JPS59144756A - 8-azaprostanoic acid compound and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R<1> is n-butyl or n-hexyl; the compound is dextrorotatory or levorotatory when the 15-OH group is alpha-configuration, and is levorotatory when it is beta-configurations). EXAMPLE:l-20-Nor-15alpha-hydroxy-9-oxo-13,14(trans)-didehydro-8-azapro stanoic acid. USE:A pharmaceutical. It has excellent prostaglandin-like activities such as durable action to suppress the bronchial constriction, the hypotensive action, etc. PREPARATION:The compound of formula I can be prepared by (1) reacting the optically active 5-formyl-2-pyrrolidone derivative of formula II (R<2> is lower alkyl) with the phosphorous acid ester compound of formula III (R<3>=R<2>), (2) reducing the 15-carbonyl group of the resultant compound of formula IV to OH to obtain a hydroxy compound, (3) subjecting the obtained compound to chromatographic treatment to decompose into 15alpha-hydroxy compound and 15beta-hydroxy compound, and (4) hydrolyzing the ester group of the product.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an optically active 8-azabrostanic acid compound represented by the general formula (representing a levorotatory compound) and a method for producing the same.

The present inventors first synthesized a racemic form of the 12-position carbon atom of the compound [Tech], and discovered that this compound has prostaglandin-like effects, such as a sustained inhibitory effect on bronchoconstriction, an intestinal motility promoting effect, etc. We have found that these compounds are useful pharmaceutical compounds (Japanese Patent Application No. 17195/1983), and we have now succeeded in obtaining optically active forms of the 12th carbon atom of these compounds. An optically active substance that has a practical prostaglandin-like effect, in particular, the 15-position hydroxyl group is α-coordinated and is levorotatory.
- discovered that the product ITJ is more potent than its racemic form and completed the present invention.

The compound fQ [IJ of the present invention is a new compound. 1. It has an excellent prostaglasin-like action. ≠ Prolonged inhibition of bronchoconstriction; 11. Intestinal motility promoting Δμ effect, antihypertensive effect,
It is a useful pharmaceutical compound that has effects such as suppressing gastric acid' and secretion, inhibiting In and W interlocking effects, and promoting uterine motility.

In the compound of the present invention, the group represented by the symbol R1 is an n-butyl group or an n-hexyl group, and water at the 15th position is present. The coordination and optical rotation of the group are whether the former is α-coordinated and the latter is levorotatory, the former is β-coordinated and the latter is levorotatory, or the former is tJ! - configuration, and the latter is dextrorotatory.

The compound [IJ of the present invention] can be produced by the method shown in the reaction formula below.

10 (R30) 2P (0) CFiICOR” [11
] No.-7- (II'I ↓ [■] (However, R2 and R' represent the same or different lower alkyl groups, and R1 has the same meaning as above.) That is, optically active 5-formyl-2-pyrrolidone Derivative (
II and a phosphite compound (TID),
The carbonyl group at position 15 of the obtained V-8-di-zabrostanic acid compound (V) is reduced to give the J5-hydroxybrotan-di-zabrostanic acid compound (V), and this compound is then subjected to chromatography to obtain the corresponding 15α
After separation into a -hydroxy compound and a 15β monohydroxy compound, the target compound [■] can be produced by hydrolyzing the ester portion of this compound.

One method will be explained in detail below.

First, the reaction in the first step can be carried out by reacting compound [IT] and compound (III) in a suitable solvent in the presence of a basic reagent according to the conventional Wittig reaction method. Suitable basic reagents include, for example, alkali metal hydrides such as sodium hydrogen. The reaction proceeds smoothly at cold to room temperature, and the compound [jV
] can be obtained.

In addition, if an optically active compound derived from optically active glutamic acid is used as the raw material compound [;1J in one step, the corresponding optically active compounds can be obtained without racemization during the nine reactions.

The reduction reaction in the second step can be carried out by reacting the compound [TV] with a reducing agent in an appropriate solvent according to a conventional method for this type of reaction. As the il'ffl agent, for example, t hasodium borohydride is preferred. The reaction proceeds suitably even when cooled, and the compound [v] can be obtained in low yield.

The compound (V'l) obtained here is a mixture of a highly polar compound and a weakly polar compound. Among these, compounds with strong polarity (for example, compounds that flow out later in silica gel column chromatography) are called 15α-coordinated compounds, and compounds with weak polarity (
For example, the compound that flows out first in silica gel column chromatography is called a compound with -115β-coordination. Separation of this mixture can be carried out using separation means such as chromatography.

In the subsequent third step, the hydrolysis reaction, the compound (
Preferably, this is carried out by reacting a Vat alkali. Suitable examples of the alkali include sodium hydroxide and potassium hydroxide.

The reaction proceeds smoothly even when cold, and the target compound [■]
can be obtained.

The raw material compound [II] can be obtained by, for example, converting a compound represented by the general formula (wherein R2 has the same meaning as above) with chromic anhydride-pyridine into an acid.

Thus, the compound of the present invention (1M) can be used as a medicine as it is as a free acid, or it can be used in place of a suitable salt that can be used as a medicinal drug. Examples of such salts include sodium, potassium,
Salts of alkali metals or alkaline earth metals such as calcium, ammonium salts, quaternary ammonium salts such as tetramethylammonium salts, methylamine, cyclopentylamine, benzylamine. Examples include salts of organic bases such as piperidine, monoethanolamine, and triethanolamine. As for the administration method, it is administered orally or parenterally in an appropriate dosage form such as a single powder tablet, capsule, solution, emulsion, or suspension.

Examples of the results of testing the chemical effects of compounds (IIO) are as follows.

Experimental example 1 Whether or not to suppress the increase in intratracheal pressure due to bronchodilating histamine-11
− Tested by

Urethane anesthesia (1 to 1.5 SI/Kg, K, P,) L,
Galamin (5ηIr/9i, V, l to guinea pigs (male 0 weight 280-350F) that suppressed self-respiration.
Artificial respiration was performed at a constant ventilation rate, and the intratracheal pressure was recorded over time, and at the same time as r0, the pressure from the carotid artery to the artery was also recorded. The surgical sequence was urethane anesthesia - artificial respiration - gallamine administration.

The effect of pre-administration of the specimen on the transient increase in air and bone levels caused by administration of histamine (2-44/Kg, i, v, ) was examined.
+) was administered into the femoral vein (1, v, l).

TP body throw is after 1, 115+, 21 juices... and 1
Throwing histamine in the corner for 0 minutes. The contraction rate 10Q is the increase in histamine (e.g. trachea) before sample administration.
<, knocking suppression rate 0%, even if histamine is administered, internal L
When no increase occurs, the suppression rate is set to 100 and is displayed as follows.

Suppression rate: 100 to 80 + 80-50 curses 50~10 Curse”- 10~　0　%　- The results are shown in Table 1.

Table 1 *(Specimen) (same as below) Control compound A Nibrostaglandin E1 Invention compound B: f-20-/Rue 15 (1'-hydroxy-9-oxo-13,14(trans)-didehydro- 8-dizabrostanoic acid C: l!-20-true 15β-hydroxy-9-13
- Oxo-13,14(trans)-didehydro-8-azabrostanic acid rl:/-15α-hydroxy-20-methyl-9-oxo-13,14<<rance]-didehydro B-y zabrostanoic acid g:/- 15 (Ill no hydroxy-20-methyl-
9-oxo-13,14()lance)-didehydro-8
-Dinozabrostanoic acid F: d-15α-hydroxy-20-methifure9-oxo-i3.14()-didehydro-8-azabrostanic acid Specimen preparation method Dissolve the specimen in 99.5<ethanol and store.

It was diluted with physiological saline before use. The ethanol concentration of the administered solution did not exceed 1<1, and no particular effect was observed when using only the 1-width ethanol solution. In addition, sometimes a sample dissolved in physiological saline in the presence of an equivalent amount of sodium bicarbonate was used (hereinafter referred to as "interval").

Experimental Example 2 Mice (ddY strain, male) weighing around 20 g were fasted for 4:14 p.m., and 0.5% carboxymethyl cellulose powder was orally administered to them (4rR9/20!7), and at the same time the specimen was intraperitoneally administered. Administer internally. Ten minutes later, the body was slaughtered and disemboweled. Measure how far the charcoal powder has traveled within the intestinal tract. The distance from the pylorus to the caecum is expressed as (.

Table 2 *(Sample) Control Compound G Nibrostaglandin E2 Example 1 (1) Under nitrogen gas stream) IJium hydrogen (6 in mineral oil)
5<) 205WII was suspended in 33 cm of dimethoxyethane, and to this was added a solution of 1.525 i of 2-oxooctyl dimethyl phosphite in 6 m/dimethoxyethane while cooling with ice water, and stirred at the same temperature for 10 minutes. After removing the cold bath and stirring at room temperature for 15 minutes.

Cool again in ice water. There, l-1-(6-medoxycarbonylhexyl)-5-formyl-2-pyrrolidone [
[α]〒-2.3° (C=2.04.Ethanol) 31
．． A dimethoxyethane 6-solution of 49y was added dropwise, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1.5 hours. Ether 50- is added to the reaction solution, washed with a saturated aqueous solution of ammonium sulfate, and dried. The solvent was distilled off and the residue (approximately 2.3P) was subjected to preparative thin layer chromatography (11-way gel; ethyl acetate:
Separate and purify with benzene-4=1), /ni9.15-
1.49 y of dioxo-20-methyl-13,14()-didehydro-8-azaprostanoic acid methyl ester is obtained as a pale yellow liquid. Yield 7166%.

IRν11q (ci'): 1735.1690.1
700°635 NMR (CDCII l (ppm): 0.8
-2.6 (271), 2.85-4.40 (3H), 3
．． 69(3H,8,0-C1(II), 6.30(1
1(,d,J=16.2゜4Y3.6.67(]H
, d of d , J = l 6,2 and 7.4°, 0 (2) Under a nitrogen gas flow, add carbon tetrachloride and sodium borohydride to a solution of 1.455' methanol in 60 m/solution under a nitrogen gas flow. Add 0.24 F of hydride and stir at the same temperature for 50 minutes. The cold bath was removed, and the temperature was allowed to rise naturally until the internal temperature reached 0°C. Then, the reaction mixture was poured into about 180 m of ice water, saturated with ammonium sulfate, and extracted with acetic acid. The extracted layer is washed with saturated ammonium sulfate and dried.

The solvent was distilled off to obtain 1.35 g of /-15-hydroxy-20-mthyl-9-oxo-13,14 (1-lance snodidehydro-8-tinozabrostanic acid methyl ester).

Quartz is a mixture of stereoisomers regarding the 15-position hydroxyl group. Bleparate thin layer chromatography (silica gel: solvent, ethyl acetate; benzene; methanol = 8:
1:1) to separate and purify 1-15/lI-hydroxy form 591~ (yield: 40.5 width) and 1-15
β-hydroxy compound 661η (yield: 45.2%) is obtained.

All are colorless liquids, I R, N M R, Ma
The data of gs is the same.

11q, -s.

I Rl', [lax (cm), 3440.1735
．． 1665NMR (CDCII, ) (ppm)
: 0.8~2BC27H), 2-7~4,3(4H)
, 3.67 (3H,s, -0-CHs), 5.
53-5.72 (2H, y-in Mass m/e: 3
67 (M"1-1?- Add concentrated hydrochloric acid to make the liquid acidic, take the precipitate and dry it to obtain coarse powder 47B" = 9. Recrystallize the crystals from ethyl acetate. Ba!-150-hydroxy-2
0-Methyl-9-2rxo-13,14(trans)-
4. Didehydro-8-azabrostanic acid as colorless needle crystals. To OO1? obtain. mp, 114~llb':+
Yield 75%.

[α] -5,6° (C=10.ethanol) I R
vNujol (cm-'): 3150-2500.1
725°1klX 66O NMR (CDCl3) (ppm): 0.8-2.
5(27H), 2.8-4.3■ +41 1-15β-hydroxy compound obtained in 121 598
η, 20<hydrous soda aqueous solution 5.52 and methanol 8
．． 5 m/ solution was treated in the same manner as in (3) to obtain /-15
β-hydroxy-20-methyl-9-oxo-13,1
4()lance)-didehydro-8-azabrostanic acid is obtained as colorless needles of 280 η. mP.

82-83°C, yield 48.7<.

-1!1- [13% -28,oo (C=0.5, ethanol) crystal (7) IR, NMR, Mags data are (
3) l-15Q! -It is the same as that of the hydroxy form.

Example 2 It was carried out in the same manner as in Example 1.

(lid-1-(6-medoxycarponylhexyl)-
5-formyl-2-pyrrolidone[α]24.5+2.
2° (c=2.25.ethanol)]1. Oy, 65 regret sodium hydrogen 133'? , 2-oxooctylsulfite dimethylene ester 1.02F and dimethoxyethane 3
0-, ci-9,15-dioxo-20-methyl-
13,14()lance)-didehydro-8-azabros monotonic methyl ester as pale yellow liquid 1.051F
obtain. Yield 73.2%.

The I RIN M R and Mass data of the crystal were obtained in Example 1-(1)! It is identical to those of one body.

(2) Crystal 955'4. Sodium borohydride 160■
and 401 rll of methanol to obtain 950·η of d-15-hydroxy-20-methyl-9-oxo-13,14(trans)-didehydro-8-azaprostanoic acid methyl ester.

Separate and purify the crystal to obtain the d-l 5α-hydroxy form as a colorless liquid. Yield: 40.1%.

The IR, NMR, and Mass data of the crystal are shown in Example 1-
At T21, it was 7 @ I one, '7] Sowa, et al. and 1 Tsukasa.

In addition, 4261 grams of d-15β-hydroxy form were obtained. Yield: 44.3.

+31d-15 to monohydroxy-20-methyl-9-oxo-13,14()-didehydro-8-azabrostanic acid methyl ester 3481~. A coarse powder of 255'trg was obtained from 3++t/20% aqueous sodium hydroxide solution and 4°5-t/methanol. When crystals are recrystallized from ethyl acetate, rl-15α-hydroxy-20-methyl-9-oxo-13,14(trans)-didehydro-8
-Azabrostanoic acid 231-9 was obtained as colorless needle crystals. mp, ] I 5-117°C, yield 69 (.

(o!]',, +5.6°CG=1.0.-1tanol) Crystal (7)I R, NtJR, Mass data were obtained in Example 1-(3)! It is identical to those of one body.

-2111 Example 3 The same straining as in Example 1 was carried out.

(1)/-]-(]6-medoxycarbonyl-
From 1.862 F of 5-formyl-2-pyrrolidone, 256.1 η65 sodium hydrogen, 1.679 η62-oxo-hexyl phosphite dimethyl ester and 6 ml of dimethoxyethane E, 1'-20-i-9.15-dioxo-13 , 14()-didehydro-8-azaprostanoic acid methyl ester as a colorless liquid 1. , f
i get 9g. Yield 6 g, 0<.

- Mass m/e: 337 (M) (2) Crystal 1.57! F, sodium borohydride 0.287 and methanol 70-, /-20-fluor-15-hydroxy-9-oxo-13,14()lance)-didehydro-8-tezabrostanic acid methyl ester as a colorless liquid 1 .511! /? I.

Separate and refine the crystal, 1-150! -Hydroxy form 60
0g (yield: 38.1<) and 580 ~ (yield: 36.8%) of 1-15βJ-hydroxy derivatives were obtained.

All are colorless liquids, I R, N M R, Ma
The data of ss22- is the same.

I RI', e, e'・(rFFn',): ,'(
400, 1735, 1f] 9ONMR (f city 1c13
) i ppm ) :
0192 (3F, no, C-CHa).

1.15-2. fi4 (20H), 2.67-4.
35(,↓H), 3.7Q(3J s.

0-Cf(3), 5.68 (2”, 'f'\]
Mass m, '8: Knee (:3 9 (
IJ”) (3) e-15ff-human o+cy body 384”
9.20 Gastric soda aqueous solution 3d and methanol 6ff
From +/, /-20-ノ” -15a!-hi M I:
I xy, g-oxo-13, I4(trans)-
Didehydro-8-esterbrostanoic acid is obtained as a colorless prism.

mT 1.55-57°C, yield 95.3<,.

[α] 5.9° ((: =2.0, etal/-l) I RL' ll,, (cm), 3600-230
0.1705°1665.975 NMR(CDCl5) (ppm
l: 0.91 (3H, e-CHs).

1.1-2.5 (201-4), 2.85-4.3
5 (4H), 5.66C2tl wood)Masur
n/θ 2 3 2 5 (M - t) +4.
) (1-15β-hydroxy compound obtained from 2+ 461°5wTg, 20% sodium chloride 3- and methanol-
-23- From rule 6- a l! -20-True 15β-hydroxy-9-oxo-13,14()lance)-didehydro-8-γ Zabrostanoic acid as pale yellow adult product 353.
can be obtained. Yield 79.8<.

[Gsuπ -26,3° (C-2,0, ethanol) I
R', 4X%'(cm-') 3300-230
0.1725+660 The data of NMR and Masn of the defective item is (3) I!
It is the same as the -15α-hydroxy form. .

515-

Claims (1)

[Scope of Claims] (1) General formula (where R1 represents an n-butyl group or n-hexyl group, and when the hydroxyl group at the 15th position is in the a-coordination, it is a dextrorotatory or levorotatory compound, When the hydroxyl group at position 15 is in β-coordination, it indicates a left-handed compound. 7'Kel (2) The 8-tezabrostanoic acid compound according to claim 1, wherein in the general formula [IJ, R1 is n-=Koreitsu group. (3) The 8-azapro2-stanoic acid compound according to claim 1, wherein in the general formula [IJ, R1 is an n-hexyl group. (4) The 8-azabrostanic acid compounds according to claims 1 to 3, which are levorotatory isomers. (5) The 8-tezabrostanoic acid compound according to claims 1 to 3, which is a dextrorotatory isomer. 113) 15 ('l' isomer) Claim 1
8-Rosebrostanoic acid compounds according to items 5 to 5. +7) The 8-diabrostanic acid compound according to claims @1 to 4, which is a 15β isomer. 7. The compound according to claim 6, which is +81/-20-true 15α-hydroxy-9-oxo-13,14()-didehydro-8-rezabrostanoic acid. 8. The compound according to claim 7, which is (9)/-20-true 15β-hydroxy-9-oxo-13,14←trans)-didehydro-8-tezabrostanoic acid. 11υ l-]5α-hydroxy-20-methyl-3
- 9-oxo-13,14 (transnodidehydro-8
- The compound according to claim 6, which is dizabrostanoic acid. fil) I! -15β-hydroxy-20-methyl-9
-Okin-13.14(trans)-didehydro-8-
8. The compound according to claim 7, which is zabrostanoic acid. Q21 d~15Q! ~Hydroxy-20-methyl-
9-oxo-13,14()lance)-didehydro-8
- The compound according to claim 6, which is Zabrostanic acid. (+, 3) An optically active 5-formyl-2-pyrrolidone derivative represented by the general formula (where Bt represents a lower alkyl group) and the general formula % formula % [111] (where R1 is an n-butyl group or n- 11. Saliva phosphoric acid ester represented by a hexyl group, and ♂ represents a lower alkyl group. The carbonyl group at position 15 of the 8-azabrostanoic acid compound is reduced to a hydroxyl group to obtain the corresponding hydroxy compound.Then, this compound is separated into the corresponding 15α-hydroxy compound and 15β-hydroxy compound by chromatography. A general formula characterized by hydrolyzing the ester moiety of a compound (However, when the hydroxyl group at the 15th position is α-coordinated, it is a dextrorotatory or levorotatory compound; In some cases, it represents a levorotatory compound, and R has the meaning as defined above.