JPH0360814B2 - - Google Patents

Description

[Detailed description of the invention]

INDUSTRIAL APPLICATION FIELD OF THE INVENTION The present invention relates to certain sulfonamides useful as antiarrhythmic agents, and intermediates thereof. PROBLEM TO BE SOLVED BY THE INVENTION The antiarrhythmic compounds of the present invention prolong the duration of action potentials in the myocardium and conducting tissues, thereby increasing refractoriness to early stimulation. They are therefore classified under the Vaughan Williams classification (Anti-Arrhythmic Action).
According to E.M. Action, E.M. Vaughan Williams, Academic Press, 1980], it is a class antiarrhythmic agent. They are effective both in vitro and in vivo in the atria, ventricles, and conducting tissues, and therefore for the prevention and treatment of a wide range of ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation. It is useful for
These do not change the speed at which the stimulus is transmitted, so
They are less likely to promote or worsen arrhythmias than currently used drugs (mostly grade-level) and produce fewer neurological side effects. Some of the compounds also have some positive inotropic effects and are therefore particularly beneficial in patients with impaired cardiac pumping function. Means for Solving the Problems Thus, the present invention provides formula (A): [In the formula, R ^a is −NO ₂ , −NH ₂ or −
NHSO ₂ R ¹ (where R ¹ is a C ₁ -C ₄ alkyl group); R ^b is -NO ₂ , -NH ₂ or R ³ {where R ³ is -
NHSO ₂ (C ₁ −C ₄ alkyl) or −CONR ⁴ R ⁵
(R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ alkyl group, or together with the nitrogen atom to which they are attached, 1-pyrrolidinyl group, piperidino group, morpholino group or N- methylpiperazin-1-yl group); provided that when one of R ^a and R ^b is _-NO2 , the other is not _-NH2 ; X is O, S or directly a bond; Y is an ethylene group optionally substituted with a methyl group; “alk” is an ethylene, trimethylene, or tetramethylene group; “alk” is optionally substituted with a methyl group; R is a _C1 - _C4 alkyl group; and ^R2 is H, halogen, _CF3 or _C1-
C ₄ alkyl group] or a salt thereof. Formula (A) includes compounds that are antiarrhythmic agents and compounds that are synthetic intermediates useful in the production of these arrhythmic agents. The compound with antiarrhythmic activity has the formula () shown below; the remaining compounds are only synthetic intermediates. Therefore, the present invention provides the formula (): [wherein R and R ¹ are each independently a C ₁ -C ₄ alkyl group; X is O, S or a direct bond; Y is an ethylene group optionally substituted by a methyl group; Yes; “alk” is an ethylene, trimethylene or tetramethylene group, “alk” is optionally substituted by a methyl group; R ² is H, halogen, CF ₃ or C ₁ -C ₄ alkyl group; and R ³ is of the formula: -NHSO ₂ (C ₁ -C ₄ alkyl) or -CONR ⁴ R ⁵ where R ⁴ and R ⁵ are each independently H or C ₁ -C ₄ Alkyl groups, or together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, morpholino or N-
methylpiperazin-1-yl group] and pharmaceutically acceptable salts thereof. "Halogen" means F, Cl, Br or I. _C3 and _C4 alkyl groups can be straight chain or branched. R is preferably _CH3 or _C2H5 , _most preferably _CH3 . R ¹ is preferably CH ₃
It is. An example of “alk” is −(CH ₂ ) _o −(n is 2,3
or 4), -CH( _CH3 ) _CH2 -,- _CH2CH
(CH ₃ )−, −CH(CH ₃ )CH ₂ CH ₂ − and −
CH ₂ CH ₂ CH (CH ₃ )−. "alk" is preferably -( _CH2 ) _o- (n is 2, 3 or 4), -
CH( _CH3 ) _CH2- or _-CH2CH ( _CH3 )-. "alk" is most preferably -( _CH2 ) _2- . X is preferably O. Y is preferably -
(CH ₂ ) ₂ −. R ² is preferably H, CH ₃ or Cl. R ² is most preferably H.
R ³ is preferably -CONH ₂ , -CONHCH ₃ , -
CON(C ₂ H ₅ ) ₂ −,

[Formula] or -NHSO ₂ CH ₃ . R ³ is most preferably -
_{NHSO2CH3 .} One preferred group of compounds comprises the formula ( ) as defined above, where R, R ¹ , R ² , R ³ and “alk”
is as defined for formula (), and Y is −
( _CH2 ) _2- , and X is O or S). Another preferred group of compounds are those of formula (), where R, R ¹ , R ² , R ³ and "alk" are as defined for formula (), X is a linear bond, and Y is −(CH ₂ ) ₂ −). Preferred individual compounds have the formula: and has. The first listed compound is most preferred. Pharmaceutically acceptable salts of compounds of formula () include hydrochloride, hydrobromide, hydroiodide, sulfate or bisulfate, phosphate or hydrogenphosphate, acetate, maleate. , pharmaceutically acceptable anions such as fumarate, lactate, tartrate, citrate, gluconate, benzoate, methanesulfonate, benzenesulfonate and p-toluenesulfonate. There are acid addition salts formed from acids that form non-toxic acid addition salts containing.
The compounds also form metal salts, preferred examples of which are alkaline earth and alkali metal salts. Most preferred are the sodium and potassium salts. These salts can be manufactured by commonly used techniques. For evaluation of the effect of the present compounds on atrial refractoriness, the right atrium of guinea pigs is fixed in a bath containing physiological saline and one end is connected to a force transducer. The tissue is stimulated at 1 Hz using field electrodes. effective refractory period (ERP)
is measured by introducing an early stimulus S ₂ after every eighth elementary stimulus S ₁ . This S ₁ S ₂ connection interval is
S ₂ is gradually increased until it reproducibly elicits the communicated response. this
Define as ERP. The concentration of compound required to increase ERP by 25% (ED ₂₅ ) is then determined. ERPs are also measured in the right papillary muscle of guinea pigs incubated in saline. The muscle is stimulated at one end using a triode electrode,
The transmitted electrogram is recorded at the opposite end via a monopolar surface electrode. ERPs are determined as described above using the extrastimulus technique. Conduction time is obtained from a digital storage oscilloscope by measuring the interval between the stimulus artefact and the electrogram peak (i.e., the time required for the stimulus to travel along the length of the muscle). . Atrial and ventricular ERPs can also be determined by extrastimulus while pacing the atrium or right ventricle to a constant heart rate in anesthetized or conscious dogs.
measurement technique). While a compound of formula () can be administered alone, it will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard manufacturing methods. These can be administered prophylactically to patients suffering from arrhythmia or at risk of developing arrhythmia. For example, they may be in the form of tablets containing excipients such as lactose or starch, or in capsules alone or mixed with excipients, or in the form of elixirs or suspensions containing flavoring or coloring agents. It can be administered orally. They may be injected parenterally, eg intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of sterile aqueous solutions that may contain other solutes, such as sufficient salt or glucose to make the solution isotonic. For administration to humans in the therapeutic or prophylactic treatment of cardiac conditions such as ventricular and supraventricular arrhythmias, including atrial and ventricular fibrillation, an average oral dose of a compound of formula () It is contemplated that for an adult patient (70 kg) the dosage will be in the range of 1 to 75 mg per day, administered in divided doses up to 4 times per day. Doses for intravenous administration would be expected to be in the range of 0.5 to 10 mg per administration, as appropriate. Severe cardiac arrhythmias are preferably treated by intravenous route to effect rapid conversion to normal rhythm. Thus, for a typical adult patient, an individual tablet or capsule will contain, for example, 1 to 25 mg of active compound in a suitable pharmaceutically acceptable vehicle or carrier. As is known to practitioners, variations will occur depending on the weight and condition of the patient being treated. Thus, the present invention provides a compound of formula () as defined above or a pharmaceutically acceptable salt thereof,
and a pharmaceutically acceptable diluent or carrier. The present invention also provides a method of preventing or reducing cardiac arrhythmia in a human, which method comprises administering to the human an effective amount of a compound of formula () or a pharmaceutically acceptable salt thereof, or as defined above. the drug composition. The present invention further provides a compound of formula () or a pharmaceutically acceptable salt thereof for use as a medicament, particularly an antiarrhythmic agent. The present invention also provides the use of a compound of formula () or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the prevention or alleviation of cardiac arrhythmia. Routes Compounds of formula () can be prepared by the following general routes. In the formula, R, R ¹ , R ² , R ³ ,
alk, X and Y are as defined for formula (). This starts with compounds where R ^a is _-NH2 : This reaction is typically carried out in a suitable organic solvent at room temperature and optionally in the presence of a base ("acid acceptor") such as pyridine, triethylamine, sodium bicarbonate or potassium carbonate. The presence of an acid acceptor is particularly useful when alkanesulfonyl chloride or bromide is used as the acylating agent. As sulfonylating agent it is preferred to use sulfonic anhydride (R ¹ SO ₂ ) ₂ O in methylene chloride or sulfonyl chloride R ¹ SO ₂ Cl in pyridine. The product () can then be isolated and purified by conventional techniques. Routes The following routes starting from intermediates where R ^a and R ^b are -NH ₂ are particularly useful when R ³ is -NHSO ₂ (C ₁ -C ₄ alkyl): R, R ² , X, Y and "alk" are as defined for formula (). Of course at least 2
This reaction can be carried out similarly to the route, although equivalent amounts of sulfonylating agent must be used and each alkylsulfonamide group will be the same in the final product (A). Route When ^R3 is _-NHSO2 ( _C1 - _C4 alkyl), the following route starting from compounds where ^Rb is _-NH2 can also be used. R, R ¹ , R ² , X, Y and “alk” are the formula ()
As defined above. This reaction also
It can be implemented similarly to the route. Obviously, this route can be used to prepare final products with different alkanesulfonamide substituents. Novel intermediates used in the route also form part of the invention and have formula (A) as defined above, with the proviso that in addition R ^a and R ^b
at least one of is a nitro group, or
At least one of R ^a and R ^b is an amino group. The starting materials for the above routes can be obtained in conventional manner, for example as follows: (d) Regarding intermediates in which X is only O or S: A variation of this route can use thiophenol or phenol in which R ³ is a nitro group. The hydrogenation step also reduces this nitro group to an amino group (as in route (c) above),
This will result in intermediates of formula () where X is S or O. −CH( _CH3 ) _CH2 −or _−CH2CH ( _CH3 )−
Another variation of this route useful for preparing certain compounds of formula (A) having "alk" as follows: The mixture of 2-nitro group-containing compounds is believed to result from competitive ring opening of the intermediate aziridinium cation formed during the reaction. Nitro group-containing intermediates can be separated by chromatography before the catalytic hydrogenation step. If the starting materials used in (a) to (g) above are not known compounds, they can be prepared by conventional techniques, for example as follows: Route Compounds of formula () can also be prepared as follows: or In the above formula, R, R ¹ , R ² , R ³ , X, Y and alk
is as defined for formula () and Q is a leaving group, e.g. chlorine, bromine, iodine, C ₁ -C ₄
An alkanesulfonyloxy group (particularly a methanesulfonyloxy group), a benzenesulfonyloxy group or a toluenesulfonyloxy group. The presence of an acid acceptor such as sodium bicarbonate, triethylamine or potassium carbonate is optional, but is preferred when Q is halogen. The reaction is typically carried out in an organic solvent, such as ethanol, at a temperature up to reflux, typically about
Performed at temperatures up to 120°C. Preferably, the reaction is carried out under reflux. The product can then be isolated and purified by conventional methods. Starting materials can also be obtained by conventional methods. When the compounds of formula () contain one or more optically active centers, the invention includes both split and undivided forms. EXAMPLES The following examples (in which all temperatures are in °C) illustrate the preparation of compounds of formula (). In these examples, 3 atmospheres is 3.04
×10 ⁵ Pa and 50 p.si is equal to 3.45 × 10 ⁵ Pa. Example 1 (A) 4-{2-[N-methyl-N-(4-nitrophenethyl)amino]ethoxy}benzamide N-methyl-4 in acetonitrile (100ml)
-Nitrophenethylamine (1.8g) [JOC,
(1956), 21, 45] and 4-(2-chloroethoxy)benzamide (see Preparation Example 12), potassium carbonate (3.0 g) and sodium iodide (1.5
g) was added and the suspension was stirred for 72 hours at reflux temperature. After evaporation, add 2N to this remaining oily solid.
After adding aqueous sodium bicarbonate solution, it was extracted three times with methylene chloride. The combined organic layers were washed with saturated aqueous brine, dried over magnesium sulphate, filtered and evaporated to give a yellow oil. When this oil is triturated with diisopropyl ether, 2.3
g of a yellow solid was obtained which was crystallized from toluene to give the title compound (1.4 g), mp 116-
118° was obtained. This was used directly without further purification. (B) 4-{2-[N-(4-aminophenethyl)-N
-methylamino]ethoxy}benzamide A solution of 4-{2-[N-methyl-N-(4-nitrophenethyl)amino]ethoxy}-benzamide (1.4 g) in ethanol (100 ml) was prepared from Raney Nickel (“Nicat 102”, trademark). Stirred for 16 hours at room temperature under 3 atmospheres of hydrogen. The reaction mixture was filtered and evaporated to dryness to give a yellow solid (1.2g). This was crystallized from ethyl acetate to give the title compound (1.1 g), melting point 110.
−112° was obtained. Analysis % Actual value: C, 69.1; H, 7.3; N, 13.05;
Calculated for C ₁₈ H ₂₃ N ₃ O ₂ : C, 69.0; H, 7.4: N, 13.4 (C) 4-{2-[N-methyl-N-(4-methanesulfonamidophenethyl)amino [Ethoxy]
benzamide 4-{2-[N- in dry methylene chloride (50 ml)
(4-aminophenethyl)-N-methylamino]-
A solution of ethoxy}benzamide (1.0 g) and methanesulfonic anhydride was stirred at room temperature for 16 hours. After evaporation, 2N aqueous sodium bicarbonate solution was added to the residue, followed by extraction three times with methylene chloride. The combined organic layers were dried over magnesium sulphate, filtered and evaporated to give a tan solid. Crystallization from toluene/ethyl acetate gave the title compound (0.31 g), melting point 147°. Analysis % Actual value: C, 58.35; H, 6.7; N, 10.45;
Calculated values as C ₁₉ H ₂₅ N ₃ O ₄ S: C, 58.3; H, 6.4; N, 10.7 Examples 2 to 5 The following compounds were prepared from the appropriate starting materials in Examples 1(A) to (C It was manufactured in the same manner as part ). Example 3
and 5, adding ethyl acetate to the solid obtained from the second evaporation stage of part (C), followed by treatment with ethereal hydrogen chloride, filtering off the resulting hydrochloride salt, and converting it into ethyl acetate/methanol The product was characterized as the hydrochloride salt by recrystallization from .

[Table] Example 6 (A) N-methyl-4-(2-methylaminoethoxy)benzamide Methyl 4-(2-chloroethoxy)benzoate (4.3 g) in a 33% solution of methylamine in industrial methanol-denatured alcohol (50 ml) (see Preparation Example 11)
and the mixture in a 130ml sealed pressure vessel.
The mixture was stirred for 16 hours while heating to 100°. After evaporation to dryness, the resulting solid was added to 10 ml of
In addition to a 2N aqueous sodium hydroxide solution, the mixture was extracted three times with methylene chloride. The combined organic layers were dried over anhydrous magnesium sulphate, filtered and evaporated to give a colorless solid. Crystallization from isopropanol gave the title compound (2.1 g), mp 95-96°. Analysis %: Actual value: C, 63.7; H, 7.6; N, 13.4;
Calculated values for C ₁₁ H ₁₆ N ₂ O ₂ : C, 63.4; H, 7.7; N, 13.45 (B) N-methyl-4-{2-[N'-methyl-N'-
(4-nitrophenethyl)amino]ethoxy}-
benzamide N-methyl-4 in acetonitrile (100ml)
Potassium carbonate (3.0 g) and sodium iodide (1.5 g) are added to a solution of -(2-methylaminoethoxy)benzamide and 4-nitrophenethyl bromide.
was added and the suspension was stirred at reflux temperature for 72 hours. After evaporation, add 2N sodium hydroxide solution,
This was followed by extraction three times with methylene chloride. The combined organic layers were washed with saturated aqueous brine, dried over magnesium sulphate, filtered and evaporated to give a yellow oil. This oil was triturated with diisopropyl ether to give the title compound as a yellow solid (2.4g). This material was used without further purification. Nmr (CDCl ₃ ) ppm, δ = 7.9 (d, 2H); 7.52
(d, 2H); 7.12 (d, 2H); 6.63 (d, 2H); 3.9
(t, 2H); 2.8 (m, 9H); 2.28 (s, 3H) (C) N-methyl-4-{2-(N'-(4-aminophenethyl)-N'-methylamino]ethoxy}benzamide N-methyl-4-{2 in ethanol (100ml)
-[N'-Methyl-N'-(4-nitrophenethyl)-
A solution of amino]ethoxy]benzamide (2.3 g) was added to Raneynickel [“Nicat 102”].
- trademark] at room temperature under 3 atmospheres of hydrogen.
Stirred for 16 hours. The reaction mixture was filtered and evaporated to dryness to give a yellow oil (2.1 g). Chromatography on silica (“Kieselgel 60”-trademark), eluting with ethyl acetate, gave the title compound as a colorless oil (1.7 g). This was used directly without further purification. Nmr (CDCl ₃ ) ppm, δ = 7.72 (d, 2H); 7.0
(d, 2H); 6.92 (d, 2H); 6.62 (d, 2H); 3.0
(d, 3H); 2.88 (t, 2H); 2.7 (s, 4H); 2.42
(s, 3H) (D) N-methyl-4-{2-[N'-(4-methanesulfonamidophenethyl)N'-methylamino]
Ethoxy}benzamide hydrochloride N-Methyl-4-{2-[N'-(4-aminophenethyl)-N'-methylamino]ethoxy}benzamide (1.6 g) and methanesulfonic anhydride (0.87 g)
A solution of g) in dry methylene chloride (50ml) was stirred at room temperature overnight. After evaporation, the remaining oily solid was treated with 2N aqueous sodium bicarbonate and extracted three times with methylene chloride. Wash the combined organic layers with saturated brine,
Drying over magnesium sulphate, filtration and evaporation, chromatography on silica ("Kieselgel 60" - Trademark) eluting with ethyl acetate gave a colorless oil (0.52 g). The oil was dissolved in ethyl acetate and an ethereal solution of hydrogen chloride was added until precipitation was complete. The colorless solid was separated and crystallized from ethyl acetate/methanol to give the title compound (0.2g), mp 160°C. Analysis %: Actual measurement: C, 54.2; H, 6.6; N,
9.25C ₂₀ H ₂₇ N ₃ O ₄ Calculation for S HCl: C, 54.35; H, 6.4; N, 9.5 Example 7 (A) 1-(4-nitrophenoxy)-2-(N-methyl-N- (4-nitrophenethyl)amino]
ethane N-methyl-4-nitrophenethylamine (1.5 g) (JOC [1956], 21 , 45) and 2-[4
−Nitrophenoxy]ethyl chloride (1.55
g) Potassium carbonate (1.25 g) into a solution in acetonitrile (50 ml) with (CA [1955], 49 , 3163e)
and sodium iodide (1.2 g) were added and the suspension was stirred at reflux for 72 hours. After evaporation to dryness, the remaining oily solid was partitioned between 2N aqueous bicarbonate and ethyl acetate. After two more extractions with ethyl acetate, the organic portions were combined and washed with saturated brine;
Dry over magnesium sulphate, filter and evaporate. The resulting orange solid (2.7 g) was crystallized from ethanol to give the title compound (1.9 g), mp 74°C.
was gotten. Analysis value %: Actual measurement: C, 58.75; H, 5.4; N,
Calculation for 12.15C ₁₇ H ₁₉ N ₃ O ₄ : C, 59.1; H, 5.5; N, 12.2 (B) 1-(4-aminophenoxy)-2-[N-(4
-aminophenethyl)-N-methylamino]ethane A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-nitrophenethyl)amino]-ethane (1.5 g) in ethanol (100 ml) was dissolved at 16
Stirred for 16 hours at room temperature under 3 atmospheres of hydrogen in the presence of Raney Nickel ("Nickel 102"-trademark). Redissolve the residual oil in ether and filter
Evaporation gave a yellow solid (1.1g) which was crystallized from ethyl acetate/60-80°C petroleum ether to give the title compound (0.9g), mp 73-74°C. Analysis value %: Actual measurement: C, 71.3; H, 8.1; N,
14.7C ₁₇ H ₂₃ N ₃ O: C, 71.55; H, 8.1; N, 14.7 (C) 1-(4-methanesulfonamidophenoxy)
-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane 1-(4-aminophenoxy)-2-[N-(4-
A solution of aminophenethyl)-N-methylamino]-ethane (0.75 g) and methanesulfonic anhydride (1.0 g) in dry methylene chloride (50 ml) was stirred at room temperature overnight. After evaporation, the resulting oil
Partitioned between 2N aqueous sodium bicarbonate and ethyl acetate. After two more extractions with ethyl acetate, the organic parts were combined, dried over magnesium sulphate, filtered and evaporated. The resulting colorless solid (1.2 g) was crystallized from ethyl acetate/methanol to give the title compound (0.6 g), mp 147-
A temperature of 149°C was obtained. Analysis value % Actual measurement: C, 51.1; H, 6.25; N,
9.45C ₁₉ H ₂₇ N ₃ O ₅ S ₂ :C, 51.9; H, 6.15; N,
9.4 Examples 8 to 14 The following compounds were prepared from parts (A) to (C) of the previous Examples except that 2-(nitrophenoxy)ethyl bromide was used instead of chloride in part (A).
They were prepared starting from the corresponding starting materials and isolated in the indicated form, following the same procedure as in Part. The hydrochloride salt was made by dissolving the residue from the last evaporation step in ethyl acetate, adding ethereal hydrogen chloride, separating the residual precipitate of the hydrochloride salt, and recrystallizing it from the described solvent. .

【table】

[Table] * Foam The starting materials 4-(3-bromopropoxy)nitrobenzene and 4-(4-bromobutoxy)nitrobenzene are respectively listed in JACS (1951), 73 , 3159.
CA, 59 , 9883.

[Table] Starting materials N-methyl-1-(4-nitrophenyl)-2-propylamine and N-methyl-2-
What is (4-nitrophenyl)-1-propylamine?
Described in JACS (1946), 68 , 1153. Examples 15 and 16 The following compounds were prepared as in Example 7, except that in part (C) of Example 7, methanesulfonyl chloride in pyridine was used instead of methanesulfonic anhydride in methylene chloride. Prepared according to the procedures in Parts (B) and (C) using the corresponding starting materials. In Example 16, the hydrochloride salt was obtained as described in the relevant notes relating to Examples 8-14.

[Table] Example 17 (A) 2-[N-methyl-N-(4-nitrophenethyl)amino]ethanol A mixture of 4-nitrophenethyl bromide (11.5g) and N-methylethanolamine (8.25g) in xylene (100ml) was stirred under reflux for 16 hours. After evaporation, the residue was partitioned between 5% aqueous bicarbonate and methylene chloride. The organic liquid was washed with saturated brine, dried (MgSO ₄ ), filtered and evaporated to give an orange oil (10.1 g). Silica (“Kieselgel 60”) eluted with ethyl acetate
Chromatography on a commercially available commercially available product, followed by collection and evaporation of the appropriate fractions, afforded the title compound as a yellow oil (7.5g). Nmr (CDCl ₃ ) ppm, δ = 8.05 (d, 2H); 7.2
(d, 2H); 3.52 (t, 2H); 2.61 (m, 6H); 2.3
(s, 3H). (B) 2-[N-methyl-N-(4-nitrophenethyl)amino]ethyl chloride hydrochloride 2-[N in dry methylene chloride (75 ml)
To -methyl-N-(4-nitrophenethyl)-amino]ethanol (8.0 g) was added thionyl chloride (3 ml) dropwise with stirring at 0°C. The mixture was allowed to warm to room temperature and stirred for 16 hours. The resulting solid was filtered, washed with dry ether, and dried to give a colorless product (7.1 g).
Crystallization from ethyl acetate/methanol gave 6.0 g of the title compound, mp 168-9°C. Analysis value: Actual measurement: C, 46.8; H, 5.8; N,
Calculated values for 9.85C ₁₁ H ₁₅ ClN ₂ O ₂ HCl: C, 47.3; H, 5.8; N, 10.0 (C) 2-[N-methyl-N-(4-nitrophenethyl)amino]-1-( 4-nitrophenylthio)
ethane 2-[N-Methyl-N-(4-nitrophenethyl)amino]ethyl chloride hydrochloride (3.0 g), 4-nitrothiophenol (1.7 g) and potassium carbonate (4.0 g) in acetonitrile (100 ml).
was stirred under reflux for 16 hours. After evaporation, the residue was partitioned between water and ethyl acetate. The organic liquid was washed with saturated brine, dried (MgSO ₄ ), filtered,
Evaporation gave an orange oil (3.6g). Silica eluted with ethyl acetate [Kieselgel 60]
Chromatography above and subsequent collection of appropriate fractions yielded, after drying, a yellow solid (3.05 g),
The title compound was obtained, melting point 56-7°C. Analysis value %: Actual measurement: C, 56.8; H, 5.3; N,
11.7C ₁₇ H ₁₉ N ₃ O ₄ S: C, 56.5; H, 5.3; N, 11.6 (D) 1-(4-aminophenylthio)-2-[N-
(4-aminophenethyl)-N-methylamino]
ethane The title compound was purified from 2-[N-methyl-N-(4-nitrophenethyl)amino]-1-(4-nitrophenylthio)ethane on Raney nickel Example 7(B)
It was prepared by hydrogenation according to the procedure of Nmr (CDCl ₃ ) ppm, δ = 7.25 (d, 2H);
6.98 (d, 2H); 6.60 (m, 7H); 2.92 (t, 2H);
2.60 (m, 6H); 2.32 (s, 3H) (E) 1-(4-methanesulfonamidophenylthio)-2-[N-methanesulfonamidophenethyl)-N-methylamino]ethane The title compound, mp 160-3°C, was prepared using methanesulfonic anhydride following the procedure of Example 7(C).
It was prepared by mesylation of the product of part (D). Analysis value %: Actual value: C, 49.5; H, 6.1; N,
Calculated values for 8.6C ₁₉ H ₂₇ N ₃ O ₄ S ₃ : C, 49.9; H, 5.95; N, 9.2 Example 18 The following compound was prepared in which the reduction step (D) was carried out in hydrochloric acid with SnCl ₂ from the corresponding starting materials in a manner analogous to the procedure of parts (A) to (E) of the previous example, except that the mesylation step (E) was carried out using methanesulfonyl chloride in pyridine. Created by departure. The starting material 2-chloro-4-nitrophenol is
CA, 34 , 5574 (1940).

[Table] Example 19 (A) 1-(4-methanesulfonamidophenoxy)
-2-[N-methyl-N-(4-nitrophenyl)amino]ethane N-methyl-4 in acetonitrile (100ml)
-Nitrophenethylamine (1.1g), 2-(4-
A suspension of methanesulfonamidophenoxy)ethyl chloride (1.5 g), sodium bicarbonate (0.5 g) and sodium iodide (0.9 g) was stirred under reflux for 4 days. Evaporate to dryness and reduce the resulting oil to 2N
Partitioned between aqueous sodium bicarbonate and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, washed with saturated aqueous salt solution, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting brown oil was eluted with ethyl acetate and transferred to silica (“Kieselgel 60”).
The title compound was obtained as a yellow solid (0.9 g) by chromatography on a commercially available commercially available commercially available product, followed by collection and evaporation of the appropriate fractions. Nmr (CDCl ₃ ), δ = 2.45 (s, 3H); 2.86 (m,
6H); 3.0 (s, 3H); 4.2 (t, 3H), 6.86 (d,
2H), 7.22 (d, 2H); 7.4 (d, 2H); 8.15 (d,
2H) (B) 1-(4-methanesulfonamidophenoxy)
-2-[N-methyl-N-(4-aminophenethyl)-amino]ethane 1-(4-methanesulfonamidophenoxy)-2-[N-methyl-N- in ethanol (100 ml)
(4-nitrophenethyl)amino]ethane (0.9
g) solution under 3 atmospheres of hydrogen at room temperature for 16 hours.
Stirred in the presence of. The reaction mixture was filtered;
Evaporated to dryness. The resulting solid was crystallized from toluene to give the title compound as yellow crystals (0.6 g, mp 155-157°C). Analysis %: Actual measurement: C, 59.9; H, 71; N, 11.2 Calculation for C ₁₈ H ₂₅ N ₃ O ₃ S C, 59.5; H, 7.0; phenoxy)
-2-[N-4-methanesulfonamido-phenethyl)-N-methylamino]ethane 1-(4-methanesulfonamidophenoxy)-2-[N-methyl-N in dry pyridine (3 ml)
Methanesulfonyl chloride (35.4 μl) was added dropwise to -(4-aminophenethyl)amino]ethane (0.15 g) and the mixture was stirred at room temperature overnight. After evaporation, the resulting oil was partitioned between 2N aqueous sodium bicarbonate and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, dried over anhydrous magnesium sulfate, filtered and evaporated. The resulting colorless solid (0.135 g) was crystallized from hexane/ethyl acetate to give the title compound (0.1 g), melting point 151-152°C.
was obtained and was confirmed spectroscopically to be equivalent to the product of Example 7(C). Analysis value %: Actual measurement: C, 51.6; H, 6.2; N, 9.2 Calculation for C ₁₉ H ₂₇ N ₃ O ₅ S ₂ : C, 51.9; H, 6.15; N, 9.4 Example 20 (A) 1- (4-Nitrophenoxy)-2-[N-methyl-N-(4-methanesulfonamidophenethyl)amino]ethane N-methyl- in acetonitrile (100 ml)
4-methanesulfonamidophenethylamine (1.0 g) (see Preparation 8), 2-(4-nitrophenoxy)ethyl bromide (1.2 g) 4C.A., 54 ,
11046a), potassium carbonate (0.67 g) and sodium iodide (0.72 g) was stirred under reflux for 3 days. After evaporation to dryness, the residual oil was partitioned between water and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The resulting yellow oil was taken up in hot methanol and cooled, and the title compound crystallized as a colorless solid (1.2g). Nmr (CDCl ₃ ): δ = 2.48 (s, 3H), 2.82 (m,
4H); 2.93 (t, 2H); 3.02 (s, 3H); 4.18 (t,
2H); 6.98 (d, 2H); 7.18 (d, 2H); 7.22 (d,
2H); 8.15 (d, 2H). (B) 1-(4-aminophenexy)-2-[N-methyl-N-(4-methanesulfonamidophenethyl)amino]ethane dihydrochloride Ethanol (50 ml) containing 5% Pd/C (0.1 g)
A solution of 1-(4-nitrophenoxy)-2-[N-methyl-N-(4-methanesulfonamidophenethyl)amino]ethane (1.0 g) was stirred under hydrogen atmosphere (50 psi) for 4 hours. . The reaction mixture was then filtered and the solvent was evaporated to give a brown oil which was purified by chromatography on silica (Kieselgel 60-trademark) eluting with methylene chloride. The appropriate fractions were combined and evaporated to give a yellow oil (0.5g), which was dissolved in ethyl acetate and an ethereal solution of hydrochloric acid was added until precipitation was complete. The resulting colorless solid was washed with dry ether to yield the title compound. Yield 0.35g, melting point 220-223℃. Analysis value %: Actual measurement C, 48.4; H, 6.4; N, 9.0 Calculation for C ₁₈ H ₂₅ N ₃ O ₃ S: C, 48.5; H, 6.3; N, 9.4 (C) 1-(4-Methanesulfone amidophenoxy)
-2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane The title compound was prepared as 1-(4-aminophenoxy)-2-[N-methyl-N-(4-methylsulfonamidophenethyl)amino] with mesyl chloride in pyridine following the procedure of Example 19(C). It was made by mesylation of ethane, dihydrochloride, and hemihydrate salt (95 ml). Yield 30 mg, melting point 147-149°C.
It was found to be equivalent to the product of Example 7(C). Analysis value %: Actual measurement: C, 51.6; H, 6.3; N, 9.3 Calculation for C ₁₉ H ₂₇ N ₃ O ₅ S ₂ : C, 51.9; H, 6.15; N, 9.4 Example 21 1-(4- Methanesulfonamidophenoxy)-
2-[N-(4-methanesulfonamidophenoxy)-N-methylamino]ethane 4-[2-(methanesulfonyloxy)methanesulfonanilide (0.3
A solution of g) and 4-[2-methylamino)ethoxy]methanesulfonanilide (0.38g) was refluxed for 6 hours. After evaporation to dryness, the residue was partitioned between 2N aqueous sodium bicarbonate and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, washed with saturated brine, dried over magnesium sulfate, filtered, and evaporated to dryness. The resulting brown oil was eluted with methylene chloride and purified on silica (Kieselgel).
60''-trademark) followed by collection and evaporation of appropriate fractions. The resulting colorless solid was crystallized from ethyl acetate to give the title compound (0.21 g, melting point 150-152°), which was confirmed spectroscopically to be equivalent to Example 7(C). Analysis value % Actual value: C, 51.9; H, 6.3; N, 9.3 Calculation for C ₁₉ H ₂₇ N ₃ O ₅ S ₂ : C, 51.9; H, 6.15; N, 9.4 Example 22 1-(4- Methanesulfonamidophenoxy)-
2-[N-(4-methanesulfonamidophenethyl)-N-methylamino]ethane 4-[2-(Methylamino)ethyl]methanesulfonanilide (0.49g) in ethanol (50ml)
4-(2-chloroethoxy)methanesulfonanilide (0.5g) and sodium bicarbonate (0.17g)
The mixture was stirred at reflux for 3 days. After evaporation and drying,
The residue was partitioned between 2N aqueous sodium bicarbonate and methylene chloride. After two more extractions with methylene chloride, the combined organic portions were washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residual oil was chromatographed on silica ("Kieselgel 60" - Trademark) eluting with methylene chloride, followed by collection and evaporation of the appropriate fractions. The residual solid was crystallized from ethyl acetate to give the title compound (0.25 g, mp 150-152°C), which was confirmed spectroscopically to be identical to the product of Example 7(C). Analysis value % Actual measurement: C, 52.3; H, 6.3; N, 9.2 Calculation for C ₁₉ H ₂₇ N ₃ O ₅ S ₂ C, 51.9; H, 6.15; N, 9.4 Example 23 (A) N, N- Bis-(4-nitrophenethyl)methylamine The title compound is a known compound isolated as a by-product (7%) from the reaction of 4-nitrostyrene with methylamine. [Journal Organic
See Chemistry, 1956, Vol. 21, p. 45. ]
However, it is preferred to make this compound by the route described below. 4-Nitrophenethyl bromide (2.6 g, 11.3 mmol), N-methyl-4 in acetonitrile
-Nitrophenethylamine (2.0 g, 11.3 mmol) and potassium carbonate (1.6 g, 11.3 mmol) were stirred at reflux temperature for 4 days. The solvent was then removed and the residue was taken up in ethyl acetate, washed three times with aqueous sodium carbonate and three times with brine, dried (MgSO ₄ ) and evaporated. The residual oil was dissolved in methanol (from 0% to 2%) on silica.
Chromatography was performed by eluting with methylene chloride containing . The appropriate fractions were combined and evaporated to give an orange oil, which was triturated with hexane to give an orange powder, which was filtered and dried, yielding 1.3 g of the title compound, The melting point is
The temperature was 70-71℃. Analytical value: Actual measurement: C, 61.7; H, 5.75; N, _{12.5 Calculation} for _C17H19N3O4 : C, 62.0; H, 5.8; N, 12.8 N,N-bis-(4- _{nitrophenethyl} ) Separate manufacturing method for methylamine 4-nitrophenethyl bromide (1.0g,
4.35 mmol) and 33% methylamine in water (10 ml) were stirred together at 55°C for 2 hours. The reaction mixture was cooled and the resulting precipitate was collected by filtration and purified by chromatography on silica eluting with methylene chloride containing methanol (0% to 5%). The appropriate fractions were combined and evaporated to give the title compound. yield
0.19g, melting point 73-75°C. Analysis value %: Actual measurement: C, 62.2; H, 5.9; N, 12.6 Calculation for C ₁₇ H ₁₉ N ₃ O ₄ C, 62.0; H, 5.8; aminophenethyl) methylamine Ethanol (50 ml) containing 5% Pd/C (0.15 g)
A solution of N,N-bis-(4-nitrophenethyl)methylamine (1.2 g, 3.6 mmol) in the solution was stirred under hydrogen atmosphere (50 psi) for 4 hours. The reaction mixture was filtered and the solvent was evaporated to give the title compound as an oil (yield 1.0 g), which was used directly without further purification. NMR (CDCl ₃ ), δ = 6.7 (q, 8H); (br s,
4H); 2.6 (s, 8H); 2.3 (s, 3H). (C) N,N-bis-(4-methanesulfonamidophenethyl)methylamine Methanesulfonic anhydride (1.29 g, 7.4 mmol)
N,N- in dry methylene chloride (50 ml)
Bis(4-aminophenethyl)ethylamine (1.0 g, 3.7 mmol) and triethylamine (1
ml, 7.4 mmol) and stirred at room temperature for 2 hours. Methanesulfonic anhydride (1.29, 7.4 mmol) was added and the reaction mixture was stirred for an additional 2 hours. The solvent was removed and the residue was taken up in methylene chloride, washed three times with aqueous sodium bicarbonate and three times with brine, dried (MgSO ₄ ) and evaporated. The resulting oil was chromatographed on silica, eluting with methylene chloride containing ethanol (from 0% to 5%), and the appropriate fractions were combined and evaporated.
The title compound was obtained. Yield 0.29g, melting point 170−
171℃. Analysis value %: Actual measurement: C, 53.15; N, 6.5; H, 9.7 Calculation for C ₁₉ H ₂₇ N ₃ O ₄ S ₂ : C, 53.6; N, 6.4; H, 9.8 ^* NMR (TFAD), δ= 7.1 (q, 8H); 3.5 (m,
4H); 3.3 (m, 4H); 3.0 (s, 6H); 2.95 (s,
3H) *The sample contains traces of methylene chloride ( ^1H −nmr
1/20 mole CH ₂ Cl ₂ as determined by spectroscopic analysis)
It contained. Example 24 (A) N-(4-nitrophenethyl)-4-nitrophenethylamine 4-Nitrophenethylamine (4g), 4-nitrophenethyl bromide (5.54g), and potassium carbonate (3.32g) were heated under reflux in acetonitrile (50ml) for 2 days. The solvent was then evaporated and the residue was taken up in ethyl acetate and washed three times with aqueous sodium carbonate solution and three times with brine. The organic phase was dried (Na ₂ SO ₄ ) and filtered.
It was evaporated and the residue was purified by chromatography on silica eluting with methylene chloride containing methanol (0% to 5%). The product containing fractions were combined and the solvent was evaporated to give a solid which was recrystallized from ethyl acetate/hexane to give the title compound. Yield 2.0g,
Melting point 86-91℃. Analysis value %: Actual measurement: C, 60.9; H, 5.6; N, 13.1 Calculated for C ₁₆ H ₁₇ N ₃ O ₄ : C, 60.9; H, 5.4; -Nitrophenethyl)ethylamine Ethyl iodide (0.37g) was dissolved in acetonitrile (20g).
ml) and potassium carbonate (0.33 g) and the reaction mixture was heated under reflux for 18 hours. The reaction mixture was then evaporated to dryness and the residue was taken up in methylene chloride.
Twice with sodium carbonate aqueous solution and twice with salt water.
Washed twice, then dried (Na ₂ SO ₄ ), filtered, and evaporated to dryness. The resulting oil was purified by column chromatography on silica eluting with methylene chloride containing methanol (0% to 2%). The product containing fractions were combined and evaporated to dryness to give the title compound as an oil. yield
0.47g. Analysis value % Actual measurement: C, 62.7; H, 6.0; N, 12.7 Calculation for C ₁₈ H ₂₁ N ₃ O ₄ : C, 63.0; H, 6.2; N, 12.2 (C) -aminophenethyl)ethylamine N,N-bis-(4-nitrophenethyl)ethylamine (0.45 g) was reduced using _H2 /Pd/C in the same manner as Example 23(B) to give the title compound. Yield: 0.32g. Collection. mr (CDCl ₃ ) δ = 7.05 (d, 2H); 6.7 (d,
2H); 3.55 (broad s, 4H); 2.70 (m, 10H);
1.1(t,3H) (D) N,N-bis-(4-methanesulfonamidophenethyl)ethylamine N,N-bis-(4-aminophenethyl)ethylamine (0.3 g) was acylated with methanesulfonyl chloride in a manner analogous to Example 19(C) to give the title compound as a foam. Yield 0.12
g, melting point <80°C. Analysis value %: Actual measurement: C, 54.1; H, 6.8; N, 9.2 Calculation for C ₂₀ H ₂₉ N ₃ O ₄ S _{2 1} /4H ₂ O: C, 54.1; H, 6.7; N, 9.5 The preparations, in which all temperatures are in °C, describe the preparation of several new starting materials, some of which also form part of the present invention. Production method 1 3-(2-chloroethoxy)benzamide 2-chloroethyl p-toluenesulfonate (55.46 g) to a solution of 3-hydroxybenzamide (21.6 g) in methyl ethyl ketone (“MEK”)
and potassium carbonate (16.0 g) were added. After stirring under reflux for 6 hours, the resulting mixture was poured onto water and the colorless solid was separated. Crystallization from ethanol gave the title compound (22.2g). Melting point 125-126℃. _Analysis value %: Actual measurement: C, 53.7; H, 5.3; _N , 6.9 Calculation for _C9H10ClNO2 : C, 54.1; H, 5.05; N, 7.0 Manufacturing method 2 2-(2-chloroethoxy)-5 -Methylbenzamide The title compound was prepared in the same manner as in Preparation 1 from the corresponding starting materials. Melting point 111-113℃. Analysis value % Actual measurement: C, 56.4; H, 5.65; N, 6.3 Calculation for C ₁₀ H ₁₂ ClNO ₂ : C, 56.2; H, 5.7; N, 6.6 Manufacturing method 3 4-{4-[2-chloroethoxy] benzoyl}
Morpholine 4-(2-chloroethoxy)benzoyl chloride (5.0 g) was dissolved in dry methylene chloride and stirred while cooling to 0<0>C. Morpholine (4.0 g) was added dropwise and the mixture was stirred at room temperature for 2 days. The resulting colorless solid was separated and the liquid allowed to stand, from which the title compound (5.5g) crystallized. Melting point 102-4°C. Analysis value % Actual measurement: C, 58.1; H, 6.0; N, 5.25 Calculation for C ₁₃ H ₁₆ ClNO ₃ : C, 57.9; H, 6.0; ethoxy)
Benzamide The title compound was prepared analogously to the previous example from the corresponding starting materials. Melting point 80-81°C Analysis value %: Actual measurement: C, 60.8; H, 7.0; N, 5.3 Calculation for C ₁₂ H ₁₈ ClNO ₂ : C, 61.05; H, 7.1; N, 5.5 Manufacturing method 5 5-Methyl-2 -Nitrophenyl 2'-bromoethyl ether 5-Methyl-2-nitrophenol (5.0g) and potassium carbonate (4.6g) in butanone (100ml)
and were stirred together for 0.5 h at room temperature. 1,2-dibromoethane (3.1 g) was then added and the mixture was stirred at reflux for 2 days. After evaporation to dryness, distilled water was added and the mixture was extracted three times with methylene chloride. The combined organic liquids were washed with water, dried over magnesium sulfate, filtered and evaporated to give a yellow solid which was removed by filtration and the solution evaporated to low volume to yield the title compound. was obtained as colorless crystals (melting point 48-49°C), Example 10
It was used in Nmr (CDCl ₃ ), ppmδ = 7.8 (d, 1H); 6.9
(m, 2H); 4.42 (t, 2H); 3.7 (t, 2H); 2.45
(s,3H) 3-Nitrophenyl 2'-bromoethyl ether and 2-nitrophenyl 2'-bromoethyl ether used as starting materials in Examples 8 and 9, respectively, are known compounds [J.Med.Chem.,
(1970), 13 (6), 1149 and CA, 61 , 601a]. Production method 6 (A) 1-{N-methyl-N-(4-nitrophenethyl)amino]-2-hydroxypropane A solution of N-methyl-4-nitrophenethylamine (1.8g) and propylene oxide (0.66g) in ethanol (50ml) was stirred at reflux for 5 hours. After evaporation to dryness, the remaining orange oil is chromatographed on silica ("Kieselgel 60" - trademark) eluting with ethyl acetate, followed by collection and evaporation of the appropriate fractions to give the title compound as a yellow oil. obtained as. Nmr (CDCl ₃ ) ppm, δ = 1.1 (d, 3H); 2.3
(m, 2H); 2.32 (s, 3H); 2.72 (m, 2H); 2.9
(m, 2H); 3.15 (broad, 1H); 3.72 (m,
1H); 7.15 (d, 2H); 8.18 (d, 2H). (B) 1-[N-methyl-N-(4-nitrophenethyl)amino]-2-chloropropane Thionyl chloride (50 ml) was added dropwise to 1-1 with stirring and cooling in an ice/water bath.
Added to (N-methyl-N-(4-nitrophenethyl)amino)-2-hydroxypropane (1.5g). After stirring for 1 hour at room temperature, the solution was refluxed on a steam bath for a further 2 hours. The solution was evaporated to dryness and the residual oil was partitioned between 2N aqueous sodium carbonate and ethyl acetate. After two more extractions with ethyl acetate, the organic portions were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The resulting brown oil was chromatographed on silica ("Kieselgel 60" - trademark) eluting with ethyl acetate, followed by collection and evaporation of the appropriate fractions to give the title compound as a yellow oil (0.75 g ) was obtained. Nmr (CDCl ₃ ), ppm δ=1.48 (d, 3H);
2.35 (s, 3H); 2.75 (m, 6H); 4.02 (q, 1H);
7.4 (d, 2H); 8.18 (d, 2H). (C) 1-[2-methyl-N-(4-nitrophenethyl)amino]-2-(4-nitrophenoxy)-
Propane and 2-[N-methyl-N-(4-nitrophenethyl)amino]-1-(4-nitrophenoxy)propane Sodium (0.075g) in ethanol (50ml)
4-nitrophenol (0.41 g) was added to the solution and the solution was stirred at room temperature for 1 hour. 1-[N-methyl-N-(4-nitrophenethyl)amino]-2
-Chloropropane (0.75g) was added and the solution was stirred at reflux for 3 days. The solution was then evaporated to dryness and the residual oil was partitioned between water and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, filtered,
Evaporate to dryness. The resulting orange oil (1.0 g) was chromatographed on silica (Kieselgel 60-trademark) eluting with 1:1 hexane:ethyl acetate. Collection and evaporation of the least polar product fraction yields the title compound listed at the beginning as a yellow oil (0.25
g) was obtained. Nmr (CDCl ₃ ), ppm: δ = 1.3 (d, 3H); 2.4
(s, 3H); 2.75 (m, 6H); 4.58 (q, 1H); 6.91
(d, 2H); 7.35 (d, 2H); 8.1 (d, 2H); 8.2
(d, 2H). Collection and evaporation of the more polar product fractions produced the second listed title compound as a yellow solid (0.3
g), which was again characterized by n,mr spectroscopy. Nmr (CDCl ₃ ) ppm: δ = 1.1 (d, 3H); 2.4
(s, 3H); 2.85 (m, 4H); 3.2 (q, 1H); 3.95
(m, 2H); 6.92 (d, 2H); 7.35 (d, 2H); 8.12
(d, 2H); 8.2 (d, 2H). Production method 7 4-[2-(methanesulfonyloxy)ethyl]
Methanesulfonanilide Methanesulfonyl chloride (50ml) in drops
4- in pyridine (350 ml) over 0.5 h.
Added to a stirred solution of aminophenethyl alcohol (41.15g) at 0°C. The mixture was allowed to warm to room temperature and stirred overnight. The mixture was then poured onto water, from which an orange solid crystallized. After that,
The solid was dissolved in methylene chloride, dried over magnesium sulphate, filtered and the liquid was evaporated again. The obtained solid was crystallized from ethyl acetate to obtain the title compound (45.5 g). Melting point 136−
137℃. Analysis value %: Actual measurement: C, 40.9; H, 5.2; N, 4.9 Calculation for C ₁₀ H ₁₅ NO ₅ S ₂ : C, 40.9; H, 5.15; )ethyl]methanesulfonanilide To a solution of 4-[2-(methanesulfonyloxy)ethyl]methanesulfonanilide (10.3g) in ethanol (20ml) was added a solution of methylamine in industrial denatured alcohol (30ml of a 33% solution).
The mixture was heated in a pressure vessel with stirring at 85 °C for 17
heated for an hour. After cooling, the resulting solution was evaporated to dryness, the residue was dissolved in water and the resulting solution was basified by adding sodium hydroxide (1.4 g) in water (12 ml). Evaporation gives an off-white solid, which is treated with silica ('Kieselgel 60' - trademark).
methylene chloride/methanol (3:1)
Chromatography was carried out by elution with Collection and evaporation of appropriate fractions yielded an off-white solid (4.8 g).
was obtained, which was crystallized from ethyl acetate/methanol to give the title compound (1.8 g). Melting point 133-135℃. Analysis value %: Actual measurement: C, 52.5; H, 7.1; N, 12.2 Calculation for C ₁₀ H ₁₆ N ₂ O ₂ S: C, 52.6; H, 7.1; ) methanesulfonanilide Triethylamine (25 ml) was added dropwise to a solution of 4-(2-chloroethoxy)aniline hydrochloride (9.5 g) and methanesulfonic anhydride (12.0 g) in methylene chloride (100 ml) with cooling. , and the mixture was stirred at room temperature overnight. the product mixture
Partitioned between 2N aqueous sodium bicarbonate and methylene chloride. After two more extractions with methylene chloride, the organic portions were combined, dried over magnesium sulfate, filtered and evaporated to dryness. After filtering out impurities, the obtained solid (9.5 g) was crystallized from methanol to obtain the title compound as faint pink crystals (5.6 g). Melting point 111-114℃. Nmr (CDCl ₃ ), ppm: δ = 2.84 (s, 3H);
3.8 (t, 2H); 4.2 (t, 2H); 6.75 (d, 2H);
7.15 (d, 2H); 9.0 (broad s, 1H). Manufacturing method 10 4-[2-(methylaminoethoxy)]methanesulfonanilide hydrochloride 4-(2-chloroethoxy) in a solution of methylamine (160 ml of 33%) in industrial denatured alcohol
A suspension of methanesulfonanilide (12.7g)
Heated overnight in a pressure vessel with stirring at 100°C.
After cooling, the resulting dark solution was evaporated to dryness. The residue was crystallized from ethanol to give the title compound as a colorless solid (10.1 g). Melting point 192−194
℃. Analysis value % Actual measurement: C, 42.9; H, _6.0 ; N, 9.9 Calculation for C10H16N2O3S.HCl: _C , _42.8 ; H, _6.1 ; N, 10.0. Manufacturing method 11 Methyl 4-(2-chloroethoxy)benzoate Methyl 4-hydroxybenzoate (15.2 g,
A mixture of 2-(benzenesulfonyloxy)ethyl chloride (28.65 g, 0.12 M), and potassium carbonate (19.15 g, 0.1 M) was stirred at reflux for 24 hours. After cooling, distilled water was added and the organic phase was separated. Evaporation to dryness gave a yellow solid which was crystallized from ethanol to give the title compound. Yield (13.3g), melting point 56-58°C. Nmr (CDCl ₃ ) δ = 8.02 (d, 2H); 6.96 (d,
2H); 4.3 (t, 2H); 3.92 (s, 3H); 3.88 (t,
2H). Manufacturing method 12 4-(2-chloroethoxy)benzamide 4-Hydroxybenzamide (194 g, 1.25 M), 2-(benzenesulfonyloxy)ethyl chloride (359
g, 1.8M), and potassium carbonate (172.8g,
1.25M) was stirred at reflux for 24 hours. After cooling, add distillation (2.0) to separate the formed precipitate,
Washed with water and dried. Crystallization from ethanol gave the title compound. Yield 232.0g, melting point
66℃. Analysis value %: Actual measurement: C, 54.2; H, 5.0; N, 6.9 Calculation for C ₁₀ H ₁₁ ClO ₃ : C, 54.25; H, 5.1; N, 7.0 Manufacturing method 13 2-(4-nitrophenoxy)ethyl chloride 4-nitrophenol (139 g, 1 mol) in methyl ethyl ketone (“MEK” - 1000 ml), 2-
(benzenesulfonyloxy)ethyl chloride (220.5 g, 1 mol - see Ber. (1920), 53 , 1836), and anhydrous potassium carbonate (138 g, 1 mol)
The mixture was stirred at reflux for 16 hours. After cooling, the mixture was poured onto water and the organic layer was separated. Following four more extractions with methyl ethyl ketone, the combined organic fractions were dried (MgSO ₄ ), filtered and evaporated. The residual solid was crystallized from ethanol to give the title compound (165.8g). Melting point 60℃. Analysis value %: Actual measurement: C, 47.65; H, 40; N, 7.0 Calculation for C ₈ H ₈ ClNO ₃ : C, 47.7; H, 4.0; N, 7.0

Claims (1)

[Claims] 1 Formula: [In the formula, R ^a is −NO ₂ , −NH ₂ or −
NHSO ₂ R ¹ (where R ¹ is a C ₁ -C ₄ alkyl group)
and R ^b is −NO ₂ , −NH ₂ or R ³ {where R ³ is −
NHSO ₂ (C ₁ −C ₄ alkyl) or −CONR ⁴ R ⁵
(R ⁴ and R ⁵ are each independently H or a C ₁ -C ₄ alkyl group, or together with the nitrogen atom to which they are attached, 1-pyrrolidinyl, piperidino, morpholino or N-methylpiperazine- 1
-yl group)}; however, R ^a
When one of and R ^b is −NO ₂ , the other is −
not _NH2 ; X is O, S or a direct bond; Y is an ethylene group optionally substituted with a methyl group; “alk” is ethylene, trimethylene, optionally substituted with a methyl group or a tetramethylene group; R is a C ₁ -C ₄ alkyl group; and R ² is H, halogen, CF ₃ or a C ₁ -C ₄ alkyl group, or a salt thereof. 2 formula: [wherein R and R ¹ are each independently a C ₁ -C ₄ alkyl group; X is O, S or a direct bond; Y is an ethylene group optionally substituted with a methyl group; “alk” is an ethylene, trimethylene or tetramethylene group, optionally substituted by a methyl group; R ² is H, halogen, CF ₃ or a C ₁ -C ₄ alkyl group; and R ³ is , formula: -NHSO ₂ (C ₁ -C ₄ alkyl) or -CONR ⁴ R ⁵ (where R ⁴ and R ⁵ are each independently H or a C ₁ -C ₄ alkyl group, or they are combined Together with the nitrogen atom that is 1
-pyrrolidinyl, piperidino, morpholino or N-methylpiperazin-1-yl group] or a pharmaceutically acceptable salt thereof. 3. Claim 2, in which R ¹ is a methyl group
Compounds described in Section. 4. The compound according to claim 2 or 3, wherein R is a methyl group or an ethyl group. 5. The compound according to claim 4, wherein 5R is a methyl group. 6. A compound according to any one of claims 2 to 5, wherein X is O. 7. The compound according to any one of claims 2 to 6, wherein Y is -( _CH2 ) _2- . 8. A compound according to any one of claims 2 to 7, wherein ^R2 is H, Cl or _CH3 . 9. A compound according to claim 8, wherein ^R2 is H. 10 R ³ is −NHSO ₂ CH ₃ , −CONH ₂ , −
The compound according to any one of claims 2 to 9, which is CONHCH ₃ , -CON(C ₂ H ₅ ) ₂ or [Formula]. 11. A compound according to claim ₁₀ , wherein 11 ^R3 is _-NHSO2CH3 . 12 Formula: The compound according to claim 2, which has the following. 13 Formula: The compound according to claim 2, having the following. 14 Y is -(CH ₂ ) ₂ - and X is O or S
The compound according to claim 2, which is 15. The compound according to claim 2, wherein Y is -( _CH2 ) _2- and X is a direct bond. 16 R ^a , R ^b , R, R ² , X, Y and alk are as defined in claim 1, provided that at least one of R ^a and R ^b is a nitro group or at least one of R ^a and R ^b is an amino group.