Method of producing 5-cyanoprostacyclines

专利摘要:
1. 5-Cyanoprostacyclines of the general formula I see diagramm : EP0130142,P10,F2 wherein A represents a _t_r_a_n_s-CH = CH- or -C -= C- group, W represents a hydroxymethylene, acetoxymethylene, see diagramm : EP0130142,P10,F3 wherein the OH or acetoxy group may have the alpha- or b¢eta-configuration, D and E together represent a direct bond or D represents a straight-chained alkylene group having from 1 to 5 C atoms or a branched alkylene group having from 2 to 5 C atoms, E represents an oxygen atom, a -C -= C- bond or a direct bond, R2 represents a C1 -C7 -alkyl group or phenyl, R1 represents a hydroxy or acetoxy group and R3 represents the acetal radicals see diagramm : EP0130142,P11,F1
公开号:SU1450739A3
申请号:SU843748000
申请日:1984-06-07
公开日:1989-01-07
发明作者:Скубалла Вернер；Дал Хельмут；Радюхел Бернд；Форбрюген Хельмут；Логе Олаф
申请人:Шеринг Аг (Фирма)；
IPC主号:

专利说明:

 cm
This invention relates to a process for the preparation of new prostacyclin derivatives, namely, 5-cyanoprostacyclin of the general formula
HE
where R {and R are hydrogen or a methyl group, which has a more prolonged and selective pharmacological action compared to known analogues. The aim of the invention is to create an improved method for the preparation of new derivatives of carbocyclic. For cleavage of water and acetylation, the obtained compound is dissolved in 150 MP of toluene and 36. ml of acetic anhydride, add 90 mg of p-toluene sulfonic acid and stir for 2.5 hours at 20 ° C. Then 130 ml of pyridine are added, stirred for 6 hours at 20 ° C. diluted with water, extracted with toluene, washed with 10% citric acid solution and water, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed with ether / hexane on silica gel. This gives 4.1 g of the desired (5E) -5-cyano-2-descarboxy--2- (5,5-dimethyl-1, 3-dioxan-2-yl) -16-methylprostacyclin-11,15 β-diacetate and as a 6dhee polar component 3.5 g of the corresponding isome20
lina with improved pharmaco-25 P (5g) -5 cyano-2-descarboxy-2- (5,5-logical effect.-dimethyl-1,3-diocan-2-yl) -16-methyl P and m e r 1. 5-Cyano .2-descarcostacyclin-11,15-diacetate. boxy-2- (5,5-dimethyl-1,3-dioxan-2-yl) -16-methylprostacyclin.
IR (CHC1): 2959, 2860, 2202, 1732 1654, 1240, 972 cm-.
14.47 g of diisopropylamine rbarabate-JQ are watered at -25 ° C for 15 minutes 56.86 g of a 15% solution of butyl lithium in hexane and stirred for 1 hour at -25 ° C. Then, 26.27 g of 5-neopentyl acetal cyanovaleric aldehyde c is added dropwise with a solution. 13.5 g ml of tetrahydrofuran are stirred for 20 minutes and then a solution of 15 g (IS, 5R, 6R, 7R) -6- (E) - (3, S, 4RS) -4-methyl-3- is added dropwise. (Tepa-hydropyran-2-yloxy) -1-octenyl) -7- - (tetrahydropyran-2-shyoxy) -2-oxabig
cycloSZ, 3.03-octane-3-pna in 11.3 ml of tetrahydrofuran and 11.3 ml of ethyl
}five
40
For cleavage, acetal is stirred with 4.1 g of the obtained diacetal in 220 ml of methanol with 5.3 g of potassium carbonate for 16 hours at 23 ° C. It is then concentrated under vacuum, diluted with ether, washed with brine until neutral and washed with water, dried over sulfate magnesium and evaporated under vacuum. The residue is purified by chromatography on silica gel.
By acting as ethyl acetate / hexane (7: 3) as eluent, 3.4 g of the title compound are obtained as an unceregated oil.
IR: 3600, 3430 (wide band).
the ether. Stirred for 30 min at, d5. 2860, 2200, 1649, 70 cm-h, remove the cooling bath, treat the 5-cyanovalene neopentyl acetal with a saturated solution of the new aldehyde chloride used in aluminum and acidify the mixture with 10%. synthesis, obtained as follows. pacTBOpot citric acid to pH 6. Neopentyl acetal 5-bromvaleria- Extract with ether / hexane (1: 1), - new. aldehyde. To 151.0 g of methanol is washed with water, dried over magnesium sulfate and. evaporated under vacuum. The residue is chromatographed with hexane-san (2: 3) on silica gel. With
5-Bromovaleric acid ester in 2500 ml of toluene under argon atmosphere and in the absence of water at -65 ...- 70 ° C is added dropwise 840 ml of DiBAH solution (20% in toluene) and stirred for 20 minutes.
This gives 18.05 g of oxynitrile in the form of an acetate oil, which is stirred for 20 hours with 600 ml of a mixture of acetic acid / water / tetrahydrofuran at 22 C. Vscharyvayut with the addition of 10
507392
luol at and elute the precipitate with ethyl acetate through silica gel. 9.5 g of 11,15-diol are obtained in the form of a colorless oil.
 For the cleavage of water and acetylation, the resulting compound is dissolved in 150 MP of toluene and 36 ,. ml of acetic anhydride, add 90 mg of p-toluene sulfonic acid and stir for 2.5 hours at 20 ° C. Then 130 ml of pyridine are added, stirred for 6 hours at 20 ° C. diluted with water, extracted with toluene, washed with 10% citric acid solution and water, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed with ether / hexane on silica gel. This gives 4.1 g of the desired (5E) -5-cyano-2-descarboxy--2- (5,5-dimethyl-1, 3-dioxan-2-yl) -16-methylprostacyclin-11,15 -diacetate and as 6dhee polar component 3.5 g of the corresponding isome 15
20
25 P (5g) -5 cyano-2-descarboxy-2- (5,5-dimethyl-1,3-dioxan-2-yl) -16-methylprostacyclin-11, 15-diacetate.
IR (CHC1): 2959, 2860, 2202, 1732, 1654, 1240, 972 cm-.
For cleavage, acetal is stirred with 4.1 g of the obtained diacetal in 220 ml of methanol with 5.3 g of potassium carbonate for 16 hours at 23 ° C. It is then concentrated under vacuum, diluted with ether, washed with brine until neutral and washed with water, dried over sulfate magnesium and evaporated under vacuum. The residue is purified by chromatography on silica gel.
By acting as ethyl acetate / hexane (7: 3) as eluent, 3.4 g of the title compound are obtained as an unceregated oil.
IR: 3600, 3430 (wide band).
. 2860, 2200, 1649, 70 cm H Neopentyl acetal of the 5-cyanovaleric – aldehyde used in the synthesis was prepared as follows. Neopentyl acetal 5-bromovaleric analdehyde. K 151.0 g methyl
5-Bromovaleric acid ester in 2500 ml of toluene under argon atmosphere and in the absence of water at -65 ...- 70 ° C is added dropwise 840 ml of DiBAH solution (20% in toluene) and stirred for 20 minutes.
Then, 420 ml of isopropyl alcohol and 420 ml of water are added at -70 ...- BS. Allow the mixture to heat31A50739
c. and stir until the precipitate is well filtered.
Filtered, washed with toluene and concentrated under vacuum to a volume of about 1000 MP. - The volume of the resulting toluene solution of 5-bromovaleraldehyde was adjusted to a volume of 1.29 g with toluene, treated with 120.8 g of 2.2-dimethylpropane-1,3-diol and 1.28 g of p-toluenesulfonic acid hydrate and heated to reflux with water separation until the water separation is complete (1.5 hours). The mixture is allowed to cool, transferred to A35 ml of a saturated solution of NaHCOj, and the phases are separated. The toluene phase is washed three times with 400 MP of water each time, with suction: 3600, 3420 (wide strip), 2958, 2860, 2200, 1650, 970 cm.
PRI me R 3. 5-Cyano-2-descarbo xi-16,1b-dimethyl-2- (5,5-Dimethyl--1,3-dioxan-2-yl) -prostacyclin.
Analogously to Example 1 of 3 g (1S, 5R, 6R, 7U-6- (E) - (SJ-4,4-Dimethyl- -3- (tetrahydropyran-2-yloxy) -1-octenyl-7- ( tetrahydropyran-2-yloxy) -2- -oxabicycloSZ, 3.03-octan-3-one, after chromatographic separation in accordance with Example 1, 1800 mg of the desired (5E) -5-cyano-2-15-decarboxy-16.16 are obtained. -dimethyl-2- (5,5-dimethyl-1, 3-dioxan-2-yl) -prostation-11,15-diacetate and as a more useful component 650 mg of the corresponding isomeric
ten
 - - -. pltss j nj ys L pi I
stitched over sodium sulfate, concentrated Q (5g) -5-cyano-2-descarboxy-16,16 is discharged under vacuum and then distilled in an oil pump vacuum. Get 154 g of the product with m. Kip. 67 ° C (0.7 mbar.).
Neopentyl acetal 5-, cyanovaleric aldehyde. 150.0 g of neopentyl acetal 5-bromovaleric aldehyde in 600 MP anhydrous dimethyl sulfoxide in an argon atmosphere are mixed with 32.2 g of sodium cyanide for 3.5 hours at. The reaction mixture was poured into 1300 MP of water and extracted three times with 500 ml of an ether / hexane mixture (1: 1) each time. The organic layers were washed five times with 120 ml of water, dried over sodium sulfate, concentrated under vacuum, and distilled in an oil pump vacuum. Obtain 100.1 g of the desired product with so Kip. 90 ° C (0.6 mbar.).
Example 2 (5g) -5-Cyano-2-des-carboxy-2- (5,5-dimethyl-1,3-dioxan--2-yl) -16-methylprostacyclin.
3.5 g of (5E) -5-cyano-2-descarboxy--2- (5,5-dimethyl-1, 3-dioxan-2-yl) -16-methylprostacyclin-11,15-diacetate (prepared according to Example 1) in 180 MP of toluene is stirred with 4.5 g of potassium carbonate for 16 hours at 23 ° C.
Then it is concentrated under vacuum, diluted with ether, washed with brine until neutral with washing water, dried over magnesium sulphate and evaporated under vacuum.
-dimethyl-2- (5,5-dimethyl-1,3-dioxan--2-yl) -prostacyclin-11,15-diacetate.
IR: 2960, 2860, 2201, 1732, 1655, 1240, 972 cm-.
25 After removing the acetate group according to example 1, 620 mg of the title compound are obtained in the form of a colorless oil.
IR: 3610, 3420 (wide band), 30 2958, 2860, 2200, 1649, 970 cm.
PRI me R 4. 5-cyano-2-descarboxy-2- (5,5-dimethyl-1,3-dioxan-2-yl) -16-phenoxy-17,18,19,20 - tetranor - prostacyclin.
25 In a manner similar to Example 1, 4 g of (IS, 5R, 6R, -7R) -6 (E) - (3R) -4-phenoxy-3- (tetrahydropyran-2-yloxy) -1-butenyl-7- (tetrahydropyran -2-yloxy) -2-oxabicyclo 3,3, O-octane-3-40-she after chromatographic separation (according to example 1) 995 g of the desired (5E) -5-cyano-2-descarboxy-2- 45 , 5-dimethyl-1,3-dioxan-2-sh1) -1-phenoxy-17,18,19,20-tetranorprostacic-45 lin-11,15-diacetate and as the more polar component 780 mg of the corresponding isomeric (5g) -5-cyano--2-descarboxy-2- (5,5-dimethyl-1,3-dioxane-2-yl) -16-phenoxy-17,18,19,20-50 - 50 tetranorprostacyclin-11,15-diacetate.
IR: 2958, 2850, 2205, 1735, 1658, 1601, 1588, 1245, 976 cm-.
After removal of the residue of the acetate, the residue is purified by chromatography on silica-5g from the E-isomers according to Example 1 on a gel. The action of ethyl acetate / hexa-710 mg specified in the title
compound in the form of a colorless casle.
IR: 3610, 3405 (wide), 2258, 2851, 2203, 1651, 1601, 1588, 974 cmL
by (7: 3), 2.8 g of the title compound is obtained as a colorless oil.
IR: 3600, 3420 (wide band), 2958, 2860, 2200, 1650, 970 cm.
PRI me R 3. 5-Cyano-2-descarboxy-16,1b-dimethyl-2- (5,5-Dimethyl--1,3-dioxan-2-yl) -procyclin.
Analogously to Example 1 of 3 g (1S, 5R, 6R, 7U-6- (E) - (SJ-4,4-Dimethyl- -3- (tetrahydropyran-2-yloxy) -1-octenyl-7- ( tetrahydropyran-2-yloxy) -2- -oxabicycloS3, 3.03-octan-3-one, after chromatographic separation in accordance with Example 1, 1800 mg of the desired (5E) -5-cyano-2-descarboxy-16,16- are obtained. dimethyl-2- (5,5-dimethyl-1, 3-dioxan-2-yl) -prostation-11,15-diacetate and as a more useful component 650 mg of the corresponding isomeric
 - - -. pltss j nj ys L pi I
(5g) -5-cyano-2-descarboxy-16,16 (5g) -5-cyano-2-descarboxy-16,16
-dimethyl-2- (5,5-dimethyl-1,3-dioxan--2-yl) -prostacyclin-11,15-diacetate.
IR: 2960, 2860, 2201, 1732, 1655, 1240, 972 cm-.
After cleavage of the acetate group according to Example 1, 620 mg of the title compound are obtained in the form of a colorless oil.
IR: 3610, 3420 (wide band), 2958, 2860, 2200, 1649, 970 cm.
PRI me R 4. 5-cyano-2-descarboxy-2- (5,5-dimethyl-1,3-dioxan-2-yl) -16-phenoxy-17,18,19,20- tetranorprostacyclin.
In analogy to Example 1, 4 g of (IS, 5R, 6R, -7R) -6 (E) - (3R) -4-phenoxy-3- (tetrahydropyran-2-yloxy) -1-butenyl-7- (tetrahydropyranyl 2-yloxy) -2-oxabicyclo 3,3, O-octan-3-it after chromatographic separation (according to example 1) 995 g of the desired (5E) -5-cyano-2-descarboxy-2-5, 5- dimethyl-1,3-dIoxane-2-sh1) -1-phenoxy-17,18,19,20-tetranorprostatin-11,15-diacetate and as a polar component 780 mg of the corresponding isomeric (5g) -5-cyano-2-descarboxy-2- (5,5-dimethyl-1,3-di-xan-2-yl) -16-phenoxy-17,18,19,20-tetranorprostacyclin-11,15-diacetate .
Example 5. 5-Cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2-yl) H15RS) -15-methylprostacyclin.
Analogously to Example 1, prepared from 2 g (IS, 5R, 6R, 7R) -6C (E) - (3RS) -.
-3-mehyl-3- (tetrahydropyran-2-yloxy) -1-octenyl-7- (tetrahydropyran-2-yloxy) -2-oxabicyclo C3,3,0-octan-3-one after chromatographic separation according to Example 1 530 mg of the desired (5E) -5-cyano-2-descarboxy-,
Ch5,5-dimethyl-1, 3-dioxan-2-yl) - (15RS) -15-metsh1 Prostacyclia-11, 15-diacetate
and as a more polar compound 15-1 3-diocan-2-shl) - (, 20-dime- enthe 432 mg of the corresponding isomethyl-18,18,19,19-tetradehydroprotic (5g) -5 -cyano-2-descarboxy-2- (5,5-cyclin-11,15-diacetate as
-dimethyl-1, 3-dioxan-2-yl) - (15RS) -15-methylprostacyclin-11, 15-diacetate.
IR: 2955, 2858; 2200, 1738, 1652, 1245, 976 cm-.
After cleavage of the acetate group from the E-isomers according to Example 1, 395 mg of the title compound are obtained as colorless mag.
IR: 3605, 3410 (wide), 2957, 2860, 2201, 1651, 974 cm.
PRI me R 6. 5-Cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2-yl) - K5) - 16-methyl-18,18,19 , 19-tetra-dehydroprostacyclin.
Analogously to example 1. from 2,85 g (13, .5R, 6R, 7R) -6-t (E) - (3S, 4RS) - 4-methyl- (tetrahydropyran-2-ShIOksi) - 1-ryten-6 -inylJ-7- (tetragamide-2-yloxy) -2-oxa-bicycle about 3.3.0-octan-3-one after chromatographic separation according to example 1, 760 mg of eluated (5E) -5-cyano are obtained. -2 -2-descarboxy-2- (5,5) -dimethyl-1,3-dioxy-2-yl) - (16RS) -16. -Methyl-18,18, 19,19-tetradehydroprostacyclin-11,15 - diacetate and, as the more polar component, 625 mg of the corresponding isomeric (5g) -5-cyano-2-des-carboxy-2- (5,5-dimethyl-1,3-dioxan--2-yl) - ( 16RS) -16-metshI-18,18,19,19-tetrahydroprocycacyclin-11,15-diacetate.
IR: 2962, 2858, 2206, 1735, 1651, 1248, 976 cm-.
After cleaving the acetate group from the E-isomers according to Example 1, 585 mg of the title compound is obtained as a colorless oil.
HKS 3604, 3410 (wide), 2959, 2857, 2204, 1652, 974 cm.
25
thirty
35
the more polar component is 630 mg of the corresponding isomeric (5Z) 20 5-cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2-yl) - (16RS) -16,20- -dimethyl-18,18,19,19-tetradehydroprostacyclin-11, 15-diacetate.
IR: 2960, 2862, 2202, 1735, 1656, 1248, 974 cm
After cleaving the acetate group from the E-isomers according to Example 1, 590 g of the title compound are obtained in the form of an acetate without oil.
IR: 3600, 3420 (wide), 2960, 2858, 2202, 1655, 974.
Example 8. 5-Cyano-2-descarboxy-2- (1, 3-dioxolan-2-yl) - (16- -methylprostacyclin.
13.47 g of diisopropylamine are treated at -25 ° C for 15 minutes with 56.86 g of a 15% butyl lithium solution in hexane. After 1 h add
40 dropwise at -76 ° C solution of 20.67 g of diethylene acetate of 5-cyanovaleric aldehyde in 12 ml of tetrahydrofuran, stirred for 20 minutes, and then a solution of 6.26 g (IS,
45 5R, 6R, 7R) -6-t (E) - (3S, 4RS) 3-oxy-4-methyl-1-octenyl-7-hydroxy-2-oxa-bicyclo 3,3,0-octane 3-she in 12 ml of tetrahydrofuran and 12 ml of ethyl ether. Stirred for 30 minutes at
The gQ removes the cooling bath, treats all with ammonium chloride solution, and acidify the mixture with 10% citric acid solution to pH 6. Extract with ethyl mixture.
55 ether / hexane (1: 1), washed with water, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed with a mixture of hexane / ether (1: 9) on silica gel. 7 t approx. 7 are obtained. 5-Cyano-2-descarboxy-2- (5,5-dimethyl-1,3-dioxan-2- -yl) - (16RS) -16,20-dimethyl-18,18 , 19,19- -tetradehydroprostaglycine.
 Analogously to example 1 of 1 g (IS, 5R, 6R, 7R) -6- (E) - (ZS, 4RS) -4-methyl-3- (tetrahydropyran-2-yloxy) t1-non-vinyl 1-7 - (tetrahydropyran-2-yloxy) -2-oxabicyclo 3,3,0-octan-3-β-one after chromatographic separation in accordance with example 1, 775 mg of the desired (5E) -5-cyano-2-descarboxy is obtained -2- (5,5-dimethyl) 5
0
five
the more polar component is 630 mg of the corresponding isomeric (5Z) 0 5-cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2-yl) - (16RS) -16,20- -dimethyl-18,18,19,19-tetradehydroprostacyclin-11, 15-diacetate.
IR: 2960, 2862, 2202, 1735, 1656, 1248, 974 cm
After cleaving the acetate group from the E-isomers according to Example 1, 590 g of the title compound are obtained in the form of an acetate without oil.
IR: 3600, 3420 (wide), 2960, 2858, 2202, 1655, 974.
Example 8. 5-Cyano-2-descarboxy-2- (1, 3-dioxolan-2-yl) - (16- -methylprostacyclin.
13.47 g of diisopropylamine are treated at -25 ° C for 15 minutes with 56.86 g of a 15% butyl lithium solution in hexane. After 1 h add
0 dropwise at -76 ° C a solution of 20.67 g of 5-cyanovaleric aldehyde diethyl acetate in 12 ml of tetrahydrofuran, stirred for 20 minutes, and then a solution of 6.26 g (IS,
5 5R, 6R, 7R) -6-t (E) - (3S, 4RS) 3-oxy-4-methyl-1-octenyl-7-hydroxy-2-oxa-bicyclo 3,3,0-octane 3-she in 12 ml of tetrahydrofuran and 12 ml of ethyl ether. Stirred for 30 minutes at
Q remove the cooling bath, treat with all; ammonium chloride solution, and acidify the mixture with 10% citric acid solution to pH 6. Extract with ethyl mixture
5 ether / hexane (1: 1), washed with water, dried over magnesium sulphate and evaporated under vacuum. The residue is chromatographed with a mixture of hexane / ether (1: 9) on silica gel. Get 7 t okU507398
ethyl ether / hexane (1: 1), the extract is washed with brine, dried over magnesium sulphate and the solvent is distilled off under vacuum. The liquid residue is distilled at 0.8 mbar. 16.6 g of product are obtained with a bp. 87 ° C.
PRI me R 9. 5-cyano-2-discarbon chromatography on silica gel with hexa-boxy-2- (1.3 dioxolan-2-yl) -16.16 and an increasing amount of ethyl dimethylprostacyclin. acetate. Thus, 2.30 g of (1S, 5R, 6R, 7R) -6- (E) - (38) -4,4-dime- (52) -5-cyano-2-descarboxy-2- (1, 3-tyl-3- (tetrahydropyran -2-yloxy) -dioxolan-2-yl) - (16K8) -16-methylprost-5 -1-octenyl - 7- (terapahydropyran-2-ylok-cyclin and 3.01 g indicated in eagolovsi) -2-oxabicyclo 3,3,0-octan-3-one
Sinytrile as an unaffected oil, which is dissolved in 120 ml of toluene for water cleavage, is treated with 70 mg of p-toluenesulfonic acid and stirred for 2 hours at 20 ° C. Then it is washed with sodium bicarbonate and water, dried over magnesium sulphate and evaporated under vacuum. Remainder
ke of the compound (5E-isomer) as a colorless oil.
IR: 3600, 3420 (wide), 2955, 2858, 2207, 1653, 974.948 cm.
Diethylene acetal 5-cyanovaleric aldehyde used in the synthesis is prepared as follows.
but. 5-Bromine-valeric aldehyde. To a solution of 48.75 g of methyl ester of 25 bromovaleric acid in 2.5 liters of toluene is added dropwise at -70 ° C with stirring 271 ml of 1.2 M solution of diisobutyl aluminum hydride in toluene, stirred for 30 minutes and added dropwise successively 50 ml isopropyl alcohol and 135 ml of water, stirred for 2 hours at 20 ° C, the precipitate is filtered off and evaporated under vacuum.
43 g of 5-bromvalerianoBogo aldehyde are obtained, which without further purification
310 g of the title compound are obtained in the form of an acetate oil.
-20 IR: 3600, 3410 (wide), 2960, 2861, 2203, 1649, 975, 948 cm
Example 10. 5-Cyano-2-descarboxy-2-diethoxymethyl- (1bK5) -16-methyl-prostacyclin.
1.347 g of diisopropylamine are treated at -25 ° C for 15 minutes with 5.666 g of a 15% butyl lithium solution in hexane. After 1 h, a solution of 2.47 g of 5-cyanovaleric aldehyde dioacetal in 15 MP of tetrahydrofuran was added in 30 drops at -76 C, stirred for 20 minutes, and then a solution of 630 mg was added dropwise (1S, 5R, 6R, 7R) -6-C (E) - (ЗS, 4RS) -3-oxy-4-methyl-1-octenyl-7-hydroxy-2-oxabicyclo 13.3.0-octan-3-one in 30 mp tetra35
310 g of the title compound are obtained in the form of an acetate oil.
IR: 3600, 3410 (wide), 2960, 2861, 2203, 1649, 975, 948 cm
Example 10. 5-Cyano-2-descarboxy-2-diethoxymethyl- (1bK5) -16-methyl-prostacyclin.
25
1.347 g of diisopropylamine are treated at -25 ° C for 15 minutes with 5.666 g of a 15% butyl lithium solution in hexane. After 1 h, a solution of 2.47 g of 5-cyanovaleric aldehyde dioacetal in 15 MP of tetrahydrofuran was added in 30 drops at -76 C, stirred for 20 minutes, and then a solution of 630 mg was added dropwise (1S, 5R, 6R, 7R) -6-C (E) - (ЗS, 4RS) -3-oxy-4-methyl-1-octenyl-7-hydroxy-2-oxabicyclo 13.3.0-octan-3-one in 30 mp tetra35
subjected to transformation.
at. 5-Bromovaleric aldehyde deethylene acetal, 43 g of 5-bromo-valerian aldehyde, 51 ml of ethylene glycol, 500 ml of p-toluenesulfonic acid and 1 l of toluene are heated under reflux with water separation. After cooling, it is shaken with a solution of sodium bicarbonate and brine, dried over magnesium sulphate and toluene is distilled off under vacuum. The liquid residue is distilled at 0.2 mbar. Get 25.06 g of product st. kip .
with. Diethylene acetal 5-cyanovale-10 mp p-toluenesulfonic acid. Then, ryanaldehyde, 32.7 g diethylene- was diluted with ethyl ether, added with 5-bromovaleric aldehyde acetal with a solution of sodium bicarbonate in 140 MP dimethyl sulfoxide over 55 P with water, dried over sulfa-1 was mixed with 16.24 g of sodium cyanide Magnesium and extruded under 6 h in an argon atmosphere at. Oh-zheniem. The residue is chromatographed
blended, diluted with 300 ml of water, on silica gel with hexane / ethyl acetate
extracted repeatedly with a mixture (1: 4) and get as more
hydrofuran and 3 ml of ethyl ether. Stir for 30 minutes at -76 ° C, remove the cooling bath, treat with saturated ammonium chloride and extract with ethyl ether / hexane (1: 1), wash with brine, dry over magnesium sulfate and evaporate under vacuum. The residue is chromatographed on silica gel with hexane / ethyl ether (1: 9) to give 720 mg of oxynitrile as a colorless oil, which is
50
Water is dissolved in 15 ml of toluene and stirred for 2 hours at 20 ° C.
15
20
polar component 200 mg of (5Z) -5-Iiano-2-descarboxy-2-diethoxy-THN- (l6RS) -16-methylprostacycline and 305 mg of the title compound (5E-isomer) as a colorless oil,
IR: 3605, 3410 (wide), 2959, 2860, 2201, 1650, 976 cm.
The 5-cyanovalerialdehyde diethyl acetal used to synthesize is prepared analogously to Example 8 c from 5-bromo-valeric aldehyde diethyl acetate by reaction with sodium cyanide: t. Bale. 82 ° C at 0.7 mbar;
Example 11. 5-Cyano-2-descarboxoxy-2- (5,5-dimethyl-1,3-dioxan-2- -yl) - (168) -16-methylprostacyclin.
8.76 g of diisopropylamine are treated at 25 ° C with 73 MP of a 1.2 M solution of butyl lithium in hexane. After 1.h, a solution of 17.08 grams of neopeptilacetal of 5-cyanovaleric aldehyde in 8 ml of tetrahydrofuran is added dropwise at 78 ° C. After 20 minutes, a solution of 9.75 g (18.5K, 6K, 7K) -6-C (E) - (35.48) -4-methyl-3- (tetrahydropyran-2-BrOxy) is added dropwise. -1, α-octenyl 1-7- (tetrahydropyran-2-yloxy) -2-oxabicyclo 3,3,0-octan-3-one in 8 ml of tetrahydrofuran and 8 ml of ethyl ether.
After another 30 minutes at -78 ° C, it is treated with a saturated solution of chloris-. In addition, ammonium is added and acidified with citric acid to pH 6. Extraction is carried out with ether / hexane (1: 1), washed with water, grown over magnesium sulphate and extruded under vacuum.
The residue is chromatographed with hexane / ether (2: 3) on silica gel, to give 12 g of oxynitrile as an oil. For cleavage, the tetrahydropyranyl ether protective group is stirred for 24 hours with 400 ml of an ethyl acetate / water / tetra-ihydrofuran mixture (65:35:10), mixed, under vacuum, and the residue is filtered with hexane / ethyl acetate-1 (2: 8) through silica gel. 6 g of 11,15-diol are obtained in the form of a colorless oil.
To remove water and acetylate, dissolve the oil in 100 ml of toluene and 23 ml of acetic anhydride, add 60 mg of toluene sulfonic acid
evaporate over magnesium sulphate and evaporate under vacuum.
The residue is chromatographed on silica gel with ether / hexane (1: 1). 2.60 g of desired (5E) -5-cyano-2-des-carboxy-2- (5,5-dimethyl-1,9-diox-gn--2-yl) - (16S) -16-methylprostacyclin are obtained. -11, 15-diacetate and, as a more polar component, 2.20 g of the corresponding isomeric (5E) -5-cyano--2-descarboxy-2- (5,5-dimethyl-1,3- -; ioxane-2 -yl) - (168) -16-methylprostacine-11, 15-diacetate.
IR (5E-isomer): 2960, 2861, 2202, 1735, 1655, 976 cm-.
For - the acetate cleavage, 2.60 g of the obtained (5E) -11.15-diacetate is stirred in 140 ml of methanol from 3.45 g of potassium carbonate for 16 hours at. For work-up, it is concentrated under vacuum, diluted with ether, washed with brine, dried over magnesium sulfate, and evaporated under vacuum. 25 The residue is purified by chromatography on silica gel with hexane / ethyl acetate (3: 7), and 2.19 g of the title compound are obtained as an uncetal oil.
IR: 3600, 3420 (wide), 2958, 2861, 2203, 1651, 974.
Example 12. 5-Cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2- -yl) - (1bK) -1b-methylprostacyclin,
Analogously to example 11, but using another 16-epimer, from 5 g (15.5K, bK, 7U-b (E) - (35.4 U-4-methyl-3-tetrahydropyran-2-yloxy) -1- octe- (tetrahydropyran-2-yloxy) -4o 2-oxabicyclo 3,3,0-octan-3-one (see J. Org. Chem. 1973, 38, 1250) take half of T, 15 g of the title. compounds in the form of oil.
IR: 3600, 3420. (wide), 2959,. 45 2861, 2202, 1650, 974 cm.
Pharmacological activity. Target compounds act as cytoprotection and bronchodilatory. They are also suitable for inhibiting the secretion of gastric juice, therefore, the new carbacyclin derivatives of general formula (I) are valuable pharmaceutical biologically active substances. In addition, when
thirty
35
50
and stirred for 3 hours at 20 ° C. Then 06-55 similar spectrum of action is compared with 85 ml of pyridine. Even after dilution with the corresponding prostaglandi, it is diluted with water for 6 hours, extracted by us they possess more specific toluene, washed with 10% solution and, mainly, essential citric acid and water, dried over a longer period of time.
evaporate over magnesium sulphate and evaporate under vacuum.
The residue is chromatographed on silica gel with ether / hexane (1: 1). 2.60 g of desired (5E) -5-cyano-2-des-carboxy-2- (5,5-dimethyl-1,9-diox-gn--2-yl) - (16S) -16-methylprostacyclin are obtained. -11, 15-diacetate and, as a more polar component, 2.20 g of the corresponding isomeric (5E) -5-cyano--2-descarboxy-2- (5,5-dimethyl-1,3- -; ioxane-2 -yl) - (168) -16-methylprostacine-11, 15-diacetate.
IR (5E-isomer): 2960, 2861, 2202, 1735, 1655, 976 cm-.
For - the acetate cleavage, 2.60 g of the obtained (5E) -11.15-diacetate is stirred in 140 ml of methanol from 3.45 g of potassium carbonate for 16 hours at. For work-up, it is concentrated under vacuum, diluted with ether, washed with brine, dried over magnesium sulfate, and evaporated under vacuum. 5 The residue is purified by chromatography on silica gel with hexane / ethyl acetate (3: 7), and 2.19 g of the title compound are obtained as an acetal-free oil.
IR: 3600, 3420 (wide), 2958, 2861, 2203, 1651, 974.
Example 12. 5-Cyano-2-descarboxy-2- (5,5-dimethyl-1, 3-dioxan-2- -yl) - (1bK) -1b-methylprostacyclin,
Analogously to example 11, but using another 16-epimer, from 5 g (15.5K, bK, 7U-b (E) - (35.4 U-4-methyl-3-tetrahydropyran-2-yloxy) -1- octe- (tetrahydropyran-2-yloxy) - o 2-oxabicyclo 3,3,0-octan-3-one (see J. Org. Chem. 1973, 38, 1250) T-half, 15 g of the title. compounds in the form of oil.
IR: 3600, 3420. (wide), 2959,. 5 2861, 2202, 1650, 974 cm.
Pharmacological activity. Target compounds act as cytoprotection and bronchodilatory. They are also suitable for inhibiting the secretion of gastric juice, therefore, the new carbacyclin derivatives of general formula (I) are valuable pharmaceutical biologically active substances. In addition, when
0
five
0
VIA. Compared to PGI, they are more resistant. High specificity with respect to the tissues of new prostaglandins is demonstrated in studies on smooth muscle organs, for example, in the ileum of guinea pigs or in the isolated trachea of rabbits, where much more reduced stimulation is observed than when using natural prostaglandins of type A, E or F.
New carbocycline analogs have TYPICAL properties for prostacyclin: a decrease in perisrial blood and coronary vascular resistance, inhibition of platelet aggregation and dissolution of benabluyut decrease in the number and length of these erosions in percent compared to the control. The width of the erosion is always 1 mm (see table).
lykh thrombus, myocardial cytozaschashi-. 20, 20 lesions (bleedings) occur, which, and thereby, a reduction in the system, by giving to the ro. Target blood pressure target compounds without simultaneously reducing systolic blood volume, stroke volume and coronary blood pressure, stroke treatment, 25 prevention and treatment of coronary heart diseases, coronary thrombosis, heart attacks, peripheral arterial diseases, arteriosclerosis and thrombosis, prevention and therapy of ischemic attacks of the central nervous system, treatment of shock, inhibition of compression of the bronchi, inhibition of secretion of gastric acid, cytozagstvuyu mucous membrane intestine, cytoprotective liver and pancreas, antiallergic properties, reduction of pulmonary vascular resistance and pulmonary pressure of blood, promoting renal blood pressure, using hemofiltration instead of heparin or dialysis, plasma preservation 45 blood, in particular for platelet conservation, inhibition of labor contractions, treatment of toxicosis during pregnancy, elevation of cranial pressure, etc. 50
In addition, the target compounds have anti-inflammatory and anti-proliferative properties. They can also be used in combination, for example, with b-blockers, diuretic agents and phosphodiesterase inhibitors.
The dose of the target compounds is 1-1500 mg / kg / day, if the target compound of example 1 has very low toxicity.
The compounds of form (I) of examples 3 and 8g10 have the same pharmacological activity.
Fore
Mule Invention
The method of obtaining 5-cyanoprostacyclin of the general formula
nг-CN
ABOUT.
Hf
 Kg
HE
HE
change to treat people. The unit dose for Pharmaceutically acceptable carriers is 0.01100 mg.
When an intravenous injection is given to awake rats with hypertension at a dose of 5, 20 and 100 mg / kg of live weight, the proposed compounds show a stronger effect on pressure reduction and a longer duration than PGE0 and PGA, without causing, as occurs with PGE -z, diarrhea and cardiac arrhythmia with PGA.
Data on cytoprotective activity. With the introduction of 20 mg / kg indomethacin first causes an erosion of the gastric mucosa in rats. Usually
Observe a decrease in the number and length of these erosion in percent compared with the control. The width of the erosion is always 1 mm (see table).
there are 20 lezya (bleedings), target compounds
there are 20 lezya (bleedings), target compounds
The target compound of example 1 has a very low toxicity.
The compounds of form (I) of examples 3, 8g10 have the same pharmacological activity.
there are 20 lezya (bleedings), target compounds
Fore
Mule Invention
there are 20 lezya (bleedings), target compounds
The method of obtaining 5-cyanoprostacyclin of the general formula
20 lezies (krodach ro active target
nг-CN
ABOUT.
Hf
 Kg
HE
HE
13.1450739U
where R ;, and R is hydrogen or M on O-RV
A group characterized in that ((/ Crj that, a compound of formula O
ABOUT
where R has the indicated meanings
 lithium diisopropylamide with subsequent dehydration and concomitant transesterification of oxy j
9.
nitrile with acetic anhydride in nature .Ii. nn i fnjLd LPL 13 ILyn -
..f -3 ORj of the presence of p-toluenesulfonic acid with
where the RS is a tetrahydropyranyl group, it is exposed to room temperature and then subjected to a reaction with a carboxylic acid to remove the acetyl obtained.
oiom, obtained by the interaction of nit-protection with hydroxyl groups. Rila. ,
nitrile with acetic anhydride in prn i fnjLd LPL 13 ILyn -
in the presence of n-toluenesulfonic acid with

权利要求:
Claims (1)
[1]
Claim
A method of obtaining 5-cyanoprostacyclins of the general formula of cerebral pressure, etc. fifty
In addition, the target compounds possess antiponosal and antiproliferative properties. They can also be used in combination with, for example, [b-blockers, diuretics 55 and phosphodiesterase inhibitors.
The dose of the target compounds is 1-1500 mg / kg / day, if their where R) and R j are hydrogen or a methyl group, characterized in that the compound of the formula where Rj is a tetrahydropyranyl group is reacted with carbany-. obtained by the interaction of nitrile. where R, has the indicated meanings, and lithium diisopropylamide with subsequent dehydration and concomitant transesterification of the obtained oxynitrile with acetic anhydride in the presence of n-toluenesulfonic acid at room temperature and subsequent removal of the obtained acetyl protection from hydroxyl groups.

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同族专利:

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公开号 | 公开日

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IL72198D0|1984-10-31|

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ES8503348A1|1985-03-01|

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ZA844766B|1985-02-27|

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NO158874B|1988-08-01|

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FI82040B|1990-09-28|

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DK299584D0|1984-06-19|

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AU2978684A|1985-01-03|

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CS474184A2|1985-08-15|

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DE3478435D1|1989-07-06|

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FI842524A0|1984-06-21|

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HU191150B|1987-01-28|

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CS243491B2|1986-06-12|

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DK299584A|1984-12-24|

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PH22431A|1988-09-12|

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US4894391A|1990-01-16|

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AT43589T|1989-06-15|

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DE3322893A1|1985-01-03|

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NO842534L|1984-12-27|

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DD220204A5|1985-03-27|

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NZ208623A|1987-11-27|

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FI842524A|1984-12-24|

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AU562506B2|1987-06-11|

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NO158874C|1988-11-09|

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IL72198A|1987-09-16|

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EP0130142B1|1989-05-31|

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JPS6036477A|1985-02-25|

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GR82122B|1984-12-13|

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EP0130142A1|1985-01-02|

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HUT34180A|1985-02-28|

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FI82040C|1991-01-10|

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CA1252088A|1989-04-04|

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ES533642A0|1985-03-01|

引用文献:

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US7776896B2|2007-03-28|2010-08-17|Bayer Schering Pharma Aktiengesellschaft|5-cyano-prostacyclin derivatives as agents for the treatment of influenza a viral infection|

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EP1975163A1|2007-03-28|2008-10-01|Bayer Schering Pharma Aktiengesellschaft|Novel 5-cyano-prostacyclin derivatives and their use as agents for the treatment of influenza a viral infection|

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US20080242713A1|2007-03-28|2008-10-02|Bayer Schering Pharma Aktiengesellschaft|Novel 5-cyano-prostacyclin derivatives as agents for the treatment of autoimmune diseases|

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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DE3322893A|DE3322893A1|1983-06-23|1983-06-23|NEW PROSTACYCLINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND THEIR USE AS MEDICINAL PRODUCTS|

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