Method of producing derivatives of alkylmelatonines

专利摘要:
beta -Alkylmelatonins are useful as ovulation inhibitors.
公开号:SU1553011A3
申请号:SU884355105
申请日:1988-02-01
公开日:1990-03-23
发明作者:Эдвард Флау Майкл
申请人:Эли Лилли Энд Компани (Фирма)；
IPC主号:

专利说明:

(QRR) -C (BQ-CCKa) -C C-CK-CH-l H
where K is CNG-CK2-CH-C (0) - and Rj C, -Cg-alkyl; K4 - (independent) H or halogen with ovulation inhibitory activity, which can be used in medicine. The goal is to create new active and low toxic substances of the specified class. The synthesis is carried out by acylation. The invention relates to the preparation of new $ -alkyl derivatives of melagonine of the general formula
Бс.0
I2
CH-CH2-NH-CO-B,
where K ,, K and R5 - C-C4-alkyl;
RJ and R4 are each independently hydrogen or halogen,
possessing ovulation inhibiting activity.
corresponding amine (introduction of the group - C (0) - K,). Yield,%, mp., ° C, brut-f-la: a) 100; 99; С „Н„ И05; b) 100; semi-solid substance; C, Vng1Shv; c) 85; C, 7H1VSH6S1; d) 66, no; Cw H1bN04Cl4. New substances are active at a minimum inhibitory dose of 1 mg / kg versus 32 mg / kg for melatonin. 1 tab.
(L
ate
ate
with
The aim of the invention is to develop, on the basis of known methods, a method of producing new derivatives of indolyl, which possess valuable pharmacological activity with low toxicity.
Example 1. Preparation of p-methyl melatonin.
To a cold (15 ° C) solution of 17.9 g (0.12 mol) of 5 methoxyindole, 17.5 g (0.12 mol) of Meldrum acid and 5.3 g (0.12 mol) of acetaldehyde in 120 ml of acetonitrile are added are 0.11 g of 1-proline. The reaction mixture is cooled to prevent the increase of
initially exothermic reaction above 25 ° C, after which the mixture is stirred for 5 h at room temperature. The acetonitrile is removed in vacuo and the resulting pale yellow oil is crystallized by cooling for a day at 0 ° C. The crystallized product is washed with petroleum ether and dried. The yield of the adduct is quantitative (ie, mp. 99 ° C).
Found,%: C, 21; H 6.14; N 4.22. , ,
Calculated, Ј: C 6, H 6,
w i, jn.
 A mixture of 39 ml of methanol and 110 ml of pyridine is passed through a stream of nitrogen to remove the air dissolved in it within a few minutes. Then, 38.5 g (0.12 mol) of the resulting adduct was added to the mixture, followed by the addition of 0.76 g of copper dust. The resulting mixture was boiled under nitrogen for 16 hours. After cooling, the mixture was filtered through a Hyflo super gel, the solvents were immediately evaporated from the filtrate, the residue obtained was dissolved in diethyl ether and the ether solution was washed with 1N. followed by washing with a Ј0% ammonium chloride aqueous solution. The organic layer is dried over anhydrous. and the crude chromate product obtained after evaporation of diethyl ether was refined on silica gel using 3% MeOH in CHClI. The purified product obtained in the form of an amber oil is identified as ethyl 3 (5-methoxy 1H-indole-3 yl) -pentanoic acid (yield 23.3 g,).
-L
Found,%: C 69.18; And 7.36; N 5.27.
,, N03
Calculated,%: C 68, H 7.33; N 5.36.
Under a nitrogen atmosphere, a mixture of 22.3 g (0.086 mole) of the obtained ester and 16.6 ml of hydrazine hydrate is boiled. After 3.5 hours, the excess hydrazine hydrate is removed in vacuo. The resulting 2-methyl-2- (5 methoxy-3-indolyl) propionyl hydrazide crystallizes on standing. The filter cake is washed with ether to give 16.5 g (78% of a colorless hydrazide, the sample of which, after recrystallization from these acetate, has a melting point of 117 ° C.
Found,% C 62.96; H 6.66;
N 17.13.
Vnw
Calculated,%: C 63, H 6.83; N 16.99.
To a stirred mixture of 16.5 g (0.067 mol) of the hydrazide obtained, 100 ml of acetic acid, 200 ml of water and 200 g of ice, a solution of 6.21 g (0.09 mol) of sodium nitrite in 11 ml of water was gradually added. The resulting acyzide is immediately extracted with cold diethyl ether. The extract is cold washed with an aqueous solution of NaHCtX, and then brine, and then dried over. The ether was evaporated in vacuo and the residual acyl azide was transferred to 200 ml of cold toluene. The resulting solution is slowly added to an additional amount of toluene (200 ml), which is mechanically stirred under a nitrogen atmosphere in an oil bath at 83 ° C. After the addition, stirring is continued for 15 minutes. The reaction mixture is allowed to cool to 5 ° C, after which a stream of dry HCl gas is passed into the solution for several seconds. The mixture is then concentrated to half the volume and the resulting insoluble product is collected by filtration. The filter cake is washed with diethyl ether and, after drying, 5.79 g (38%) of 1-oxo-methyl-6-methoxy-1,2,3, A-tetrahydro-9H-pyrido (3, A-b ) indole, m.p. 220 ° C.
Found,%: C 67, H 5.97; N 12.37.
C "H14N4 ° 4t 0
Calculated,%: C 67.81; H 6.13; .N 12.17.
Under a nitrogen atmosphere, a suspension of the tetrahydropyridoin obtained in a solution consisting of 85 ml of ethanol, 60 ml of water and 8.5 g of KOH is boiled for 24 hours. After cooling, the ethanol is evaporated in vacuo. The remaining aqueous solution is cooled to approximately with a decrease in the pH of the solution to 6 by the addition of 1N. hydrochloric acid. The precipitated amino acid is collected and dried under vacuum without heating. The yield of crude tox-3- (1-amino-2-propyl) indole-2-carboxylic acid is quantitative.
Immediately, the obtained amino acid is decomposed by boiling in 150 ml of 5 M methanesulfonic acid n-solution in nitrogen atmosphere for 7 min.
After cooling, the solution is alkalinized by adding 5 M aqueous NaOH solution. The decarboxylation product is extracted with ether. The ether extracts are dried over NazSd4 and, after evaporation of the ether, 3.9.2 g of crude tryptamine is obtained as a gummy solid. By washing the crude product with a small amount of cold toluene, 2.8 g of crystalline product (8%) are obtained, which is a purified 5 methoxy-3- (1-emino-2-propyl) indole.
A solution of 2.8 g of tryptamine (0.012 mol) in 18 ml of toluene and k, $ ml of pyridine is treated with 2.5 ml of acetic anhydride, after which the mixture is stirred for 3 hours. The solvents are then removed in vacuo, the resulting residue is taken up in CH4C12 and the mixture is stirred for several hours with an aqueous solution of NaHCO to destroy residues of acetic anhydride. The solution of CH2Cl is then dried over Na2SO4 and the solvent is evaporated. Chromatography of the crude product on silica gel using ethyl acetate for leaching afforded 2.5 g (95%) of pure (α-methyl mepatonin as a colorless glassy substance.
Found,%: C 68.07; H 7.50;
N
11.17.
%: C 68.27; H 7.37; Receiving (L-ethyl
2
Calculated N 11.37.
An example of melatonin.
In Example 1, 5 methoxy-sindole, propionaldehyde, and Meldrum acid are condensed. Since the reaction in this case proceeds somewhat more slowly, a 50% excess of propionaldehyde is used and the reaction mixture is left overnight. The yield of the adduct, which is a pale yellow semi-solid, is quantitative.
N
Found,%: -C b5.6; H 6.58; 3.99.
C, 6HZ, N05
Calculated,%: C 65, H 6.59; N a, 23.
In example 1, the adduct is solvilized in the presence of pyridine and copper dust. Decarboxylation proceeds somewhat less actively than in the previous case. After boiling the mixture for 19 hours, it becomes necessary to distill off ethanol and complete
15
Yu
2Q
reaction by boiling at 115 ° C for another 6.5 h. The yield of ethyl ester 3 (L methoxy-1H-indole-3-yl) pentanoic acid after chromatography on silica gel was used to elute 2% EtOAc in toluene with 60%. C, 69.53; H 7.0;
N
N
25
Found%:
5.01.
C (feH2, NO,
Calculated,%: C L9.79; H 7.69;
5.09.
The ester obtained is boiled in hydrazine hydrate according to the indicated procedure. The reaction is completed within 6.5 m. The yield of 2-ethyl-2- (5-methoxy-3-α-indolyl) propion hydrazide after recrystallization from 5% ethyl acetate, m.p. 101 -.
Found,%: C, 20; H 7.53; JN 15.88.
CWHiyN ° 2
Calculated,%: C 6.35; H 7.33;
N 16.08.
By example
five
0 5
1 The corresponding hydrazide is converted to an acyl azide, the azide is subjected to thermal rearrangement and cyclization to obtain the lactam 1-oxo-ethyl-6-methoxy-1,2,3, -tet-ra-hydro-pyrido (3, -b) indole. Instead of leaving the final product to crystallize out of the concentrated reaction mixture, the toluene in this case is completely evaporated to obtain a residue, which is crude lactam, yield 75%. A sample of lactam was recrystallized for analysis from acetone-water. Found,%: C 68.68; H 6, 11.37.
C14
Calculated,%: C 68.83; H 6.60;
11.47.
The hydrolysis of the lactam is carried out according to Example 1. The yield of crude 2-carboxy-3- (1-amino-2-butyl) -5 methoxyindole is 96%. As before, decarboxylation was carried out without prior purification of the product (the difference from Example 1 is the use of a 3 M solution of methanesulfonic acid). The reaction is complete within a few hours. The yield of tryptamine but-2-butyl) -5 methoxyindole1 36%. The crude product in the form of an oil is directly acetylated without prior purification of Example 1 to obtain the j-methyl derivative. The resulting p-ethylmelatonin representedN
N
0
five
It is a colorless glassy substance after chromatography on silica gel.
Found,%: C, 25; H 7.99;
N 10.59.
C (5 H20N1 ° 2
Calculated,%: C, 69.20; N 7L
N 10.76.
II p and me R 3. Getting Ji-methyl-6-chlormelatonin.
In Example 1, a solution of 10 g (0.055 mol) of 5-methoxy-6 xdorindole 3, 1 ml (-2, | nd g, 0.055 mol) of acetaldehyde and 7.9 g (0.055 mol) of meldrum acid in 90 ml of acetonitri - la. After removal of the solvent in vacuo, the resulting adduct is recrystallized by dissolving in hot toluene and quenching. The resulting adduct is slightly pink crystals, m.p., yield 16.5 g (85%). Elemental analysis of the product showed a slightly overestimated value of carbon. However, the NMR spectrum confirmed the purity of the product and the structure.
Found,%: C 59, M 5.15; , N 3.84; C1 9.69.
C, 7H, BN05C1,
Calculated,%: C 58, H 5.16; N 3, V8; C1 10.08.
Solvolysis and decarboxylation of the adduct (11 g, 31, 3 mmol) were carried out as in example 1 using ethanopa, pyridine and copper dust. After chromatography on silica gel using 10% EtOAc-90% toluene, yield 3 (5-methoxy-6-chloro-1H-indol-3-yl) pentanoic acid, ethyl ester, obtained as a pale yellow oil, 8.68 g (9).
Found,%: C 60.67; H 5.86; N 4.93; C1 11.73.
C "HWN05C1
Calculated,% C 60,91; H 6.13; N 4.74; C1 11.99. F
An 8 flask equipped with an air cooler heated a mixture of 8.68 g (29.3 mmol) of the obtained ethyl ether and 6 ml of hydraenohydrate. After 6.5 hours, the excess hydrazine hydrate was removed in vacuum. The resulting 2-methyl-2- (5-methoxy-6-chloro-3-indolyl) propionhydrazide is recrystallized from ethyl acetate, yield 7.13 g, m.p. 15 -155 ° C.
Found,%: C SSJ1; H 5.51; N 14.49; C1 12.78.
C, 5H, 6M ()
Calculated,%: C 55.2; H 5.72;
N 14.91; C1 12.58.
The resulting hydrazide (7.13 g, 25 mmol) is converted to the corresponding acyl azide, which is subjected to thermolysis and rearrangement in toluene at 80CC, and the rearrangement product is cyclized in the presence of HC1 in example 1. The yield of raw light brown lactam-ox-β-methyl-6 - methoxy-7 chloro-1, ("-tetrahydro-EN-pyri-Do (3, -b) indole, 77 g (12%), mp 2 9-252 ° С.
Found,%: C H, 77; N 10.72.
C "H4 Nt °" C1
Calculated,%: C 58.99; H, 95;
N 10.58.
Crude lactam C, 77 g, 18 mmol) is hydrolyzed with a water-ethanol solution of KOI in example 1. The yield of the crude amino acid 2-carboxy-3 (1-amino--2-propyl) -5 methoxy-6-chloroindole is 3.98 g ( 78%). The crude product (3 g, 1U, 6 mmol) is decarboxylated in Example 1 by boiling for 100 ml of 100 ml of 3 M HC1 solution. The acidic solution is decolorized with activated yi-lem and alkalinized with 5 M NaOH solution. The resulting amine is extracted with diethyl ether. After drying the ether extract, diethyl ether is removed in vacuo to obtain the crystalline, tryptamine 3 (1-amino-2-propyl) toxy-6-chloroindole residue, m.p. . The yield after recrystallization from a mixture of toluene - hexane is 1.62 g (6b%).
Found,%: C 60.11; H 6.05; N 11, 93; C1 15, Ob.
C, ZH N OC1
Calculated,%: C 60.38; H 6.33; N 11.74; C1 14.85.
A solution of 1.51 g (6.3 mmol) of the resulting tryptamine in 10 ml of toluene and 2.5 ml of pyridine is treated with 1.5 ml of acetic anhydride. After keeping the reaction mixture at room temperature for 3 hours, the volatile components are removed in vacuo. The residue is dissolved in ethyl acetate and washed with an aqueous solution of NaHCOj and brine. The ethyl acetate solution is dried over Na S04, and after 1 "solvent pairing, the obtained" is crystallized from toluene-hexane to give 1.09 g
20
(61%) b-chloro-p-methylmelatonin, t, pl. 133-135 ° C.
Found,%: C 6i, 03; H 6.22; N 9.7b; (L 12.92.
CHHi7Nz ° “Cl5
Calculated,% C 59.89; H 6.1;
N 9.98; C1 12, b3.
An example. Preparation of p-methyl-6, 7 dichlormelatonin.
In a 1 l three-necked round-bottomed flask equipped with a nitrogen pass and a stirrer, 13.2 ml of 4-amino acid are added to a cooled solution (below 0 ° C) of 13.2 ml of boron trifluoride etherate in 125 ml of methylene chloride. 2,3 Dichloranisol and 65 ml of methylene chloride. The addition is carried out for 20 minutes with vigorous stirring. A solution of 10.6 ml of tert-butyl nitrite in 65 ml of methylene chloride is then added dropwise to the reaction mixture over 30 minutes. After the completion of the dropping, the reaction mixture is stirred at a temperature below OIS for 40 minutes. Then 3/5 ml of pentane is added to decolubilize 2,3 Dichloro-4-methoxybenzene diazonium formed in the reaction of fluoroborate. The diluted reaction mixture is stirred for another hour, then filtered. The filter cake, consisting of salt, diazonium, is dried under vacuum to give a white powder with m.p. (with decomposition).
To a solution of 2.81 g (9.6 mmol) of fluoroborate 2,3 Dichloro-4-methoxy-benzenazonium in 38 ml of water and 46 ml of acetic acid was added 1.5 g (9.67 mmol) of 3 acetyl-5 methyl- 2-peridone. The precipitation of 3 Ј2- (2., 3 Dior-4-methoxy) -phenylhydrazono} -5 methyl-2-piperidone begins within 1 minute. After 20 minutes of stirring, 21 ml of water are added and stirring is continued for another 1 hour. Then the reaction mixture is cooled for several hours and separated 3 by filtration (substituted
at 100 C. The hot solution is diluted by slow addition of 18 ml of water, at which point the release of 1-oxo-4-methyl-6-methoxy-7,8-dichlor2, 3,4-tetrahydro-9H-pyrido (3, 4-b) indola formed in the reaction. After cooling for several hours in the reaction mixture, the resulting product is collected by filtration and recrystallized from methanol. The yield of a colorless crystalline product 1.85 g (68%).
Found,%: C 52.32; H 4.15; 15 N 9.19.
С „Н НЈ02С1г
Calculated,%: C 52.19; H 4.04; K 9,3b.
25
thirty
In Example 1, 21.85 g (6.18 mmol) of 1 -oxo-4-methyl-6-methoxy-7,8-dichloro-1 2,3,4-tetrahydro-9H-pyrido (3.4 b) in - Dale hydrolyzed in a water-alcohol solution of KOH. The yield of the crude amino acid 2-carboxy-3 (1-amino-2-propyl) -5-methoxy6.7 Dichloroindoles resulting from hydrolysis is quantitative. The amino acid is decarboxylated without prior purification according to the procedure of Example 2 for 48 hours using 3 M hydrochloric acid to obtain 3 (1-amino-2-propyl) toxy-6, / - dichloroindole.
The hydrolysis product solution is cooled and alkalized by adding 1 M NaOH solution. After cooling, the product is filtered off and dried. After washing the filter pyro with 40 hectares of cold CH2Cl, 1.05 g (62%) of 3- (1-amino-2-propyl) -5-methoxy- 6.7 dichlorindole are obtained in the form of a light brown solid.
Found,%: C 52.52; H 5.36; N 9.97.
3S
45
CttH14ntocla
Calculated: 4: C, 52.76; H 5.17; N 10.26.
Acetylation of 1.05 g (3.8 mmol)
phenylhydrosone) -5 methyl-2-piperidone, 5Q tryptamine acetic anhydride provot. pl. 211-214 C. Yield 2.87 g (). Found: With 9.5b; H 4.90;
N 13.20.
C “H ,. N.O .C1,
Calculated,%: C 9.38; H 4.78; N 13.29.
A mixture of 2.87 g (9.08 mmol) of hydrozonopiperidone and 90 ml of 85% formic acid is heated for 1 hour
d t according to the method of example 2. The obtained p-methyl-b, 7-dichloromelatonin is purified by boiling in ether. The colorless product yield 0.8 g (66%). 55 Found,%: C 53.09; H 5.15; N 9.06; (L 22.51.
c, H "N" ° tcit
Calculated,%: C 53.35; H 5.12; N 8.89; C1 22.5.
53011
ten
five
Yu

at 100 C. A hot solution is diluted by slow addition of 18 ml of water, at which point the release of 1-oxo-4-methyl-6-methoxy-7,8-dichlor1, 2,3,4-tetrahydro-9H-pyrido ( 3,4-b) indola formed in the reaction. After cooling the reaction mixture for several hours, the resulting product is collected by filtration and recrystallized from methanol. The yield of a colorless crystalline product 1.85 g (68%).
Found,%: C 52.32; H 4.15; 15 N 9.19.
С „Н НЈ02С1г
Calculated,%: C 52.19; H 4.04; K 9,3b.
In Example 1, 21.85 g (6.18 mmol) of 1 -oxo-4-methyl-6-methoxy-7,8-dichloro-1, 2,3,4-tetrahydro-9H-pyrido (3.4 b) Indole is hydrolyzed in a KOH water-alcohol solution. The yield of the crude amino acid 2-carboxy-3 (1-amino-2-propyl) -5-methoxy6.7 Dichloroindoles resulting from hydrolysis is quantitative. The amino acid is decarboxylated without prior purification according to the procedure of Example 2 for 48 hours using 3 M hydrochloric acid to obtain 3 (1-amino-2-propyl) toxy-6, / - dichloroindole.
The hydrolysis product solution is cooled and alkalinized by adding 1 M NaOH solution. After cooling, the product is filtered off and dried. After washing the filter cake with cold CH2Cl, 1.05 g (62%) of 3- (1-amino-2-propyl) -5-methoxy- 6.7 dichlorindole is obtained in the form of a light brown solid.
Found,%: C 52.52; H 5.36; N 9.97.
CttH14ntocla
Calculated: 4: C, 52.76; H 5.17; N 10.26.
Acetylation of 1.05 g (3.8 mmol)
d t according to the method of example 2. The obtained p-methyl-b, 7-dichloromelatonin is purified by boiling in ether. The colorless product yield 0.8 g (66%). Found,%: C 53.09; H 5.15; N 9.06; (L 22.51.
c, H "N" ° tcit
Calculated,%: C 53.35; H 5.12; N 8.89; C1 22.5.
PRI me R 5- Preparation of K - (-) - and 5 - (+) - 3-Ethoxycarbonyl-5 methyl-2-peridone.
To a stirred mechanical stirrer of a mixture of (1) -mentol (156 g, 1 mol) and 1032 g of sulfuric acid was added a solution of 220 g (2.2 mol) of chromium trioxide in 1032 g of 35% sulfuric acid at a rate such that reaction does not exceed 30 ° C. Stirring is continued for 3.5 hours at 30 ° C, after which the reaction mixture is extracted several times and then extracted with 1 M aqueous NaOH solution. The aqueous extract is acidified with 12N. hydrochloric acid and, then, extracted several times with diethyl ether. The ether extracts are combined, washed with brine, and dried over NajSO. After evaporation of the diethyl ether, the residue consisting of S - (+) - 3,7-dimethyl-6-oxo-acanoic acid, is dispersed. The output of re-distilled keto acids 74 g (40%), BP. 104 ° С (0.05 mm Hg), р6 + 7.8 ° (, MeOH).
Found,%: C 64.41; H 9.48.
SY, .N "° Calculated
From
s
C, 64.49; And 9.7.
A solution of trifluoride acetic acid, prepared by slowly adding 1.6 ml (0.6 mol) of 30% hydrogen peroxide to a mixture of 100 ml (149 g, 0.71 mol) of trifluoroacetic anhydride and 100 ml of methylene chloride, is slowly added to mixtures of 74 g (0.4 mol) of S - (+) - 3.7 dimethyl-6-oxo-octanoic acid, 400 ml of methylene chloride and 102 g (and 72 mol) of disodium hydrogen phosphate. The reaction mixture is stirred for 48 hours at room temperature (24ffC) and then washed thoroughly, first with water and with brine. After drying over NaB04, the solvent was evaporated, and the remaining liquid product was distilled to give 64.2 g (73%) of 5 - (+) - 3-methyl-5-isopropoxycarbonylpentanoic acid, b.p. 101-107 ° С (0.05 mm Hg), + 6.4 ° (с 10, MeOH).
Found,%: C 59.23; H 8.69,
c, (U
Calculated,%: C 59.39; II B, 97.
A solution of 50 g (0.25 mol) of the obtained isolrolyl ether in 250 ml of anhydrous 2 M ethanolic solution
0
The sodium ethoxide is stirred for 3 hours at 0 ° C. The cooled solution is taken up in a mixture of ice and an excess of 2 M hydrochloric acid and extracted with diethyl ether. The ether extracts are washed with brine and cyi iaT. After evaporation of the ether and distillation of the liquid residue, 33.2 g (71%) of 8 - (+) - 3-methyl-5- -ethoxycarbonylpentane a new acid are obtained, b.p. NSh ° C (0.03 mm Hv),
n 6.6 ° (s Found,
g-ch Oh 1b 4
10, MeOH). C 57.46; H 8.28.
5Calculated, /: C 57.43; H 6.57.
In a 500 ml three-necked flask, sodium ethoxide is obtained by dissolving 13.1 g (0.57 g - atom) of sodium in 100 ml of absolute ethanol. Most of the ethanol was stripped off in vacuo, after which 260 ml of ethyl carbonate and 9 g of Adogen 464 (phase transfer catalyst) were added. The flask is equipped with a mechanical stirrer, a dropping funnel on
750 ml (without side drain for pressure equalization) and a Widmer column 21 cm long with a jacket. Heating the flask in an oil bath to 1BO C leads to the distillation of the ethanol residue and the loading of ethyl carbonate by slowly distilling it through a Widmer column. After one hour of heating at 160 ° C, 26.8 g (0.14 mol) of H - (+) - 3 methyl-5-ethoxycarbonylpentanoic acid are added.
5 100 ml of ethyl carbonate and heating continue for an hour. During this time, the distillation of ethanol is stopped and the temperature of the distilled ethyl carbonate reaches 12S-126 ° C. After cooling the mixture, the sodium salt of S- (+) 3 methyl-5 bis (ethoxycarbonyl) pentanoic acid is collected and quickly washed with a small amount of THF. The salt is then added to ice and an excess of 2 M HC1 and extruded with diethyl ether. The ether extracts are washed with brine and dried over NajSO. - After evaporation of diethyl ether, the residue is subjected to HPLC on a column filled with silica gel.
0 Prep 500 from Waters, using methylene chloride for leaching and then 1% methanol in ethylene chloride. Fractions containing S- (+) - 3 methyl-5-bis (ethoxy5 carbonyl) pentanoic acid according to TLC are collected and after removal of the solvent from the combined fractions, S - (+) - 3-megyl-5 bis (ethoxycarbonyl) pentane is obtained acid.
133
A solution of 4.31 g (16.6 mmol) of S - (+) In a similar way, in the reaction of sy- -3-methyl-5 bis (ethoxycarbonyl) penta-mixture of 1 g (1 mol) of (-) - menthone new acid is treated one equivalent of (+) - isomentone (sodium ethoxide obtained was hydrogenated, after sodium (+) pulgon over Pd-C) t suspended ethanol was removed in vacuum, and obtained in 687 g of 35% sulfuric the salt is dried thoroughly. Then the acid, with a solution of 146 g (1.46 mol) of the salt, is suspended in cold chromium benzene trioxide in 687 g of 35% sulfur and treated with 1.44 ml (2.1 g of acid) obtained from K - (-) -3 ethoxy-16.5 mmol) oxalyl chloride. On the window is yucarbonyl-5 methyl-2-piperidone. When the initial violent reaction of chromium nitride is dissolved, the solution is filtered off, the benzene is distilled, so that the reaction temperature in vacuum, the resulting acid chloride does not exceed 30 ° C. The stirring of the acid prod- uct is dissolved in a little more 3.5 hours, after which the mixture is formed of acetone and R-(-) -3.7 Dimethyl-6-oxohistor 1.19 g (17%) added to the growth agent. mmol) sodium octane azide, the acid is extracted with di- in 6 ml of water at such a rate that ethyl ether. The ether extract was kept within the limits of concentrated and extracted with 1 M water - 10-15 C. After 1 h, benzene was extracted with NaOH extraction solution. The aqueous extract is ruled with 5 - (+) - 3-methyl-5-bis (ethoxycarboxylic acid; 12N hydrochloric acid and nyl) pentanoyl chloride. The extract is dried extract with diethyl ether. The Na2SO4 ether and the solvent are removed by an obvious extract, washed with brine, and vacuum. The residue is dissolved in a little over Na2SO4 and the ether is removed in vacuo of dioxane (-v 0.5 ml) of mind. Distillation of the residue is obtained and added dropwise to a benzyl alcohol heated to 2574.7 g (40%) K - {-) - 3.7 Dimethyl-6-ca. - 140 ° C. After nag-co-octanoic acid, bp. 110 ° C roar for an additional 30 minutes excess (0.05 mm H). The resulting product of an idenzyl alcohol is removed in a vacuum to the oxidation product (l) - mentto, yielding 2.9 g (48%) of benzyl-NS-la, but has the opposite sign (+) - 2-methyl-4 -bis ( ethoxycarbonyl) bu-30optic rotation, thyl carbamate. A small amount Carrying out for the k - (-) - keto acid of the obtained substance is subjected to the same steps as for 5 - (+) - iso-pure purification by chromatography of the meter, B - (-) - 3 ethoxycarbon silica gel, oi + C ° (c 10, nyl-5-methyl-2-liperidone, which is in MeOH). 35 in all relations is identical to S - (+) - coe. Found,%: C 62.26; H 7.51; the connection, with the exception of the sign of rotation N 3.72. "Nor the plane of polarized light.
Ci9Hi7NO P r and IN e p 6. Getting $ - (-) - (Calculated,%: C 62.45; H 7.45; -methyl melanthonine and K - (+) - p-methyl melaN 3.83.40 tons.
The solution obtained carbamate For example 4, the mixture of 2.5 g (mmal)
(2.7 g, 7.4 mmol) in 200 ml of ethanol; K - (-) - X-ethoxycarbonyl 5 methyl-2-pyridated over 0.5 g. Of 10% Pd-C. After peperidone and 40 ml of 0.75 M NaOH for resorption of hydrogen absorption, the catastrophe was sewed for 20 hours at room temperature, the lyser was removed by filtration, and (24 ° C), and then cooled to.
the filtrate is left for 48 hours with a com — Addition of 3 M hydrochloric acid pH
natal temperature (24 ° С). After evaporation to about 3.5 and 3 g (13.5 mmol) (5 - (+) - 3 ethoxycarbonyl-5-methyl-2-pi-so of tetrafluoroborate n-anisyl diazonium) are added in small portions of the solvent obtained by lactam in small amounts. (perididone) crystallized from diethyl prepared from p-anisole according to example 4). ether to obtain 1.1 g (80%) of the cris; The reaction mixture is cooled to about a tall product, m.p. (C, to 0 ° C during the day. Crude product + 36.7 ° (10, MeOH). Collected by filtration, washed
Found, Sj: C 58.23; H 7.68; 55 with cold water and dried. Raw yield
N 7,60. Hydrazone k - (-) - 3- (p-methoxyphenyl)
CnHJTO, hydrazono-5 methyl-2-piperidone 2.5 g
Calculated,%: C 58.35; H 8.16; (75%), m.p. 201 ° C.
N 7.56. Hydrazone undergoes further
15
purification by passing a short column of silica gel using ethyl acetate for leaching, about}} -82 ° (c 9.5, MeOH).
Found,%: C 62.97; And 6.80; N 16.88.


s, n „and, u
Calculated,%: C 63, H 6.92; N 16, V9.
A mixture of 2.3 g of hydrazone (9.3 mmol) and 17 ml of 85% formic acid is heated for 3 hours at. Water is then added until signs of crystallization appear. The crystallized mixture is cooled and kept on a cold day. The crude product is separated by filtration, washed with water and dried. The yield of crude S - (-) - lactam (S- (-) - 1-oxo- | 4-methyl-6-methoxy-1, 2,3, 4-tetrahydro-9H-pyrido (3,) indole) 1, M g (66%), so pl. 215 ° C. A small sample of the substance is recrystallized from an acetone-water solvent mixture.
water. After stirring for one hour at 0 ° C, the solution is filtered and the filtrate is slowly added to an ice-cooled solution of 2.6 g
10 (2k mmol) of sodium fluoroborate in 8 ml of water. After stirring for one hour at 0 ° C, the salt formed is collected and washed successively with cold 5% fluoroborate solution.
15 Sodium, cold methanol and ether. Dried fluoroborate 3 chloro-4-methoxy-benzene diazonium was obtained in the amount of 2.2 g (69%).
A mixture of 2.03 g (11 mmol) K - (-) - 3
20-ethoxycarbonyl-5 methyl-2-piperidone and 30 ml of 0.75 M NaOH are stirred for a day at room temperature (). Then the solution is cooled to 0 ° С and by adding 3 M hydrochloric acid the spectral ideas ideate the pH to 3.5. Slightly tedious to the racemate specified in the example.
1, optical rotation vb g - 6 ° (, MeOH).
Found,%: C 67.51; H 5.99; N 11.94.
С „НГГОг
Calculated,% C 67,81; H 6.13;
The diazonium salt (2.8 g, 10.9 mmol) is added in amounts and the reaction mixture is cooled to about 0 ° C overnight. The resulting R - (-) - 3 (3-chloro-methyl-30 syphenyl) hydrazono-5-methyl The -2-piperidone is collected, washed with water and dried. N 12.17. The yield of 2.3 g (75%), so pl. 205 ° C.
Transformation of 8 - (-) - lactam into S - (-) - A small sample of a substance is subjected to - | -methylmela- tononin was carried out as described in example 35 for further purification by chromatography 1 to obtain a racemate. The final short column of silica gel with a 8- (-) - p-methylmelatonin spectral index to wash out ethyl acetate,
identical to the racemate, optical rotation “QI5 - 58 (s - 11), MeOH). -5.6 ° (, MeOH). Found, c / 0: C 55.79; H 5.78;
According to this method based on 4C N 14.72; C1 12, b9. S - (+) -3-ethoxycarbonyl-5 methyl-2-pip-s. - H,
Ridone is synthesized by K - (+) - S-methylme-Calculated,% C 55.2; H 5.72;
Latonin, spectrally identical to S - (-) - N 14, yi; ci 2,5b. -isomer, but with opposite sign45
A mixture of 2.2 g (7.8 mmol) K .- (-) - hydrazone and 20 ml of 90% formic acid is heated for 3 hours at 85 ° C and then slowly diluted with an equal volume of water. The mixture is allowed to cool and
optical rotation com.
Example. Preparation of S - (-) - - -methyl-b-chlormelatonin and R - (+) - - | & methyl-6-chlormelatonin.
A solution of Cg (21 mmol) of 3-chloro-β-methoxynitrobenzene in 200 ml of toluene 50 eem is left in the cold for a day, hydrogenated over 0.4 g of platinum with 5 g per oxide. The dark precipitate is collected and washed with aluminum. The catalyst was filtered off and the solvent was evaporated from the filtrate. The resulting crude 3-chlorohydrate and, after recrystallization from an acetone-water mixture, 1.2 g (60%) of S- (-) -1 -oxo-1 + -methyl-6-methokanizidine are obtained, dissolved in diethyl ether 55 c-7 chlorine -1, 2,3, g + -tetrahydro-9Npyrire, treated with ethereal solution up to (3, -b) indole, so pl. 248 ° C
- 12.2 ° (c 10, MeOH).
HC1 to produce hydrochloride, which is collected, and after drying the floor, 2.48 g (61%).
sixteen
A solution of 2, k g (12.4 mmol) of chlorohydrate 3 of chloroanisidine in 7 ml and M HC1 is treated at U ° C with 11.86 g
(12.5 mmol) of sodium nitrite in 5 ml
water. After stirring for one hour at 0 ° C, the solution is filtered and the filtrate is slowly added to an ice-cooled solution of 2.6 g
(2k mmol) of sodium fluoroborate in 8 ml of water. After stirring for one hour at 0 ° C, the salt formed is collected and washed successively with cold 5% fluoroborate solution.
sodium, cold methanol and ether. Dried fluoroborate 3 chloro-4-methoxy-benzene diazonium was obtained in the amount of 2.2 g (69%).
A mixture of 2.03 g (11 mmol) K - (-) - 3
-ethoxycarbonyl-5 methyl-2-piperidone and 30 ml of 0.75 M NaOH are stirred for a day at room temperature (). Then the solution is cooled to 0 ° C and the pH is lowered to 3.5 by addition of 3 M hydrochloric acid. Small to 14, yi; ci 2,5b.
A mixture of 2.2 g (7.8 mmol) K .- (-) - hydrazone and 20 ml of 90% formic acid is heated for 3 hours at 85 ° C and then slowly diluted with an equal volume of water. The mixture is allowed to cool and
Then leave for a day in the cold, the dark precipitate is collected, washed
Then leave for a day in the cold, the dark precipitate is collected, washed
water and after recrystallization from a mixture of acetone - water get 1.2 g (60%) of S- (-) -1 -oxo-1 + -methyl-6-methoxy-7 chlorine-1, 2.3, g + tetrahydro -9No (3, -b) indoles, so pl. 248 ° C, IV
- 12.2 ° (c 10, MeOH).
Found,%: C 59.16; K M8; N 1U, 8; C1 13.15.
С Н N 04С1
Calculated,%: C 58.9U; H 1.95; N 1U, b8; C1 13, J9.
17, 155301118
blow under a microscope for the presence of eggs, reducing the number of ovulating non-controlled rats by 50% relative. Converting S - (-) - lactam to S - (-) - 5 but the number of ovulating control rats -6-chloro-p-methyl-melatonin transform indicates activity
according to example 3. Received 5 - (-) - -me blocking ovulation and gives a minimum
Tyl-6-chlormelatonin is a spectrally ideal- NU ° effective dose required for a racemate, but it is of importance to inhibit ovulation, the tical rotation is 13.2 ° (the SE table shows the results
a 1U, MeOH). obtained by testing some g
K - (+) - 6-chloro-p-methylmelatononin was synthesized from S - (+) - 3-ethoxycarbonyl-5 methyl-2-piperidone using the indicated procedure. The stereoisomer is identical to the S-15 - (-) - isomer with the exception of the sign of optical rotation.
The compounds of the invention are inhibitors of ovulation. The degree of inhibitory activity of ovulation was determined by -20 according to the following procedure.
Adult female rats with regular extruder cycles of four days are used. The extrusion cycle consists of two days25 diesters, followed by a day of proestrus and then a day of estrus. Vaginal swabs are noted daily and the rats are selected after they have shown at least two consecutive four-day estrus cycles where RiH and s are C4-C4-alkyl; la After noon per day of proestrus, in R3 and K4, each independently drinking the blood of animals through the pineal gland or halogen, which is different, aj luteinizing hormone (LH) is administered. due to the fact that the amine of the general formula LH enters the ovary, where it causes 35 ovulations, which appear in the ovoduct, on the day of estrus.
The test compound is administered orally to uncontrolled rats at noon (4V).
days proestrus. As control, so 40T N
and uncontrolled rats are killed.
the next day (estrus). Each K-R has the indicated ratchets, which remove the oviduct, which is subjected to acylation of the research.
methyl melatonins according to the indicated procedure (melatonin is included in the table for comparison).
P-Alkyl derivatives also have a longer-acting acovulating effect as compared to ai-methyl derivatives and monohalo derivatives of the same order.

权利要求:
Claims (1)
[1]
Invention Formula
The method of obtaining derivatives of alkyl melatonins of the general formula
2
BDO
I CH-CH2-NH-CO-R
-CH-CH2-NH2
K - (+) P methylmelatonin
ft-methyl-b-chlormelatonin
(B-ethylmelatonin
R- (+) - -methyl-b-chlormelatonin
 where Ri is H and s is C4-C4-alkyl; R3 and K4 are each, independently, water methylmelatonins according to the indicated procedure (melatonin is included in the table for comparison).
P-Alkyl derivatives also have a longer-acting acovulating effect as compared to ai-methyl derivatives and monohalo derivatives of the same order.
Invention Formula
The method of obtaining derivatives of alkyl melatonins of the general formula
2
BDO
I CH-CH2-NH-CO-R
drawing general formulas
-CH-CH2-NH2
2 1
9155301120
Table continuation; .i imii S (-) - p-methyl-b-chloromelatonin 5
-methyl-6,7 Dichloromelatonin 15
 Noncontrolled rats against control rats at a given dosage were blocked.

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JPWO2014010603A1|2012-07-10|2016-06-23|アステラス製薬株式会社|Pharmaceutical composition for treatment or prevention of stress urinary incontinence or mixed urinary incontinence, and screening method for compounds contained in the pharmaceutical composition|

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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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US1025987A| true| 1987-02-02|1987-02-02|

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