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    • 专利摘要:
    The invention relates to heterocyclic compounds, in particular to the preparation of thiazoloazepine derivatives R-A-CHz-K where A is the group of the f-C (1C) CH-, (k4) -, -c (-sn -sng-, -sn (ok, d) -sng - or (SND) n - 233 or 4; Ke is H or a metal group; K4 is C, -C-alkyl or phenyl group; 5H, methyl or ethyl, which is indicated by an asterisk св. is associated with the radical R ,,; Rf is a phenyl radical, unsubstituted or monosubstituted by a halogen atom, certain groups, or A is a carbon-carbon bond and R f is 1H-inden-2-or , 1,2-dihydronaphthalen-3-yl- or 211-1-benzopyran-3- R 2 is H, an acetyl or propionyl group, substituted or substituted in the position with an omega-phenyl or 4-methoxyphenyl radical, or their addition salts with inorganic or organic acids that have analgesic and anti-inflammatory effects. development of a method for the preparation of more active compounds. The preparation is carried out from the corresponding unsubstituted in the 6 position 4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJ azepine and the compound R A-CHg-X, where A and R are indicated; X - Nuk.,: Eofile split group. 1 tab. (L with xi cj o o
    公开号:SU1731061A3
    申请号:SU894614323
    申请日:1989-06-19
    公开日:1992-04-30
    发明作者:Грелл Вольфганг；Хурнаус Рудольф；Рейффен Манфред；Заутер Роберт；Пихлер Лудвиг；Кобингер Вальтер；Энтцерот Михаель；Шингнитц Гюнтер；Мирау Иоахим
    申请人:Др.Карл Томэ Гмбх (Фирма)；
    IPC主号:
    专利说明:

    This invention relates to a process for the preparation of new thiazoloazepine derivatives that have valuable pharmacological properties, in particular, to a method for the preparation of thiazoloazepine derivatives of general formula I
    NGA-CH2-KEG1MSN

    WITH
    where A is a group of the formula
    CH.
    —C (R) CH—, (R4) —f —CH — CH—,
    , -CH CH-CH2 -, -CH (OR) -CH2 or - (CHz) n, where, 3 or 4;
    a hydrogen atom or a methyl group;
    an alkyl group with 1 to 3 is JQ carbon mami or a phenyl group.
    a hydrogen atom, a methyl or ethyl group, the carbon atom 15 indicated by an asterisk is bound to the radical
    ;
    R,
    phenyl radical, unsubstituted or monosubstituted by a halogen atom, an alkoxy group with 1-4 carbon atoms, methyl, trifluoromethyl, phenyl, nitro, amino, dimethylamino, piperidine-, acetylamino, methylthio, methylsulfinyl, methylsulfonate phonyl, cyano, aminocarbonyl, carboxy, methoxycarbonyl, ethoxycarbonyl, benzyloxy, or hydroxyl group, phenyl radical, disubstituted with methoxy groups, or hydroxygroup, 4-hydroxy-3,5-dichlorophenyl, 4 -hydroxy-3,5-dibromophenyl, 4-amino-3,5-dichlorophenyl, 4-a min-3,5-dibromophenyl, 3,4,5-trimethoxyphenyl, 6-chloro-2-pyridyl, paftilna, quinolyl, isoquinolyl, indolyl, furyl, thienyl, (2-indolinon) -4-yl, belzotiofloshnna or a pyridyl group unsubstituted or substituted by a methyl group; or A is a “carbon-carbon bond;
    R, - ° | H-inden-2-yl, 1,2-dihydronaphthalen-3-yl- or 2H-1-benzopyran-3-yl group :, Re is a hydrogen atom or an acetyl or propionyl group, unsubstituted or substituted in the omega position by a phenyl or 4-methoxyphenipone radical,
    or their acid addition salts with inorganic or organic acids having valuable pharmacological
    five
    five
    These properties, in particular, the selective effect on the dopaminergic system, caused by stimulation of (primarily Dg.) dopamin receptors, as well as analgesic, anti-inflammatory, and serotonin-2 antagonistic effects.
    Thiazoloazepine derivatives are known, in particular 2-amino-6-allyl-4,5, 7,8-tetrahydro-6H-thiazolo Q, pin, which have valuable pharmacological properties, in particular for the treatment of diseases of the central nervous system, such as as parkinsonism, hyperprolactinemia and schizophrenia, and for the treatment of cardiovascular diseases
    The purpose of the invention is to obtain new thiazoloazepine derivatives with improved pharmacological properties
    The goal is achieved based on the reaction of the alkylation of amines by a process for the preparation of thiazoloazepine derivatives of the formula I, which consists in the fact that a compound of the general formula II
    h a-CH2-X
    where a and r
    have the indicated meanings; X denotes a nucleophilic leaving group, such as a chlorine atom or a bromine, a methanesulphonyloxy, trifluoromethanesulphonyloxy or a tosyloxy radical,
    interact
    the General formula III
    N4G
    five
    in which Rg has
    neither
    with the subsequent selection of the target
    product in free form or as
    additive salt. with inorganic or
    organic acid ,,
    The reaction is carried out in a solvent medium (for example, acetone, dioxane, 0 ofuran tetrahydro, methylene chloride, chloroform, acetonitrile, dimethylformamide or dimethyl sulfoxide) in the presence of an acid acceptor (for example, potassium carbonate, triethylamine, pyridine) or an excess of a compound of formula III amounting to 1-3 equivalents, at a temperature of from -10 to 100 ° C, preferably from 0 to 80 ° C. In addition, it is advantageous to carry out the reaction
    in protective gas such as nitrogen
    The examples below illustrate the invention.
    Example 1, 2-Amino-6-cinnamyl-4,5,7,8-tetrahydro-6H-thiazolo 5,4-dj azepine.
    After stirring to a mixture of 2.50 g (14.8 mmol) of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-sG | azepine and 2.10 g (15.2 mmol a) potassium carbonate in 25 ml of anhydrous dimethylformamide is added a solution of 2.3 g (15.1 mmol) cinnamyl; 4% yield of theory; t „pl. 134 - 138 C.
    Calculated,%: C 68.67; H 6.44; N 14.13,
    Found,%: C 68.86; H 6.40; N 13.97.
    1 b) 2-amino-b- (1,2-dihydronaphtalip-3-yl-methyl) -4,5,7,8-tetrahydro-6H-thia-, 4-sPazepin,
    Prepared from 2-amino-4,5,7,8-tetra-rHftpo-6H-THa3ono J, 4-dJa3enHHa, potassium carbonate, and 3-chloromethyl-1,2-dihydronaphthalene (obtained from 1,2-dihydro- naphthalene, paraformaldehyde and con
    20
    25
    thirty
    L
    35
    in 10 ml of anhydrous dimethylforma-j-centered hydrochloric acid) in anhydrous dimethylformamide for 2 hours at
     Yield 29% of theory; mp, 158-160 ° C (ethyl acetate),
    Calculated,%: C 69.43; H 6.80; N 13.49,
    Found,%: C 69.26; H 6.86; N 13.26,
    EXAMPLE 2. 2-Acetylamino-6-cinnamyl-4,5,7,8-tetrahydro-bH-thiazolo 5,4-dj azepine.
    A mixture of 2.60 g (7 mmol) of 2-atsotshtamino-4,5,7,8-tetrahydro-bH-thiazolo 5,4 zepine dihydrobromide and 2.13 g (15.4 mmol) of potassium carbonate in 30 ml of anhydrous dimethylformamide is stirred for 30 minutes at 80 ° C, cooled to room temperature, 1.07 g (7 mmol) of cinnamyl chloride is added and the mixture is heated for 2 hours at 80 ° C. It is then evaporated in vacuo and the residue from evaporation is partitioned between water and chloroform, the dried and filtered chloroform solution is evaporated in vacuo. The residue from the evaporation is purified by chromatography on a column of silica gel (chloroform / methanol 25: 1).
    The output of 1.52 g (66% of theory); t „pl„ 133 - 135 ° С (simple ether).
    Calculated,%: C, 66.04; H 6.47; N 12.84,
    Found,%: C 65.90; H 6.43; N 12.95,
    In Example 2, the following compounds are prepared.
    2a) 2-acetylamino-6- (3- (4-chloro-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-a azepine x 0.25 Н20 „
    Prepared from dihydrobromide 2-ace-55 tilamino-4,5,7,8-tetrahydro-6H-thiaeolo P 4-dJa3enHHa, potassium carbonate and 4-chlorocinnamyl chloride in anhydrous dimethylformamide o
    chloride
    Mamida. After heating for 2 hours in a bath at 80 ° C, evaporated in vacuo and the residue from evaporation is partitioned between water and chloroform. From the dried over sodium sulfate, filtered chloroform extract by evaporation in vacuo, 6 g of a red-brown oil are obtained, which is purified by chromatography on a column of silica gel (chloroform / methanol in a 5: 1 ratio),
    Yield 1.90 g (45% of theory); mp. 122-125 ° C (ether).
    Calculated,%: C, 67.35; H 6.71; N 14.73.
    Found,%: C 67.45; H 6.75; N 14.89.
    To transfer to the hydrochloride, to a solution of 1.88 g (6.6 mmol) of this base in 30 ml of methanol was added 6.6 ml of 1N. hydrochloric acid and evaporated in vacuo to dryness. The resulting foam is dried in vacuum over 5 μ phosphorus oxide starting at 60 ° C and at the end for 2 hours at 100 ° C. 1.80 g of 2-amino-6-ccnnamyl-4,5,7,8-tetrahydro-6H-thiazo-, 4-a azepine hydrochloride hydrate are obtained. 120-125 ° C
    Calculated,%: C 58.09; H 6.70; C1 10.72; N 12.70,
    Found,%: C 58.22 ;, H, 6.60; C1 11.09; N 12.66.
    In Example 1, the following compounds are prepared:
    1a) 2-amino-6- (1P-inden-2-yl-methyl) -4,5,7,8-tetrahydro-bH-thiazolo Ј5,4-dla3enHH.
    Prepared from 2-amino-4,5,7,8-tetra-hydro-bB-thiazolo 5,4-dJa3enmm, potassium carbonate and 2-chloromethyl-1H-inden (obtained from 1H-inden, paraformaldehyde and concentrated hydrochloric acid ) in anhydrous dimethylformamide
    45
    50
    for 2 hours at 50 C.
    20
    25
    thirty
    35
    45
    50
    Yield 68% of theory; t, pl "190-195 (simple ether).
    Calculated (x 0.25),%: C 58.96; H 5.70; N 11.46.
    Found,%: C 59.15; H 5.54; N 11.35.
    26) 2-acetylamino-6- (3-phenyl-propyl) -4,5,7,8-tetrahydro-bH-thiazolo JJ5,4-dJ azepine hydrochloride.
    It is obtained from 2-acetylamino-4,5,7,8-tetrahydro-6H-thiao di-5,4-dj azepine dihydrobromide, potassium carbonate and 3-phenyl-n-propyl bromide in anhydrous dimethylformamide. The obtained base in ethanol is added to the hydrochloride by the addition of hydrochloric acid
    Yield 49% of theory; tpl 260-262 C (decomp.).
    Calculated,%: C 59.08; H 6.61; N 11.48; C1 9.68.
    Found,%: C 58.97; H 6.81; N 11.35; C1 9.87o I
    1 in
    EXAMPLE 2-Amino-6- (3- (2-thienyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo-5,4-dJ azepine.
    A solution of 1.0 g (6.2 mmol) of 3- (2-nyl) allyl chloride (freshly prepared from 3- (2-thienyl) allyl alcohol in chloroform is added dropwise an equivalent of thionyl chloride at 0 ° C and after 15 minutes by evaporation in vacuum at 25 ° C) in 10 ml of chloroform is added dropwise at room temperature to a suspension of 1.0 g (5.9 mmol) 2-amine 4,5,7,8-tetrahydro-6H-thiaoolo 5,4- dJ azepine and 0.86 g (6.2 mmol) of potassium carbonate in 40 ml of chloroform. Stir for 90 minutes, add 80 m of chloroform and shake twice with water. The chloroform solution obtained after drying and filtering is evaporated in vacuo. The evaporation residue is purified by chromatography on a column of silica gel (chloroform / / methanol in a ratio of 10: 1). 0
    Yield 0.46 g (26.7% of theory); tpl 1.16 - 120 ° С „
    Calculated,%: C 57.70; H 5.97; N 14.42.
    Found,%: C 57.70; H-5.86; N 14.21.
    In Example 3, the following compounds are prepared:
    For) 2-amino-6- (3- (3-thienyl) allyl) 4,5,7,8-tetrahydro-6H-thiazolo, 4-dJ azepine,



    eight
    Prepared from 3- (3-thienyl) allyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo Jj5,2-C azepine, in chloroform in the presence of 1 equivalent of potassium carbonate.
    Yield 8% of theory; m.p. 128 - (isopropanol) „
    Calculated,%: C 57.70; H 5.88; 0 N 14.42 „
    Found,%: C 57.93; H 5.89; N 14.28.
    36) 2-amino-6- (3- (3-furyl) allyl) - 4,5,7,8-tetrahydro-6H-thiazolo 5,4-cQ 5 azepino
    Prepared from 3- (3-furyl) allyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-a azepine in chloroform ,, 0 Yield 30% of theory; Temperature: 130-136 ° С.
    Calculated,%: C 61.06; H 6.22; N 15.26
    Found,%: C 61.18; H 6.21; N 14.97.
    5 Sv) 2-amino-6CHZ- (3,5-dichloro-4-oxy-phenyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo 5,4-a} azepine x 0, five
    Prepared from 3,5-dichloro 4-hydroxy-cypaneamyl chloride and 2 equivalents of 2-amn-0-but-4,5,7,8-tetrahydro-6H-thiazolo, - lL5,4-djazepine in chloroform for 12 h at room temperature. Yield of 9% theory, tpl 197ffC. Calculated (x 0.5 H20),%: C 50.66; H 4.78; N 11.08,
    Found,%: C 50.49; H 5.06; N 10.98.
    3g) 2-amino-b- (3-phenyl-2-propyn-1-yl) -4,5,7,8-tetrahydro-bH-thiazolo 0 15 4th} azepine x 0.5.
    Prepared from 3-phenyl-propargyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo pi, 4-dJ azepine in chloroform „
    Yield 16% of theory:, ToPl. 142 5
    S
    146 C (ether).
    Calculated (x 0.5 H20),%: c 65.74; H 6.20; N 14.38.
    Found,%: C 65.56; H 6.01; N
    A) 2-amino-6- (3- (2-chlorophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo p, 4-dJasenHH,
    Prepared from 2-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro 6H-thiazole 6 in, 4 3 azepine in chloroform in 1 in the presence of 1 equivalent of potassium carbonate.
    Yield 20% of theory; . 80 ° C.
    917
    Calculated,%: C 60.08; And 5.67; N 13.14,
    Found,%: C 60.20; H 5.61; N 13,12s
    From the base, by dissolving in ethanol, adding excess simple hydrochloric acid and ether, 2-amino-6- (3- (2-chlorophenyl) allyl) -4,5,7,8 tetrahydro-bH-thiazolo dihydrochloride is obtained. G5,4-cff azepine with tpl, 236 - 240VS „
    Calculated,%; C 48.93; H 5.18; N 10.70.
    Found,%: C 49.03; H 5.31; N 10.55.
    Ze) 2-amino-6- (3- (3 chlorophenyl) allyl) -4,5,7,8 tetrahydro-6H-thiazolo p, 4-dla3enHH.
    Prepared from 3-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetra hydro-6H-thiazolo 5,4-c azepine in chloroform in the presence of 1 equivalent of potassium carbonate „
    Yield 20% of theory; m.p. 132 - 13 (-. ° С
    Calculated,%: C 60.08; H 5.67; N 13.14
    Found,%: C 60.20; H 5.60; N 13.26.
    WL) 2-amino-6- (3- (2-nitrophenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo p, 4-dJa3enHH.
    Prepared from 2-nitrocinnamylchloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4-e azepine in chloroform.
    57% yield of theory; m.p. 125-128 C (simple ether).
    Calculated,%: C 58.17; H 5.49; N 16.96.
    Found,%: C 57.99; H 5.70; N 16.73.
    3h) 2-amino-6- (3- (3-nitrophenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJasenHH.
    Prepared from 3-nitrocinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo of 5,4-suazepine in chloroform.
    Yield 56% of theory; m.p. 165-168 ° C (ether).
    Calculated,%: C 58.17; H 5.49; N 16.96.
    Found,%: C 57.97; H 5.34; N 16.89.
    Zi) 2-amino-6- (3- (4-nitrophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-cG | azepine x 0.5 H20.
    061tO
    Prepared from 4-nitro-cini-amyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo | J5,4-dJaa epine in chloroform.
    Exit 38% of theory; m.p. 186 - 191 ° С (simple ether) о
    Calculated (x 0.5 H20),%: C 56.62; H 5.64; N 16.51.
    0 Found%: C 56.60; H 5.71; N 16.63.
    3k) 2-amino-6- (3- (4-methoxy-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3enHH3
    r Prepared from 4-methoxy-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-. tetrahydro-6H-thiazolo 5,4-djasennna in the presence of 1 equivalent of potassium carbonate in chloroform.
    0 Exit 10% of theory; m.p. 155 - 160 C (simple ether).
    Calculated,%: C 64.73; H 6.70; N 13.32 ,,
    Found,%: C 64.58; H 6.55; 5 N 13.16.
    Zl) 2-amino-6- (3- (2-methyl-phenyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo 5,4 a zepin „
    Prepared from 2-methyl-cinnamylchloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4 azepine in chloroform.
    Yield 52% of theory; m.p. 112-115 C (ethyl acetate).
    Calculated,%: C 68.21; H 7.07; 5 N 14.04.
    Found,%: C 68.15; H 7.15; N 14.24.
    SM) 2-amino-6- (3-methyl-phenyl) allyl) -4, 5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3enHH0
    Prepared from 3-methyl-tshshamyl-chloro-: da and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3enHHa in chloroformj 5 Yield 47% of theory; m.p. 116-119 ° C
    Calculated,%: C 68.21; H 7.07; N 14.04 o
    Found,%: C 68.14; H 7.25; N 14.34.
    3N) 2-amino-6- (3- (4-methyl-phenyl) -llyl) -4,5,7,8-tetrahydro-bH-thiazolo Ј5,4-d3a3eraiH.
    Prepared from 4-methyl-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-bH-thiazolor5,4 | azepsch1a
    in acetonitrile in the presence of 1 equivalent of potassium carbonate at a temperature of 80 ° C for 40 minutes.
    0
    0
    eleven
    173 126-130 ° С
    7.07; 7.17;
    Yield 33% of the theory: t m pl (simple ether).
    Calculated,%: C 68.21; H N 14.04,
    Found 7; C 68.36; H N 14.02
    Zo) 2-amino-6- (3- (2,3-dimethoxy-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-cG azepine „
    Prepared from 2,3-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-bH-thiazolo 5,4-s Lazepi-chloroform "
    on in
    Toplo 87 - 91 ° С 15
    20
    35
    m.p. 122- 126 С
    45
    N
    Yield 39% of theory; (ether).
    Calculated,%: C, 62.58; H 6.71; N 12.16 „
    Found,%: C 62.70; H 6.89;
    N 12.19
    Zp) 2-amino-6 (3- (2,5-dimethoxyenyl) allyl) -4,5,7,8-tetrahydro-bN-azolo 5,4-cPazepin "
    From 2.5 dimethoxy-cinnamyl chloride (obtained at -5 C, 10 min), 25 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo (5,4-e} azepine) j
    loroform about
    Yield 4% of theory; Topl. 112 - 115 ° СN
    (simple air) o30
    Calculated,%: C, 62.59; H 6.71; 12,17s
    Found,%: C 62.46; H 6.67; 11.94.
    Mole peak (m / z) - calculated: 345; found: 345.
    Sp) 2-amino-6- (3- (3,4-dimethoxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thia-, 4-dJ azepine.
    Prepared from 3,4-dimethoxy-cinnamyl-dd chloride (obtained at 5 ° C, 10 min) 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bN-thiazolo 5,4-dJ azepine chloroform.
    Yield 7.7% of theory; (ether).
    Calculated,%: C, 62.58; H 6.71; N 12.16,
    Found,%: C 62.70; H 6.84; N 11.90.
    3c) 2-amino-6- (3- (3,5-dimethoxy-phenyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo-5,4-dQ azepine.
    Prepared from 3,5-dimethoxy-cinnamide chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine in chloroformo
    on
    4, az
    at 20
    (x
    4 az
    at 20
    (x
    N
    N
    4, az
    ate dri te in
    (P
    N
    N
    55
    Yield 21% of theory; t (petroleum ether).
    , PL0 114-119 С
    0
    five
    0
    N
    N
    12 C, 62.58; H
    6.71;
    Calculated,%: 12.16 „Found,%: C 62.57; H 6.57;
    5 j
    11.95.
    3g) 2-amino-6- (3- (4-dimethylaminophenyl) allyl) -4,5,7,8-tetrahydro-6H-i thiazolo 5,4-b1azepine.
    Prepared from 4-dimethyl-amino-cinnamyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-bN-thiazolo | 5,4-сГ | azepine in pure chloroform for one hour at 50 ° С „
    Yield 2.4% of theory; t „pl, 85-90 ° С.
    Mole peak (m / z) - calculated: 328; found: 328.
    Doo) 2-amino-6- (3- (1-naphthyl) allyl) - 4,5,7,8-tetrahydro-bH-thiazolo 5,4-dj azepine
    Prepared from 3- (1-naphthyl) allyl) chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-sG | azepine in chloroform for 3 days at 20 ° C.
    Exit 31% of theory; mp ,, 178-180 ° С (chloroform / methanol 100: 1)
    Calculated,%: C 71.62; H 6.31; 12.53 ° Found: C 71.33; H 6.28;
    N
    1 o -50
    I Ј-, J4. about
    ZF) 2-amino-6- (3- (2-naphthyl) al l) - 4,5,7,8-tetrahydro-bH-thiazolo G5,4-dJ azepine.
    Prepared from 3- (2-naphthyl) allyl) chloride and 2 equivalents of 2-ammonium-4,5,7,8-tetrahydro-bH-thiazolo (5,4-dJa3ertHHa in chloroform for 3 days at 20 ° C „
    Yield 20% of theory; t, pl „164 - (chloroform).
    Calculated,%: C 71.62; H 6.31; N 12.53.
    Found,%: C 71.49; H 6.43; N 12.45
    3x) 2-amino-6- (3- (2-biphenyl) allyl) - 4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine.
    D Prepared from 3- (2-biphenyl) allyl) chloride and 2 equivalents of 2 amino-4,5,7,8-tetrahydro-LH-thiazolo 5,4-dJ azepine in chloroform for 5 hours at 50 ° C.
    57% yield of theory; t „pl. 154 - (simple air) with
    Calculated,%: C 73.11; H 6.41; N 11.63.
    Found,%: C 73.00; H 6.44; N.
    1317
    3) 2-amino-6- (3- (4-biphenyl) allyl) 4,5,7,8-tetrahydro-6H-thiazole; 5,4-cf azepine x 0.25,
    Prepared from 3- (4-biphenyl) allyl) - chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-6H-thiazolo 5,4-dJ acepine in chloroform
    Yield 54% of theory; (ether).
    Calculated,%: (x 0.25 H C 72.19; H 6.47; N 11.48.
    Found,%: C 72.11; H N 11.33.
    3p) 2-amino-6- (3- (2-benzyloxyphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine.
    Prepared from 2-benoyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-bH-thiazolo 5,4-dJa3e- in chloroform for 5 hours at 50 C.
    178 120) 6.12;
    80 ° C
    Exit 36% of theory; t „flat 103-107 C (simple air) about
    Calculated,%: C, 70.57; H 6.44; N 10.73 °
    Found,%: C, 70.42; H 6.63; N 11.01.
    Ssh) 2-amino-b- (3- (3-benzyloxy-phenyl) allyl) -4,5,7,8 tetrahydro-bN-thiazolo p, 4-cG | azepine „
    Prepared from 3-benzyloxy-cinnamyl-hporide and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-bH-thiazolo 5,4-suazepine in chloroform for 5 hours at.
    Yield 59% of theory; tgt, 7 & - (simple),
    Calculated,%: C, 70.57; H 6.44; N 10.73.
    Found,%: C, 70.45; H 6.54; N 10.72.
    3) 2-amino-6- (3- (4-benzyloxy-phenyl) allyl) -4,5,7,8-tetrahydro-BH-thiazolo Ј5,4-dJ azepine.
    Prepared from 4-benzyloxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-bH-thiazolo 5,4-dJ azepine in vloprophome for 60 minutes at 50 ° C.
    Yield 13% of theory; m.p. 135-140 ° С (simple ether)
    Calculated,%: C, 70.56; H 6.44; N 10.73.
    Found,%: C, 70.80; H 6.42; N
    10.52.
    EXAMPLE 4 o 2-Amino-6- (3- (2-amio no-4-thiazolyl) allyl) -4,5,7,8-tetra-rnn, po-6H-THa3onoЈ5, azepine.
    14
    0 ° C
    107 C
    four;
    and- bn-
    mil 4.5, grains
    ;
    -
    to
    4-cf
    ) - -4.5, aze
    and- 6H-
    amyl- -4,5, a3e- with
    15
    20
    To 0.58 g (3.7 mmol) of 3- (2-amipo-4-thiazolyl) allyl alcohol in 10 ml of chloroform is added dropwise while stirring, 0.81 ml (11.1 mmol) of thionyl chloride is added at room temperature and stirred for 1 hour. Evaporated in vacuo, drying the foamy residue from evaporation of syrah hydrochloride of 3- (2-amino-4-thiazolyl) allyl chloride at 20 ° C / 0.1 Torr and dissolving it in 10 ml of anhydrous dimethylformamide 0 K To this solution, a solution of 2.5 g (14.8 mmol) of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo Ј5,4-d ja3enHHa in 20 ml of dimethyl form is continuously added dropwise under nitrogen. - mida. Stir for 90 minutes at 50-60 ° C, evaporate in vacuo, remove residual dimethylformamide at O, 1 Torr and purify the residue directly by chromatography on a column of silica gel (chloroform / methanol / / concentrated ammonia in a ratio of 25: 5 1: 0.15) o
    Yield 0.40 g (35% of theory); t „pl„ 186 - 190 ° С (acetone).
    Calculated,%: C 50.81; H 5.58; N 22.79.
    30% found: C 50.61; H 5.67; N 22.60.
    In Example 4, the following compounds were prepared:
    4a) 2-amino-6- (3- (1-isoquinoligyl) allyl) -4,5,7,3-tetrahydro-bN-thiazolo 35 5,4-dJa3enHH х 0.25 Н20 „
    Prepared from 3- (1-isoquinolinyl) -allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H- .Q thiazolo 5.4 7 azepine in chloroform
    Yield 20% of theory; t „pl. 156 - 157 С (simple ether) „
    (x 0.25 H20): N 16.44.
    Calculated,% C 66.93; H 6.06;
    Found,%: C, 66.82; H 6.02; N 16.29.
    EXAMPLE 5 2-Amino-6- (3- (2-furyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3ennH.
    A solution of 1.25 g (10 mmol) of 3- (2-furyl) allyl alcohol in 25 ml of anhydrous ether is stirred and 0.73 ml (10 mmol) of thionyl chloride is added dropwise at -5 ° C. Stir for 15 minutes at -5 ° C, evaporate in vacuo at a bath temperature of 0-5 ° C, immediately dissolve the residue from evaporation (crude 3- (2-furyl) allyl chloride) in a cold (-5 ° C)
    chloroform, 3.08 g (10 mmol) of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo G5,4-cG azepine was added and stirred for 50 hours at 50 ° C. The solution was mixed with water, dried, filtered chloroform solution and evaporated in vacuo. The residue from the evaporation is purified by chromatography on a column of silica gel (chloroform / methanol: 10: 1).
    The output of 0.38 g (13.8% of theory); ToPL. 112 - 119 ° С (ether) о
    Calculated,%: C 61.06; H 6.22; N 15.26,
    Found,%: C 60.89; H 6.17; N 14.92.
    In Example 5, the following compounds were prepared:
    5a) 2 amino-6- (3- (4-chlorophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo p, 4-djazepine.
    Prepared from 4-chloro-cinnamyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo-5,4-azepine in chloroform.
    Yield 26% of theory; m.pl 148 - 153 C (ether).
    Calculated,%: C 60.08; H 5.67; N 13.14.
    Found,%: C 59.89; H 5.51; N 12.93o
    56) 2-amino-6- (3- (2-fluoro-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo (j, 4-dJ az epine
    Prepared from 2-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-: 3,5,7,8-tetrahydro-bH-thiazolo 5,4- (CG azepine
    in chloroform.
    Exit 36% of theory; m.p. 96 - 102 С (simple air) „
    Calculated,%: C, 63.34; H 5.98; N 13.85.
    Found,%: C 63.25; H 6.03; N 13.73.
    5c) 2-amino-6- (3- (3-fluoro-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-G azepine.
    Prepared from 3-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3ennna in chloroform.
    Yield 44% of theory; . 128 - 132 ° C (ether).
    Calculated,%: C, 63.34; H 5.98; N -13.85.
    Found,%: C 63.43; H 6.12; N 13.60.
     )
    five
    0
    ..
    five
    S
    5g) 2-amino-6- (3- (4-fluoro-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo Ј5,4-сГ) azepine
    Prepared from 4-fluoro-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo p, 4-ε-azepine in chloroform.
    Yield 13% of theory; t „pl. 142-146 S.
    Calculated,%: C, 63.34; H 5.98; N 13.85.
    Found,%: C 63.25; H 5.97; N 13.70.
    5d) 2-amino-6- (3- (2-methoxy-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo Ј5,4-dj azepine.
    Prepared from 2-methoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4-dTa3enHHa in chloroform.
    Yield 13% of theory; m.p. 80-84 S.
    Calculated,%: C 64.73; H 6.71; N 13.32o
    Found,%: C 64.57; H 6.82; N 13.14o
    5e) 2-amino-6- (3- (3-methoxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo Ј5,4-d azepine.
    Prepared from 3-methoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4 azepine in chloroform.
    Yield 21% of theory; mp 120-124 ° C.
    Calculated,%: C 64.73; H 6.71; N 13.32.
    Found,%: C 64.80; H 6.48; N 13.15
    5g) 2-amino-6- (3- (4-methylthio-phenyl) allyl) -4,5,7,8-tetrahydro-bH-TH33ono 5,4-d a3enHH x 0.25.
    Prepared from 4-methylthio-ciniamyl chloride and 2 equivalents of 2-amino-4,5, 7,8-TeTparHflpo-6H-Tna3ono 5,4-d ja3e- pin in chloroform
    Exit 31% of theory; m.p. 152-157 C.
    Calculated (x 0.25 H20),%: C 60.74; H 6.45; N 12.51.
    I
    Found,%: C 60.53; H 6.23; N 12.36.
    5c) 2-Amino-6- (3- (4-methyl-sulfinyl-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJasenHHa hydrate.
    Prepared from 4-methylsulfinyl-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiaeolo 5,4-d azepine in chloroform.
    Yield 48% of theory; m.p. 171-176 C (ether),
    Calculated N 11.50 „
    17%: C 55.88; H 6.34;
    C, 56.07; H 6.32;
    one
    157
    158
    Found, N, 11.43.
    5i) 2-amino-6- (3- (4-methylsulfonylphenyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo 5,4-sPazepin.
    Prepared from 4-methylsulfonyl-cinnamyl chloride and 2 equivalents of 2-amine 4,5,7,8-tetrahydro-6H-thiazolo Ј, azepine in chloroform „
    Yield 21% of theory; t. pl „157-161 (simple ether).
    Calculated,%: C 56.17; H 5.82; N 11.56.
    Found,%: C 56.27; H 5.73; N 11.48
    5k) 2-amino-6- (4-phenyl-3-butei-1-yl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJa3enHH ,,
    Prepared according to Example 8 from A-Lenil-3-buten-1-yl-bromide (mp. 93 ° C./1.5 Torr; obtained from 1-cyclopropyl-1-phenyl-carbinol and phosphorus tribromide) and 4 equivalents of 2-amino-4, 7,8-tetrahydro-bN-thiazolo, pina in pure chloroform for 8 h at 60 ° C „
    Output 39% of the theory, so pl. (chloroform / toluene).
    Calculated,%: C 68.19; H 7.07; N 14.03o
    Found,%: C 68.06; H 7.09; N 14.01.
    5l) 2-amino 6- (3- (2,6-dimethoxyphenyl) allyl) -4,5,7,8-tetrahydro-6H-thiaeolo | 5.4 7azepine x 0.5 NgO
    Prepared from 2,6-dimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5 7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine in chloroform.
    Yield 10% theory :,. 100 - 102 ° C (ether).
    Calculated (x 0.5 H, 0),%: C 60.9 N 6.82; N 11.85.
    Found,%: C 60.95; H 6.75; N 11.91.
    5m) 2-amino-b- (3- (3,4,5-trimethoxy-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-d Ta3enmia hydrate.
    Prepared from 3,4,5-trimethoxy-zin milchloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine in chloroform. 0
    Yield 17% of theory; t "pl 70-73 C exploded.). I
    Calculated (x 1 H40),%: c 57.99; H 6.99; N 10.68,
    1731061
    18
    15
    20
    25
    ° С
    thirty
    five
    l-
    o- 10 j
    WITH
    a 5

    l-,
    9; s

    but-
    N
    N
    N
    Found,%: C 58.15; H 6.86; 10.49.
    5H) 2-amino-6- (3- (4-isobutoxyphenyl) allyl) -4,5,7,8-tetragro-6H-thiazolo 5,4-dJa3enHH.
    Prepared from 4-isobutoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-6H-thiazolo 5,4-d azepine in chloroform.
    Yield 6% of theory; m.p. 110-113 ° C (ether).
    Calculated,%: C, 67.20; H 7.61; 11.76.
    Found,%: C 67.01; H 7.71; 11.50.
    5o) 2-amino-6- (2,3-diphenyl) allyl) - 4,5,7,8-tetrahydro-6H-thiazolo 5, azepine.
    Prepared from 2,3-diphenyl-allyl) chloride and 2 equivalents of 2-amino-4,5,7,8-TeTparaflpo-6H-THa3ono | 5,4-dJ azepine in chloroform.
    Yield 19% of theory; m.p. 112 - (petroleum ether)
    Calculated,%: C 73.11; H 6.41; 11.63.
    Found,%: C 72.92; H 6.50; 11.57.
    Example 6. Hemihydrate of 2-amino-6- (3- (2-methyl-4-thiazolyl) allyl) -4,5, 7,8-tetrahydro-bH-thiazolo 5,4-d 7a3ePINZo
    A solution of 3.1 g (20 mmol) of 3- (2-methyl-4-thiazolyl) allyl alcohol in 120 ml of anhydrous ether is stirred and 2.9 ml of dropwise added under nitrogen at a temperature of 5-10 ° C. (40 mmol) thionyl chloride. A colorless precipitate is formed.
    115 ° C
    N
    N
    40
    Stir for 10 minutes and evaporate at 20 ° C in vacuo. The residue from evaporation of the crude hydrochloride of 3- (2-methyl-4-thiazolyl) allyl) chloride is dissolved in 20 ml of chloroform and a solution of 10.1 g (60 mmol) of 2-amino-4,5,7,8 tetrahydride is continuously added - ro-bN-thiazolo-5.4 zepin in 150 ml,. chloroform. 2.76 g added
    (20 mmol) of potassium carbonate and stirred for 3 hours at 80-90 ° C with slight reflux. 250 ml of chloroform are added, the mixture is cooled to room temperature and shaken three times with water. The chloroform solution obtained after drying and filtration is evaporated in vacuo. The evaporation residue is purified by chromate.
    -19 17
    a carafe on a silica gel column (chloroform / methanol 5: 1) „
    Yield 2.80 g (45% of theory); m.p. 182 -.
    Calculated (x 0.5 HgO),%: C 53.32 H 6.07; N 17.77.
    Found,%: C 53.48; H 5.86; N 17.79.
    In Example 6, the following compounds were prepared:
    ba) 2-amino-6- (3-phenyl-2-buten-1-yl) -4,5, .7,8-tetrahydro-bN-thiazolo
    5,4-dJa3emiH x 0,25
    Prepared from 3-phenyl-2-buten-1-yl chloride and 1 equivalent of 2-amino-4,5, 7,8-tetrahydro-6H-thiazolo 5, pin in anhydrous dimethylformamide% in the presence of 1 equivalent of potassium carbonate for 12 h at room temperature
    Exit 34% of theory; m.p. 131 - 135 ° (simple ether).
    Calculated (x 0.25 H20),%: C 67.18; H 7.13; N 13.83
    Found,%: C 67.35; N. 7.12; N13.75
    bb) 2-amino-6- (2-methyl-3-phenyl-2-propen-1-yl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-clJ azepine „
    Prepared from 2-methyl-3-phenyl-allyl chloride and 2 equivalents of 2-amino-4,5 7,8-tetrahydro-6H-thiazole o, 4-dJ azepine in chloroform for 2 hours at room temperature.
    Yield 8% of theory; t, pl, 112 - 115 °
    Calculated,%: C 68.21; H 7.07; N 14.04,
    Found,%: C 8.03; H 7.17; N 14.27,
    Example 7. 2-amino-6- (3- (b-chloro-2-pyridyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo, 4-cPazepin.
    Mix a solution of 0.90 g (5.3 mmol) of 3- (6-chloro-2-pyridyl) -allyl alcohol in 20 ml of anhydrous ether and slowly add a solution of 0.38 ml ( 5.3 mmol) of thionyl chloride in 0.5 ml of anhydrous ether. A precipitate forms. The mixture is stirred for 20 minutes and evaporated at room temperature under vacuum. The residue from evaporation of Gsroy hydrochloride 3- (6-chloro-2 pyridyl) allyl chloride is dissolved in 10 ml of chloroform. This solution is added dropwise to a solution stirred at 50-60 ° C. 2.70 g (15.9 mmol) 2-amino-4,5,7,8
    five
    to
    15
    20
    25
    061
    55
    thirty
    35
    40
    45
    20
    tetrahydro-bn-thiazolo | 5.4-113 azepine in 41 ml of chloroform. Stir for 5 hours at 50-60 ° C, dilute with 200 ml of chloroform and shake with water several times. The chloroform solution, after drying and filtration, is evaporated in vacuo. The residue from the evaporation is purified by chromatography on a column of silica gel (toluene / ethyl acetate / methanol 4: 2: 1).
    Yield 1.1 g (64% of theory); m.p. 161-164 ° C (ether).
    Calculated,%: C 56.15; H 5.34; C1 11.05; N 17.46
    Found,%: C 56.28; H 5.41; C1 10.99; N 17.43.
    In Example 7, the following compounds were prepared:
    7a) 2-amino-6- (3- (2-pyridyl) allyl) - 4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine.
    Prepared from 3- (2-pyridyl) allyl) chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-bH-thiazolo L5,4-dJasenHHa in chloroform.
    Yield 33% of theory; m.p. 162 - 165 s.
    Calculated,%: C, 62.92; H 6.34; N 19.57,
    Found,%: C 63.16; H 6.35; N 19.36
    The base is dissolved in methanol, 1 equivalent of 1 is added and hydrochloric acid is evaporated in vacuo and dried over phosphorus pentoxide at 60 ° C / 20 Torr. 2-Amino-b- (3- (2-pyridyl) allyl hydrochloride is obtained) ) -4,5, 7,8-tetrahydro-6H-thiazolo 5,4-dJa3e-pin x 1.5 H20.
    . Yield 84%; m.p. 100 - 120 ° С
    Calculated (x 1.5 H20),%: C 51.50; H 6.34; N 16.02,
    Found,%: C 51.60; H 6.41; N 16.00 „
    76) 2-amino-6- (3- (3-pyridyl) allyl) - 4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine x 0.25.
    Prepared from 3- (3-pyridyl) allyl) chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo Ј5,4-dja3ennHa in anhydrous dimethylformamide by stirring for 2 days at room temperature
    Yield 59% of theory; t „pl„ 166 - 169 ° С (acetone).
    Calculated (x 0.25 HЈ0),%: C 61.93; H 6.41; N 19.26,
    21
    Found,%: C 61.97; H 6.35; N 19.51.
    7c) 2-amino-6- (3- (4-pyridyl) allyl) 4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine x 0.4.
    Prepared from hydrochloride of 3- (4-pyridyl) allyl) chloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-e1-azepine in chloroform.
    Yield 28% of theory; m.p. 210 - 215 ° C (ether).
    Calculated (x 0.4),%: C 61.36; H 6.45; N 19.08.
    Found,%: C 61.14; H 6.28; N 19.07,
    7g) 2-amino-6- (3- (3-pyridyl) propyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJazepin.
    Prepared from hydrochloride of 3- (3-pyrimyl) propyl chloride and 1 equivalent of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo Ј5,4-dJa3ennHa in anhydrous dimethylformamide in the presence of 2 equivalents of potassium carbonate for 90 min at 80 ° C.
    Yield 8% of theory; m.p. 90 (simple air).
    Mole peak (m / z) - calculated: 288; found: 288.
    7d) 2-amino-6- (3- (4-amino-3,5-di-bromo-fennl) allyl) -4,5,7,8-tetrahydroby-thiazolo, 4-t J azepine.
    Prepared from 4-amino-4,5-dibromo-cinnamyl chloride hydrochloride obtained from 4-amino-3,5-dibromo-cinnamyl alcohol and 1.2 equivalents of thionyl chloride in chloroform and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-6H-ti-asono 5,4-dJa3enHHa in chloroform.
    Yield 12% of theory; m.p. 198-199 ° C
    Calculated,%: C, 41.94; H 3.96; N 12.23.
    Found,%: C 41.80; H 3.99; N 12.17. -.
    17
    7e) 2-amino-6- (3- (4-amino-3,5-dichlorophenyl) allyl) -4,5,7,8-tetrahydro-6H-thiaeolo 5,4 Dazepin x 0.5 NgO.
    Prepared from 4-amino-3,5-dichloro-cinnamyl chloride hydrochloride obtained from 4-amino-3,5-dichloro-cini-amyl alcohol and 1.2 equivalents of thionyl chloride in chloroformJ and 2 equivalents of 2-amino-4 , 5,7,8-tetrahydro-6H-thiazolo 5,4-| azepine in chloroform.
    Yield 7% of theory: tplo 163 - 165 ° C.
    Calculated (x 0.5 H20),%: C 50.79; H 5.06; N 18.74.
    -.
    jg
    ,five
    - 20

    35 -
    . 40
    45
    25

    50 - 55
    3106122
    Found,%: C 50.98; H 5.17; N 18.80,
    7g) 2-amino-6- (3- (4-hydroxy-phenyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJazepin x 0.6
    Prepared from 3- (4-hydroxy-phenyl) allyl chloride and 2 equivalents of 2-amino-4,5, 7,8-tetrahydro-bH-thiazolo 5,4-dJ acepine in chloroform.
    Yield 1% theory; , 153-161 C (ether), sintering at 105 C.
    Calculated (x 0.6),%: C 61.55; H 6.52; N 13.49,
    Found,%: C 61.50; H 6.40; N 13.08,
    7h) 2-amino-6- (3- (4-chlorofesh) propyl) -4,5,7,8-tetrahydro-6H-giazo 5,4-dj azepine.
    I get from 3- (4-chlorofesh) propyl chloride and 2 equivalents of 2-amino-4,5,
    7,8-tetrahydro-6H-thiazolo azepine in anhydrous dimethylformamite.
    Yield 37% of theory; m.p. 153 ° C.
    Calculated,%: C 59.71; H 6.26; N 13.05.
    Found,%: C 59.53; H 6.06; N 13.21,
    7i) 2-amino-6- (3- (3-methyl-2-pyridyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-d JasemtH.
    Prepared from 3- (thyl-2-pyridyl) allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4 azepine in chloroform.
    Yield 45% of theory; , 188 - 190 ° С (simple ether).
    Calculated,%: C, 63.98; H 6.71; N 18.65,
    Found,%: C 63.87; H 6.59; N 18.62.
    7k) 2-amino-6- (3- (5-methyl-2-pyridyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJazepin.
    Prepared from 3- (5-methyl-2-pyridyl) allyl chloride hydrochloride and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-) azepine in chloroform.
    Yield 22% of theory; m.p. 172 - 175 ° C (isopropanol) o
    Calculated,%: C, 63.98; H 6.71; N 18.65.
    Found,%: C 63.82; H 6.59; N 18.61,
    7l) 2-amino-6- (3- (6-methyl 2-pyridyl) allyl) -4,5,7,8-tetrahydro-bH-thia, 4 zepine x 0.5,
    Prepared from 3- (6-methyl-2-pyridyl) allyl chloride and 3 equi30 hydrochloride
    2-amino-4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJazepine valentines in chloroform
    Yield 21% of theory; t „pl. 122 - 125tfC (petroleum ether).
    Calculated (xSOF, 5 H20),%: C 62.10; H 6.84; N 18.11.
    Found,%: C 62.13; H 6.80; N 17.98.
    7m) 2-amino-6- (3- (6-methyl-3-pyridyl) zllyl) -4,5,7,8-tetrahydro-6H-thiazolo p, 4-dja3enHH.
    3- (b-methyl-3-pyridyl) allyl chloride and 3 equisomeric compound 2-amino-6- (1- (2- (1-piperidino) phenyl) -2-propen-1-yl) - 4,5,7,8-tetrahydro-6H-thiazolo D 4rdJa3enHH 7% of theory; m.p. 85 g 95 ° C (simple sfir) 3, and then the above compound
    Yield 6% of theory; m.p. 113-115 0 (ether) about
    1P Calculated,%: C 68.45; H 7.66; N 15.20.
    Found,%: C 68.36; H 7.96; N 15.15.
    Example 2-amino-6- (3- (2-bromo-valents 2 amino-4,5,7,8-tetrahydro je Phenyl) allyl) -4,5,7,8-tetrahydro-bN-bN-thiazolo 5,4- dJazepine in chloroform. thiazolo 5,4-e | azepine.
    Prepared according to Example 1 from 2-amino-4,5,7,8-tetratidro bN thiazolo (~ 5,4-d azepine, potassium carbonate and 2-bromo-20 cinnamyl bromide in anhydrous dimethylformamide for 2 hours at 20 ° C. Yield 42% of theory; mp 103 - 106 ° C (diisopropyl ether).
    Calculated,%: C, 52.75; H 4.98; 25 Br 21.94; N 11.54.
    Found,%: C 52.84; H 4.98; Br 22.14; N 11.53
    EXAMPLE 9 2-Amino-6- (3- (3-trifluoromethyl-phenyl) allyl) -4,5,7,8-tetrahydro-bN-thiazolo 5,4 3azepine.
    Prepared according to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiaeolo 5,4-dJ azepine, potassium carbonate and 3-trifluoromethylcinnamyl bromide in anhydrous di-methylformamide for 60 minutes at
    7o) 2-amino-6- (3-phenyl-2-n-propyl- 35 20 C.
    2-propen-1-yl) -4,5,7,8-tetrahydro-6H- Yield 41% of theory; m.p. 102-105 ° C thiazolo 5,4 azepine. (Petroleum ether).
    Calculated,%: C 57.77; H 5.13; N 11.89; Вг 9,07о
    “O- Found,%: C 57.91; H 5.08; N 11.97; Вг 9,38.
    EXAMPLE 2-Amino-6- (3- (2-cyano-phenyl) allyl) -4,5,7,8-tetrahydro-BH-thiazolo 5,4-dj azepine. Prepared according to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiaeolo p, 4-dJ azepine, potassium carbonate, and 2-cyanoincinnyl bromide (mp. 69 - 71 ° C) in anhydrous dimethylformamide in 15 hours at 20 ° С.
    Yield 30% of theory; m.p. 180 - 184 ° C (ether).
    Calculated,%: C, 63.98; H 6.71; N 18, 65.
    Found,%: C 63.79; H 6.72; N 18.44.
    7n) 2-amino-6- (2-ethyl-3-phenyl-2-propen-1-yl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJasenHH.
    Prepared from 2-ethyl-1-chloro-3-feiyl-2-propene and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo | 5,4-dJ azepine in chloroform.
    Yield 22% of theory; m.p. 110 - 113 ° C (petroleum ether).
    Calculated,%: C 68.98; H 7.40; N 13.41.
    Found,%: C 68.68; H 7.27; N 13.55.
    Prepared from 1-chloro-3-phenyl-2-n-propyl-2-propene and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo, 4-dJ azepine in chloroform.
    Yield 15% of theory; m.p. 77 - 80 C (petroleum ether),
    Calculated,%: C, 69.70; H 7.70; N 12.83.
    Found,%; C, 69.64; H 7.57; N 12.66.
    7p) 2-amino-6 (3 (2- (1 piperidino)
    phenyl) -2-propen-1-yl) -4,5,7,8-tetra-hydro-bN-thiazolo 5,4-dJ azepine.
    Prepared from hydrochloride 2- (1-piperidine) -cinnamyl chloride and 3 equivalents; Yield 31% of theory; m.p. 140 -144 ° C ribbons 2-amino-4,5,7,8-tetrahydro-6H- (acetone).
    thiazOlo 5,4-d azepine in chloroform Calculated,% C 65.79; H 5.85; for 5 h at 50 ° C. For cleaning 55 N 18.05.
    by chromatography on a silica column; Found,%: C 65.74; H 5.75; kagel (toluene / ethyl acetate / methanol N 18.10. in a ratio of 4: 2: 1) is eluted first
    Example 11 of 2-amino-6- (3- (3-cyanophenyl) allyl) -4,5,7,8-tetrahydr bH-thiazolo P, 4-dJ azepine „
    Prepared according to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine, potassium carbonate and 3-cyaioocinnamyl bromide (mp 52 - 55 ° C) in anhydrous dimethylformamide for 2 h at 20 ° C.
    Yield 48% of theory; m.p. 136 - 140 (simple) about
    Calculated,%: C 65.79; H 5.85; N 18.05.
    Found,%: C 65.54; H 5.88; N 18.27.
    Example 12 "(E) -2-amino-6- (3- (4-cyanophenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJazepin.
    Prepared according to Example 1 from 2-amino-4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJ azepine, potassium carbonate and 4-cyanoancinnamyl bromide (mp. 79-82 C) in anhydrous dimethylformamide for 60 minutes at 20 ° C. After distilling off dimethylformamide in vacuo, the residue from evaporation is partitioned between ethyl acetate and water. After drying, filtering and evaporating the organic phase, the evaporation residue crystallizes out from acetone, and the crystallized acid is washed with ether
    Yield 49% of theory; m.p. 199 - 205 ° С (decomposition).
    Calculated,%: C 65.79; H 5.85; N 18.05.
    Found,%: C 65.51; H 6.02; N 18,12 „
    Example 13. 2-Amino-6- (3- (2-quinolinyl) allyl) -4,5,7,8-tetrahydro-BH-thiazolo 5,4-d azepine x 0.2 HgO.
    To a solution of 3.1 g (16.7 mmol) of 3- (2-quinolinyl) allyl alcohol in 20 ml of chloroform, stirring and cooling with ice, at a reaction temperature of 5 ° C, a solution of 1.2 ml (16, 7 mmol) of thionyl chloride in 10 ml of chloroform. Stir for another 15 minutes and evaporate in vacuo at 20 ° C. The residue from evaporation of 3- (2-quinolinyl) allyl chloride hydrochloride at room temperature is dissolved in 50 ml of anhydrous dimethylformamide. 8.5 g (50 mmol) of solid 2-amino-4,5,7,8-tetrahydro-bH-thiazolo Ј5,4-dJ azepine is added and stirred for 12 hours at room temperature. Evaporated in vacuo10
    15
    0
    five
    0
    five
    0
    five
    0
    five
    disperse the residue between water and chloroform. After drying and filtration, the chloroform solution is evaporated in vacuo. The evaporation residue is purified by chromatography on a column of silica gel (chloroform / methanol in a ratio of 10: 1).
    Yield 2.6 g (46% of theory); m.p. 165-170 ° C (ether).
    Calculated (x 0.2 H20),%: C 67.10; H 6.04; N 16.56.
    Found,%: C 67.11; H 6.03; N 16.45.
    In example 13, receive the following connection:
    13a) 2-amino-6- (3- (3-isoquinolinyl) allyl) -4,5,7,8-tetrahydro-6H-thiazolo 5,4-dJa3enHH x 0.5 H2b,
    Prepared from hydrochloride of 3- (3-isoquinolinyl) allyl chloride. Obtained from chloroform from corresponding apyl alcohol and thionyl chloride at room temperature and 3 equivalents of 2-amino-4,5,7,8-tetrahydro-bN-thiazolo, 5,4 -djazepine in anhydrous dimethylformamide for 4 h at 50 ° C,
    Yield 45% of theory; t „pl. 196 - 199 ° C (ether).
    Calculated (x 0.5 H20),%: C, 66.06; H 6.13; N 16.22.
    Found,%: C 65.98; H 6.01; N 16.14.
    Example 14. 2- (3- (4-Methoxy-phenyl) propionyl-amino) -6- (3- (3-pyridyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo, 4-dJ azepine;
    ,, Mix the mixture with 1.0 g (3.5 mmol) of 2-amino-6- (3- (3-pyridyl) -allyl) -4,5, 7,8-tetrahydro-bN-thiazolo 5,4-сPaz - pina and 0.53 ml (3.8 mmol) of triethylamine in 40 ml of anhydrous chloroform and then a solution of 3- (4-methoxy-phenyl) -propionyl chloride (mp. 150 ° C) is added dropwise at room temperature. C / 15 Torr) in 7 ml of chloroform. Stir for 3 hours at 60 - 70 ° C, cool and shake with water. After drying and filtration, the chloroform solution is evaporated in vacuo, the residue from evaporation is purified by chromatography on a column of silica gel (chloroform / methanol in a ratio of 5: 1),
    Yield 0.74 g (47% of theory); m.p. 168 - 170 ° C (ether) about
    Calculated,%: C, 66.95; H 6.29; N 12.49 „
    ten
    20
    27 Found,%: C, 66.74; H 6.21; N 12.51,
    In Example 14, the following compound is obtained:
    14a) 2- (3- (4-methoxy-phenyl) propionyl) -amino-6- (3- (2-pyridyl) -allyl) - 4,5,7,8-tetrahydro-bN-thiazolo Ј5.4 -dj azepine x 0.5 HC1,
    Prepared by reacting 2-amino-6- (3- (2-pyridyl) -allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJ azepine with 3- (5-methoxy-phenyl) -propionyl chloride.
    Yield 42% of theory; m.p. 37 - 40 ° C.
    Calculated (x 0.5 HCl),%: C 64.33; 5 N 6.15; N 12.00; C1 6.86.
    Found,%: C 64.11; H 6.03; N 11.98; C1 6.90.
    Compounds No.o are also prepared in the above examples I - XI
    I. (2) -2-amino-6- (3- (2-pyridyl) -2-propen-1-yl) -4,5,7,8-tetrahydro-6H-TH33ono 5,4-dJa3enHH x 0 , 25 pp. 156 - 158 ° С (acetone) o
    Calculated (x 0.25 H20),%: C 61.95; H 6.41; N 19.27
    Found,%: C 61.93; H 6.21; N 19.16.
    I (g) -2-amino-6- (3- (3-pyridyl) -2-propen-1-yl) -4,5,7,8-tetrahydro-6H-thiazolor, 4 1 azepine with Topl. 125 - 126 ° С (acetone).
    Calculated,%: C, 62.92; H 6.34; N 19.57.
    Found,%: C 62.89; H 6.53; N 19.32.
    III (g) -2-amino-6- (3-phenyl-2-propen-1-yl) -4,5,7,8-tetrahydro-6H-thia- 3Ono | 5,4-dJa3enHH with m.p. 140 - 142 ° C (acetone).
    Calculated,%: C, 67.35; H 6.75; N 14.73
    Found,%: C 67.33; H 6.89; N 14.89,
    Iv. 2-amino-6- (3-phenyl-2-propyn-1-yl) -4,5,7,8-tetrahydro-bH-thiazolo C5,4-D azepine with m.p. 155 - 159 ° С (acetone) „
    Calculated,%: C, 67.83; H 6.05; N 14.83,
    Found,%: C 67.89; H 6.12; N 14.69,
    V-, 2-Amino-6- (3- (3-pyridyl) allngO173106128
    Found,%: C 63.72; H 6.32; t N 19.42.
    Vi. 2-amino-6- (3- (4-cyano-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-d a3enHH with m, pl. 199 - 205 ° C (Razi.).
    Calculated,%: C 65.79; H 5.85; N 18.05,
    Found,%: C 65.59; H 6.00; N 17.88,
    VII, 2-Amino-b- (3- (2-hydroxy-phenyl) a-lil) -4,5,7,8-tetrahydro-bH-thiazolo jJ, 4-dJa3eraiH x 0.5 N «0 s t. mp, 50 ° C (simple, ether); foamy.
    Calculated (x 0.5 H20),%: C 61.9 H 6.50; N 13.54.
    Found,%: C 61.98; H 6.58; N 13.45,
    VIII, 2-Amino-6- (3- (2-Amshu-phenyl allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-d a3enHH with so pl. 111 - 116 ° C ( ether).
    Calculated,%: C, 63.98; H 6.71; 25 N 18.65.
    Found,%: C 63.70; H 6.50; N 18.43s
    IX, 2-Amino-6- (2-phenyl-1-cyclopropyl-methyl) -4,5,7,8-tetrahydro-6H-thiazolopj, 4-dj azepine with t, pl. 109 - 113 ° С (isopropanol) 0
    Calculated,%: C 68.21; H 7.07; N 14.04,
    Found,%: C 68.25; H 7.11; N 14.10.
    X „2-Amino-6- (3- (4-chlorophenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3ennH with tlsh. 145 - 150 ° C. Calculated,%: C 60.08; H 5.67; N 13.14. 40 Found,%: C 60.15; H 5.48;
    N 12.97.
    Xi. 2-Amino-6- (3-phenyl-propyl) -4,5,7,8-tetrahydro-6H-thiazolo-5,4-dJ azepine dihydrochloride x 0.33 5 with pl. 221 - 225 ° С „
    Calculated (x 0.33 H20),%: C 52.47; H 6.42; N 11.47.
    Found,%: C 52.68; H 6.47; N 11.74. ® Biological experiments.
    , 1. Determination of affinity with Dopamine Dz-peceptors by displacement using ZNT-spiperone.
    Membrane drug. ,
    thirty
    35
    4,5,7,8 ttetrahydro-6H-thiazolo b, male rats of the strain Chbb: THOM, vesezepin with m.p. 162 - 1659 C. som approximately 200 g were killed
    Calculated,%: C, 62.92; H 6.34; blow to the back of the head. The brain was removed, which was N 19,57, which was opened on ice. Striped
    ten
    20
    ; five
    73106128
    Found,%: C 63.72; H 6.32; t N 19.42.
    Vi. 2-amino-6- (3- (4-cyano-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-d a3enHH with m, pl. 199 - 205 ° C (Razi.).
    Calculated,%: C 65.79; H 5.85; N 18.05,
    Found,%: C 65.59; H 6.00; N 17.88,
    VII, 2-Amino-b- (3- (2-hydroxy-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo jJ, 4-dJa3eraiH x 0.5 N "0 s so pl , 50 ° С (simple, ether); foamy.
    Calculated (x 0.5 H20),%: C 61.93; H 6.50; N 13.54.
    Found,%: C 61.98; H 6.58; N 13.45,
    VIII, 2-Amino-6- (3- (2-Amshu-phenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-d a3enHH with so pl. 111 - 116 ° C (ether).
    Calculated,%: C, 63.98; H 6.71; 25 N 18.65.
    Found,%: C 63.70; H 6.50; N 18.43s
    IX, 2-Amino-6- (2-phenyl-1-cyclopropyl-methyl) -4,5,7,8-tetrahydro-6H-thiazolopj, 4-dj azepine with t, pl. 109 - 113 ° С (isopropanol) 0
    Calculated,%: C 68.21; H 7.07; N 14.04,
    Found,%: C 68.25; H 7.11; N 14.10.
    X „2-Amino-6- (3- (4-chlorophenyl) allyl) -4,5,7,8-tetrahydro-bH-thiazolo 5,4-dJa3ennH with tlsh. 145 - 150 ° C. Calculated,%: C 60.08; H 5.67; N 13.14. 40 Found,%: C 60.15; H 5.48;
    N 12.97.
    Xi. 2-Amino-6- (3-phenyl-propyl) -4,5,7,8-tetrahydro-6H-thiazolo-5,4-dJ azepine dihydrochloride x 0.33 5 with pl. 221 - 225 ° С „
    Calculated (x 0.33 H20),%: C 52.47; H 6.42; N 11.47.
    Found,%: C 52.68; H 6.47; N 11.74. ® Biological experiments.
    , 1. Determination of affinity with Dopamine Dz-peceptors by displacement using ZNT-spiperone.
    Membrane drug. ,
    thirty
    35
    55 Male rats of Chbb: THOM strain weigh approximately 200 g.
    291731061
    the body was removed, weighed and homogenized in 25 volumes of Tris buffer (50 mM Tris-HCl, 1 mM ethylenediaminetetraacetic acid (hereinafter EDUC), 5 mM magnesium chloride and 1 mM ascorbic acid) for 30 s using an Ultra- Turrax operating at maximum speed, followed by homogenization at 1400 rpm in a Potter-Elwayte appliance. After centrifugation at 50,000 g and 4 ° C for 15 minutes, the residue was reabsorbed in 25 ml of tris buffer and centrifuged under the conditions described above. The supernatant was removed, the resulting residue was incubated in 25 ml of Tris buffer for 30 min at 37CC, again
    I About 1
    ten
    15
    25
    centrifuged at 50,000 g and 4 C 20 for 15 min. Then, the resulting residue was diluted with a ratio of 1: 500 (calculated on the weight of the striatum) by adding Tris buffer.
    Binding Analysis
    Aliquots of 1 ml of the membrane preparation were incubated in 1 ml of a solution of 0.25 nM / 3H / Spiperone (0.75 GBq / mmol, Dupont NEN) with increasing concentrations of the test substance (from) and at room temperature in for an hour. The incubation was stopped by adding 5 ml of cold, like ice, Tris buffer, and filtered with a filter Gat / B filter. The filters were washed twice with 5 ml of cold, like ice, buffer. The radioactivity of the filters was determined by means of bone scintillation and medium-stagel (Kenberra Packard). Nonspecific bond was determined in the presence of 10 M haloperidol (Sigma ChemicalCo)
    J data analysis
    From the data obtained, the curves were extrusions. The test substances displaced the radioligands in a typical agonist biphasic manner. Indicated values
    . c. (cc | UK1, with CL and K meaning the concentration or constant dissociation of the radio- 50 ligand used, refer to the dopamine receptor form, which has a high affinity.
    2. Determination of affinity with alpha receptors by displacement using / 3H /-clonidine. 55
    Membrane drug.
    Male rats of strain ChbbrTHOM weighing approximately 200 g were killed35.
    - 40
    t p / y with pr prka on Fi no no k l
    pr we
    cr G.
    and but on wed you
    of
    Zg Zd ZZ Zi Zk Zl Zm Zn Zo
    31061
    ten
    15
    25
    20
    35
    40
    thirty
    rum in the back of the head. Removed the brain. The cerebral cortex was weighed and homogenized in 25 volumes of Tris buffer (50 mM Tris-HCl, 50) for 30 s using an Ultra-Turrax device operating at maximum speed, followed by homogenization in a Potter-Elway device at 1400 vol. / min The homogenate was diluted with Tris buffer at a ratio of 1:50 (calculated on the weight of the cerebral cortex). Binding assay. Aliquots of 1 ml of membrane preparation were incubated in a 1 ml medium solution of 1 nM j3Hj-clonidine (2.2 TBq / / mmol of Dupont NEN) with increasing concentrations of the test substance (from 10 (to 10) for 3 hours at room temperature. The incubation was stopped by adding 5 ml of ice-cold Tris buffer and filter using a Watman GF / B filter. The filters were washed twice with 5 ml of cold ice-cold buffer. The radioactivity of the filter was determined by liquid scintillation in medium Canberra Packard installing company.
    The non-specific bond is determined in the presence of oxymetazoline from Sigma Chemical Co. Data analysis.
    From the data obtained, the extrusion curves were compiled using the G. Heinzel program.
    The table shows the values; and about 2-qt 0 test compounds. The quotient TL is an indicator of the relative affinity of a substance for dopamine-12 receptors compared to o-adrenoceptors. The higher the number, the higher the D7- / tx,
    f- tf
    selectivity.v
    Зг) Zd) Zj) Zi) Zk) Zl) Zm) Zn) Zo)
     Known connected
    Comparison of the data in the table indicates the superiority of new compounds over known ones.
    The novel compounds are classified as medium toxic substances.
    权利要求:
    Claims (1)
    [1]
    Invention Formula
    The method of producing thiazoloazepine derivatives of the general formula
    RrA-chrx
    Frequency converter
    where A is a group of the formula
    BUT
    45
    —C (Rf) CH—, (R4) S —CH —CH—, —CgC-9 —CH — CH — CH 2 -, —CHCOR —CH j, or - (CH)
    where n - 2,3 or 4;
    C is hydrogen or methyl group;
    R. alkyl group with 1 to 3 carbon atoms or phenyl group; 55
    Ry is hydrogen, methyl or ethyl, with the carbon atom indicated with an asterisk associated with the radical Rf;
    s
    five
    five
    0
    five
    R is a phenyl radical, unsubstituted or monosubstituted by a halogen atom, an alkoxy group with 1-4 carbon atoms, methyl. trifluoromethyl, phenyl, hydroxyl, benzyloxy-, nitro-, amino-, dimethyl-amino-, piperidine-, cyano-, aminocarbonyl, methoxycarbonyl, ethoxycarbonyl, methylthio, methylsulfonyl or methylsulfonyl - a group, or dimethoxyphenyl, dihydroxyphenyl, 4-hydroxy-3,5-dichlorophenyl, 4-hydroxy-3,5-dibromophenyl, 4-amhyu-3,5-dichlorophenyl, 4-amino-3 , 5 dibromophenyl, 3,4,5-trimethoxyphenyl, naphthyl, 6-chloro-2-pyridyl, thienyl, furyl, quinolyl, isoquinolyl, benzothiophenyl indole flax or ivdol-LIN-2-OH-4-IL group or pyridyl group unsubstituted or substituted by methyl group, or A is a carbon-carbon bond and
    - 1H-indi-2-yl-, 1,2-dihydro-naphthalen-3-yl- or 2H-1-benzopyran-3-yl group; Rg is hydrogen, acetyl or propionic group, unsubstituted or substituted in the omega position by a phenyl or 4-methoxy-phenyl radical,
    or their additive salts with inorganic acids, characterized in that the compounds of general form. mules
    RrA-CHj, -X
    where A and R have the indicated meanings; X - nucleophilic detachable
    Group,
    subjected to interaction with the compound of the General formula
    where pЈ has the indicated values, followed by isolation of the desired product in free form or as an addition salt with an inorganic or organic acid.,
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    同族专利:
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    DE3820775A1|1989-12-21|
    JPH0245489A|1990-02-15|
    NO176357C|1995-03-22|
    ZA894636B|1991-02-27|
    DE58907706D1|1994-06-30|
    FI89492B|1993-06-30|
    NO892435L|1989-12-21|
    FI892991A|1989-12-21|
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    NO892435D0|1989-06-13|
    KR910000742A|1991-01-30|
    EP0347766A2|1989-12-27|
    PT90907B|1994-12-30|
    AU3659389A|1989-12-21|
    US5068325A|1991-11-26|
    CA1337195C|1995-10-03|
    IE64661B1|1995-08-23|
    PH30664A|1997-09-16|
    JP2776892B2|1998-07-16|
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    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
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    法律状态:
    优先权:
    申请号 | 申请日 | 专利标题
    DE3820775A|DE3820775A1|1988-06-20|1988-06-20|NEW 4,5,7,8-TETRAHYDRO-6H-THIAZOLOAZEPINES, THEIR PREPARATION AND THEIR USE AS DRUGS|
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