Method of hetrazepine derivatives synthesis

专利摘要:
Hetrazepines of the formula <IMAGE> in which A, Z, n, X, Y, R1, R2, R3 and R4 have the meaning mentioned in the description. The novel compounds are to be used for the treatment of pathological conditions and diseases in which PAF (platelet-activating factor) is involved.
公开号:SU1738089A3
申请号:SU894614791
申请日:1989-08-17
公开日:1992-05-30
发明作者:Гейнц Вебер Карл；Гарройз Альбрехт；Штрански Вернер；Вальтер Герхард；Казальс-Штенцель Иорге；Муацевич Гойко；Гойер Губерт；Бехтель Вольф-Дитрих
申请人:Берингер Ингельгейм Кг (Фирма)；
IPC主号:

专利说明:

This invention relates to methods for producing new derivatives of hetrezepine with valuable pharmacological properties, in particular, to methods for preparing derivatives of heterazepine of general formula I
about
(SNg) „
R3
de A - condensed singly unsaturated 5, 6 - or 7-membered ring, n - 0 or 1;
X is a group C-RЈ-, where R is hydrogen or methyl, or a nitrogen atom; R v is hydrogen, not branched
alkyl group with 1 carbon atoms, unsubstituted or substituted with a hydroxyl group or halogen, cyclopropyl, unbranched alkoxy group with 1-4 carbon atoms, or halogen}
And EZ are the same or different and mean hydrogen, phenyl alkenyl with 2 or 3 yl-atoms, branched or unbranched alkyl with 1-18 carbon atoms, unsubstituted or substituted by hydroxyl, methoxy, nitroamino or alkylamino with 1- 4 carbon atoms or morpholinocarbonyl, if E3 is hydrogen, or R3 is thiazoline and thiazole, if RZ. hydrogen,
whether
R gi
R-3 together with the nitrogen atom forms morpholine and piperazine, unsubstituted or one or two substituted by straight-chain alkyl with 1-4 carbon atoms; phenyl, substituted by halogen, having valuable pharmacological properties, in particular antagonistic effect on the platelet-activating factor.
The use of benzodiazepine-alprazolam and
1C
triazolam as platelet-activating factor antagonists.
 the invention is the production of new diazepine derivatives having better properties compared with the known benzodiazepine derivatives.
The goal is achieved by the method of obtaining derivatives of hetrezepine of the formula I, namely, that the compound of the general formula II
20
HOOS- (CH2) p
where R (} R, X and n are specified
values
5 or its reactive derivative is reacted with a compound of general formula III
/ R2 HN
Xr3
where Kg and R3 have the indicated meaning, followed, if necessary, by transferring the obtained compound of formula I, where R is hydrogen, to the compound, where R is unsubstituted alkyl or halo, or by translating the obtained compound of formula I, where R {is halo, to a compound where R (is an alkoxy group), and isolating the desired product as a racemate or diastereomers.
Interaction4 free acid of the formula II with the compound of the formula III
5 is carried out in the presence of a carbodiimide, for example cyclohexylcarbodiimide, carbonyldiimidazole or sulphonyldiimidazole in an inert solvent, such as, for example,
0 dimethylformamide, tetrahydrofuran, dioxane or halogenated hydrocarbons, at a temperature of from 0 ° C to the boiling point of the reaction mixture. In the case of using the reaction5 of an incapable derivative of a compound of formula II, for example anhydride or acid halide, the reaction is carried out in an inert solvent such as, for example, dimethylforma5
mid, tetrahydrofuran, dioxane or a suitable hydrocarbon, such as toluene, at a temperature ranging from room temperature to the boiling point of the reaction mixture, and an acid binding agent, such as sodium carbonate, sodium bicarbonate or a tertiary organic base, such as pyridine or triethylamine, is added, if necessary.
If the compound of formula III is liquid, the reaction can also be carried out in an excess of this compound without additional solvent,
Example 1. 4- (Morpholin-4-yl-carbonyl) -6- (2-chlorophenyl) -11-methyl--2,3,4,5 tetrahydro-8H-ij benzothieno
3, A-triazolo SCHZ-a-Gb / 0 diazepine.
10 g (0.024 mol) 4-carboxyl-6- - (2-chlorophenyl) -11-methyl-2,3,4,5-tetrahydro-8H-p benzothieno 3,2-g l, 2.4 - triazolo-4,3-a-diazepine is mixed in 60 ml of methylene chloride with C, 2 g (0.026 mol) of carbonyldiimidazole and stirred for 45 minutes at room temperature. After adding 2.2 g (0.025 mol) of morpholine, stirring is continued for 4 hours. The reaction mixture is then washed with a saturated solution of sodium hydrogencarbonate and water, the organic phase is dried with sodium sulfate, the solvent is evaporated and the residue is brought to crystallization with ether. 9.6 g (83%) of colorless crystals are obtained, which can be recrystallized from isopropanol.
Melting point: 242-243 ° C.
Calculated,%: C 59.80; H 5.02, N 14.53.
Cr4n2 ..)
Found,%: C 59.63, H 4.95; N 14.73.
The original acid is obtained as follows.
a) 50 g (0.29 mol) of 3-hydroxycyclohexanecarboxylic acid ethyl ester, Tgpd: 135-140 ° C (obtained by hydrogenating oxybenzoic acid ester 3) are mixed in 600 ml of acetone with 92.5 ml of chromic sulfuric acid ( 133 g of chromium trioxide, 115 ml of concentrated sulfuric acid, diluted with water (up to 500 ml) and stirred for 30 minutes at 35 ° C. Solution
ten
five
20
25
380896
is separated from the dark green oil and the oil is extracted once more with acetone. The extraction products are evaporated under vacuum, the residue is taken up in methylene chloride and the solution is washed with water, dried and evaporated. 50 g of ethyl cyclohexanocarboxylic acid ethyl ester are obtained as a light yellow oil. ,
b) 50 g (0.29 mol) of the above compound, 51 g (0.29 mol) of o-chlorocyanoacetophenone, g of sulfur and 130 ml of dimethylformamide are mixed and the mixture is mixed at 30-35 ° C with 25.9 ml of tri- ethylamine. The mixture is stirred for 30 minutes, the dimethylformamide is distilled off, the residue is taken up in ethyl acetate and washed with water. After drying, it is evaporated and chromatographed over silica, a mixture of methylene chloride and methanol () being used for elution. From the eluate, 35-40 g of yellow crystals of 2-amino-5-ethoxycarbonyl-3 (2-chlorobenzoyl) -4.5,6.7 tetrahydro-benzo X of thiophene are obtained as the main fraction. Mp 136-137 ° C.
c) 34 g (0.02 mol) of aminoketoi, prepared analogously to example b, are used to create 8.5 ml of bromoethylbromide in 300 ml of dioxane in the presence of 7.5 ml of pyridine 38 g of N-bromoacetyl compound with mp 105 –10 ° C, which
35 is dissolved in 650 ml of anhydrous ethyl acetate. At room temperature, ammonia is added with stirring for 2 hours and left standing overnight.
40 Then 100 ml of ice-cold water is added, the organic phase is separated, dried and concentrated. 30-32 g of reddish oil is obtained, which is subjected to the absorption of 60045 700 ml of toluene for the cyclization of diazepine. Then 150 g of silica was added and the mixture was stirred for 2 hours at reflux temperature using a water separator. The solvent is separated and the residue is repeatedly extracted with methanol. The methanol extracts are evaporated and the residue is recrystallized from acetic ester. The yield is 23-25 g of 7 carbethoxy-5- (o-chlorophenyl) 55 6,7,8,9-tetrahydro-1H, MHD benzothieno 2,3-e diazepin-2-one with mp 209-211 ° C.
d) 36.2 g (0.97 mol) of the given diazepinone are absorbed by 350 ml of di30
glycol dimethyl ether, 15 g of sodium hydrogencarbonate and 30 g of phosphorus pentasulfide are added and stirred for 4-5 hours at. After cooling to room temperature, 350 ml of water are slowly added, and diazepinthion crystallizes. Then the crystals are filtered off with suction, washed with water, dissolved in methylene chloride, the solution is dried and evaporated. The crystal crystallizes after the addition of ether. The yield is 30-32 g of yellow crystals with a T of 197-198 ° C.
e) 14 g (0.03 mol) of diazepinone described above is dissolved in 170 g of tetrahydrofuran and mixed with 2.7 g of hydrazine hydrate. Then it is stirred for 30 minutes at room temperature, the solvent is distilled off and the residue is mixed with ether. The yield is 13 g, Tnft 199 199 ° C crystals, they are taken up in 100 ml of ethanol and, after the addition of 50 ml of triethyl orthoacetic acid ester, are refluxed for 1 h. The solvent is then distilled off and the residue is chromatographed on silica.
(methylene chloride and methanol 98: 2 are used as solvent). The residue of the main fraction is recrystallized from acetic ester. The yield is 11.8 g (81% of theory.) Of colorless crystals of 4- (ethoxycarbonyl) -6- (2-chlorophenyl) -11-methyl-2,3,4, 5-tetrahydro-8n- (J Zbenzothieno 3,2-fJ Ј1, 2,43 tri-aaolo 4,3-a l, 4-diazepine with T „to 183-184 ° С.
f) 15 g (0.036 mol) of the ester described above are mixed for 30 minutes at room temperature with ml of caustic potash in ethanol.
rahidrofuran and 20 ml of dimethylformam1 | yes with 1.2 g (7, mmol) carbonyldiimi
Dazole for 1 h at room temperature.
Then 1.8 g (7.6 mmol) of S-leucine morpholine hydrochloride and 0.77 g (7.6 mol) of triethylamine are added. The reaction solution is then stirred for three days, concentrated under vacuum, the residue is taken up in dichloromethane and extracted several times with water. After drying, the organic phase is evaporated and the residue is separated into both diastereomers by chromatography on RP 18 silica gel as eluent. mixtures of acetonitrile, a 0.01 molar solution of ammonium carbonate and diethylamine (35: 65: 0.1). 20 The first fraction after evaporation of the solvent is crystallized from dimethyl ether.
The yield is 90 mg (2%) with T n = 158-1 ° C.
25 Calculated,%: C 58.76j H 6.08; N 13.71.
SeoH65C1H6038 NgO (613.18)
Found%: C 58.27 J H 5.82J N 13.46.
The secondary fraction is also crystallized from diethyl ether.
The yield is 80 mg (2%) with a Tpd of 162-165 ° C.
Calculated,%: C 59.64; H 6.01; N 13.91} Cl 6.87; S 5.31. 35 C30H35-C1N605 0.5HZ0 (604,17)
Found,%: C 59.65, H 6.04; N 13.80; ci 5.73, s 5.36.
Example 3. 3 (Morpholin-4 yl-carbonyl) -6- (2-chlorophenyl) -11-methyl-0 -2,3,4-, 5 tetrahydro-8HC benzothieno 3,, 2.4 Triazols |; 4, , 4 diazepine.
thirty
16 g (0.04 mol) of 3-carboxy-6, then the solution is evaporated under vacuum, (2-chlorophenyl) -11-methyl-2 3,4,5-tv-. the residue is taken up in water and when ohranhydro-8H; p is benrthieno 3,2-ЈJ 1,2, and the mixture is cooled with ice, the pH is adjusted to 2 n with hydrochloric acid. The carboxylic acid is extracted with methylene chloride. Crystals are obtained with Tnft 312-315 ° C.
Example 2. NJ.6- (2-chlorophenyl) -2,3,4,5-tetrahydro-8H-1J benzote, 2-f 1,2,4 triazolo 4,3-aJ D, 4J diazepin-4- (R, S) -yl-carbonyl-leucine morpholide.
3 g (7.25 mmol) of racemic cyclohexanecarboxylic acid according to Example 1 are stirred in a mixture of 55 ml of tet-.
43triazolo 4,3-a D, 4} diazepine and 5.3 g of N-hydroxylbenzotriazole are suspended or dissolved in 150 ml, ft of dimethylformamide and mixed with 3.4 g (0.04 mol) of morpholine. While stirring and cooling with ice, add 9.7 g (0.04 g mol) of dicyclohexylcarbodiimide are added and stirring is continued for 20-24 h at 0-5 ° C. The selected dicyclo, hexylurea is sucked off and the filtrate is evaporated under vacuum. The residue is dissolved in 100 ml of 0.5 N hydrochloric acid and sucked off
rahidrofuran and 20 ml of dimethylformam1 | yes with 1.2 g (7, mmol) carbonyldiimi
Dazole for 1 h at room temperature.
Then 1.8 g (7.6 mmol) of S-leucine morpholine hydrochloride and 0.77 g (7.6 mol) of triethylamine are added. Then the reaction solution is stirred for three days, concentrated under vacuum, the residue is taken up in dichloromethane and extracted several times with water. After drying, the organic phase is evaporated and the residue is separated into both diastereomers by chromatography on RP 18 silica gel using a mixture of acetonitrile, 0.01 molar solution of ammonium carbonate and diethylamine (35: 65: 0.1) as eluent. . 0 The first fraction after evaporation of the solvent is crystallized from diethyl ether.
The yield is 90 mg (2%) with T n = 158-1 ° C.
5 Calculated,%: C 58.76j H 6.08; N 13.71.
SeoH65C1H6038 NgO (613.18)
Found%: C 58.27 J H 5.82J N 13.46.
The secondary fraction is also crystallized from diethyl ether.
The yield is 80 mg (2%) with a Tpd of 162-165 ° C.
Calculated,%: C 59.64; H 6.01; N 13.91} Cl 6.87; S 5.31. 5 C30H35-C1N605 0.5HZ0 (604,17)
Found,%: C 59.65, H 6.04; N 13.80; ci 5.73, s 5.36.
Example 3. 3 (Morpholin-4 yl-carbonyl) -6- (2-chlorophenyl) -11-methyl-0 -2,3,4-, 5 tetrahydro-8HC benzothieno 3,, 2.4 Triazols |; 4, , 4 diazepine.
0
(2-chlorophenyl) -11-methyl-2 3,4,5-twt-. rahydro-8H; p benztieno 3,2-ЈJ 1,2,
43triazolo 4,3-a D, 4} diazepine and 5.3 g of N-hydroxylbenzotriazole are suspended or dissolved in 150 ml of dimethylformamide and mixed with 3.4 g (0.04 mol) of morpholine. While stirring and cooling with ice, add 9 , 7 g (0.04 g mol) of dicyclohexylcarbodiimide and continue stirring for 20-24 hours at 0-5 ° C. The selected dicyclo, hexylurea is sucked off and the filtrate is evaporated under vacuum. The residue is dissolved in 100 ml of 0.5 N hydrochloric acid and sucked off
undissolved components. The filtrate is neutralized and extracted with methylene chloride. The residue of the methylene chloride phase is recrystallized with methylene chloride. The residue of the methylene chloride phase is recrystallized from ether and ethyl acetate to give g of the title compound with a melting point of 253-255 ° C.
Calculated,%: C 59.80; H 5.02; N 14.53.
C24H24C1% 02 (482.0) Found,% C 59.61; H 5.17;
N And, 07.
Example 4, C- (Morpholin-4-yl-carbonyl) -11-cyclopropyl-6- (2-chlorophenyl) -2,3,4, 5 tetrahydro-8H-benzothieno 3,2-f p, 2.4 triazolo 4,3-a i, 4 diazepine.
Starting from 15 g (0.037 mol) of 4-β-carboxy-11-cyclopropyl-6- (2-chlorophenyl) -2.3, 4,5-tetrahydro-8H-ij benzothieno 3,2-fJ (j, 2 , 4J triazolo Ј4,3-a l, 4 diazepine is obtained by reacting with 32 g of morpholine dimethylformamide according to the method described in example 3, 13.7 g of the above compound as a pale yellow powder, which begins to form-° C.
c 61.47; n 5.53;
catas at 175
Calculated,% N 13.78.
S2bNgbS1% Og
Found,%: C 61, 17; H 5.18; N 13.65,
The starting material is prepared as follows.
9.14 g (0.022 mol) of 7-carbethoxy-5- (2-chlorophenyl) -6,7,8,9-1H, j benzothieno 2,3-e diazepin-2-thione is dissolved in 100 ml of dioxane or suspended and after adding 2.1k r of hydrazide, cyclopropanecarboxylic acid is boiled for 3 hours under reflux. After evaporation of the solvent, the residue is chromatographed over a silica-packed column and eluted with methylene chloride and methanol (98: 2). 8.6 g of a viscous reddish oil are obtained, which is further subjected to saponification into acid 85 ml of 2N. solution of caustic potash in ethanol.
Example 5. 4-tert-Butylaminocarbonyl-6- (2-chlorophenyl) -11-methyl- -2,3, 5-tetrahydro-BN-Sobenzothieno 3, 2-f 1,2,4 triazolo 4,3 -al, 4J diazepine,
2.9 g (7 mmol) of the original diazepine used in Example 1 are mixed with 1.3 ml (18 mmol) of thionyl chloride in 40 ml of anhydrous dichloromethane and stirred for 30 minutes at room temperature. The suspension is concentrated and, after addition of 25 ml (240 mmol) of tert-butylamine, heated for 3 hours under reflux. then evaporated to dryness, taken up in dichloromethane, extracted with water, the residue of the organic phase is chromatographed on silica gel
with dichloromethane and methanol (95: 5) and then recrystallized from ethanol and ether. The yield is 1.2 g of said compound with
 P/
273 ° C.
Calculated: C 61.59; H 5.60; N 14.96; ci 7.58; s 6.85.
Found,%: C 61.49, H 5.83; N 14.74, C 7.49, S 6.74.
Example 6. 3 (Morpholin-4-yl-carbonyl) -6- (2-chlorophenyl) -2,3,4,5-tetrahydro-8H-G benzothieno 3,2-fJ j, 2, b triazolo 4, 3-el Јl, 4J diazepine with a melting point of 254-256 ° C.
Example 7. 11-Bromo-3- (morpholin-4-yl-carbonyl) -6- (2-chlorophenyl) -.-2,3,4,5 tetrahydro-8n-1 benzothie-, 2.4 triazolo1} 1,, 4 diazepine.
To 6.1 g (0.013 mol) of the compound
of Example 6 in 50 ml of chloroform and 2.5 ml of pyridine are added dropwise 0.9 ml of bromine dissolved in 10 ml of chloroform and stirred overnight at room temperature. The reaction solution is washed with water, dried, concentrated, and subjected to silica chromatography. From the remainder of the eluate get the target product with Tm 253 ° C.
Example 8. 11-Methoxy-3- (morpholin-4-yl-carbonyl) -6- (2-chlorophenyl) -2,3,4,5 tetrahydro-8H-l benzothieno 3,2-fl, 2, 4} triazoloЈ4,3-а2 l, 4 diazepine.
2.4 g of the desired product of example 7, and 2.5 g of potassium hydroxide are dissolved in 250 ml of methanol and heated for 1 hour under reflux. Then methanol is distilled off, the residue is taken up in methylene chloride and the solution is washed with water. It is then dried, evaporated and the residue is mixed with ether. The yield is 1.4-1.6 g, mp 207 ° C.
eleven
to
15
Calculated,%: C 57.88; H 4.86; N 11, About.
C24ng4s1% ° ъ, 0) Found,% C 57.92; H 1.81; N And, 01.
Example 9. 3- (Morpholin-4- -yl-carbonyl) -5 (2 chlorophenyl) -10-methyl-3, -dihydro-2H, 7H-cyclopent k, 5 thienoG, 3-f 1, 2, 4J triazolo H 3-a 1, diazepine.
15 g (0.038 mol) 3-carboxy-5- - (2-chlorophenyl) -Y-methyl-3.-Dihydro-2H, 7H-cyclopenta, 5 thieno 3, J 1, 2, triazolo pt, P, diazepi - reacted with 3.5 g of morpholine in the presence of dicyclohexylcarbodiimide according to example 3. 15 g of powder with Tnft 150 ° C are obtained. After recrystallization from ethanol, the compound melts at a temperature of 1-7-7-8 ° C. The compound contains 1% crystalline alcohol. H-NMR (CDC13), $ t 7.22-7.59 (m, aryl-H); , 9 (s, broad., 2H, CH2-7 ring); 2.06–4.00 (m, 13H, cyclopentyl-H, morpholine-H)} 2.67 (s, 3N, CH3-triazole, -ring).
Analogously to Example 3, the following compounds are prepared.
Example 10. 3- (n-Hexadecyl-amino-carbonyl) -5- (2-chlorophenyl) -10- -methyl-3, Dihydro-2H, 7H-cyclopenta O, 5 thieno 3,2-f 1,2, k triazolo LA 3-a 1, h diazepine as a light yellow oil. H-NMR (CDC), b: 7.26-7.53 (, m, aryl-H); 5.86 (1H, t, J 7 Hz, NH), 86 (2H, s, wide ,, СН4-7-ring); 2.71 (3N, s, CH3) 1.39-3.3 (7H, m, cyclopentyl-H, NCH), 40. N 10.99. 1.26 (28H, s, hexadecanil); 0.88 (ZN, t, J 6 Hz, ZN, CH3-hexadekanil) ,. -.
Example 11. 3 (dioctylamino i3 a p, diazepine as white
foam,
 H-NMR (CDC) .ff: 7.22-7.5 (m, H, aryl-H) j, 9 (s, broad ,, 2H, 5 CHt 7-ring), 2.69 (s, 3N , CH3-C N) 1.23-3.1 (m, 13H,, cyclopentyl-H, K-CH2 CH2-CH3), 0.82 (t, J = 7 Hz, 6H, S-CH2-CH2-CH 2) .
Example 13. (Morpholin-C- -yl-carbonyl) 5- (2-chlorophenyl) -10- -methyl-7H-cyclopentaG / 1.51thieno, 2-f 1, 2, k triazolo, 3-a D, fl diazepmn with Trp 298-300 ° C (methylene chloride and ether).
Calculated,%: C 59.03 j H b, 7k
N-1M7.
C23H ClNjO (W7.9)
Found,%: C 58.8A; H 4.73} 20 N C, 69.
Example 1. 5 (morpholine- -yl-carbonyl) -7 (2-chlorophenyl) -12- -methyl-3, 5 6 tetrahydro-2H, 9H-cyclohepta Thienor-E p, 2.4 25 triazolo,. 1, G | diazepine with Tm 290-291 ° C,
Calculated,%: C 60.53l, H 6.28; N 1.12.
C25H26C1N50. " C + 96.0) Found,% C 60,12; H 5.36; 30 N And, 93.
Example 15. - (Morpholin-4- -yl-carbonyl) -6- (2-chlorophenyl) -11-2.3.3, S-TeTparnflpo-CH-fl benzothienor, 2-E imidazo1,, diazapine with TP „2 8-250 ° С.
Calculated,%: C 62, H 5,
N 11.65.
C2SHzs-ClN4OzS (81.0)
Found,%: C 62.31, H 5.36;
Example 16. 3 (I-Hexadecylamino-carbonyl) -5 (2-chlorophenyl) -1 -1-methyl-3, -dihydro-2H, 7H-cyclo-carbonyl) -5- (2-chlorophenyl) -10- methyl. 45 penta C1, 5 thieno 3,2-E imidazo, 2-a
-3,4-dihydro-2H, 7H cyclopenta, 51 thieno 3,2-f 1,2, triazolo k, 3-a J (1, diazepine as a viscous oil.
1 H-NMR (CBC1), Ј: 7.33-7.55 (m, aryl-H); C, 92 (s, broad. 2H, SNg-7-ring), 1 2.7 (s, 3N,) {1,, 81 (m, 3ZN, cyclopentyl-N, octylamino-C 11), 0, 89 (t, Hz, CH-octylamine).
Example 12, 3- (Dipropylaminocarbonyl) -5- (2-chlorophenyl) -1O-methyl-3, 1-digirro-2I, 7H-cyclopenta 5 thieno 3.2-f l, 2, triazolo
(, Udiazepine in the form of a viscous oil.
f H-NMR (CDd), 5: 7.25-7.9 (m, i + H, aryl-H) -; 6.89 (sq. Hz, 1H, CH); 5.69 (t, J 6 Hz, 1H, NH) 50 117 (s. Broad ,, 2H, SNg-7 ring) -, 3.05-3.37 (m, 7H, CHZ, CH, 5-ring , NCH2), 2, M (d, Hz, 3N, CH3-C) 0.99-1.53 (m, 28H, N-CHt- (CH2) l4.); 0.88 (t, J 8 Hz, ЗН, СНЭ- (СН2) П). Example 17, - (Diethylaminocarbonyl) -6- (2-chlorophenyl) -11-methyl--2,3, 5-tetrahydro-BN-P benzothieno Zr2-51 imidazoЈ1,, diazepine with Tnft 201-203 ° C.
55
to
15
 , 40. N 10.99.
7380B9. 12
 p, diazepine as white
foam,
 H-NMR (CDC) .ff: 7.22-7.5 (m, H, aryl-H) j, 9 (s, broad ,, 2H, 5 CHt 7-ring), 2.69 (s, 3N , CH3-C N) i 1.23-3.1 (m, 13H,, cyclopentyl-H, K-CH2 CH2-CH3), 0.82 (t, J = 7 Hz, 6H, S-CH2-CH2-CH3 ).
Example 13. (Morpholin-C- -yl-carbonyl) 5- (2-chlorophenyl) -10- -methyl-7H-cyclopentaG / 1.51thieno, 2-f 1, 2, k triazolo, 3-a D, fl diazepmn with Trp 298-300 ° C (methylene chloride and ether).
Calculated,%: C 59.03 j H b, 7k
N-1M7.
C23H ClNjO (W7.9)
Found,%: C 58.8A; H 4.73} 20 N C, 69.
Example 1. 5 (morpholine- -yl-carbonyl) -7 (2-chlorophenyl) -12- -methyl-3, 5 6 tetrahydro-2H, 9H-cyclohepta Thienor-E p, 2.4 25 triazolo,. 1, G | diazepine with Tm 290-291 ° C,
Calculated,%: C 60.53l, H 6.28; N 1.12.
C25H26C1N50. " C + 96.0) Found,% C 60,12; H 5.36; 30 N And, 93.
Example 15. - (Morpholin-4- -yl-carbonyl) -6- (2-chlorophenyl) -11-2.3.3, S-TeTparnflpo-CH-fl benzothienor, 2-E imidazo1,, diazapine with TP „2 8-250 ° С.
Calculated,%: C 62, H 5,
N 11.65.
C2SHzs-ClN4OzS (81.0)
Found,%: C 62.31, H 5.36;
N 10.99.
Example 16. 3 (I-Hexadecylamino-carbonyl) -5 (2-chlorophenyl) -1 -1-methyl-3, -dihydro-2H, 7H-cyclopenta C1, 5 thieno 3,2-E imidazo, 2-a
penta C1, 5 thieno 3,2-E imidazo, 2-a
(, Udiazepine in the form of a viscous oil.
f H-NMR (CDd), 5: 7.25-7.9 (m, i + H, aryl-H) -; 6.89 (sq. Hz, 1H, CH); 5.69 (t, J 6 Hz, 1H, NH); 117 (s. Broad ,, 2H, SNg-7 ring) -, 3.05-3.37 (m, 7H, CHZ, CH, 5-ring, NCH2), 2, M (d, Hz, 3N, CH3 -C) i 0.99-1.53 (m, 28H, N-CHt- (CH2) l4.); 0.88 (t, J 8 Hz, ЗН, СНЭ- (СН2) П). Example 17, - (Diethylaminocarbonyl) -6- (2-chlorophenyl) -11-methyl--2,3, 5-tetrahydro-BN-P benzothieno Zr2-51 imidazoЈ1,, diazepine with Tnft 201-203 ° C.
Calculated 12.00. CfcyHtfClN OS
ABOUT .
/ s:
13 from 64.29;
(467.2).
n 5.83;
one
C, 64.08; H 5.90 {
Found, N, 11.87.
Example 18. 4- (Diethylaminocarbonyl) -6- (2-chlorophenyl) -10-methyl--2,3,4,5-tetrahydro-8H-Shbenzotiye-, 2-Ј imidazo {), 2-a 1 , 4 diazepine with Tm 225-228 ° C.
Example 19. 3 (Morpholin-4-yl-carbonyl) -5 (2-chlorophenyl) -9-methyl-1O-bromo-3,4-DIHIDRO-2H, 7H-cyclo-, 5 thieno 3,2-fj imidazo ft, 2 1, 4 diaaepine (starts to bake at
135 ° C).
Similarly to the examples given, the compounds of formulas A and B are given in the table.
Rl.
$
Ј & v
.XLJ) N
A R.

V, -.
R
If a
then X means nitrogen, nile, p - O,
Nothing else. P 4 The H-NMR spectra of the compounds of Examples 45-47, 50-57 are reported below.
Example 45. H-LMR (CDClj), b; 7.18-7.72 (4n, m, aryl-H); 5.89 (1H, KB, J 2 Hz, CH); 4.80-6.00 (6H, m,), 5.39 / 4.10 (2H, AB-system LDB 12 Hz, CH2-7-ring oK 3.73-4.01 (4H, m, NCH2 ); 3.50-3.73 (1H, m, cyclohexenyl-N); 2.41 (3N, d, J: 2 Hz), 1.56-200 (6H, m, CH-cyclohexenyl).
Example 46 H-NMR (CDC15), 6: 7.11-7.64 (4H, m, aryl-H); 6.90 (1H, KB, J 12 Hz, CH); 5.42 / 2.12
738089
14
-
ten
    w I t, J 12-Cyclohexenyl). 50. H-NMR (CDClO.ft
15
20
25
(2H, AV-system JAB- 12 Hz, SNg-7- -ring); 2tk2 (3N, d, J 2 Hz,) -; 1.08-3.8 (15H, m, cyclohexenyl-N, N- (CH2CHz-)), 0.83 (6H, 2 t, N 7 Hz), (CHZCH2QJ13) 2.
Example “7. H-NMR (CDC13), tf: 7.20-7.60 C "H, m, aryl-H); , 80- 5.97 (6H, m,)} it, 21 / 5J7 (2H, AB system J / j6 12 Hz, CI2 -7 ring); .O (5H, mg, CH2N, CH-cyclohexyl); 2.67 (); 1.56-3, (CH, m, CH,
Example
7.21-7.56, m, aryl-H); t, 67-6.09 (6H, m,), A, 89 (2H, s, broad., CH2-ring G, 1.89-, 13 (9H, m, NCH2, cyclopentenyl-H), 2.68 (ZN, s, CH3-).
Example 51. H-NMR () D: 7.33-7.550 (H, m, aryl-H) 1, 4.92 (2H, s, broad., CHg-7-ring)} 2.7 (ZN, s,,; 1.04-3.81 (ZZN,. m, octylamine-CH, cyclopentenyl-H) j 0.89 (6H, 2 t, J 6 Hz, CH3-cyclo-octyl).
Example 52 H-NMR (CDC13), 0: 7.22-7.58 (4M, m, aryl-H) -; 4.9 fi (2H, s, broad ,, CH2 7-ring), 2.69 (3N, s,); 1.23-3.41 (13H, m,
30 M-CH2CH2OTs), 0.82 (6H, t (
N-CHZCH2CH3).
J 7 Hz
five
Example 53. H-NMR (CDCl,) j (f: 7.22-7.56 (AN, m, aryl-H); 6.91 (TH, J 2 Hz, CH); 4.80 (2H, with,
square
broad., CHg ring), 1.22-3.93 (13H, m, H-CH2CHH-CH3, cyclopentenyl-H); 2.43 (ZN, d, J 2 Hz,
SI,), 0.84 (6H,
7 Hz
AND-SNGCHN2S1TS).
Example 54. H-NMR (CDCl,),: 7.19-7.51 (4H, m, aryl-H), 6.88 (1H, sq. J 2 Hz, CH); 4.90-5.99 (6H,
m,), 4.70 (2H, s, wide CH-7-ring); 1.81-4.06 (9H, m,
Nch
2
cyclopentenyl-N) / 2.42 (3N, d, 2 Hz, СН% -С С)
Example 55. H-NMR (CDCl3) fd: 7.28-7.54 (4H, m, aryl-H) -, 7.28, 7.20, (2H, 2d, J 2 Hz,); 4.98, 4.82 (2H, AB-system, JAB 15 Hz, SNg-ring), 1.93-3.93 (13H, m, cyclopentenyl-H, morpholine-H).
Example 56 / H-NMR (CO1E): 7.20-7.53 (4H, m, aryl-H); 5.22 (2H, cj wide., СН2. -7 ring), 2.25 (3N, s,); 1.86-3.87 (13H, m, cyclopentenyl-N, morpholine). „
15
Example 57, H-NMR (CDClJ, fiV 7.18-7.53 (4H, m, aryl-H); 7.00 (fH, KB, J {.gHz, CH); 4.83 (2H, c, broad ,, CH2-7-ring), 1.91-3.87 (13H, m, cyclopentenyl-H, morpholine-H 2.26 (3N, d, J L2 Hz,).
The antagonistic effect of compounds of the formula I, which belong to the category of low-toxic substances, to platelet activating factor is examined by determining the inhibition of platelet aggregation.
In vitro studies: inhibition of platelet aggregation.
In order to determine the antagonistic effect of the test substances on the platelet activating factor, in vitro induced aggregation of human platelets was induced by the platelet activating factor.
In order to obtain platelet-rich plasma, blood was taken from a non-stagnant vein by means of a plastic syringe containing 3.8% sodium citrate solution. The ratio of sodium citrate solution and blood is 1: 9. After gentle mixing, citrate blood is centrifuged at 1200 rpm for 20 minutes. Platelet aggregation was determined by the method of Born and Cross, J, Physio. 168, 178 (193), and platelet-rich plasma is added with a constant stirring activating platelet factor as a pathogen of aggregation.
The test compound was added 2–3 minutes before the aggregation was initiated in a volume of 10 µl. Distilled water, acetone and / or dimethylsulfoxide were used as solvents. In the control experiments used only the appropriate amount of these solvents. After registration of the initial absorption (2-3 minutes), aggregation was induced by a platelet activating factor (5-10-8M).
To determine the effectiveness of the compounds under study, the first wave of aggregation was used. The maximal factor induced by platelet activating factors - the degree of absorption (-maximal aggregations 100%) was studied simultaneously in the control experiment and used as a 100% value.
V
1738089
sixteen
For each test compound used in concentrations, an inhibitory effect on the platelet aggregation factor induced by the platelet activating factor is determined. The results obtained at three concentrations were used to form an action / concentration curve and the CT value was determined. concentration to achieve 50% inhibition (aggregation).
The results of the experiment are as follows:
five
0
five
five
0
five
0
,
Compound
Alprazolam (known)
Triazolam (known)
Example compounds
one
2
3
C
5 7 8
9 10 11 12
13
14
15 17 18 19 20 21 22
23 2k
25
26
27
28
29
thirty
31
32
33
35
36
37
40
42
4h
The value of KT50, µmol / l
14 9
0.5 1.2 2.5 3.0 0.3 4.0 M
oh w
3.0 3.0 0.3 0.2 2.0 0.3 0.4 0.4 0.3 3.3 OL 1.8
2.7
1.0
2.0
0.7
ten
1.2
1.2
4.8
0.4 0.5 0.5 1.7 3.6 1.0 1.2 1.2 1.3 0.8

about

N-C- (CH2)
20
25
, coos (CH2) p
de A - condensed singly unsaturated 5, 6 - or 7-membered ring, n - 0 or 1,
X is a C-Rg group, where R is hydrogen or methyl, or nitrogen / -Ri is hydrogen, an unbranched alkyl group with 1-4 carbon atoms, unsubstituted or substituted with a hydroxyl group or halo, cyclopropyl, unbranched al- a coxy group with 1-4 carbon atoms, or halogen;
2 and V. are the same or different and
means hydrogen, phenyl, al-, kenyl with 2 or 3 carbon atoms, branched or unbranched alkyl with 1-18 carbon atoms, unsubstituted or substituted by hydroxyl, methoxy, nitro, | 3mino or alkylamino
where R., R ,,, X and p have the indicated.
values
| or its reactive derivative is reacted with a compound of general formula III
,AT:
HN
N
3
where K2 and C3 have the indicated meaning, followed, if necessary, by transferring the obtained compound of formula I, where R is hydrogen, to the compound, where R is unsubstituted alkyl or halo, or by translating the resulting compound of formula I, where R is halo, a compound where R is an alkoxy group and the isolation of the target product as a racemate or diastereomers,
21
17380Р9
22
Table continuation

权利要求:
Claims (1)
[1]
Formula of the invention, characterized in that the compound of general formula II
A method of obtaining derivatives of hetrazepine of the general formula I where A is a single condensed but unsaturated 5 “, 6- or 7-membered ring, η is 0 or 1,
X is a group C-βξ., Where P ^ - is hydrogen or methyl, or nitrogen;
- hydrogen, an unbranched alkyl group with 1-4 carbon atoms, unsubstituted or substituted by a hydroxyl group or halogen, cyclopropyl, an unbranched alkoxy group with 1-4 carbon atoms, or a halogen;
K ₂ and P ^ are the same or different and mean hydrogen, phenyl, alkenyl with 2 or 3 carbon atoms, branched or unbranched alkyl with 1-18 carbon atoms, unsubstituted or substituted by hydroxyl, methoxy, nitro, ι amino or alkylamino where P ^, K4, Xil have the indicated.
the values &'or its reactive derivative are reacted with a compound of the general formula III ³⁵ 4 /
ΗΝ
In r to ₃ where Ρ _{ζ and} Р ₅ have the indicated meaning, 'followed by, if necessary, converting the obtained compound of formula I, where K <is hydrogen, to a compound where K * is unsubstituted alkyl or halogen, or by *. the irradiated compound of formula I, where K, is a halogen, to the compound where P ^ is alkoxy, and the isolation of the target product in the form of a racemate or diastereomers.
ExampleΝ ’ , to ₂ - <Кз * < Formula PositionniegroupsΪ Receiving byan example T ° ¹ PL ^'s 1 2 3 4 5 6 7
20 M (s _r n ^) ₂sun ₃A 3 3 226-228 21 N (s ₂ n ₅ ) ₂SNZ A 4 1 206-209 22 - ^ Г ^ М-Сиз sun ₃A 4 1 . 253-255 CH ₃ 23 HO- (CH _{2) r} s sun ₃A 4 1 250-251 CHz N  ‘ 24 but-with- (sn _g ) _2- n sun ₃A 4 1 237-238 SNZ 25 N cn ₃A 3 3 220-212 ort s - (sn ₂ ) ₂ 4 SNZ 26 CH3 V HO-CH ₂ > CH CH ₃A . 4 1 198 SNZ 27 ' n_ 1 CHA A 4. 1 223-224 NgN-SNg-SNg-N- 28 n _g m sun _3>A 4 280 CHs> 29th <0n- sun ₃A 4 1 230-231 CH ₃ SPZ thirty > sn _hB 4 3 . 317-318 SNZ 31. sun _iB 4 3 251-253 with ₂ n ₅ . 32 R- n- _g -base ₃B 4 3 244-246 33 / ~ L0 ΪΓ * -! -base ₃A 4 8 207-209 34. o_k-so-sn ₂ -m- sun ₃B 3 9 221-223 35 g - ™ CH ₃A 4 1 267-268 36 H ₃ SouCH Ϊ0ΝΗ- sun ₃A 4 1 318 37 -ΝΉ-iso C} H ₇sun ₃A 4 1 280 38 -Ν (μ-Π ₅ Η ₇ ) ₂sun ₃A 4 1 208 39 -№1С (СН ₃ ) ₅SI A . 4 1 273
Table continuation
1 Y '- - ----- T> ..... Ί G ““ 7 ----- -R- 5....... n 40 -M- (CH _g ) ₂ -HH-C _g H ₅sun ₃A 4 1 166-167 41 -INS (CH ₃ ) ₃SC ₃A 4 1 278 , main ₃x = sn 42 sun ₃A 4 1 258 . OCH x = sn 43 -ΝΗ-Xd) sun ₃A 4 Ί 270 44 s (s ₃ n ₇ ) ₂sn. A 4 t 224-226 45 -n (sn ₂ -sn = sn _g ) ₂sun ₃A 4 1 Oil x = sn 46 -K (C, H ₇ ) ₂sn A 4 1 Oil A x = sn 47 -and (sn ₂ -sn = sn ₂ ) ₂CH at A 4 1 Oil 48 eRoCH_L CH ₂ C1 A 4 9 240 ° C 49 / “*-Ν 0 sun ₂ he A 4 9 242 ° C fifty th (CH ₂ —CH = CH ₂ ) _gCH ₃B 3- 1 Amorn. 51 -n [(sn _g ) ₇ sn ] _gsn B 3 1 Oil 52 -H (C ₃ H ₇ ) ₂sn B 3 1 Oil 53 -P (s ₅ n ₇ ) ₂sun ₃B 3 1 Oil 54 '. -th (sn ₂ -sn = sn ₂ ) ₂sun ₃B 3 1 Oil X-CH 55 -ΐΡ o sun ₃B 3 9 Beginning with ν- / 95 ° C decomp. 56 -ιΡο Vg B 3 9 Beginning with x = sn 135 ° C decomp. 57 . / - -'C ⁰n B x = s-ck ₃3 9 Starting at 85 ° C decom. 58 > -1P0 _ / . ^snB 3 9 130-131 • x = sn 59 h-K 0V— * sun ₃B 3 9 186 n = 1

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法律状态:

优先权:

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申请号 | 申请日 | 专利标题

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DE3624647|1986-07-22|

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