RU2015964C1 - Process for preparing substituted amine derivatives - Google Patents

Abstract

FIELD: substituted amine derivatives of the formula 1: R₁-NHCO(X₁)CH(R₃CH₂)-N(A-Y)-CH₂CH(R₄)NHCO(X₂)-R₂ have antiarrhythmic activity wherein R₁ end R₂ are each lower alkyl; R₃ end R₄ are each hydrogen or lower alkyl; A is a carbon chain having two or more carbon atoms which may form a cyclic or aromatic ring; X₁ end X₂ are each an oxygen or sulfur atom; Y is a phthalimic group. SUBSTANCE: a compound of the formula 1 is prepared by reacting a compound of the formula 11: R₁-NHCO(X₁)CH(R₃CH₂)-N(A-OH)-CH₂CH(R₄)NHCO(X₂)-R₂ with phthalimide. EFFECT: improved properties of the amine derivatives.

Description

N-A-Y где R₁ и R₂ каждый представляет собой низший алкил;
R₃ и R₄ каждый означает атом водорода или низшая алкильная группа;
A - углеродная цепь, имеющая два или более углеродных атомов, которая может образовывать циклическое и/или ароматическое кольцо;
X₁ и X₂ каждый означает атом кислорода или атом серы;
Y - фталимидогруппа, заключающемуся в том, что осуществляют взаимодействие соединения формулы:

N-A-OH где R₁, R₂, R₃, R₄ и A каждый определен выше, с фталимидом.The invention relates to methods for producing substituted amine derivatives of the general formula I

NAY where R ₁ and R ₂ each represents lower alkyl;
R ₃ and R ₄ each represents a hydrogen atom or a lower alkyl group;
A is a carbon chain having two or more carbon atoms, which may form a cyclic and / or aromatic ring;
X ₁ and X ₂ each means an oxygen atom or a sulfur atom;
Y is a phthalimido group, which consists in the fact that they carry out the interaction of the compounds of the formula:

NA-OH where R ₁ , R ₂ , R ₃ , R ₄ and A are each as defined above, with phthalimide.

 Arrhythmia is one of the diseases often observed especially in the elderly, and in serious conditions it poses a danger to life. In recent years, the number of coronary heart diseases has been increasing rapidly, and therefore, countermeasures against fatal cases of arrhythmia resulting from these diseases have become a matter of serious concern.

 As therapeutic agents for the treatment of arrhythmias, a wide variety of pharmaceutical preparations (e.g. disopyramids) have been developed and are clinically used. Since the causes of cardiac arrhythmias are so complex, they constantly search for antiarrhythmic agents that are effective against many types of arrhythmias and give fewer undesirable side effects, because conventional antiarrhythmic agents vary in effectiveness depending on the symptoms.

 The invention is directed to a method for producing compounds of the formula I and their salts, useful as anti-arrhythmic agents.

 As the lower alkyl represented by formula I, there is mentioned, for example, a straight or branched chain alkyl group having about 1-6 carbon atoms such as methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl , iso-propyl, iso-butyl, iso-pentyl, iso-hexyl, sec-butyl, tert-butyl, tert-pentyl and neopentyl.

 The compound of formula I may have, as the case may be, an asymmetric carbon atom in the molecule, and in this case, each isomer and their mixture are included in the scope of the present invention.

 Examples of salts of compound 1 include pharmaceutically acceptable salts, for example, a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric, phosphoric or nitric acid; and salts with organic acids such as acetic, lactic, tartaric, benzoic acid, citric acid, menosulfonic, ethanesulfonic benzenesulfonic or toluenesulfonic acid. Among them, salts with an inorganic acid such as hydrochloric, hydrobromic or hydroiodic acid are preferred.

 Salts of compound I can in some cases be obtained using the method of obtaining compound I, but they can be obtained if necessary by adding acid to compound I.

 Compounds I and their salts have excellent antiarrhythmic activity, and they are useful as prophylactic and therapeutic agents for the treatment of arrhythmias. Compounds I and their salts can be safely administered to mammals for oral or non-oral administration, in powder or liquid form as they are, or as a suitable pharmaceutical composition. Along with other factors, the dosage depends on the subjects, symptoms of the disease, or route of administration, and in the case of an intravenous injection, it is convenient to administer compound I or its salt in a single dose for the prevention and treatment of arrhythmia, usually in an amount of about 0.01-20 mg / kg body, preferably in an amount of about 0.1-10 mg / kg body weight when taken from one to about five times a day, preferably from about one to three times a day. In the case of oral administration for the prevention and treatment of arrhythmia, it is convenient to prescribe compound I or its salt in a single dose in an amount of usually about 0.5-100 mg / kg body weight about 1-3 times a day.

 The prescribed pharmaceutical compositions contain an effective amount of compound I or its salt and a pharmaceutically acceptable carrier, excipient or diluent, and they are formulated in dosage forms suitable for oral or non-oral administration. As a carrier, excipient and diluent, conventional substances used in the pharmaceutical field are used. As dosage forms, an agent for injection (intravenous injection, including drip, subcutaneous injection, intramuscular injection, etc.), tablets, capsules, powder, pills, granules, liquids, medical candles and others are mentioned.

 These pharmaceutical compositions may contain any other active ingredients, unless they cause adverse reactions with compound I or its salt.

 EXAMPLES Production examples describe the invention in more detail, but it should be understood that the present invention should not be limited to them.

 Production Example 1.

1-amino-3-bis (n-butylthiocarbamoyloxyethyl) -aminopropane dihydrochloride (16)
1) Synthesis of 1-phthalimido-3-bis (n-butylthiocarbamoyloxyethyl) aminopropane (15).

Compound (8) [1.462 g (5.0 mmol)] synthesized in Production Example 4-1) and n-butylisothiocyanate [3.0 ml (27.3 mmol)] were heated in a sealed tube at 130 ^{° C} for 2 days The reaction mixture was cooled and concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (silica gel: 80 g; eluent: n-hexane / ethyl acetate = 2: 1), giving the desired product (15) 1.034 g (39.6%) (colorless oily substance )

TLC (silica gel; n-hexane / ethyl acetate (1: 1): Rf = 0.34
NMR (90 MHz, CDCl ₃ ) δ: 0.93 (6H, m), 1.11-1.96 (20H, M.), 2.51-3.09 (6H, m.), 3.16 -4.70 (10H, m), 6.06 (2H, broad), 7.65-7.93 (4H, m).

IR (film) cm ^-1 : 3300, 2945, 2910, 2850, 1760, 1700, 1520, 1460, 1390, 1360, 1330, 1180, 755, 720.

 2) Synthesis of 1-amino-3-bis (n-butylthiocarbamoyloxyethyl) aminopropane dihydrochloride (16).

 The compound [1.0.34 g (1.98 mmol)] synthesized in 1) was dissolved in methanol (35 ml). Hydrazine hydrate [0.383 ml (7.91 mmol)] was added to the solution, and the mixture was heated under reflux in a nitrogen atmosphere. The reaction mixture was cooled and concentrated under reduced pressure. Chloroform was added to the residue, and insoluble matters were removed, and then the mother liquor was concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (silica gel: 40 g; eluent: methanol / conc. Ammonia water = 40: 1); giving the free base [180 mg (23.2%)]. This free base was treated with ice-cooling with ether saturated with hydrogen chloride to give the desired product (16) [213 mg (colorless powder)].

 (Free base).

 TLC (silica gel; methanol / conc. Ammonia water 19: 1): Rf = 0.26.

NMR (90 MHz, CDCl ₃ ) δ: 0.94 (6H, m), 1.11-1.81 (12H, m), 2.51-3.01 (8H, m), 3.14 -3.67 (4H, m.), 4.44 (4H, m.).

IR (KBr) cm ^-1 : 3225, 2925, 2850, 1510, 1460, 1410, 1190.

 Production Example 2.

 N, N-bis (n-butylcarbamoyloxyethyl) -2- (4-fluorophenyl) ethylenediamine dihydrochloride (72).

 1) Synthesis of 2- [N, N-bis (n-butylcarbamoyloxyethyl) amino] -1- (4-fluorophenyl) ethanol (70).

A mixture of 4-ftorepoksistirola [1.17 g (8.47 mmol)] and N, N-bis (n-butyl carbamoyloxyethyl) -amine [2.53 g (8.47 mmol)] was stirred at ¹¹⁰ ° C for nights. After cooling, the crude product was subjected to silica gel column chromatography and eluted with hexane-ethyl acetate (1: 1) to give the alcohol compound (70) [3.37 g (90.1%)] as a brown oily substance.

IR (clear) cm ^-1 : 320 (wide), 1700 (wide), 1600.

NMR (90 MHz, CDCl ₃ ) δ: 0.7-1.1 (6H, m), 1.1-1.9 (8H, m), 2.44 (1H, dd, I = 10 , 15 Hz), 2.6-3.0 (5H, m), 3.15 (4H, q, I = 6 Hz), 3.7-4.3 (4H, m), 4, 58 (1H, dd., I = 3.10 Hz), 4.95 (2H, m), 7.00 (2H, t., I = 9 Hz), 7.34 (2H, dd., I = 6.9 Hz).

 2) Synthesis of N - [[2- [N ', N'-bis (n-butylcarbamoyloxyethyl) amino-1- (4-fluorophenyl)] ethyl] phthalimide (71).

 Diethyl azodicarboxylate [1.41 ml (9.16 mmol)] was added dropwise with stirring at room temperature to a solution of compound (70) [3.37 g (7.63 mmol)] synthesized in step 1), phthalimide [1 35 g (9.16 mmol)] and triphenylphosphine [2.40 g (9.16 mmol)] in anhydrous tetrahydrofuran (90 ml) and the mixture was stirred for 30 minutes at room temperature. The solvent was distilled off, and the residue was subjected to silica gel column chromatography and eluted with a mixture of hexane and ethyl acetate (2: 1) to give phthalimido compound (71) [2.57 g (59.0%)] as a yellow oily substance.

IR (clear) cm ^-1 : 3325 (br.), 1770, 1710 (br.), 1600.

NMR (90 MHz, CDCl ₃ ) δ: 0.7-1.1 (6H, m), 1.1-1.7 (8H, m), 2.82 (4H, t, I = 6 Hz), 2.8-3.3 (5H, m), 3.86 (1H, dd, I = 11.14 Hz), 4.00 (4H, t, I = Hz), 4, 86 (2H, m), 5.45 (1H, dd, I = 5.11 Hz), 7.00 (2H, t, I = 9 Hz), 7.40 (2H, dd, I = 6.9 Hz), 7.4-8.0 (4H, m).

 3) Synthesis of N, N-bis (n-butylcarbamoyloxyethyl) -2- (4-fluorophenyl) ethylenediamine dihydrochloride (72).

 A solution of compound (71) [2.06 (3.61 mmol)] synthesized in step 2) and hydrazine hydrate [0.21 ml (4.33 mmol)] in methanol (15 ml) was heated for 2 hours under reflux with reflux condenser. After cooling, the solvent was distilled off, and chloroform was added to the residue. The precipitates were filtered off and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography and eluted with a mixture of methanol and ethyl acetate (1:10) to give a free amine compound of 1.30 g (81.7%) as a yellow oily substance.

IR (clear) cm ^-1 : 3320 (wide), 1700 (wide), 1600.

NMR (90 MHz, CDCl ₃ ) δ, 0.7-1.1 (6H, m), 1.1-1.7 (8H, m), 2.47 (1H, dd, I = 10 , 13 Hz), 2.72 (1H, dd., I = 5, 13 Hz), 2.82 (4H, t, I = 6 Hz), 3.15 (44, q, I = 6 Hz ), 3.98 (1H, doublet of doublets, I = 5.10 Hz), 4.14 (4H, t, I = 6 Hz), 5.03 (2H, m), 7.00 (2H, t., I = 9 Hz), 7.35 (2H, dd., I = 6.9 Hz).

 The specified free amine compound [1.30 g (2.95 mmol)] was dissolved in a 3.5 M solution of hydrogen chloride in methanol, and the solvent was distilled off to obtain the desired product (72) [1.38 g (74.4% based on to compound 71)] as a yellow oily substance.

 Example of preparation 41.

 1-amino-2-bis (n-butylcarbamoyloxyethyl) amino-2-phenylethane dihydrochloride (107).

 1) Synthesis of 2-phthalimido-1-phenylethanol (104).

 2-amino-1-phenylethanol [5.0 g (36.45 mmol)] and N-carboethoxyphthalimide [7.99 g (36.45 mmol)] were dissolved in methylene chloride (40 ml). Triethylamine [5.08 ml (36.45 mmol)] was added to the solution, and the mixture was stirred for 3 hours at room temperature. The reaction mixture was concentrated under reduced pressure, and the crude product thus obtained was recrystallized from n-hexane-methylene chloride mixture, resulting in the desired product (104).

 [8.01 g (83.5%, colorless crystals)].

TLC [silica gel; CHCl ₃ methanol (40/1)]: Rf = 0.50.

NMR (90 MHz, CDCl ₃ ) + CD ₃ OD) δ: 3.90 (2H, m), 5.04 (1H, dd), 7.14-7.57 (5H, m) 7.62-8.00 (4H, m.).

 2) Synthesis of 1-bromo-2-phthalimido-1-phenylethane (105).

 The compound [5.266 g (20 mmol)] synthesized in 1) and carbon tetrabromide [7.959 g (24 mmol)] were dissolved in chloroform (80 ml). Triphenylphosphine [6.295 g (24 mmol)] was added to the solution upon cooling, and then the mixture was heated for 3 h at reflux temperature. After cooling, the reaction mixture was concentrated under reduced pressure and the residue was purified by column chromatography (silica gel: 150 g; eluent: chloroform), resulting in the desired product (105) [6.62 g (100%, yellow crystals)].

 TLC [silica gel; n-hexane / ethyl acetate (1/1)]: Rf = 0.70.

NMR (90 MHz, CDCl ₃ ) δ: 4.32 (2H, m), 5.48 (1H, t), 7.14-8.07 (9H, m).

 3) Synthesis of 1-bis (-n-butylcarbamoyloxyethyl) amino-2-phthalimido-1-phenylethane (106).

The compound [1.321 g (4 mmol)] synthesized in 2), triethylamine [0.42 ml (3 mmol)] and the compound [910 mg (3 mmol)] synthesized in Production Example 8-3) were added to toluene (10 ml). The mixture was heated at 100-130 ^C for 3 days. After cooling, water was added to the mixture, and the latter was subjected to extraction with chloroform. The organic layer was dried over anhydrous potassium carbonate, and then the solvent was distilled off under reduced pressure. The crude product was purified by column chromatography (silica gel: 60 g; eluent: n-hexane / ethyl acetate = 1/1) to give the desired product (106) [779 mg (47.0%, colorless oily substance)].

 TLC [silica gel; n-hexane / ethyl acetate (1/1)]: Rf = 0.40.

NMR (90 MHz, CDCl ₃ ) δ: 0.90 (6H, n), 1.40 (3H, m), 2.42-2.93 (4H, m), 3.08 (4H, sq.), 3.70-4.58 (7H, m.), 5.02 (2H, br.), 7.31 (5H, s.), 7.57-7.93 (4H, m. )

IR (film) cm ^-1 : 3320, 2950, 2915, 2855, 1765, 1705, 1520, 1464, 1400, 1250, 1110, 1020, 760, 725, 715, 705.

 4) Synthesis of 1-amino-2-bis (n-butylcarbamoyloxyethyl) amino-2-phenylethane dihydrochloride (107).

 The compound [770 mg (1.393 mmol)] synthesized in step 3) was dissolved in methanol (10 ml). Hydrazine hydrate (0.25 ml) was added to the solution, and the mixture was heated for 1 h at reflux temperature in a nitrogen stream. After cooling, the reaction mixture was concentrated under reduced pressure. Chloroform was added to the residue and insoluble matter was removed. The mother liquor was concentrated under reduced pressure. The crude product thus obtained was purified by column chromatography (silica gel: 25 g; eluent: methanol / concentrated ammonia water = 240 (1) to obtain a free amine [461 mg (78.4%, colorless oily product)]. The free amine was treated with cooling with ethyl ether, unsaturated with hydrogen chloride to obtain the desired product (107) [541 mg (colorless powder)].

 TLC [silica gel; methanol / concentrated ammonia water (240/1)]: Rf = 0.30.

NMR (90 MHz, CDCl ₃ ) δ: 0.93 (6H, m), 1.43 (8H, m), 2.44 (3.33 (10H, m), 3.66 (1H, m.), 4.11 (4H, m.), 5.24 (2H, br.), 7.33 (5H, m.).

IR (film) cm ^-1 : 3315, 2950, 2925, 2855, 1700, 1560, 1250.

Claims (1)

METHOD FOR PRODUCING SUBSTITUTED AMINE DERIVATIVES of General Formula

NAY
where R ₁ , R ₂ is each lower alkyl;
R ₃ and R ₄ are each hydrogen or lower alkyl;
A is a carbon chain having two or more carbon atoms, which may form a cyclic or aromatic ring;
X ₁ and X ₂ are each oxygen or sulfur;
Y is a phthalimido group,
characterized in that the compound of the general formula

NA-OH
where R ₁ - R ₄ And have the indicated meanings,
subjected to interaction with phthalimide.