JPS607618B2 - 8-Azaprostanoic acid compounds and their production method - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an 8-azaprostanic acid compound represented by the general formula (where RI represents an alkyl group having 7 to 10 carbon atoms) and a method for producing the same. The present inventors previously discovered that a compound in which the group represented by the symbol RI of compound [1] is an n-pentyl group is useful because it has an excellent brostaglandin-like effect, such as a gastrointestinal motility promoting effect and a labor promoting effect. We discovered that it was a medicinal compound and applied for a patent (Japanese Patent Application No. 72,614/1989).We have now synthesized homologues with an even greater number of carbon atoms, and these compounds are more effective than the above-mentioned compound or prostaglandin E. It was discovered that it has a significantly superior prostaglandin-like effect. At the same time, they also succeeded in obtaining optically active forms at the 12th and 1g positions, confirmed that three of these optically active forms had similar effects, and completed the present invention. The compounds [1] of the present invention are all new compounds, and have excellent prostaglandin-like effects, such as sustained suppression of bronchoconstriction, intestinal motility promotion, antihypertensive, gastric acid secretion suppression, gastric motility suppression, and uterine It is a useful pharmaceutical compound that has prokinetic effects. The compound [1] of the present invention is a compound in which the group represented by the symbol RI is an n-heptyl group, n-octyl group, n-nonyl group, or n-decyl group, and
It is a compound that is an optically active form or a racemic form due to the two asymmetric carbon atoms in the ears. Compound [1] of the present invention can be produced by the method shown in the following reaction formula. (However, R2 and R3 represent the same or different lower alkyl groups, and RI has the same meaning as above.) That is,
Optically active or racemic 5-formyl-2-pyrrolidone derivatives

8-Azaprostanoic acid compound [W] obtained by reacting [0] with a phosphite compound [m]
15-hydroxy-8 by reducing the 19-carbonyl group of
-Azaprostanoic acid compound [V], then if necessary, this compound is treated with chromatography to separate into the corresponding 15Q-hydroxy compound and 158-hydroxy compound, and the ester moiety of this compound is hydrolyzed to obtain the target compound [ 1] can be manufactured. This method will be explained in detail below. First, the reaction in the first step can be carried out by reacting compound [b] and compound [m] in an appropriate solvent in the presence of a basic reagent, according to the conventional Wittig reaction method. Suitable basic agents include, for example, alkali metal hydrides such as sodium hydride. The reaction proceeds smoothly from the time of preparation to room temperature, and the compound [W] can be obtained in good yield. In addition, if an optically active compound derived from optically active glutamic acid is used as the raw material compound [b] in this step, the corresponding optically active compound can be obtained without racemization during the reaction. The reduction reaction in the second step can be carried out by reacting the compound [W] with a reducing agent in an appropriate solvent according to a conventional method for this type of reduction reaction. As the reducing agent, for example, sodium borohydride is preferred. The reaction proceeds suitably even when cold, and compound [V] can be obtained in high yield. The compound obtained here [V
] is a mixture of a strongly polar compound and a weakly polar compound. In this specification, among the four isomers occupying the 12th position and the 1st asymmetric carbon atom, a highly polar compound (for example, a compound that flows out later in silica gel column chromatography) is used for the 15Q-configuration. Compounds with weak lattice properties (for example, compounds that flow out first in silica gel column chromatography) are called 158-monocoordinated compounds.
This mixture can be separated by using separation means such as chromatography. The third to follow
The hydrolysis reaction in the step is preferably carried out by reacting the compound [V] with a caustic alkali in an appropriate solvent. For example, sodium hydroxide, potassium hydroxide, etc. are suitable as the caustic alkali. The reaction proceeds smoothly even when cold, and the target compound [1] can be obtained. In addition, the raw material compound

[0] can be produced, for example, by oxidizing a compound represented by the general formula L (wherein R2 has the same meaning as above) with chromic anhydride-pyridine. The thus obtained compound [1] of the present invention can be used as a medicine as a free acid, or can be used in place of a suitable medically acceptable carboxylate. Such salts include, for example, alkali metal or alkali metal salts such as sodium, potassium, calcium, ammonium salts, quaternary ammonium salts such as tetramethylammonium, methylamine, cyclobentylamine, benzylamine, Examples include salts of organic bases such as piveridine, monoethanolamine, and triethanolamine. As for the administration method, it is prepared into an appropriate dosage form such as powder, tablet, capsule, solution, emulsion, or suspension, and is administered orally or parenterally.
Examples of the results of testing the pharmacological effects of compound [1] are as follows. Experimental Example 1 Bronchodilatory effect Tested to see if it suppresses the increase in intratracheal pressure caused by histamine. Guinea pigs (male, weighing 280-350 mm) were anesthetized with urethane (1-1.5 poly/k9, i.p.) and had suppressed self-respiration with galamine (5 females, i.v.). A constant volume of artificial respiration was performed, and intratracheal pressure was recorded over time. At the same time, arterial pressure from the carotid artery was also recorded. The surgical sequence was urethane anesthesia, artificial respiration, and gallamine administration. The effect of preadministration of the specimen on the transient increase in intratracheal pressure caused by the administration of histamine (2-4 french #'k9, i.v.) was examined. The specimen (3 kg) was administered intrafemorally (iv). Histamine is administered at minute intervals, 1 minute, 11 minutes, 21 minutes after the sample administration. The increase in intratracheal pressure due to histamine before administration of the sample is defined as a contraction rate of 100%, that is, the inhibition rate is 0%, and the case where no increase in internal pressure occurs even when histamine is administered is defined as a suppression rate of 100%.
Display as follows. Suppression rate 100-80% W Suppression rate 80-50% 50-10% 10-10% The results are shown in Table 1. Table 1 *(Specimen) (hereinafter the same) Control compound A: Brostaglanson's ear - Compound B of the present invention: secreted-20-ethyl 15Q-hydroxy-9-oxo-13,14(trans)-didehydro-8-azaprostane Acid C: Mu20-ethyl-15o-hydroxy-
9-oxo-13,14(trans)-didehydro 8
-Azaprostanoic acid D:〃-20-ethyl-15-hydroxy-9-oxo-13,14(trans)-didehydro-8-azabrostanoic acid E: Mu150-hydroxy-9-oxo-20-n-bropyl-13 ,14(
trans)-didehydro-8-azafrostanoic acid F:〃
-20-n-Butyl 15o-hydroquine-9-oxo-13,14(trans)-didehydro-8-azaprostanoic acid Sample solution preparation method Dissolve the sample in 99.5% ethanol and store it, then add physiological saline before use. The ethanol concentration of the administration solution did not exceed 1%, and no special effects were observed with 1% ethanol solution alone. A dissolved sample was used. (The same applies hereinafter) Experimental Example 2 Mice (ddY strain, male) weighing around 2M were fasted for 4 hours, and charcoal powder was added to 0.5% carboxymethyl cellulose solution for 2 hours.
% suspension of 10 [/k9 (charcoal powder amount 4
(September 20, 2015) Oral administration, and at the same time, the specimen was administered intraperitoneally. After 1 minute, the animal is sacrificed and its abdomen is dissected, and the distance the charcoal powder has traveled through the intestines is measured and expressed as a percentage of the distance from the pylorus to the cecum. The transport rate ratio is the quotient obtained by dividing the average transport rate of the sample administration group by the average of the untreated group. The results are shown in Table 2. Table 2 *(Sample) G: Brostadalandin E2 Example 1 '1} Under nitrogen gas flow, 65% sodium hydrogen 129
The solution (dispersed in key oil, washed with n-hexane before use) was suspended in 12 dimethoxyethane, and added 2-oxo-n-nonyl dimethyl phosphite 875 and 4 dimethoxyethane under cooling with ice water. [Add the solution and stir at the same temperature for 30 minutes. Then, a solution of d1-1-(6-methoxycarbonylhexyl)-5-formyl-2-pyrrolidone 850 dimethoxychetane 4' was added and stirred at the same temperature for IQ minutes and at room temperature for 2 days. Add saturated aqueous ammonium sulfate to the reaction solution and extract with ether. The extracted layer was washed with saturated aqueous ammonium sulfate, dried, the solvent was distilled off, and the residue was subjected to preparative thin layer chromatography (
Solvent; ethyl acetate; benzene = 4:1) to separate and purify dl-9,15-dioxo-20-ethyl-13,1
667-9 is obtained as 4(trans)-didehydro-8-azaprostanoic acid methyl ester as a pale yellow oil.
Yield 53%. N female Sm/e: 379 (M 10) ■ Methanol 95 at 1.24 pm under nitrogen gas flow
Sodium borohydride 0.19 was added to the solution under cryogen cooling.
Add 9 evenings. After stirring at the same temperature for 2 hours, 10% hydrochloric acid was added to the mother = 4
Methanol is removed at about 40 qo. Add saturated ammonium sulfate solution to the residue and perform Yamaichi Teru extraction. The extracted layer was washed with saturated aqueous ammonium sulfate, and after drying, the solvent was removed and d1-20-ethyl-15-hydroxy-9-oxo-13,14(trans)-didehydro-8-azaprostanoic acid methyl ester was obtained as a candy-like substance at 1.27 t. obtain. quantitative. This product is a mixture of stereoisomers related to the 13-hydroxyl group. Separate and purify by preparative thin layer chromatography (solvent: ethyl acetate:benzene = 2:1). dl-15
Q-hydroxy form: 244-9, white powder, mp. 38-40qC (recrystallized from petroleum ether) dl-158-hydroxy form: 150 min, white powder, mp. 27-2800 (recrystallized from petroleum ether) Nsm/e (M+) (both isomers) [31 Under a nitrogen gas stream, add d1-15Q-hydroxy form 234.7 to a solution of methanol 3 and ice water. Under cooling 2
Add two sides of 0% caustic soda aqueous solution and stir at room temperature for 2 hours. Methanol is removed, hydrochloric acid is added to the residue when cold to make the liquid pH 3, and the mixture is extracted with ethyl acetate. The extracted layer is washed with saturated aqueous ammonium sulfate, dried, and the solvent is distilled off to obtain dl-20-ethyl-15Q-hydroxy-9-oxo 13,14 (
Trans)-didehydro-8-azaprostanoic acid is obtained as a white solid in 9 of 230. quantitative. When this product is recrystallized from a mixture of ethyl acetate and petroleum ether, it becomes colorless plate crystals with mp. 74-7yo is shown. N is SSm/e:36
7 (M10) Elemental analysis value: C2, day 3704N Calculated value: C, 68.63: day, 10.15; N, 3.8
1 Experimental value: C, 68.56: day, 10.26: N, 3.
76'4) dl-158-hydroxy compound 1 obtained in [2}
42.5 female, treated in the same manner as {3} with 1 volume of 20% caustic soda aqueous solution [and 2 volumes of methanol] to obtain dl-20
-ethyl-156-hydroxy-9-oxo-13.1
4(trans)-didehydro-8-azaprostanoic acid is obtained as a tart substance in 9 of 146. quantitative. Leave it in the fridge overnight to solidify. When this product is recrystallized from a mixture of ethyl acetate and petroleum ether, it becomes white needle-shaped crystals with mp. It shows 76-77°C. N female Sm/e: 367 (M 10) Elemental analysis value: C2, day 3704N Calculated value: Same as leg Experimental value: C, mottled. 69; Sun, 10.06:N, 3.77
Example 2 In the same manner as in Example 1, (1) 1-1-(6-methoxycarboerhexyl)-5-formyl-2-pyrrolidone [[Q]Customer 2.30 (
C=2.04 ethanol)] 2.16 evening, 2-oxone n nonyl phosphite dimethyl ester 2.33 evening, 6
9 of 5% sodium hydrogen 297.1 and 64 of dimethoxychetane (hereinafter referred to as DME), 1-9.15
-Diixo-20-ethyl-13014(trans)-didehydro-8-azaprostanoic acid methyl ester was obtained as a colorless transparent liquid in an amount of 2.275 g. Yield 70.9%. Massm/e: 379 (M 10) ■
1-20-ethyl-15-hydroxy-9-oxo-13,14(trans)-didehydro-8-azabrostanic acid methyl ester was obtained as a pale yellow oil from 2.275 M of this product, 0.364 M of sodium borohydride, and 180 M of methanol. 20? obtain. Separate and purify this product. 1-15Q-hydroxy form: 957-9, mp. 51-5〆○, yield 41.9%. 1-1158-Hydroxy form 965 evening, mp. 40-41°C, yield 42.2%. NEssm/e: 381 (M 10) (both isomers) '31
1-15 is -hydroxy body 415 9, 20% caustic soda aqueous solution 3 I and methanol 6 skin, 1-20-ethyl-15Q-hydroxy-9-oxo 13.14 (
Trans)-didehydro-8-azaprostanoic acid as a colorless transparent prism crystal. mp. 76-7
70 (recrystallized from a mixture of ethyl acetate and petroleum ether), yield 84%. [Q] Shoichi 4-40 (C=1-0, Eta/R) NES
Sm/e: 367mm) Elemental analysis value: C2, day 370
4N Calculated value: C, 68.63: Day, 10.15: N, 3.8
1 Experimental value: C, 68.70; H; 10.19 N, 3.
78{41[1-158-hydroxy compound obtained in 21 44
0 of 9, 20% caustic soda aqueous solution 3 of
-Azabrostanoic acid as a colorless transparent prismatic crystal 342
Get a female. mp. 60-6100 (recrystallized from ethyl acetate/petroleum ether hawk liquor), yield 80.6%. Medium [Q] Keiichi 27.4o (C=1.0 ethanol) N
bssm no e: 367 (M 10) elemental analysis value: C2, day 3
704N Calculated value: Same experimental value as '3}; C, thigh. 71; Sun, 10.09:N, 3.80
Example 3 In the same manner as in Example 1, [1---1-(6-methoxycarbonylhexyl)
From 1.63 m of 5-formyl-2-pyrrolidone, 1.856 m of 2-oxo-decyl phosphite dimethyl ester, 0.224 m of 65% sodium hydrogen, and 49 m of DME, 20 m of 1-9,15-dioxo. -Propyl-
1.556 ta of 13,14(trans)-didehydro-8-azaprostanoic acid methyl ester was obtained as a colorless oil. Yield 62%. N female Sm/e: 393 x M 1) [2] This product contains 1.556 ml, sodium borohydride 0.241 ml and methanol 100 ml, 1-15-hydroxy-9-oxo 20-n-propyl 13.14 (Trans)-didehydro-8-azaprostanoic acid methyl ester was obtained as a pale yellow liquid in 1.56 hours. Separate and purify this product. 1-15Q-hydroxy form: Colorless transparent liquid, 9 of 604, uneven yield. 6%. This product will solidify. mp. 37-38oo (ethyl acetate)
Recrystallized from petroleum ether mixture). 1-1158-hydroxy compound pale yellow liquid, 9 of 585.4, yield 38.4%. Nnessm/e: 395 (M+) (both isomers) (3'
9 of 1-15Q-hydroxy compound 523.5, 20% caustic soda aqueous solution 3 [and methanol 6] ~ 1
-15Q-Hydroxy-9-oxo201n-propyl-13114(trans)-didehydro-8-azabrostanoic acid is obtained as a pale yellow liquid in 504-9. quantitative. [Q] Steal -5. Finishing (C=2. ethanol)N Sagis
sm/e: 381 (M+) Example 4 Same as Example 1 '1) 1-11 (6-methoxycarbonylhesacyl)
-5-formyl-2-pyrrolidone 1.2 hours, 2-oxo n-undecyl phosphite dimethyl ester 1.437 hours
evening, 65% sodium hydrogen 0.165 evening and DM old 36
From the shout, i-20-n-butyl-9,15-dioxo-
1.035 ta of 13,14(trans)-didehydro-8-azaprostanoic acid methyl ester is obtained as a pale yellow liquid. Yield 54%. Nnessm/e:407kuM1) (2)
1 day of this product, 0.15 days of sodium borohydride and 70 degrees of methanol, 1-201n-butyl-15-hydroxy-9-oxo-13,14(trans)-didehydro-8-azaprostanoic acid methyl ester was made into a pale yellow liquid with 990 degrees of Get 9. Separate this product. 1-15Q-hydroxy form: pale yellow liquid, c of 423, yield 42.2%. 1-1153-hydroxy form: pale yellow liquid, 426 female, yield 42.5%. When this product solidifies and is recrystallized from ethyl acetate/petroleum ether tear fluid, it becomes white needle-shaped crystals with mP. 54 to 55 qo. MEssm/t: 409 (M 10) (both isomers) [3'
1-15Q-hydroxy body 395 female, 20% caustic soda aqueous solution 3 [and methanol 6 [], 1-20-
n-butyl-15Q-hydroxy-9-oxo13.
14(trans)-didehydro-8-azaprostanoic acid is obtained as a pale yellow liquid in 9 of 370. Yield 97%. [Q] Customer-4.20 (C=1.0, ethanol) N Satoshi sm/e 3395 (M ten) IRyS side 13 (
Arc-1): 3600-2250 (OH, C〇〇H), 1
705 (C〇〇H), 1665 (lactam), 970 (
Transolefin) Example 5 In almost the same manner as in Example 1 (1- 65% sodium hydrogen 0.1
75 minutes (mineral oil dispersion "washed with n-hexane before use)" DM
Suspend it in E9 and add 2-oxone dodecyl phosphite dimethyl ester to it under ice water cooling at 1.599 DM.
Add E5' solution and stir at the same temperature for 10 minutes and at room temperature for 1 hour. Then, under cooling with ice water, 1-1-(6-methoxycarbonylhexyl)-5-formyl-2-pyrrolidone was added to the reaction product.
．． Add the solution of DM Old 5 on the 27th night and stir at room temperature for 2 hours to complete the reaction. After a conventional work-up, the resulting crude oil was purified by silica gel chromatography (solvent: methylene chloride; ether = 231) to give 1-9, 15-
1.012 ta of dioxo-20-n-bentyl-13.14(trans)-didehyde o-8-azaprostanoic acid methyl ester is obtained as a colorless oil. NEssm/e
: 421 (M 10) '21 This product 1.0127 evening, sodium borohydride 0
．． 1463 and methanol 7, 1-15-hydroxy-9-oxo 201-benzene 13.1
4(trans)-didehydro 8-azaprostanoic acid methyl ester is obtained as a pale yellow oil. Separate and purify this product. 1-15Q-hydroxy form; pale yellow oil, 408.8-9. 1-158-Hydroxy form: "Cold Color Crystal" 398.5-2, mp. 59-6100 (crude product). Nnessm/e: 423 (M+) (both isomers) '3'
1-15Q-hydroxy body 400 female, 20% caustic soda aqueous solution 3' and methanol 6', 1-15Q
・-Hydroxy-9-Oxo-20-1n-Benzyl m1
385 ml of 3.14(trans)-didehydro-8-azaprostanoic acid was obtained as a colorless liquid.

Claims (1)

[Claims] 1. An 8-azaprostanoic acid compound represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (where R^1 represents an alkyl group having 7 to 10 carbon atoms). 2. The 8-azaprostanoic acid compound according to claim 1, wherein in the general formula [I], R^1 is an n-heptyl group. 3. The 8-azaprostanoic acid compound according to claim 1, wherein in the general formula [I], R^1 is an n-octyl group. 4. The 8-azaprostanoic acid compound according to claim 1, wherein in the general formula [I], R^1 is an n-nonyl group. 5. The 8-azaprostanoic acid compound according to claim 1, wherein in the general formula [I], R^1 is an n-decyl group. 6. The 8-azaprostanoic acid compound according to claims 1 to 5, which is a racemate. 7. The 8-azaprostanoic acid compounds according to claims 1 to 5, which are levorotatory isomers. 8 Claims 1 to 7 which are 15α isomers
8-Azaprostanoic acid compounds described in . 9 Claims 1 to 7 which are 15β isomers
8-Azaprostanoic acid compounds described in . 10 dl-20-ethyl-15α-hydroxy-9-
9. The compound according to claim 8, which is oxo-13.14(trans)-didehydro-8-azaprostanoic acid. 11 dl-20-ethyl-15β-hydroxy-9-
The compound according to claim 9, which is oxo-13.14(trans)-didehydro-8-azaprostanoic acid. 12. The compound according to claim 8, which is 1-20-ethyl-15α-hydroxy-9-oxo-13,14(trans)-didehydro-8-azaprostanic acid. 13 The compound according to claim 9, which is 1-20-ethyl-15β-hydroxy-9-oxo-13.14(trans)-didehydro-8-azaprostanic acid. 14 1-15α-hydroxy-9-oxo-20-n
-Propyl-13,14(trans)-didehydro-8
- The compound according to claim 8, which is azaprostanoic acid. 15 1-20-n-butyl-15α-hydroxy-9
-oxo-13,14(trans)-didehydro-8-
9. The compound according to claim 8, which is azaprostanoic acid. 16 1-15α-hydroxy-9-oxo-20-n
-pentyl-13,14(trans)-didehydro-8
- The compound according to claim 8, which is azaprostanoic acid. 17 General formula ▲ Numerical formulas, chemical formulas, tables, etc. are available▼ (However, R^2 represents a lower alkyl group) 5-formyl-2-pyrrolidone derivative and the general formula (R^3
O)_2P(O)CH_2COR^1 [III] (However,
R^1 represents an alkyl group having 7 to 10 carbon atoms;
3 represents a lower alkyl group) and the general formula obtained by reacting with a phosphite compound represented by ▲ There are mathematical formulas, chemical formulas, tables, etc. )
The 15th-position carbonyl group of the 8-azaprostanoic acid compound represented by is reduced to a hydroxyl group to form the general formula ▲ mathematical formula, chemical formula,
There are tables etc.▼ (However, R^1 and R^2 have the same meaning as above)
The general formula is characterized by obtaining a 15-hydroxy-8-azaprostanoic acid compound represented by the formula and hydrolyzing the ester moiety of this compound ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 is the same as above) Production of 8-azaprostanoic acid compounds represented by (having the same meaning). 18 General formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (However, R^1 represents an alkyl group having 7 to 10 carbon atoms, and R^2 represents a lower alkyl group) 8-
The 8-azaprostanoic acid compound according to claim 17, wherein the azaprostanoic acid compound is separated into the corresponding 15α-hydroxy compound and 15β-hydroxy compound by chromatography, and then the ester part of this compound is hydrolyzed. Manufacture.