Method of preparing tetrapeptides

专利摘要:
Tetrapeptide amides of the formula <IMAGE> wherein R1, R8, Rx, B and D represent certain specified substituent groups. The compounds exhibit pharmacological activity when tested in vitro in the transmurally stimulated guinea pig ileum preparation indicating their affinity for opiate receptor sites, and also in vivo tests, with intravenous administration, indicating their analgesic effects, and hence their utility as analgesic agents.
公开号:SU793386A3
申请号:SU782699407
申请日:1978-12-14
公开日:1980-12-30
发明作者:Арнольд Морган Барри
申请人:Рекитт Энд Колман Продактс Лимитед (Фирма)；
IPC主号:

专利说明:

or it is protected. a derivative, where the values for B and C are indicated above, followed by the removal of the protective groups and the desired product is isolated, the case when
X: NMe or NMePh, optionally oxidized with hydrogen peroxide or methachloroperbenzoic acid, to form a compound of formula 1, where X: N (0) Mez, N (0) MePh. The following abbreviations are used in the text:
tert-butyloxycarbonyl
all over
8i
t-butyl
JBC - Isobutyl ) on silica gel plates (Kieselgel CF254) in the following systems WE - methanol, chloroform 1: 2 3F - methanol, chloroform 1:19 2B - chloroform, methanol, acetic acid 19: 9: 1 FOR - chloroform, methanol, acetic acid, water 60 : 18: 2: 3 (1) in e - Phe-NHCH2.CH2.NHCOCH3K to a cooled to -20 solution of BOe-Ph-OH (2.65 g) in 20 ml of methylene chloride, n-methylmorpholine (1.01 g) and isobutyl chloroformate (1.37 g) are added, then after 2 minutes, injected with H2NCH, jCH2NHCOCH3 (l / 2 g). The temperature of the reaction mixture was raised to room temperature and the mixture was stirred at that temperature for 21 hours, after which the solvent was distilled off, and the resin was dissolved in chloroform. The solution is washed with a saturated solution of NaHCO.j, 10% aqueous citric acid, water until completely neutralized, and finally with a saturated saline solution. The organic phase is dried with sodium sulfate sodium and evaporated to dryness, the solid residue is crystallized from ethyl acetate.
for - chloroform, methanol, acetic acid
30: 18: 4: 6 acid, C water - chloroform, methanol, acetic acid
90: 27: 2: 3 acid, water 30 - chloroform, methanol, acetic acid,
30:20: 2: 3 water
4A -. isobutanol, ethyl acetate, acetic acid
1: 1: 1: 1 acid, water 5B - isobutanol,
3: 1: 1 acetic acid, water 7B - ethyl acetate, pyridine, acetic acid,
60: 20: 6: 11 water
7c - ethyl acetate, pyridine, acetic acid,
120: 20: 6: 11 water
7 O - ethyl acetate, pyridine, acetic acid,
240: 20: 6: 11
water
7F - ethyl acetate, pyridine, acetic acid,
480: 20: 6: 11
water
8A - chloroform, iso3: 1
propanol
8B - chloroform, iso9: 1
propanol
Example 1. 1-Tyrosyl-0-alaylglycyl-1-phenylalanine-2-acetamidothylamide.
It is obtained according to the following manual OHNHaCHgCHaNH-COCIfj -ISIHCHaCHaNFfCOCHj xxSN2: SuccSHGNH2C H2MGSOSShz. : N HCH: gC3i2KHcocH5 tata, amide 1 is obtained (3.0 g), RI 7F 0.35. () ce-H Ph-NHCH CHaNHCOCH 3 g of BOC-Ph-NHCH CH NHCOCH is dissolved in 5 M neC in ethyl acetate (20 ml) and 2.6 M neb in acetic acid (5 ml), and the solution is stirred at ambient temperature Wednesday for 30 min. The solvent is distilled off and the residue is triturated several times with anhydrous diethyl ether. Hydrochloride (2) is obtained as a hygroscopic solid (0.45 g), Rf BF J0.5). (4) GCy Ph NHCH CHxNHCOCHj. This compound is prepared by any of the following methods. A. To a solution of BOe-GCy-Ph-OH (1.0 g) and H2, NCH2 CH NHCOCH5 (0.4 g) in dimethylformamide, precipitated in an ice bath with a salt, add 0.78 g N-oxysuccinimide and 0.668 g dicyclohexyl carbodiimide. The temperature of the reaction mixture was raised to room temperature, and the precipitated axes were filtered off during the course of the night, and the filtrate was evaporated. The residue is dissolved in chloroform, washed with saturated sodium bicarbonate solution (250 ml), 10% aqueous citric acid (ml) and water until completely neutralized, and then with saturated brine. The organic phase is dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on a silica gel column (, 4 cm). Elute first with a mixture of chloroform isopropanol in the ratio (19: 1), then in the ratio (4: 1). The title compound is obtained in the form of a resin (0.60 g) Rr 8B 0.4; Rp 7F 0.2. B. To a solution of 1.072 BOC-CEu-OH in methylene chloride mixed with carbon tetrachloride in methylene chloride, mixed with carbon tetrachloride, 0.618 g of N-methylmorpholine and 0.836 g of isobutyl chloroformate are added. C. H. MHC HgCH NH COCH 3 (1.75 g) and 0.618 g of M-methylmorpholine are added at the same temperature after 2 minutes and the temperature is raised to room temperature. The reaction mixture is treated after stirring overnight as described for the compound 1. The residue is purified according to A. The product is obtained in the form of a resin (0.65 g). Rr. 8B 0.4; Rn 7F 0.2. (5) BOS - Tug (BLJ-D-ABa-Gey-Ph NHCH2.CH2.NHCOCH3 (i) is treated with 0.64 g of BOC-y-Ph-NHCH CHaNHCOCHT, 5.5 M of it in ethyl acetate (5 ml ) and 2 "6 M of it in acetic acid (5 m at ambient temperature. Tour DAla. After 45 minutes, the solvent is distilled off and the residue is dissolved in diethyl ether. Dipeptide hydrochloride is obtained in the form of a hygroscopic solid (0.54 g), R 3D 0.45. (M) BOC-Tyr (Bu-t) -Oab-OH (g) and CE H Gey-Ph-NHCH2CH2lJHCOCH (0.5 g) is dissolved in 3 ml of dimethylformamide and cooled in an ice bath with salt. Then, 0.355 g of N-oxysuccinimide and 0.303 g of dicyclohexylcarbodiimide are added to the solution, and then 1.48 g of N-methyl morpholine. The temperature of the reaction mixture is raised to room temperature and stirring is continued overnight. The precipitated dicyclohexyl urea is filtered off and the solvent is distilled off and the residue is partitioned between ethyl acetate and water. The organic layer is washed with saturated sodium bicarbonate (2x50 ml). , 10% aqueous citric acid (ml), water until neutralized, finally with brine. The organic layer is dried over sodium sulfate and evaporated. The tetrapeptide is obtained in the form of a resin (0.65 g) Rf 7C 0.65; R 3D 0.8 (6) H-Tu-D-Aea-GEy-Ph-NHCH2CH2NHCOCH 30, 65 g BOC-Tyr (Bu) -D-Aea-GEy-Ph NHCHgCH2NHCOCH3 (0.65 g) is treated with 2.6 M HCF in acetic acid taken in excess for 45 minutes at ambient temperature. The solvent is distilled off and the residue is chromatographed on a column of silica gel (5 cm) in the SO system. The resulting resin was freeze-dried to give the title compound (O, 45 g). R FOR 0.3, ci -6,95 ° (, OMF). Example 2. i-Tyrosyl-1-alanylglycyl-M-methyl-1-phenylalanine-3-dimethylaminopropylamide.
(1) BOC-MePh-NHCHiCHiCHaNMe.
A solution of N-chot-butyloxycarbonyl-N-methylphenylalanine (2.79 g), 1.01 g of N-methylmorpholine in dichloromethane 0. (20 ml) is cooled to -20 s with stirring, then 1BCF (1, -37 d) and after 5 min NH2CH2 CH2 CH, jNMe2. (l, 02 g). Stirring is continued for 1 hour at -20 s, after 5
the temperature is raised to room temperature and stirring is continued for 12 hours. The mixture is evaporated, the residue is dissolved in ethyl acetate (50 ml). The ethyl acetate solution is washed with an aqueous solution of sodium bicarbonate (saturated, 50 ml), water (2 x 50 ml, fi with 10% aqueous acetic acid (12 x 50 ml)). The acidic extracts are combined and alkalinized with a sodium bicarbonate solution and extracted with ethyl acetate (ml). The ethyl acetate extracts were combined, dried over sodium sulfate, and evaporated to give the title compound as an oil, Co. IE 0.24; Rn FOR 0.37. (2) H-MePhe-NHCH2CH2.CH2NMe ,. 2NCE. The oil, the preparation of which is described in stage (.1), is dissolved in ethyl acetate (10 ml), HCC is added in acetic acid (6.63 M, 6 ml) and HC in ethyl acetate (5.7 M, 6 ml). The solution is stirred for 2 hours, and the product is evaporated as a hydrochloride salt (2.2 g), Ro IE 0.02; Rr - 0.08. (3) BOC-GCy-MePh-NHCHjCH CHjNMe. A solution of tert-butyloxycarbonylglycic (1.05 g) and 0.606 g of N-methylmorpholine in dichloromethane (12 ml) is cooled to -20 ° C with stirring. 0.819 g (6 mmol) of isobuty chloroformate is added and the mixture is stirred for 5 minutes before adding (2 ), above (2.02 g) in 5 ml of dimethylformamide. The solution is stirred for 1 hour at -20 ° C and for 12 hours at room temperature, then evaporated. The residue was dissolved in a mixture of ethyl acetate (50 ml) and an aqueous solution of sodium bicarbonate (10% 50 ml). The organic phase is separated, washed with aqueous sodium bicarbonate (10%, ml) and water (50 ml). The ethyl acetate solution is dried over sodium sulfate and evaporated to give the title compound as an oil. R IE 0.21; R FOR 0.37. (4) AND - b t- y - M e P h - N H C H 2 C H 2 C H N H s The protected dipeptide (h) is treated by the indicated method (2), I get hydrochloride dichloride (4) (2,0 g 3 as a white solid, Rr IE 0.03; Rr ZA 0.03., (5) BOC-Tyr () -DAEa-Cey-MePh-NHCH2 CH2CH, 2NMe2. Solution BOC-Tyr (BU) -D- Ata-OH (1.22. R), H-Gey-MePh-NHCH2CH2CH2NMe2 V2HCe (1.18 r), 0.345 g of N-oxysuccinimide and 0.30 g of N-methylmorpholine in 20 ml of anhydrous dimethylformamide are cooled to. (0.680 g), the mixture is stirred for 18 h, then evaporated. The residue is dissolved in ethyl acetate (50 ml and 1pp Ibl aqueous sodium bicarbonate (10%, 2-.50 ml), water (50 ml), sectionthe ethyl acetate layer is dried, it is over sodium sulfate T DAla Gly and evaporated to dryness. The residue is dissolved in methanol, carried on a silica gel column (35 to 2 cm) and the product is eluted with an IF system. The fractions containing the desired compound are collected and evaporated and the residue is dissolved in ethylacetate (100 ml). The ethyl acetate solution is washed with aqueous sodium bicarbonate (10%, 3X100 ml), dried, evaporated to give the tetrapeptide compound (5) as a white solid Cl IE 0.18; RO FOR 0.39..t (6) H-Tyr-D-AEa-Cey-MePh-NHCH2 .CH-2CH2NMe2. To a solution of 500 mg of the protected tetrapeptide (5) in 5 ml of ethyl acetate with stirring is added a solution of hydrogen chloride B to ethyl acetate (5.7 M, 2.5 ml). After 1 h, the reaction mixture was filtered and the residue was washed with petroleum ether, dried and lyophilized from water to obtain the product (380 mg) as a white solid. Rr 4A 0.27, Rr ЗВ О, 47, oL J Jl + + 23.6 (, 0.1 M of it). Example 3. 1-Tyrosyl-0-alanylglycine-N-L-phenylalanine-2-dimethylaminopropylamide-M-oxide. (1) BOC-Tug (Bu) -0-Aea-CEy-MePh-NHCH2CH2 .CH2N (0) Me2. To a solution of 500 mg of BOSB Tu g (Vi) - D-Aea-GEy-MePhe-NHCH2 .CH2. CH2NMe. (500 mg) in 10 ml of methanol is added an aqueous solution of hydrogen peroxide (30%, 0.16 ml ) and the solution is stirred for 48 hours at room temperature. The precipitate formed is filtered off, the mother liquor is evaporated, the desired protected N-oxide is obtained in the form of a gum. Rr-IE 0.08; Rf FOR 0.41. (2) HTyr-O-Ata-GSy.-MePh-NHCH2CH2CH2N (0) Me2. The resin obtained in step (1) is dissolved in 5 ml of ethyl acetate and a solution of HCg in ethyl acetate (2.63 M, 1 ml) is added to the solution. The solution is stirred for 1 hour, filtered, the solid is dried and lyophilized from water to give the desired product (240 mg) as a white solid. R 4A 0.56, Rj3B 0.52, roiJ / + + 18.8 ° (with l; 0.1 M). Example 4. 1-Tyrosyl-0-alanylglycyl-M-methyl-1-phenylalanine-2-dimethylaminoethyl-id. This compound is prepared according to the following method. MeRh. (1) BOC-MePh-NHCH CH NMe. BOC-MePh-OH and N, N-dimethylethylenediamine are condensed under the conditions described in Example 1 (1) to give the amide as an oil. (2) HMePhe-NHCH2.CH2NMe2. 2CE. The M-protected amide from this step (1) is released under the conditions described in Example 1 (2) to give the desired hydrochloride salt as an oil, (3) BOC-Tyr (Bu - t -) - D-Ala-Gly -MePh-NHCHxNHCH CHjiNM .. To a solution of 700 mg (1.5 mmol) of BOC-Ter (Bu) -DAla-Gly-OH in 7.5 ml of anhydrous tetrahydrofuran was added 15.2 mg (1.5 mmol) of N-methyl-mrpholine , the solution is cooled to -15 ° C, no. 205 mg (1.5 mmol) of isobutyl chloroformate is added, stopping stirring. After 5 min, a solution of 2HC IH.-MeP.h-NHCH.CH2NMe (568 mg, 1.5 ml) was added, followed by 303 mg (3 mmol) of M-methyl1-1Orfoline. After 18 h, the reaction mixture was evaporated and the residue was distributed between 50 ml of ethyl acetate and saturated aqueous sodium bicarbonate solution (50 ml. The ethyl acetate layer is separated, washed with saturated aqueous sodium bicarbonate solution (50 ml), water (2 x 50 ml) and brine (50 ml) is dried over sodium sulfate; The residue is chromatographed on silica gel using the 7B system. Suitable fractions containing the product are combined, evaporated, and the target is obtained. tetrapeptide amide (700 mg) in the form of a glass-like solid. (4) 2HC I HTyr-DAIa-Gly-MePh-NHCHjCHjNMCj, The protected peptide obtained as described in step (H) is unblocked under the conditions of Example 2 (6), is obtained Target product. After lyophilization, get tetpe amide amide (200 mg) as a white solid, R 7B 0.04; Rr 0.07; Rf 4A 0.23., 2 ° (with 0.50, DMF) Example 5. i-Tyrosyl-O-alanylglycyl-L - phenyl alanine nthiomorpholine amide-S-oxide. . BOC-P 1-N J A solution of 1.32 g of BOC-Ph-OH and 680 m of isobutyl chloroformate in 10 ml of dimethyl formamide, cooled to -2 ° C and 520 N-methylmorpholine was added to it with stirring. After 2 minutes, add a cold suspension consisting of 690 mg of thiomorpholine hydrochloride (690 mg) and 520 mg of N-methylmorpholine in 8 ml of dimethylformamide. Stirring is continued for 30 minutes at -20 ° C and then at room temperature overnight. The solvent is distilled off, the resulting material is partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate layer is separated and washed with a saturated solution of sodium bicarbonate, twice with a 10% solution of citric acid in water and then with water and finally with a saturated solution of sodium chloride. The ethyl acetate jpacTBOp is dried over sodium sulfate, evaporated, and the thiomorpholinamide is obtained in the form of a resin (1.5-6) g. / - (2) H-Pii-: t js With stirring, a solution of hydrogen chloride in acetic acid (2.6 M, 3 ml) is added to a solution of 1 -L 1.05 g S in 3 ml of acetic acid and at 2-hour intervals add another 3 ml in two portions. The solvent and hydrogen chloride are distilled off, the residue is triturated with anhydrous diethyl ether, the ether is decanted, and the residue is triturated with freshly distilled anhydrous ether to give phenylalanin thiomorpholamine in the form of a solid (788 mg). (3) BOC --- Gly-Ph - Gly-Ph-N S 384 g of BOC-Glv-OH (384 mg) is condensed with Ph-N S-HC (572 mg) using the procedure described above for BOC-Pti —N S using 258 mg of isobutyl chloroformate and 424 mg of N-methylmorpholine. 774 mg of dipeptide amide are obtained, (4) BOC-Tyr (Bu) -BA1-Oly-Ph-I 697 mg of BOO-O y-Ph-7 S are mixed with aqueous trifluoroacetic acid (water: trifluoroacetic acid 1: 9.9 ml ) within 1 1/2 hours. The acid is distilled off and the residue is triturated with diethyl ether, a powder is obtained which is dissolved in 5 ml of anhydrous 1 mg (5 ml) and adjusted to pH 8 with N-methylmorpholine (wet indicator paper ). BOC-Tyr (Bu) -DAIa-OH (680 mg), N-oxysuccinimide (211 mg) in 3 ml of dimethylformamide, and then 377 mg of dicyclohexylcarbodiimide are added and the mixture is stirred overnight at room temperature. The solid is filtered off and the filtrate is evaporated to dryness. In the residue, a gum is obtained which is distributed to a fine using ethyl acetate and saturated aqueous sodium bicarbonate. The ethyl acetate is washed twice with saturated single bicarbonate. Sodium, then rhiode with 10% citric acid in water, then with water and saturated sodium chloride solution. Dry over sodium sulfate; evaporated and get protected tetrapentythiomorphine (1.09 g). , (5) Tyr-BAla-Gly-Fh-J S ;: The protected tetrapeptide thiomorphol amide {1.0 g) is stirred in aqueous trifluoroacetic acid (H20: CFgCOO 1: 9.9 ml) for. 11/2 h .. After evaporation and. rub with diethyl ether get a solid, which is purified by chromatography on silica gel (chloroform: methanol: ux on acid 60: 18-1: 1.5) and then by ion exchange chromatography (Sephadex SP resin, pyridinium form using a gradient from 2 % pyridine in water up to 5%. pyridine and 1% acetic acid in water). The product is lyophilized, get tetrapeptide thiomorpholine (495 mg). Tug-BA1a -1, / -V Tour-M1a-C1u-Pii- (10 O mg) in ethanol (50 ml), treated in successive three portions (20% by volume) of hydrogen peroxide (0.3 ml each a) at intervals of 45 minutes with stirring at room temperature. After further stirring for 1 h, the solution is evaporated to dryness, the residue is dissolved in water (20 ml) and lyophilized, a white solid is obtained (98 mg R) 0.15} R 1C 0.06; R. 5B 0.38 ° 5 - + 53.1 (from 0.47, in 0.1 H.-I-ICI). Example: 1-Tyrosyl-0-alany glium-1-phenylalanine-2-aminoethyl Tyr-DAIa-Gl y- MePhe-NH Cfl. CH2NH Z (obtained by the method described in measure 4) (350 ME) is dissolved in 20 methanol and 10% palladium on coal (100 mg) in 10 ml of water is added to the suspension. The catalyst is filtered off and the solvent is distilled off under reduced pressure. create in a small amount of 1% pyridine in water and add to the column with Sephadex 3R (eluting with a gradient of 1% aqueous pyridine — 1 aqueous pyridine acetate — 5% aqueous pyridine adatate). and the solvent is distilled off in vacuo, the Product (220 mg) is freeze-dried from water, Ri VB 0.45; Ri 4A 0.56; +22.22 (with 0.98; 0.1 M HCl). Example .. 1 -Tyrosyl-0-ala nylglycyl-N-methyl-L-phenyl-n-n-3-trimethyl-IvIonyl propyl amide acetate-. - .... (1) BQ.C; -; T: yr (-: Bu% D A la-Gly-HePhe. -NHCH-2 CH; 2;: c; H2; NHej-OAf .. To the solution; : b 4 6 mg B O C - T y g (B and) -DA I aG.i: y.-MePh ..- NHC (: l2; CH.; 2.CHiNMe2 (640 mg). in 5. ; ml of ethanol. Methyl iodide (5; 72: Mg.) / is added and the solution is stirred at room temperature for -48 hours. Then, the solution is evaporated. This solution is dissolved in ethyl acetate and chromatographed on a silica gel column (40x2 cm), the product is eluted with ethyl acetate: Pyridine: acetic acid: water 90: 20: 6: 1.1 The fractions containing the objective compound are separated. evaporated, get a solid (320: mg.). R. FOR 0.17; R ЗВ 0.74 ;.; R. 4 A .0.47. (2) .H-Tu rD.AI a-GLy-MeP.he- N HC I. CH, C H H e ,,. .CET at At. Dissolve-. Said, protected tetrapeptide (ZOO mg) in ethylacetate (10 ml) and granule. While stirring, a solution of HCl in ethyl acetate is added (3, 9 M, 4. ml). After 1 ml the mixture is evaporated, the residue is dissolved in water and. on a CM 52 cellulose column (35 X. 3 cm), the product is eluted. a linear concentration gradient from 0.05% aqueous pyridine to 1% aqueous pyridine sulfate. . Combine the fractions containing the desired compound and evaporate. and the residue is lyophilized from water to give the desired product (110 mg) as a white solid. R. PO 0.17; R 4A 0.13; Rr 5B 0.05; ci. /, -37.75 ° (s. 0.5, DMF). Example 8. 1-Tyrosyl-0-methioNILglycyl-N-methyl-L-phenylal an-in-2-dimethylaminoethylamine-N-oxide. (1) all-Giy-MePh-NH (01-12) 2 N (O) Meg. A BOC-Gly.-MePh-NH (CHa) NMe-j extractor, 1.23 g of m-chloro nadbenoic acid was added to 200 mg of methanol. The reaction mixture was stirred at 22 ° C for 2 hours, then left at 18 hours. The solvent is distilled off under reduced pressure and the residue is dissolved in 150 ml of ethyl acetate, the solution is washed with a saturated aqueous solution of sodium bicarbonate (2 x 30 ml), over sodium sulfate and evaporated to give. N-OKHCb (1.9 g); Rr FOR 0.76; R 4A 0.64. . (2) HC1 HGI y-MePh-NH (042) 2. (0) The indicated protected N-oxide (1.8 g) was dissolved in 10 ml of ethyl acetate and acetic acid (10 ml) was added to a crasty. A solution of hydrogen chloride in ethyl acetate (3.9 M, 12 ml) is then introduced into the solution and the mixture is stirred at 21 ° C for 30 minutes. The solvent is distilled off in vacuo and the resulting solid is triturated with anhydrous diethyl ether (2 X 40 ml), the M-hydrochloride hydrochloride (1.5 g) is filtered, R 4A 0.40.
(3) BOC-Tyr (But) -DMet-GI y-MePh-NH (CH ,,) 2 N (0) Me2.
To a solution of 1.8 g of BOC-Tu g (Bu) -Det-OH in 10 ml of anhydrous THF is added 0.87 g of N-oxysuccinimide,
1.5 g of HCI-HGIy-MePhe-NH (CH2) 2N (0) Me2 and and 84 ml of N-methylmorpholine are dissolved in 2 ml of anhydrous THF. Both solutions are mixed, cooled to -10 ° C, and 0.87 g of dicyclohexylcarbodiimide is added to the mixture. The mixture is stirred at -10 ° C for 2 hours, then at 20 ° C for 18 hours.
The reaction mixture is filtered and the transparent mother liquor is evaporated under vacuum. The resulting resin was partitioned between ethyl acetate (60 ml) and water (10 ml), the organic phase was separated and washed with 10% aqueous sodium bicarbonate solution (1x10 ml), and then extracted with 10% aqueous citric acid solution (5x15 ml ). The pH of the aqueous phase is adjusted to 7 using solid sodium bicarbonate, and the product is extracted with ethyl acetate (3 x 40 ml). The organic phase is dried over sodium sulfate and evaporated to give a gum (1.35 g). Rn FOR 0.48
(4) HCI -H-Tyr-OMet-Gly-MePh-NH (CH2) 2.N (0) Me2.
1.11 g of BOC-Tyr () - DMet-GI in.-MePh-NH (CH2) 2 N (0) Mea is dissolved in a mixture of trifluoroacetic acid (36 ml) and water (4 ml) containing anisole (0, 2 ml). The mixture is stirred for 30 minutes at 22 ° C, then evaporated in vacuo. The product is purified by chromatography on silica gel using a gradient system (solvent system) as eluent. The material after purification on a Q-column with silica gel is transferred to a column with carboxymethylcellulose, eluted with a gradient from 0.1% aqueous pyridine to 1.5% aqueous pyridine acetate.
The appropriate fractions are combined, evaporated, the residue is dried by repeated freezing from diluted HCI, and the desired hydrochloride (341 mg) is obtained.
.Rf SV 0.31; R 4A 0.44; Rf 5S 0.19; Cd ::; g + 29.30 ° (c 0.99, O, 1 N. H C I).
Example 9. L-Tyrosyl-O-methionyl (sulfoxide) glycyl-M-methyl-L-phenylalanine-2-dimethylaminoethylamide-H-oxide.
To a solution of 418 mg of HCl-H-Tyr-DMet-Gly-MePh-NH (CH2) 2N (C) Me2 in 150 ml of ethanol, 1.46 ml of hydrogen peroxide was added. The solution was stirred at 21 ° C for 24 hours, after which the solvent was distilled off under reduced pressure and the resulting material was purified by chromatography on cellulose CM. using a gradient, elution from 0.1% aqueous I pyridine to. 1.5% aqueous pyridine acetate.
The material obtained after purification on a column is dried by repeated freezing from HCl; the desired hydrochloride is obtained (354 mg).
R SV 0.32; Rf 4A 0.43; R 5B 0.32; Co (. ° ° + 9.16 ° (c 1.05; 0.1 n-HCl).
Table 1 shows the details of the preparation of other compounds of formula I by the methods described in the indicated examples.
Other typical compounds of the present invention are listed below:
) Wa-Cib-Me, PVi (napa-ce,) - NHCH2CH2N (oMej H-T4r-D№Q-Qt-Ph (nQpa-Ct) -NHCHaCH2.N (.
H-lVn-MU- Gly-KePh-NC
(o) MWG
J it-tpef if
H-Tyr - DAla - Cly-TTePJi-N:
SNGCH2M (0) Meg
H - Tour - DAla - Cty-IGERY- K fJ
CH2CHzN (0) Me2
L - Tug - D Ala - Cly N

ОН2СНгТ Р (о) Мег
SNGNG
H-Tyjp - HAIa- Cly -MePh TV

CIH2CH2N (0) Me2
H-Typ-DAla-Oly-MePh N
iH-tyr-DAla-OIy-MePh N
CHgCHaWtOjKee
CHgCHs
/
H-Typ-HAla-Ciy-WePh
CHaCHsNfOlMeg
SPGSNe H-TyP-DAla-Gly-MeFh Nci
CHgCHaNlOlMea
CHg CIS Cly - KePh IT
SNGOTg 10) Me2
SNaSgly-WrePJh. ISTOI
С 2СЛ2Т 1о) Gei caijCHa OH25 H Tyi - DAla - GJy -MePn N, CH2GH2N (o), -l CH3CH2-C U-OM (| .1., A1a-O y-MeP1da 30 CH2CH2N (0) M.2 CH2CH2N-TUR -DAla - Oly -MePli - N - ohm CH2CH2N (0) M-e2 SNAGTZ I -Tug - DVU a - 0 y- TePh-K. OKE S1G2CHNTCH (o) Mea H - Here - BA1- Gly - IePh-WiCH2.CH2K (0) MeCH2CH2 aij f-TUR GlY-MePh-ZSNO SMGSHRJA N-Tyr-UAla-Cly-MeFH -NHOtia HHWicoTfiicHs HzCiij. H - Tug-DAla - Cly-Ph -N SO-HH-THiicHs HzCiij. - Cly-KeFh-. Li Tour HAla - Cly -HePti - (/
Me
-N N
e
H-T f-DA a-Gbv-Ph
CH, .COO
J
for
H-T4r-DAEa-Ge.4-ANepti-N :: ;; 2C2P
5.CH CH NCOWEj
n-t g-wAea-yyu-meRN chnsn2Sn, n (H-Tyr-DVae. -GeN-MePhNHCH,. (. o) Me2 H -D-Ley-cey -MePti NHCH2 CH2H (.o) Me2
H-Tvr-DNbe.u-Ge-y N e, PViNHCH2 CHjNCOW62,
H-Tyr - DTra-c, ey-Me, PhNviCH.jCH2N (o) ,. H -Tsr -DAta - Qe.i -Wepti NHCH- CH NHMe
20 H-jyv-D) - eph lncn2al,.,)
H-T jr-VKSH- aE -MePVi HHCH2 CH2 Yu :; -Ü2 Q 50 55 Qth 5 HT r-Dfkta -Gt -MePti NHCH2CH, HT l - DA &amp; a-GE-JN ePliKHCH2CH, .t2 The starting amines of the formula HNRgRX used in the preparation of compounds / described in the above with P ® if they are not commercially available, can be obtained by known methods, or as described in the following examples. PRI me R A. N-Isoyl-NN-dimethylethylenediamine. (1) Me, CHCH5CONHCI-U CH2NH2:. A solution of 5 g (38 mmol) of isovaleroyl chloride in dichloromethane is added dropwise with stirring to a solution of N, N-dimethylethylenemamine (3.38 g, 38 mmol) and N-methylmorpholine (7.75 g, 76.7 mmol) in dichloromethane, at 0 ° C. Raise the temperature of the reaction mixture to room temperature and continue stirring for 4 hours, then the solvent is distilled off. The residue is dissolved in 50 ml of 5 M hydrochloric acid and extracted with ethyl acetate (2 x 100 ml). This mixture was washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated. The residue is dissolved in diethyl ether. 10 ml of 5 M HCI in ethyl acetate is added to it. The precipitated product is filtered off, washed with diethyl ether (5x10 ml) and dried under high vacuum. Yield 5.43 g; R for 0.40. (2) Me2 CHCH2, CH2.NHCH2 ,. A solution of this amide (5 g) in anhydrous tetrahydrofuran (50 ml) is added dropwise, with stirring, added to a suspension of LiA 1HD (4) in anhydrous tetrahydrofuran (20 ml) at
room temperature. The reaction mixture is then refluxed for 4 hours, after which, using thin layer chromatography, the absence of starting material is detected. The excess LiAIH is quenched with a saturated aqueous solution of sodium sulfate. The resulting suspension is filtered, the mother liquor is acidified with 10 ml of 4 M HCl. The separator is distilled off, the residue is triturated with diethyl ether, filtered and the precipitate is dried.
Output 5.51 g.
Example B. N-Phenethyl-N, N-dimethylethylenediamine
(1) PhCH CONHCHj CH NH - HC I.
This compound was prepared (pg by the method described in Example A {1), by combining phenacetyl chloride (1.0, 47 mmol) with N, N-dimethylethylenediamine (0.42 g, b, 47 mmol) in the presence of N-methylmorpholine.
Yield 1.38 g; R FOR 0.80.
(2
PhCH2 CH2NHCH, CH2NH.- HCl,
The target compound is obtained by reducing the above amide (10 g) with LiAH IN4, as described in Example A (2). The product obtained is purified by chromatography on a column of silica gel, using the FOR system as eluent.
Exit 4 ,.
Example C. N - (2-Aminoethyl) -Nm-dimethylurea.
(1) PhCHjiOCONHCH CH NHCONMe.
A solution of dimethylcarbamoyl chloride (1.39 g) in diethyl ether (15 ml) was added dropwise to a stirred solution of N-methylmorpholine (1.57 g) and 2-benzyloxycarbnyl minostilamine (3.02 g) in 110 ml of diethyl ether. The mixture was stirred for 4 hours, then left for two days. The ether is distilled off, the solid product is distributed between 10% aqueous citric acid and ethyl acetate. The ethyl acetate layer was separated and washed with 10% aqueous citric acid, saturated sodium bicarbonate solution and saturated sodium chloride solution, and then dried over sodium sulfate and evaporated, to give a solid (1.7 g). After recrystallization from mixtures of ethyl acetate and petroleum ether (bp 60–80 s), a product with m.p. 81-82 with.
(2) H2NCH2CH2NHCONMe2.
1.06 g of N-benzyloxycarbonyl compound is dissolved in 30 ml of ethanol containing 2.1 ml of 2N. aqueous hydrochloric acid and subjected to hydrogenolysis over 10% (100 mg)
for 1.5 hours. The mixture is filtered, the mother liquor is evaporated, and the desired compound is obtained as the hydrochloride salt, which is used without further purification.
- Example D. N-Isoamyl-N-me tylethylenediamine.
11) BOC-Gly-N (Me) CH.jCH2 CHMe.
To a solution of 17.5 (0.1 mol) BOC-GlyOH in 100 MP of anhydrous methylene chloride, 10.1 g (0.1 mol) of N-methyl morpholine and 13.7 g (0.1 mol) of JBCF are added with -15 ° C. After 2 minutes, 13.7 g (0.1 mol) of M-methylisoamylamine hydrochloride and
 10.1 g of N-methylmorpholine. The reaction mixture was stirred at 15 h and at room temperature overnight. The solvent is distilled off and the oil is dissolved in ethnyl acetate, extracted with saturated sodium bicarbonate (2x100 ml), 10% aqueous citric acid (2x100 ml), washed with water until neutral, dried over sodium sulfate and evaporated.
5 Get the oil. Yield 27 g (quantitative); RO 70 0.79.
(2) H2NCH. (Me) CH2CH CHMe2.
0 12 g BOC-GIy-N (Me) CH2CH2CHMe2
dissolved in 90% aqueous trifluoroacetic acid (: CPT, COOH 1: 9.35 ml). After 2 minutes, the solvent is distilled off, the remaining oil is dissolved in 50 ml of freshly dried tetrahydrofuran and added to diborane in tetrahydrofuran (1M, 150 ml) under nitrogen atmosphere at -20 ° C. The temperature was raised to room temperature and the reaction mixture was stirred overnight. Carefully add 100 ml.
methanol to decompose excess diborane, the solvent is distilled off, an oil is obtained. The oil is then treated with 50 ml of 6 M HCI. The reaction 5 mixture was heated under reflux for 3 hours and the mixture was evaporated. The resulting oil is treated with 2M NaOH for 1 h, acidified and evaporated. The oily residue is purified by column chromatography on silica gel (2.5 x 80 cm column), eluting the target product with a system of solvents.
The output of 4.4 g, R FOR 0.20. g Example E. Dimethyl- (2-amino-4-methylphenyl) -amine.
(1) BbC-Leu-NMe2.
To a solution of 4.62 g (20 mmol) of BO C-Leu-OH-in methylene chloride,
0 cooled to -20 ° C, 2.25 ml (20 mmol) of N-methylmorpholine and 6.0 g (20 mmol) of chlorodiphenylphosphate oxide (6.0 g, 20 mmol) are added, and after 15 min, 5.6 g
5 (125 mmol) dimethylamine. Through
3 hours while the solution is evaporated and the residue is partitioned between ethyl acetate and water (50 ml each). The organic phase is separated and washed with 10 &apos; -aic aqueous citric acid, aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate and the residue is evaporated, to give the desired amide (5.15 g
(2) Me2, NCH2CH (NH2,) CH2.CHMe2.
A solution of 1.3 g (5 mmol) of BOC-Leu-NMe 2 in aqueous trifluoroacetic acid (: 9: 1.20 ml) is stirred for 1 hour. The solvent is distilled off and the residue is dissolved in anhydrous tetrahydrofuran. The stirred solution is cooled, cooled to -20 ° C under a nitrogen atmosphere and a solution of diborane in tetrahydrofuran (1m, 30 ml) is added. After 5 hours, 10 ml of methanol is added at room temperature, the solution is stirred for 12 hours and then evaporated. The residue was dissolved in 15 NUI aqueous 2m hydrochloric acid and stirred for another 12 hours, the reaction mixture was evaporated. The residue is purified by chromatography on silica gel (system). The appropriate fractions are combined, evaporated, the target diamine is obtained in the form of an oil which, on standing, crystallizes. In biological tests, the obtained preparations of male or female guinea pigs (strain Duncan Hartley) are killed by a blow to the head, part of the ileum is removed and placed in a bath for individual organs of 50 MP. Get a convulsive reaction at low frequency (0.1 Hz)
HTyr-DAIa-GI y-Ph-NH (CH2) e CONH-j,
HTyr-DAIa-Gly-HePh-NH (CH), CONMe2
HTyr-DAla-Gly-MePh-NH (CH) 2NH
HTyr-DAIa-Gly-MePh-NH (CH2) COOMe
HTyr-DAIa-GIy -MePh-NH (CH) COOH
STIG4ULATION with rectangular pulses of 0.5 ms. The test compound is dissolved in distilled water to obtain a stock solution at a concentration of 1 mg / ml. Subsequent dilutions are made using Krebs solution to have a concentration of 10 mg, 1 mg and 0.1 mg / ml. The compound is tested by adding from 0.1 to 0, 3 ml of solutions to an organ bath. The dose-response relationship is then determined and compared to the metkecephalin dependence.
In rat tail withdrawal tests, hot water (maintained with) is used as the nociceptive 5 of the 1st stimulus.
The results are presented in table 2, are obtained when testing compounds according to the invention using the guinea pig ileum, activity compared with methynecephaline when tested according to Gendercote et al. and in rat tail pressure testing.
The pharmaceutical compositions may, for example, be in a form suitable for parenteral administration, such as sterile aqueous or oily solutions or suspensions for injection. Parenteral dosage forms suitable for intravenous administration within 1NII or subcutaneous administration contain from 0.1 to 50 mg / ml of the compound according to the invention (or an equivalent amount of a pharmaceutically acceptable salt thereof). Dose levels will, as a rule, for pain relief, range from 0.1 to 100 mg depending on the route of administration.
Table 1
 +52.8 (c 1.04; 0.1 H.
HC I)
Гс / .3в ° -43,3
(with 1; DMF)
 +26,1
(c 1.0; 0.1 n.
NA I)
n
Wljo +23,0
(from 0.85; 0.1 n.
NA))
, +25,5
(from 1.07; 0.1 n.
NA)
Continuation of table 1
Continued tablgt
25
Note. A - hydrolysis approx.11.

权利要求:
Claims (1)
[1]
1. Schröder E., Ljubke K. Peptides, Part I., M., Mir, 1967, p. 116.

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同族专利:

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CS210679B2|1982-01-29|

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引用文献:

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DK28377A|1976-02-02|1977-08-03|Sandoz Ag|PROCEDURE FOR PREPARING POLYPEPTIDE DERIVATIVES|

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NZ183712A|1976-04-08|1979-10-25|Ici Ltd|Polypeptide analogues of enkephalins, and pharmaceutical compositions|US4259234A|1976-09-27|1981-03-31|Eli Lilly And Company|Analgesic compounds|

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US4316892A|1980-11-03|1982-02-23|G. D. Searle & Co.|2,6-C-Dimethyltyrosine1 -D-amino acid2 -ε-amino caproic and γ aminobutyric acid5 derivatives of methionine enkephalin|

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EP0076557B1|1981-06-22|1985-11-13|Imperial Chemical Industries Plc|Peptides and pseudopeptides in which the n terminus bears two substituents|

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US4603121A|1983-10-06|1986-07-29|G. D. Searle & Co.|Enkephalin analogs|

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US4495178A|1983-10-06|1985-01-22|G. D. Searle & Co.|Enkephalin analogs|

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FR2788518B1|1999-01-14|2001-03-02|Centre Nat Rech Scient|NOVEL STABLE ACTIVE CARBAMATES, THEIR PREPARATION PROCESS AND THEIR USE FOR THE PREPARATION OF UREA|

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US7777030B2|2005-12-29|2010-08-17|Centre National de la Recherge Scientifique |Compositions and methods for the treatment and prevention of disease|

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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GB5223777|1977-12-15|

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GB1384578|1978-04-08|

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