, 1H), 3.82 (q,
1H), 6.97 (m, 3H) ( _CDCl3 , TMS). b Production of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-benzyl-N-tert-butylaminoethanol hydrochloride 0.013 mol (3.8 In a solution of g) styrene oxide dissolved in 60 ml of ethanol,
0.015 mol (2.4 g) in 60 ml ethanol
of benzyl-tert-butylamine was added.
The mixture was stirred under reflux for 18 hours, then the solvent was evaporated. The residue was dissolved in isopropyl alcohol and acidified with isopropanolic hydrogen chloride. Addition of diethyl ether precipitated 3.6 g of the impure title compound, which was subjected to column chromatography on silica 60 (CHCl ₃ /
Further purification with EtOH; 10/1) gave 1.3 g of the title compound. NMR: δppm: 1.63 (s, 9H), 3.00 (m, 1H),
3.02 (s, 12H), 3.80 (m, 1H), 4.20 (m,
1H), 4.85 (m, 1H), 5.65 (m, 1H), 6.25
(d, 2H), 6.80 (t, 1H), 7.50 (m,
3H), 7.95 (m, 2H), ( _CDCl3 , TMS). This compound is 3′,5′-bis-(N,N-dimethylcarbamoyloxy)-2-N-benzyl-
It was consistent with a reference sample prepared by reducing tert-butylaminoacetophenone with _NaBH4 . c Production of 1-[bis-(3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 0.01 mol (4.9 g) of the compound obtained in b) 120ml
The solution in EtOH was hydrogenated in the presence of 0.2 g of 10% Pd/C at atmospheric pressure and ambient temperature. After the calculated amount of hydrogen had been used, the melting medium was removed and the liquid was evaporated in vacuo. The crystalline residue was recrystallized from isopropanol/diethyl ether. Yield: 3.8g Cl ^-calculated value: 8.8% Cl ^-measured value: 8.8% HPLC: 99.8% Example 12 (Method C) 1-[Bis-3',5'-N,N-dimethylcarbamoyloxy)phenyl] -2-N-Tertiary-butylaminoethanol hydrochloride production Add 0.73 g to a solution of 1.7 g (0.006 mol) of bis-3,5-(N,N-dimethylcarbamoyloxy)styrene oxide dissolved in 100 ml of ethanol.
(0.01 mol) of tert-butylamine was added. The solution was refluxed for 18 hours and the solvent was evaporated. The residue was dissolved in isopropanol and ethanolic hydrogen chloride was added. After evaporation, the residue was crystallized from isopropanol/diethyl ether to give the title compound. Yield: 1.4g NMR was consistent with that from Example 1 compound. The starting material was prepared as follows. Bis-3,5-(N,N-dimethylcarbamoyloxy)styrene oxide 3.5 g (0.01 mol) dissolved in 50 ml dioxane
of bis-3',5'-(N,N-dimethylcarbamoyloxy)-2-bromoacetophenone of 0.8 g (0.02 mol) dissolved in 10 ml of water.
A solution of _NaBH4 was added. Mix this mixture at room temperature for 3
After stirring for an hour, the solvent was evaporated. The residue was extracted with diethyl ether/water. The ether phase was then dried with MgSO ₄ , filtered and evaporated to give an oil. Yield: 2.7g. Colorless oil. NMR: (CDCl) ₃ δppm: 2.75 (1H, m), 3.15
(1H, m), 3.85 (1H, m), 7.00 (3H,
m). Structural formula of the obtained compound Example 13 (Method E) Preparation of 1-[bis-3',5'-N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride Preparation of starting material a Bis-3 ,5-(N,N-dimethylcarbamoyloxy)phenylglyoxal monoethyl acetal In a solution of 5.9 g (0.02 mol) of bis-3,5-(N,N-dimethylcarbamoyloxy)acetophenone dissolved in 100 ml of dioxane 4.4g
(0.04 mol) of SeO ₂ in water was added. The resulting mixture was refluxed under stirring for 18 hours. After filtration and evaporation of the solvent, remove 100 ml of the remaining oil.
of ethanol and refluxed for 10 minutes. The residue obtained after evaporation was dissolved in diethyl ether and washed twice with water. Dry the ether solution with _MgSO4 ,
Filtration and evaporation to dryness gave a pale yellow oil. Yield: 4g NMR (CDCl ₃ ) δppm: 1.15 (3H, m), 3.10
(12H, d), 3.65 (3H, m), 5.65 (1H,
s), 7.60 (3H, m). b 4 g (0.011 mol) of the compound obtained in step a) above
Add 1.3ml to a solution of 100ml of ethanol.
(0.012 mol) of tert-butylamine was added. This solution was refluxed for 1 hour. The compound obtained in this step, i.e. the formula The compound represented by was not isolated but used in the form of a solution obtained. c. To the reaction solution obtained in step b) above, add 0.8 g (0.02 mol) of NaBH ₄ in 20 ml of water,
The mixture was stirred at room temperature for 30 minutes. The residue obtained after evaporation was dissolved in diethyl ether/water,
The ether phase was further washed with water. Ethereal hydrogen chloride was then added to the ether phase and the resulting solution was then evaporated to give the title compound in the form of an oil, which was crystallized from isopropanol/diethyl ether. Yield: 2.4g. NMR was consistent with that from the compound of Example 1. The following examples illustrate how compounds of the invention can be incorporated into pharmaceutical compositions. Example 14 Aerosol for inhalation 1-[bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 0.75g Miglyol 0.20g Frigen 11/12 /113/114
Amount to make a total amount of 100.0g Example 15 Tablet 1-[Bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 6.0mg Morokoshidono) Powder 25.0mg Lactose 206.0mg Gelatin 1.5mg Talc 10.0mg Magnesium stearate 1.5mg 250.0mg Example 9 Suppositories Each suppository contains: 1-[Bis(3′,5′-(N, N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 6.0mg Ascorbyl palmitate 1.0mg Base for suppositories (Imhausen H)
Amount to make total amount 2000.0 mg Example 7 Syrup 1-[bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 0.60g Liquid glucose 30.0 g Sucrose 50.0g Ascorbic acid 0.1g Sodium pyrosulfite 0.01g Disodium edelate 0.01g Orange essence 0.025g Legally fixed colorant 0.015g Purified water Amount to make total amount 100.0g Example 18 Inhalation solution 1 - [Bis(3) ',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 0.75g Sodium pyrosulfite 0.10g Disodium edelate 0.10g Sodium chloride 0.85g Purified water Total amount 100.0 ml Example 19 Solution for rectal administration (rectal vial) 1-[bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol) Hydrochloride 6.0mg Sodium pyrosulfite 1.5mg Disodium edenoate 0.3mg Sterile water Amount to make a total volume of 3.0ml Example 20 Sublingual tablet 1-[Bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl) ]-2-N-Tertiary butylaminoethanol hydrochloride 3.0mg Lactose 83.0mg Agar 5.0mg Talc 5.0mg 100.0mg Example 21 Drop 1-[Bis(3',5'-(N,N-dimethyl Carbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 0.60g Ascorbic acid 1.00g Sodium pyrosulfite 0.10g Disodium edelate 0.10g Liquid glucose 50.00g Absolute ethanol 10.00g Purified water Make total volume 100.0ml Amount Example 22 Tablets Each tablet contains: 1-[bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 6.0 mg 1-(3′,5′-dihydroxyphenyl)-2-
Tertiary butylaminoethanol sulfate (terbutaline) 2.0mg Corn starch 25.0mg Lactose 204.0mg Gelatin 1.5mg Talc 10.0mg Magnesium stearate 1.5mg 250.0mg Example 23 Tablets Each tablet contains: 1-[Bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 6.0mg α-(tertiary)-butylaminomethyl-4- Hydroxy-m-xylene-α-diol sulfate (salbutamol) 2.0 mg Corn starch 25.0 mg Lactose 204.0 mg Gelatin 1.5 mg Talc 10.0 mg Magnesium stearate 1.5 mg 250.0 mg Example 24 Tablets Each tablet contains the following: 1-[Bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 6.0mg 1-(3',5'-diisobutyryloxy) -Phenyl]-2-[tertiary butylamino]-ethanol hydrochloride (ibuterol) 2.0mg Corn starch 25.0mg Lactose 204.0mg Gelatin 1.5mg Talc 10.0mg Magnesium stearate 1.5mg 250.0mg Example 25 Tablets Each tablet is Contains: 1-[bis(3',5'-(N,N-dimethylcarbamoyloxy)phenyl]-2-N-tert-butylaminoethanol hydrochloride 6.0mg 1-(3',5') -dihydroxyphenyl)-2-
(Isopropylamino)ethanol sulfate (orciprenaline) 2.0mg Corn starch 25.0mg Lactose 202.0mg Gelatin 1.5mg Talc 10.0mg Magnesium stearate 1.5mg 250.0mg Example 26 Syrup 1-[Bis(3',5'-( N,N-dimethylcarbamoyloxy)phenyl]-2-N-tertiary butylaminoethanol hydrochloride 0.060g 1-(3',5'-dihydroxyphenyl)-2-
(Tertiary butylamino)ethanol sulfate (terbutaline) 0.020g Liquid glucose 30.0g Sucrose 50.0g Ascorbic acid 0.1g Sodium pyrosulfite 0.01g Disodium edelate 0.01g Orange essence 0.025g Legally fixed colorant 0.015g Purified water Total amount Amount to make 100.0 ml The results of pharmacological tests on the compounds of the present invention are shown below. A. Persistence study of serum levels of terbutaline after administration of a compound of the invention to unanesthetized dogs. Five dogs (beagles,
Males, weighing 13-18 kg) were used repeatedly. Each dog was used a maximum of once a week. The night before the experiment, food was removed from the animals (water was provided ad libitum). The test compound was dissolved in 8 ml of distilled water and applied to the back of the tongue using a syringe and short tube. This oral administration was followed by an 8 ml water wash. Blood was collected from the upper veins of the forelimbs by the use of vacuum tubes. Diisopropylfluorophospheate (DFP), an esterase inhibitor
was added, the sample was centrifuged (+5°), and the amount of terbutaline in the plasma was determined by mass spectrometry (mass spectrometry).
fragmentography). Serum levels of terbutaline indicate the extent of the bronchospasmodic effect of the test compound. The amount of test substance to be administered is such that the level of terbutaline is the serum level obtained in patients in clinical use and found to be effective, i.e. at least 2 ng/ml serum for a period of 6 to 8 hours. chosen to correspond to terbutaline levels. The dosage of the test substance of the invention was chosen such that the serum level of terbutaline obtained corresponds approximately to the serum level obtained after administration of terbutaline itself. The test results are given in Table 1 below, where the serum levels of terbutaline in the test animals over time are given. Each set of serum levels is the result of testing in one dog. The time intervals in the box represent the time intervals during which clinically effective terbutaline serum levels are obtained. Thus, the intervals within the box represent the clinically useful duration of the test compound.

Table 1 shows that the test substances of the invention give serum levels of 2 ng/ml or more for 16 hours or more. The reference substance, terbutaline, gives comparable serum levels for about 8 hours, the duration normally obtained in clinical use of terbutaline. B Bronchodilator effect of the compound of the invention itself B1 In vitro tests on isolated guinea pig trachea Guinea pig trachea is excised, cut into spirals and placed in an organ bath containing Krebs solution at 37° C. and aerated with carbogen. Ten
Transfer to ml. The tracheal segment is twitched with pilocarpine (4 x 10 ^-6 mol/) to create a tension of approximately 1.5 g. Isometric recordings were performed using a transducer FT03 and a glass polygraph 7D. Before administering the test compound, the esterase inhibitor eselin was added to this bath at 1×10 ^-6 mol/kg.
added to the concentration of The concentration of the test substance giving a 50% relaxation of the pilocarpine spasm trachea (EC50) as well as the enhancing or inhibitory effect of the test substance of the invention on the relaxing effect of terbutaline were recorded. In this last test, muscle specimens were pretreated with the test compound for 5 minutes before recording terbutaline responsiveness. The test results are given in Table 2 below.

【table】 \ \

N−C− N−C−
＞200 3 None
／ ／

CH ₃ CH ₃

It can be seen from Table 2 that the test substance does not produce any bronchodilator effect. No potentiating or inhibiting activity of the test substance was observed on the bronchodilator effect of terbutaline. B2 Bronchospasm alleviation effect of test compound after oral administration to guinea pigs Dunkin Hartley male guinea pigs (150~
200g) were used in this study. Animals were fasted for approximately 15 hours (water provided ad libitum) before administration of test compound or vehicle (control) via intragastric tube. Maximum plasma levels of terbutaline produced from hydrolysis of certain precursor drugs of terbutaline were determined to establish a sufficient time period between administration and histamine exposure.
Briefly, blood samples were collected from guinea pigs at various times after administration of the test compound (preliminary experimental system) and plasma levels of terbutaline were determined by mass spectrometry. Plasma terbutaline peaks 50-60 minutes after administration
minutes, and this time was chosen as the histamine initiation time. Histamine Aerosol is 0.02% Histamine HCl
and 3% glycerol using a Bird in-line atomizer. Its protective effect was estimated from the delay in the appearance of anoxic signs in drug-treated animals. With this aerosol used, more than 90% of controls showed hypopnea within 3 minutes. Drug-treated guinea pigs that did not show any signs of respiratory effects from histamine during this first 3 minutes were scored as protected. The test results are given in Table 3 below.

【table】 \ \

N−C− N
−C− 2.7 6.7〓10 ⁻³
／ ／

CH ₃ CH ₃

Table 3 shows that the test compound is less active on a molar basis than the reference substance terbutaline in protecting test animals against histamine-induced bronchospasm. C Effect of test compound on isolated heart specimen C1 In vitro test on isolated guinea pig auricle Dunkin Hartley male guinea pig (400-500
g) was used. After exsanguination and removal of the heart, the atrial appendage is cut away from the ventricular portion, and
Submerged in 37° carbogen-aerated Grebs solution. The frequency and force of this spontaneously pulsating specimen was measured using a glass transducer.
Recorded by FT03. Polygraph (glass 7D)
In , the signal from the isometric transducer sends a trigger function from the drive amplifier to the tachograph to record the velocity. Before adding the drug to be tested, the esterase inhibitor eselin was added to the organ bath at a concentration of 1 x 10 ^-6 mol/. The intrinsic activity of the test compounds on cardiac specimens is determined by their effects on cardiac rate (chronotropic effect) and cardiac force (inotropic effect) and their possible interaction with terbutaline. Researched. The test results are given in Table 4 below.

【table】 \ \

N−C− N
−C− 0 0
／ ／

CH ₃ CH ₃

It can be seen from Table 4 that the test compounds did not exhibit any chronotropic or inotropic effects. The potential potentiating or inhibiting response of the test compound to the chronotropic and inotropic effects of terbutaline was also examined by adding the test compound to the organ bath at the same concentration as terbutaline.
No enhancing or inhibiting effects were observed for the test compounds on the chronotropic and inotropic effects of terbutaline. C2 In Vivo Study of the Effect of Test Compounds on Heart Rate in Dogs Five dogs (male beagle, 13-18 kg) were used repeatedly in this study. Each dog may receive up to 1 per week
Used twice. Food was removed from the animals the night before the experiment (water was provided ad libitum). The test compound was dissolved in 8 ml of distilled water and applied to the back of the tongue using a syringe and short tube. This oral administration was given with a water rinse of approximately 8 ml. Blood was collected from the upper veins of the forelimbs by the use of vacuum tubes.
Add the esterase inhibitor diisopropylfluorophosphate (DFP) and centrifuge the sample (+5°).
Then, the amount of terbutaline in plasma was measured by mass spectrometry. The serum level of terbutaline indicates the extent of the bronchospasm-relaxing effect of the test compound. The amount of test substance to be administered should be such that the level of terbutaline when administered as such is the serum level obtained in patients in clinical use and found to be effective, i.e. for at least 6 to 8 hours.
It was chosen to correspond to a serum level of 2 ng/ml.
The dosage of the test substance of the invention was chosen such that the serum level of terbutaline obtained approximately corresponds to the serum level obtained after administration of terbutaline itself. Heart rate is the average of 3 measurements over 10 minutes measured with a stethoscope before drug administration and before each blood sample collection). The relative effect of the test compound on heart rate in test animals was demonstrated by plotting the heart rate increase measured at the diaphragm terbutaline serum concentration against the logarithm of the terbutaline concentration in the serum. . Only values before and up to the maximum increase in heart velocity were used. This method yields a graph consisting essentially of straight lines. When such a line is constructed for each test compound, the slope of the line provides an indication of how the heart rate correlates with the serum concentration of the test compound. In this test, the slope of the line and the correlation coefficient were examined for the reference material terbutaline and test compound No. 1. The results are given in Table 5.

【table】 \ \

N-C- N-C-
0.3～3 0.63 0.9324 10
／ ／

CH ₃ CH ₃

It can be seen from Table 5 that the test compounds produce relatively much lower heart rate increases than the reference compound terbutaline. C3 In Vivo Study of the Duration of Action of Test Compounds Measured as Effects on Heart Rate in Dogs Tested using beagle dogs. Each dog was used a maximum of once a week. Animals were fasted the night before the experiment (water provided ad libitum). 8ml of test compound
It is dissolved or suspended in distilled water and injected into the back of the mouth using a syringe and short tube. This oral administration was followed by a rinse with approximately 8 ml of water. The dose of the test compound was determined to provide the same level of bronchospasm alleviation effect. Terbutaline was used as a control. Cardiac velocity was measured using a stethoscope for 5 minutes;
It was calculated as the average value of three times. The following compounds were used as test compounds. Terbutaline was used as a known compound. The dose of the compound of the present invention was 0.6 mg/Kg, and the dose of terbutaline was 0.1 mg/Kg. The test results are shown in Figure 1. In Figure 1 -○・
- indicates D2454, -△- indicates D2456, and -•- indicates the cardiac velocity curve of terbutaline. From FIG. 1, it can be seen that the compound D2454 of the present invention and
It appears that D2456 has an exceptionally long duration of action compared to terbutaline. Comments on test results from pharmacological studies It is first observed that the compounds of the present invention are hydrolyzed in serum and body fluids to form the compound terbutaline, which in turn exhibits a bronchodilatory effect. That such hydrolysis is occurring is indirectly evident from drug testing in which serum levels of terbutaline and others are consistently measured. In test A, the compounds of the invention were administered for at least twice as long as the reference substance terbutaline gave corresponding serum levels (8 hours vs. 16 hours).
Clinically useful terbutaline serum levels (2 ng/ml serum or more) for hours or more
It is shown that it gives In test B1 (in vitro bronchodilator effect in isolated guinea pig trachea) it was shown that the test compound did not exhibit any intrinsic bronchodilator effect. No enhancing or inhibiting activity of this test compound on the bronchodilator effect of terbutaline was observed. Test B2 shows the bronchospasmolytic effect of the test compound in an in vivo test in guinea pigs. The bronchospasmolytic activity of the test compound upon oral administration was approximately 5 times less than that of the reference compound terbutaline on a molar basis. In test C1, in an in vitro test,
It is shown that the compounds of the invention do not themselves have any inotropic or chronotropic effects on isolated guinea pig heart preparations. An esterase inhibitor was added to confirm that the effect was specific to the test compound being measured and not to the hydrolysis product terbutaline. Test C2 shows, by in vivo testing in dogs, that the test compounds of the invention have a significantly reduced heart rate stimulating effect compared to that of terbutaline. In conclusion, the compounds of the invention are bronchospasmolytic agents with a very long duration of action and they also exhibit reduced cardiac effects compared to the prior art compound terbutaline. The long-term persistence of activity, measured as the period of time during which serum levels of the hydrolysis product terbutaline are at least 2 ng/ml or greater, indicates that the compounds of the present invention will last for 24 hours during which an asthmatic patient must take the drug. This means making it possible to reduce the number of hits. In particular, a duration of therapeutic activity of about 16 hours or more, which by use of a single dose of the active substance can be effective for patients during normal sleep periods,
And it makes it possible to protect with fewer side effects. Effects of Bambuterol and Terbutaline on Rat Myometrium in Vitro Bambuterol, a carbamate ester brodrug of terbutaline, and pure terbutaline were compared for their effects on oxytocin-induced contractions of rat uterus in vitro. Method Female Sprague-Dawley rats (170-200
g) was used. Steroids 4-6 days before the experiment
Animals were brought into oestrus by subcutaneous administration of Estradurin (2.5 mg/Kg). The rat was exsanguinated and the uterus was removed. The horn-like structures were longitudinally dissected and placed in an organ gun bath in Locke's solution at 33°C and aerated with Carbogen. Oxytocin produces standard contractions, and this octapeptide is administered 10 minutes after administration of bambuterol or terbutaline and at a dose (0.01
IE/ml) was added to the bath. There were no esterase inhibitors present in the bath. Tension change (5~
35mN) is record isometrically
(Grass transducer FP03 and polygraph
7B) was done. Results Eight animals were used in this study. The results obtained are shown in the graphs of FIGS. 2 and 3.
In the graph, the percent oxytocin-induced contraction (vertical axis) can be correlated to the concentration (moles/liter) used of the two drugs (horizontal axis). From Figure 2, bambuterol is 1×10 ^-4 mol/
It can be seen that even concentrations up to a liter have no obvious effect on the myometrial preparation. Unesterified terbutaline shows concentration-related inhibition of induced contractions, with 50% efficacy (EC ₅₀ )
was approximately 3×10 ^-8 mol/liter. Pretreatment of uterine specimens with terbutaline or bambuterol does not differ in response from subsequent administration of bambuterol or terbutaline, respectively. Summary Oxycytosine-induced contractions of rat uteri in vitro were neither appreciably suppressed nor enhanced by the presence of bambuterol. On the other hand, pure terbutaline suppresses the contractile response in a relationship with the concentration, with an EC ₅₀ of 3×
It was 10 ^-8 mol/liter. Thus, terbutaline exhibits a tocolytic effect, but as mentioned earlier, the compound of the present invention is hydrolyzed in serum and body fluids to produce the compound terbutaline, so the compound of the present invention can also be administered in vivo. When used, it exhibits uterine tocolytic effect. Furthermore, it has already been reported in Ginecologia Y Obstetricia De that terbutaline exhibits uterine contraction inhibitory effects.
It has also been reported in Mexico, vol. 36, Agosto, 1974, pp. 75-88, etc. Furthermore, the results of an acute toxicity test on the compound of the present invention were as follows.

【table】

【table】 [Brief explanation of drawings]

FIG. 1 is a graph showing the relationship between the elapsed time after drug administration and the heart rate. FIGS. 2 and 3 are graphs showing the relationship between the concentration of bambuterol or lerbutaline and the rate of uterine tocolysis, respectively. In Figure 1, -○・- is D2454, -△- is
D2456, --- shows the graph when terbutaline was administered, respectively.

Claims (1)

[Claims] 1 formula {wherein R is selected from the group consisting of -C(CH ₃ ) ₃ , [formula] and [formula], R ¹ is selected from the group consisting of H and R ² , and R ² is [formula] [formula] in which R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are
If R ³ is hydrogen, R ⁴ is hydrogen and R ³ is 1
- in the case of an alkyl group containing 3 carbon atoms, R ⁴ is hydrogen or combined as an alkyl group containing 1 to 3 carbon atoms} and Therapeutically acceptable salts thereof. 2. A compound according to claim 1 in the form of a substantially pure optical isomer and a therapeutically acceptable salt thereof. 3 R ¹ and R ² together (wherein R ³ and R ⁴ are hydrogen or an alkyl group containing 1 to 3 carbon atoms),
Compounds according to claim 1 and therapeutically acceptable salts thereof. 4 R ¹ is hydrogen and R ² is and therapeutically acceptable salts thereof, wherein ^R3 and ^R4 are hydrogen or an alkyl group containing 1 to 3 carbon atoms. 5. Compounds and therapeutically acceptable salts thereof according to any of claims 3 and ⁴ , wherein R ³ and R 4 are CH ₃ — or CH ₃ CH ₂ —. 6. A compound according to any one of claims 1 to 5, wherein 6R is -C( _CH3 ) ₃ . 7 formula and therapeutically acceptable salts thereof. 8 formula and therapeutically acceptable salts thereof. 9 formula and therapeutically acceptable salts thereof. 10 formula and therapeutically acceptable salts thereof. 11 formula and therapeutically acceptable salts thereof. 12 formula {In the formula, R is selected from the group consisting of -C(CH ₃ ) ₃ , [Formula] and [Formula], R ¹ is selected from the group consisting of hydrogen and R ² , R ² is [Formula] [In the formula] R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen,
(b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are hydrogen when R ³ is hydrogen and R ^{3 is} 1 to 3;
R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms. In preparing acceptable salts thereof, the formula (wherein R, R ¹ and R ² are as defined above and when R ¹ or R ² is hydrogen the resulting hydroxyl substituent may be protected with a hydroxy protecting group, and R ⁶ is hydrogen or N
- protecting group), then optionally replacing the remaining protecting group with hydrogen to obtain a compound of formula, and then optionally subjecting the compound of formula thus obtained to an optical counter. A method comprising splitting into the polar forms and/or converting into a therapeutically acceptable salt. 13 formula {In the formula, R is selected from the group consisting of -C(CH ₃ ) ₃ , [Formula] and [Formula], R ¹ is selected from the group consisting of hydrogen and R ² , R ² is [Formula] [In the formula] R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen,
(b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are hydrogen when R ³ is hydrogen and R ^{3 is} 1 to 3;
R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms. In preparing acceptable salts thereof, the formula The compound with the formula By reacting with a compound of formula and then optionally replacing the protecting group with hydrogen to obtain a compound of formula (wherein
R, R ¹ and R ² are as defined above, R ⁶ is hydrogen or an N-protecting group, and X is a halogen or a functionally equivalent group thereof capable of reacting with an amine), and then A process comprising optionally resolving the compound of formula thus obtained into its optical antipodes and/or converting it into a therapeutically acceptable salt. 14 formula {In the formula, R is selected from the group consisting of -C(CH ₃ ) ₃ , [Formula] and [Formula], R ¹ is selected from the group consisting of hydrogen and R ² , R ² is [Formula] [In the formula] R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen,
(b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are hydrogen when R ³ is hydrogen and R ³ is 1 to ³ ;
R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms. In preparing acceptable salts thereof, the formula Formula the compound of By reacting with a compound of formula and then optionally replacing the protecting group with hydrogen to obtain a compound of formula (wherein
R, R ¹ and R ² are as defined above and R ⁶ is hydrogen or an N-protecting group), and then optionally the compound of formula thus obtained is resolved into its optical antipodes. and/or converting into a therapeutically acceptable salt. 15 formula {In the formula, R is selected from the group consisting of -C(CH ₃ ) ₃ , [Formula] and [Formula], R ¹ is selected from the group consisting of hydrogen and R ² , R ² is [Formula] [In the formula] R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen,
(b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are hydrogen when R ³ is hydrogen and R ^{3 is} 1 to 3;
R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms. In preparing acceptable salts thereof, the formula Reduction of the compound, followed by optional replacement of the protecting groups with hydrogen, yields the compound of formula (wherein
R, R ¹ and R ² are as defined above), and then optionally the compound of formula thus obtained is resolved into its optical antipodes and/or converted into a therapeutically acceptable salt. A way of doing things. 16 Formula in combination with a pharmaceutically acceptable carrier {wherein R is selected from the group consisting of -C(CH ₃ ) ₃ , [formula] and [formula], R ¹ is selected from the group consisting of H and R ² , and R ² is [formula] [formula] in which R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are
If R ³ is hydrogen, R ⁴ is hydrogen and R ³ is 1
~ R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms, in the case of an alkyl group containing from 1 to 3 carbon atoms A bronchodilator preparation containing an effective amount of as an active ingredient. 17. The formulation according to claim 16 in dosage unit form. 18. A patent comprising as an active ingredient a first component comprising a compound according to claim 16 in combination with a second component comprising a commonly used bronchospasmolytic agent with a rapid onset of action. The formulation according to claim 16. 19. The formulation of claim 18, wherein the second component is selected from the group consisting of terbutaline, buterol, orciprenaline, salbutamol, epinephrine, isoprenaline and efuedrine. 20 Formula in combination with a pharmaceutically acceptable carrier {wherein R is selected from the group consisting of -C(CH ₃ ) ₃ , [formula] and [formula], R ¹ is selected from the group consisting of H and R ² , and R ² is [formula] [formula] in which R ³ is selected from the group consisting of (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, and R ⁴ is (a) hydrogen, (b) selected from the group consisting of alkyl groups containing 1 to 3 carbon atoms, provided that R ³ and R ⁴ are
If R ³ is hydrogen, R ⁴ is hydrogen and R ³ is 1
~ R ⁴ represents hydrogen or an alkyl group containing from 1 to 3 carbon atoms, in the case of an alkyl group containing from 1 to 3 carbon atoms A preparation for human uterine relaxation containing as an active ingredient an effective amount of.