JPS58150575A - Novel prostaglandin derivative - Google Patents

Abstract

NEW MATERIAL:The prostaglandin derivative of formulaI(X is O or S). EXAMPLE:(12S,15S)-(+)-S-Aza-10-thia-11-deoxyprostaglandin E1. USE:A bronchodilator. PROCESS:The compound of formulaIcan be prepared by (1) oxidizing the compound of formula II (R is lower alkyl), (2) subjecting the resultant compound of formula III to Wittig reaction with the compound of formula VI to obtain the compound of formula IV, (3) reducing the product to the compound of formula V, and (4) hydrolyzing the product. The compound of formula II is also new substance, and can be synthesized by (1) esterifying cysteine or serine, (2) reacting with phosgene in the presence of a base, (3) reducing the resultant thiazoline derivative, (4) protecting the hydroxyl group of the product, (5) N-alkylating the compound in the presence of a base, and (6) eliminating the protecting group of the hydroxyl group.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a prostaglandin conductor represented by the main formula (1).

IH (In the formula, X means 8) The prostaglandin derivative represented by the general formula (1) of the present invention is a new compound, and is produced, for example, by the method shown below.

(In the formula, X means the same as above, and R means a lower alkyl group) In the reaction formula, compound (1) is a new compound,
It is synthesized from cysteine or serine by the method shown below.

(Method A) (■ Ri
(Vl+)CHs (in the formula, X and Rti have the same meanings as above) Compound (v4) is esterified with alcohol in a conventional manner, for example, to obtain compound (■).
Compound (1) is obtained by N-alcoholization in the presence of a base such as sodium hydrogen carbonate, pyridine, etc. and a base such as sodium hydride, and then removing the hydroxyl group in accordance with a conventional method.

( Method B ) (
- After forming the alkyl compound, the compound is cyclized by reaction with phosgene in the same manner as the method, followed by reduction to obtain the compound.

In Method A or Method B, the starting materials are cysteine, serine! The lower alkyl esters of circles are used, but by using optically active cysteine or serine as starting materials, thiazolidines or oxazolidines obtained by reaction with phosgene are both optically active forms. It is. Note that even in the final product, compound (1) of the present invention, these optical properties are maintained as they are.

The compound of the present invention thus obtained has a bronchodilator effect and is useful as a medicine.

a) D-cysteine salt rf1 salt hydrate 4f was dissolved in 100 dl of methanol, hydrogen chloride gas was introduced for 10 minutes under water cooling, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure to obtain a colorless crystalline residue 3.911. This crystalline residue $3.91
1, 6.3 f of sodium hydrogen carbonate, 45 d of water, and 3 o of chloroform, 15 m of toluene was added under water-cooling and stirring.
Add nine phosgene'L52 little by little and cool for 20 minutes under water cooling.
Stir for a minute. The remaining phosgene was removed, the chloroform layer was separated, washed with saturated saline and sulfuric acid), dried over IJum, and the solvent was distilled off under reduced pressure. Methyl (8) -C+) - in chloroform:methanol (10:1)
2-oxothiazolidine-4-carboxylate (■1
).

■ 几spectrum 611-”: 3270, 174G
.

1680.121O NM Spectrum J: 166 (2H, m), X7
1 (3H.

s,, ), 4.51 (IH, dd, J-7,,
2,5Hz>, 7.05 (IH,s) Mass spectrum"/,: 161(M"), 102((
)”j+49.8°(0=lOJtOH)b) Methyl(
8) -(+) -2-oxothiazolidine-4-carboxylate (ms+) 173ft ethanol 50sd
0.77ft of sodium borohydride dissolved in water and cooled with water.
-Add little by little and stir for 1 hour while cooling with water. 10x
Salt! After adding IIt, the solvent was distilled off under reduced pressure, and the residue was extracted with ethyl acetate. After drying with sodium sulfate, the solvent was distilled off under reduced pressure and the resulting oil was subjected to silica gel column chroma, Togelafy (solvent chloroform: ethanol-10
:1) for purification. This was recrystallized from ethyl acetate to produce needle-colored prism crystals (8) with a temperature of 1015 to 104.5°C.
1.73 ft of -(+)-2-oxo-4-hydroxymethylthiazolidine (lXg) is obtained.

IR spectrum ts, 3250.164ON114
Spectrum: 11-4.1 (51 (, 憔), 4.7
4 (2H, sung) Max
) D+0.8@(0-LO, gtOH)c) (8)
-(+) -2-Oquino 4-Hydroxymethylthiazolidine (Km) L42 t, ethyl vinyl ether 5.1d,) Riff Shitoko acetic acid 0.14r and dimethoxyethane 20df) Acetic acid after stirring the metal metal for 6 hours at room temperature. Extract with ethyl. Ethyl acetate was washed successively with aqueous sodium bicarbonate solution and S saline solution, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance (0(a)1).
Get 18F.

I RX vector txt, 3250.168ON
M Rx Hel) Lua: 120 (3H-t
) *l-3i(3Hsd), 3.0~3.9(5
H, m), 4.03 (2H, q), 4.76 (IH
, q), a59(IH, s) A suspension of d was added dropwise on ice-cooling in a nitrogen gas stream. 1 at room temperature
After stirring for an hour, cool with water again, and dimethylformamide (ethyl 7-iodobutanony) 3.32F (lOIILl).
Add # solution and stir at 55°C for 15 hours. Pour into 50 d of ice water and extract with ethyl acetate.

Wash the ethyl acetate layer with saturated saline, dry with sodium sulfate 4
After that, the yellow oil obtained by distilling off the solvent under reduced FOE was purified by silica gel column chromatography (solvent: benzene: ethyl acetate - 5:1) to obtain compound Ofim) 3.57f as a pale yellow oil. .

I RX pect km, 1730.168 ONMR spectrum: L21 (3H,t), 1.26 (3H.

t), L33 (3H, d), L4 (8H, br)
, 2. ．． 30 (2H, t), 19-19 (9) (, m
), 415 (2H, q).

4.76 (IH,Q) C) Compound OIN) &57f was dissolved in a mixture of 350 d of p-toluenesulfonic acid and 50 d of ethanol at room temperature.
After stirring for an hour, the solvent was distilled off under reduced pressure and the resulting residue was dissolved in ethyl acetate. Dissolved, washed sequentially with saturated aqueous sodium bicarbonate and saturated brine, dried over sodium sulfate, and distilled off the solvent under reduced pressure to obtain ethyl (8)-(+) as a pale yellow oil.
-7-(4-Hydroxymethyl-2-oxorenazolidine)heptanoate (厘a)2. ．． Obtain 671F.

■ R spectrum has a 3450e1730°16
8G, , 165O NMR spectrum δ: 1-26 (3H,t),
1.4 (8H, br), 130 (2H, t),
2. 'J-19 (8H, s).

4.14(2H,q) Mass spectrum”/’: 289(M+), 212(El
)", 7+ 42.5" (0-10, i?tOH)
f) Compound (Ia) 1489, dicyclohexylcarbodiimide 5.31? , pyridine 0.7t/
,) A mixture of 33 MI of rifluoroacetic acid, 13 of dimethyl sulfoxide, and 13 rxl of benzene is stirred at room temperature under a stream of argon gas for 13 hours. After separating the non-@#Bt-F, the P solution is washed with saturated saline. @IIE acidsu) I
) After drying with a ram, the solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (solvent: benzene:
Ethyl (8) -(+) -7-(4-formyl-2-oxo-3-thiazolidine)heptanoate (Table a) 131
Obtain 1F.

I&xbec) le;i1:1730.1675N
MR spectrum: 1.26 (3H,t),
1.4 (8H.

br), 2L31(2H,t), 3.0-19(
4H,s).

4.15 (2H, q), 4.80 (IH, br), 9.
78 (IH.

d, Jsw2Hz) Mass spectrum”/: 287 (M+), 212 [
α〕. +264” (0-1, OJtOH) 60%
Sodium hydride 1951! dimethyl(2-oxoheptyl)phos-7onate L 08 f suspended in 50% of tetrahydrofuran under a nitrogen gas stream and water-cooled.
1 dissolved in 20ml of tetrahydro7ran t-
After dropping, the mixture was stirred at room temperature for 1 hour, and finally at 50°C for 10 minutes. The mixture was cooled again on ice, and a solution of compound (■a) dissolved in 1°1ft of tetrahydrofuran (20d) was poured down. 1 at room temperature
After stirring for an hour, the medium was completely distilled off under reduced pressure. The residue is extracted with dichloromethane and washed with saturated brine. Sulfuric acid) Oil obtained by distilling off the solvent under reduced pressure after drying with IJum Silica gel column chromatography (solvent benzene: ethyl acetate - 10:1) K slightly colored oil ethyl (8)
-(+)-7-(4-(3-oxo-trans-1-octenyl)-2-okino-3-thiazolidine]heptanony) (1/a) 910 wg is obtained.

IR spectrum am-”: 1730, 168 O
NMR spectrum J: 0.89 (3H, t), 1
．． 24 (3H.

t), 1-4(141(,br), 129(21,t)
, 2.59 (2H, t), 3.05 (21 (, s), 3
．． 50 (2H, t).

4.13 (21 (, Q), 4.35 (li (, 嘱), Kaishadera Village 〒6.25 (IH, d, J=16 [(g), 6.76 (IH, dd)
, J-7, 16Hz) Mass spectrum 19/: 383 (M+), 238 [α]
. +55.2@(0-LO,gtOH)h) Compound (N
a) Add sodium borohydride 83119 to a 695 Ilv ethanol 25d bath solution under ice cooling and stir for 20 minutes under ice cooling. Residue F obtained by adding 10% hydrochloric acid and distilling off the solvent under reduced pressure! ! After drying over +7 μm, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel pre-validation TLO (thin layer chromatography). Additionally, a more polar compound (Va-1) than the solvent benzene:ethyl acetate-3:1) and a less polar compound (v+++
-1) Obtained at 290 R91.

・Compound (Va-1) IFL spectrum tym, 3450.1730.16
7ONMR spectrum: 0.88 (3H,t)
, 1.23 (30°t), 1.4 (16H, br
) , 2.27 (2H, t) , 2.35 (11-1,
i), 176-156 (5H, inertia), 410 (2H
.

q), 4.25(ll-1,br), 5.38~5
．． 82 (2H, alcohol) Mass spectrum: 385 (M”)
, 212 [α] + 45.3” (0 cabinet LO, NtOH)
・Compound (Vm-1) I RX pect ktym, 3450.1730.1
66ONMR spectrum J: 0.9G (3H, t
), 1.25(3)L@), 1.4(16H,
br), 2.30 (2H, t), 2.45 (IH-→,
2.80=160 (5H, s), 4.12 (
2) Lq).

430(It(,br), 5.41-5.86(2H
, fable) ma x : x he/ ) le m/: 385 (M
”) + 367 [α), + 212' (0-LO,
R10H) 1) Compound (V!l-1) 23 g '1
14? (r) engineering fi/-le 4.5- solution under ice cooling 2
After adding N sodium hydroxide water α46dt-, at room temperature
, stir for 5 hours. The residue obtained by distilling off the solvent under reduced pressure is dissolved in water, made edible with 10% shiochi, and then extracted with ethyl acetate. The ethyl beak layer was washed with Japanese brine, dried over sodium sulfate, and the solvent was distilled off under reduced pressure to obtain crystalline (12
, s, i 58) -(+) -8-aza-10-thia-11-deoxyglostaglandin gl (Iho-1)
218~t-obtain.

Melting point: 93-94°C (recrystallized from ethyl acetate-hexane).

IR spectrum I21+, 3600-2400.

1730.164O NM 几spectrum J: Q, 89 (3H, t L
1.4 (16H.

br), 2.32(2H,t), 172-3.62
(4H, s).

4.04-4.36 (2H, s), 5.64-5.8
9 (2H, sacrifice).

6.09 (2H, s) Mass spectrum”/:357 (F/), 86 [a] D
+4&6” (0-1,0JtO)f)j) Compound (V
a-2) 176M9, 2N sodium hydroxide water 0
．． Crystalline (128,15R)-(+)
-8-af-10-thia-11-deoxyprostaglandin Il (1 g-1) 160~ is obtained.

Melting point: 70-71°C (recrystallized from vinegar, ethyl-hexane) IR spectrum: 3600-2400°1730.
164O NMR spectrum: o, 90 (3H,t),
1.4 (16H.

br),! 33(21(,t), 2.70~3.6
0(4H,s).

4.04-4.38 (2H, s), 5.65-5.9
0 (2H, lead.

5.98 (2H, s) Mass spectrum: 357 (M+), 8g [α)'', ' 4215 @ (0 trout LO, pull OH) Conducted M 2゜L-cysteine was used as the output I substance and the following was carried out Treated in the same manner as in Example 1, (12115B)-(-)-8-aza-10-+
7-11-7' Oxybu tetrastagrange 7B*(Ib-
s) and (121158)-(-)-8-aza-10-thia-11-deoxyprostaglandin 81 (1b-
z).

recrystallized from IfL spectrum i'': 360G to 240G.

1730.164O NMR spectrum a: 0.90(3H,t), 1
．． 4 (16H.

br), 134(2H,t), 2.68-3.70
(4H, s).

4.05~4.37 (2H, wa), 5.67~
5.92 (2H, Ant).

6.03 (21-1, Crow) Mass spectrum: 357 (M+), 212 [α)”
7-4a5@(0-LO,gtOH)01'I Melting point 72-73℃ (recrystallized from ethyl acetate-di-hexane) IR spectrum scratches, 3600-2400゜1730.1
64O NMR spectrum J: α90(31(,t), 1.4
(16H.

br), 2.35(2H,t),! 72-3.6
2 (4H, s).

4.07-4.40C2H, 5.66-5.91
(21(,嘱).

5.74(2)(,s) Mass spectrum %: 357(M”), 86[α)”,
' -213@(0=LO, gtOH) Example 1 (χ1llc) (uc)a)6
-Nitoxycarponylhexanal 1B, 4f.

DL-serine ethyl ester filtrate 1&14 and hydrethylamine 11dt-360- were dissolved in ethanol and stirred at room temperature for 30 minutes, followed by 1096 palladium-carbon 29f.
In addition, contact reduction occurs. (Consuming 1.941 hydrogen gas in 25 hours) Insoluble matter eF was separated, the solvent was distilled off under reduced pressure, and the resulting residue was dissolved in dichloromethane and washed successively with saturated aqueous sodium bicarbonate and saline solution. After drying over sodium sulfate, the solvent was distilled off under reduced pressure, and the resulting oil was subjected to silica gel column chromatography (solvent: chloroform:ethanol-10:1) to obtain ethyl N-(6
-nitoxycarbonylhexyl)seline-) ()I
c) 1 5.6 IP? Good, see.

■ 几spectrum ffl': 3400, 1735.11
9ONMB spectrum It: L24(3H,t),
1.28 (3H.

t), 1.4 (8H, br), Z29 (2H, t
) , 2.60 (2H, br) , 169 (2H, s
), 121-3.49 (IH.

s), 160-3.82 (2H, m), 414 (2
H,q).

421 (2) 1.4) Mass spectrum: 29G (M+1), 288 (M-1
).

216 b) Compound □Ic) 11.56 f, pyridine 6,
329 was added dropwise to 120 x g of toluene, and a solution of 4°5 t of phosgene dissolved in 40-g of toluene was added dropwise under water cooling. After stirring for 30 minutes under water cooling, insoluble matter is separated, washed with saturated saline, and dried over sodium sulfate. The oil obtained by evaporating all the solvent under reduced pressure was subjected to silica gel column chromatography (solvent: benzene: ethyl acetate - 4 = 1) to give a pale yellow oil of ethyl 7-(4-ethoxycarbonyl-2).
-oxo-3-oxazolidine)heptanoate 001
1c) Obtain Q, 12 f.

■ Ordinary spectrum ear, 1760.1735.
1205fMRX vector 1t24 (3H, t), t3
1(3H,t), 1.4(8H,br), 2.3
0(2H,t).

3.30 (2H, m), 4.15 (2H, q), 4
．． 28 (2H.

q), 440 (3H, br) vxx Bec)le"/:315 (M"), 196C) Compound (Xllc) 8.58 ft Dissolved in 250 yards of ethanol and cooled with water in sodium borohydride 1.24
F was added little by little, and the mixture was stirred for 1.5 hours under water cooling, and then the solvent was completely distilled off under reduced pressure. Add a small amount of water to the residue, extract with ethyl acetate, wash with saturated brine, and dry over sodium sulfate. When the solvent was distilled off under reduced pressure, a pale yellow oily substance, ethyl-7-(4
-Hydroxymethyl-2-oquino-3-oxazolidine)heptanoate (jc) 7.12 ft- is obtained.

I Spectrum cm * 543o, t7so.

1730.1260.119O NMI (spectrum J: 1.25 (31-1, t
), 1.4(8)(.

br), 2.30 (2H, electric) = 3.20
(2H,s), 3.55(IH,s), 3.63(
2H,br), 3.95(IH,s).

4.13(2H,q), 4.31(2H,s) mass spectrum Iy: 273(M'), 196d) Compound (
Ic) 5.46 t, dicyclohexylcarbodiimide 12.38f, pyridine 1.62m/,) refluoro vinegar 1110.77M1. dimethyl sulfoxide 3
A mixture of 0d and benzene 30d is stirred at room temperature under a stream of argon gas for 14 hours. After removing all insoluble matter, wash with water and dry with sodium sulfate. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (solvent benzene:ethyl acetate 1:l) to obtain ethyl 7-(4-formyl-2-oxo-3-oxazolidine) as a colorless oil. Hebutanoate (Seal c) 40f is obtained.

IR spectrum txi, 1750.173ONMI
'L spectrum δ: 1.25 (3H, t), 1.4 (
8)(.

brLλ30 (2H, t), 3.25 (2H, br),
4.14 (2H=q) * 4.30 (3H-b
r) -9,75 (IH, d 1J-2Hz) -qxxvep Tor m/:271 (M+) 1196e)
Suspended in 60% sodium hydride 1.07 f if tetrahydro 7 run 200s+7 and dimethyl-2-oxoheptyl 7 male 7 onate under ice cooling in a stream of chlorophyll gas.
95f'150m dissolved in tetrahydrofuran was added dropwise and stirred at room temperature for 1 hour and at -50°C for 15 minutes. Cool again on ice and compound (LIC) 3°639'f-50
+E/ dissolved in tetrahydrofuran is added dropwise. After stirring at room temperature for 1 hour, the reagent was distilled off under reduced pressure. Dissolve the residue in dichloromethane, wash with saturated saline, and dilute with sulfuric acid)
After drying with IJum, it was subjected to Jooh Roux 9:1) to give a slightly yellow oily substance, ethyl 7-[4-(3-oxo-trans-
1-octenyl)-2-oxo-3-oxazolidine]
(Me) 1.67 gold obtained.

IR spectrum image! 750.1735°1680.
1635 NM Lux vector δ: 0.90 (3H,!),
1.24 (3H.

t), 1.4 (14H, br), 2.29 (2H, t
), λ60 (21-I, t), 3.20 (2H, sacrifice),
4.12 (2H, q).

4.40 (2H, call), 4.00 (IH, +a) Ma
X Heku) k”/: 367 (M”), 222f
) Compound (II/c) 45211 p'i Dissolved in 20 yd of ethanol, added 56~ of sodium borohydride at -15°C, stirred at the same temperature for 40 minutes, and then dissolved in 10% salt #! Add. The oily substance obtained by distilling off the solvent under reduced pressure was subjected to Prevalatep TLO (silica gel, solvent chloroform:ethanol - 30:1) to obtain a colorless oily compound (Vc-1).
150M11 and the compound as a colorless oil.

(Vc-1)17359 is obtained.

・Compound (Vc-s) ■ 几spectrum tx, 3450.1750.17
35NMR spectrum: 0.90 (3H,t)
, 1.25 (3H.

t), 1.4 (16H, br), 2.29 (IH,
s), 2JO(2H,t), 3.14(2H,s)
, 3.96 (2H, s).

4.13 (2H, q), 4.37 (2H, Tsumugi), 5.
61-6.08 (2H, m) Mass spectrum"/: 370 (M+1), 172 compound (Vc-2) IR spectrum ex, 3450, 1750.1735
N M R: x to l ) Le J: 0.90 (3H, t)
, 1.25 (3H.

t), 1.4 (16H, br), 2.30 (2H,
t) , 2.62 (IH, a) , 114 (2H, *)
, 3.96 (2H, s).

4.13 (2H, q), 4.37 (2H, s
), 5.61-6.08 (2H1 sacrifice)? X
Compound (Vc-1) 14 G'lft' Dissolved in 3 MI of ethanol and diluted with 0.3 2N sodium hydroxide solution under water cooling.
- was added, and after stirring at room temperature for 2 hours, the solvent was removed under plate pressure.

The residue was acidified with 0% hydrochloric acid and extracted with ethyl acetate. After washing with saturated brine and drying over sulfuric acid, the solvent was distilled off under reduced pressure to obtain a crystalline residue 128I9. This was recrystallized from ethyl acetate exohexane with a melting point of 53~
Colorless needle-like crystals of compound (le-1) are obtained at 54°C.

I RX vector ffi 63600~2500
.

1750.173O NMR spectrum δ: 0.89 (3H, t), 1.4 (
16H,br), 2.33(2H,t), 3.
13 (2H, s).

3.82-4.56 (4H, +%), 5.60-6.0
8 (2H, s).

6.32 (2H,s) Mass spectrum: 342 (M+1), 252h) Compound (Vc-z) 170a9t Ethanol λ7- and 2
Compound (Ic-1) 1501111 with a melting point of 56-58°C was treated in the same manner as in Example 3g) using 0.37 ml of IJum water (N hydroxide). Get 'fr.

I RX vector am, 3600-2500.

1750.173O NMR spectrum δ: 0.90 (3H, t), 1.4 (
16H.

br), λ33(2H,t), 3.13(2H,m)
, 3.82-4.56 (4H, 嘱), 5.60-6-0
8(2)1. (worry).

5.98 (2H, s) Mass spectrum ffl/: 342 (M+1),
196 Applicant Chugai Pharmaceutical Co., Ltd.

Claims (1)

[Claims] A prostaglandin derivative represented by the general formula (wherein X means 0 or s).