JPS6112687A - Eburnamonine oxime derivative, its salt, and preparation thereof - Google Patents

Abstract

NEW MATERIAL:A compound shown by the formula I [R is H, (alkoxy or oxiranyl)alkyl, group shown by the formula II - formula III (R1 and R2 are H, 1-4C alkyl, aryl, aralkyl, or linked to neighboring N to form heterocyclic group; n is 2, or 3)] and its salt. EXAMPLE:(3alpha,16alpha)-Eburnamoine oxime. USE:An improver for cerebral blood circulation, etc. Having improved durability, obtainable in high yield. PREPARATION:Eburnamonine oxime shown by the formula IV is reacted with hydroxylamine hydrochloride in a condition preferably at the boiling point of an organic solvent such as ethanol, etc. in the presence of an excess amount of an alkali metal carbonate (preferably potassium carbonate), to give a compound shown by the formula I (R is H). Then, the reaction product is reacted with an alkali hydride in an anhydrous organic solvent (e.g., DMF, etc.), and the prepared alkali metal salt is reacted with a compound (e.g., diethylaminoethyl chloride, etc.) shown by the formula R<0>X (R<0> is alkyl, etc.; X is halogen).

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to the formula (where R represents a hydrogen atom, an alkyl group, an alkoxy/alkyl group, an oxysilanylalkyl group, or a group),
1 and R2 are a hydrogen atom, an alkyl group having 1 to 4 carbon atoms,
means an aryl group, an aralkyl group, or R1 and R2
together with the adjacent nitrogen atom means an unsubstituted or substituted heterocyclic group, n means an integer of 2 or 3) and its acid addition salts, and It concerns the manufacturing method.

The compound represented by formula (2) has excellent pharmacological effects, ie, cerebral vasodilatory activity and cerebral metabolic activation activity, and is therefore useful as a medicine.

(Conventional technology) ・V [nea m1nor L, Apoc
yaaaae) contains vincamine (vlneamln).
s ), pincin (vlnclne), pincarninin (vincarninin@), pincinin (vlnc
Vincamine contains various alkaloids such as lnlne), in particular vincamine, which has an excellent cerebral vasodilatory effect and has been used as a cerebral circulation improving agent for the treatment of cerebrovascular diseases.

However, vincamine has the drawback of having a short effective action time.

In order to improve this defect to some extent, for example, the following vincamine derivatives have been synthesized and developed.

, I(cooc 5.R5 [Pharmacomatpies, 10 (2
), 199-206.1975] b) (Arzneim Forsch s 26 (10a
), 1976] C) 3M series υL-c2h5 (Belgian Patent No. 823409 and British Patent No. 1492579) d) (Arznelm Forgch, 29.1094
．． (1979) (Problems to be Solved by the Invention) The above known vincamine derivatives have problems in that the strength of their pharmacological action is considerably low and their duration of action is not sufficient. ing.

Therefore, the present invention aims to solve the above problems by replacing vincamine and the vincamine derivatives synthesized since then with its closely related compounds.

(Means for Solving the Problems) According to the present invention, the above problems are solved by the formula C2H3 (wherein R means a hydrogen atom, an alkyl group, an alkoxyalkyl group, an oxiranylalkyl group, or a group, R1 and R2 mean a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group, an aralkyl group, or R4 and R2 together mean an unsubstituted or substituted heterocyclic group together with the adjacent nitrogen atom, and n means an integer of 2 or 3) and its acid addition salt.

Regarding the meaning of the group R, alkyl groups include methyl, ethyl, propyl, n-butyl groups, etc., and alkoxyalkyl groups include methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl, propyloxyethyl groups, etc.

Regarding the meanings of groups R1 and R2, alkyl groups include methyl, ethyl, propyl, n-butyl groups, etc., and aryl groups include phenyl, 〇- or p-methoxyphenyl groups,
0- Also, ha-chlorophenyl group, benzoyl group, etc., and aralkyl group include benzyl group, phenylethyl group,
benzoylmethyl group, etc.; unsubstituted heterocyclic groups include pyrrolidinyl group, piperidino group, sulfolino group, piperazyl group, piperazino group, etc.; substituted heterocyclic group refers to substituted piperazino group; Examples include alkyl groups such as ethyl, propyl, isopropyl, and 〇- or p-
It can be an aryl group such as methoxyphenyl N O- or hap-chlorophenyl.

The compound of the formula (2) in which the group R represents a hydrogen atom, that is, the epurnamonine oxime represented by the formula 2H5, is the epurnamonine thione [H, Behrin ff-(H,
French Patent No. 2253 of Behringer et al.
No. 502 specification and C, A, 84: 90391q
] can be prepared by reacting with hydroxylamine hydrochloride in an organic solvent and in the presence of an alkali metal carbonate. In this case, it is advantageous to use an excess of potassium carbonate as the alkali metal carbonate and to carry out the reaction under conditions of the boiling point of, for example, ethanol as the reaction solvent. After the completion of the reaction, the solvent is distilled off under reduced pressure to concentrate the reaction product, methanol is added to this, the methanol-insoluble matter is removed in an oven, washed with water, dried, and then recrystallized from ethanol to obtain the desired product. Esolnamonine oxime (compound 1-a) can be obtained.

Compounds of the formula 1, in which the group R is an alkyl group, an alkoxyalkyl group, an oxiranylalkyl group or a group, in which R4, R2 and n have the meanings given above, i.e. compounds of the formula 2H5, in which RO is an alkyl group, (representing an alkoxyalkyl group, an oxiranyl alkyl group or a group, and R4, R2 and n have the above-mentioned meanings) is an epurnamonine oxime derivative represented by the above formula I-a. The oxime is reacted with an alkali metal hydride in an anhydrous organic solvent, and the obtained eburnamonin osime alkali metal salt has the formula % formula % () (wherein R0 has the above meaning and X means a herodan atom ) in an anhydrous organic solvent.

Compounds of formula 1 in which the radical R means a group (wherein R4 and R2 have the meanings given above), ie eburnamonine oxime derivatives of the formula (wherein R1 and R2 have the meanings given above), The ebrunamonine oxime represented by the above formula I-a is reacted with hydrogen-absorbed naralkali metal in an anhydrous organic solvent, and the resulting niburnamonine oxime alkali metal salt has the formula (wherein X means a halodan atom). ) in an anhydrous organic solvent, and then reacted with a compound represented by the formula K (wherein and R2 have the above-mentioned meanings).

Examples of anhydrous organic solvents include trimethylformamide, trimethylacetamide, dimethyl sulfoxide, and the like. be able to. The reaction temperature is 0 to 100°C, especially 0 to 6
0°C is preferred. The epurnamonine oxime derivative produced can be purified by silica column chromatography or other methods known per se.

The compounds represented by formula I (formulas 1-a, I-b and I-c) can be prepared, if necessary, by a method known per se into pharmaceutically acceptable acid addition salts such as hydrochloride, sulfate, phosphate,
succinate, maleate, fumarate, citrate,
malate, lactate, tartrate, methanesulfonate,
It can be converted into benzoate, sulfate, etc.

(Effects of the Invention) The method of the present invention has the effect that a desired compound can be obtained relatively easily and in a high yield starting from eburnamonine thione obtained based on a known method. There is.

Epurnamonin oxime (Formula I-&) and its derivatives (Formula 1-b and I-a) according to the present invention have excellent cerebral vasodilatory effect and cerebral metabolic activation effect, and therefore are agents for improving cerebral blood circulation. and as a cerebral metabolism improving agent for various diseases caused by cerebrovascular disorders and/or decreased cerebral oxygen utilization, such as -
It is useful for the treatment of cerebral hemorrhage, cerebral thrombosis, cerebral embolism), cerebral arteriosclerosis, hypertensive cerebral circulatory insufficiency, sequelae of head trauma, vascular memory disorder, headache, hearing loss, tinnitus, dizziness, Meniere's disease, retinopathy, etc. In this case, conventional compounds such as mother pa (
Compared to phosphorus and vincamine derivatives, it has a higher pharmacological effect and is excellent in persistence, so it has the effect of making it possible to reduce the amount of administration or the frequency of administration.

(Production Examples and Test Examples) Production Example 1 = (3α, 16α)-epurnamonine oxime (3α,
16α)-epurnamonin-14(15H)-thione 2
fl (8.1 mmol) and hydroxylamine hydrochloride 0.62. ! i+ (9.7 mmol), potassium carbonate 3.37 g (24.2 mmol), and ethanol 2
The mixture with oml was refluxed for 4 hours under nitrogen flow. The solvent was distilled off under reduced pressure, and methanol 100% was added to the residue.
ml, remove methanol insoluble materials, wash with methanol and then with water, and then dry to obtain 1.78 g of crude crystals of the desired compound.

If further recrystallized from ethanol, the melting point is 285-29
1.619 colorless crystals at 0° C. (decomposed) are obtained.

Yield: 64 mm Spectrum (m/e): 309 (M
+) NMR spectrum (DMSO-d') δppm:
8.2-7.8 (jH,m, Ar-H)7, s
-6,5CsH, m, Ar4) J, 80
(IH, wide a, C3(1-H)3, 5-1.17
(14H1m%-CH2)o, tts
(JH, wide t% J = O θHz, -c H2CS) Hydrochloride melting point; 288-291°C (decomposition) (methanol) colorless crystal elemental analysis C4, H2, N30/HC6 theory C65,
98H6, 99N13.15 actual measurement C66, 07H6,
94N1200 Production Example 2 (3α, 16α)-Esolnamonin〇-(:,?-(
N,N-diethylamino)ethyl]oxime (3α,16α)-epurnamonine oxime o,5zl (x,o I mol) obtained by the method described in Preparation Example 1 was dissolved in dimethyl under a nitrogen stream. 66 Sodium thihydride s smy (L55 ml) suspended in formamide 5d and at 0 °C.
was added, stirred at room temperature (30°C) for 2 hours, added 0.5d of quethylaminoethyl chloride, and further stirred at room temperature for 2 hours.
Stir for hours. The solvent was distilled off under reduced pressure, and 5 m t-
The combined extracts are washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 0.52I of the desired compound as a yellow oil. Column chromatography (silica tal, triethylamine:ether:n-hexane=1:1:10-1
:4:6), it becomes a 0.349 light yellow clear autumn product.

Yield: 84% M, , snictor (rrv/e): 4 ot
tNMR spectrum (CDC23) δppm: a, 5
-8.2 (IH, m, Ar-H).

7, e -y, o (3H%m%Ar'Jri4.
22(2H1t% J=6-OHz 1-ocI
ll(,-)3,8.9 (JH, wide 8, C
5a-H) 2.84 (2H, tl J=6
．． OHt,, -C)l, -N-)s, e -i o (
14H,m, -yi-2-')2,62(4I(-
q 1'J=7. OHz, N-C2H3)0,9
5 (6H,t, J=7.OHz, N-C
2H3) 0.92 (3H, wide t, J=7
．． 0Hz, -C2H5) Dihydrochloride/-hydrate Melting point 2 198-201℃ (decomposition) (ethanol/ether) Colorless crystal elemental analysis C25H66N40/2HC1-H20 theory C60,11, H8,07, N11.22 actual measurement C6
0,17,H1O1NILII Production Example 3 (3α, 16α)-F8lunamonine〇-[2-hydroxy-s-[4-(2-methoxyphenyl)-1-bi(radinyl]propyl]oxime described in Production Example 1 0.319 (1.0 mmol) of (3α,16α)-eburnamonine oxime obtained by the method of 5 mmol) and stirred for 2 hours at room temperature (so°C), then added epichlorohydrin Q,19 (1.1 mmol) and stirred for further 2 hours at room temperature.
Stir for 50 to 6 hours and then add 0.211 c 1.1 mmol of 2-(2-methoxyphznylpiperazine).
The mixture was heated to 0°C and further stirred for 2 hours. The reaction mixture is then treated as in Preparation Example 1 to obtain the desired compound.

Yield near 5 coefficient Ma s m spectrum (m/e): 5s sn@
@t-1.

IR spectrum of vrn&x.

3450 (OH) 1640 (C=N) NMR spectrum (CDct5) δppm: 0, 9
'0 (JH,t, J=7.0Hz, -CIH
2-0%) 1, s ~ s, s (t4H,m,
-CH2-) 3.78 (IK, wide s,
C3cL-H) 3,5 (3H, s 1-OCH
5) 4, 25 ('2H%ts J=6.0 Hz
, -CH2-0-N=)7.2-8.5 (8H,
Broad, Ar-H) dihydrochloride Melting point: 200-210°C (decomposition) Experiment: After anesthetizing a male mongrel dog weighing 10 kg, various compounds were administered into the vertebral artery at a dose of 14 μg. When changes in vertebral artery blood flow, blood pressure, and heart rate were measured, the results shown in Table 1 below were obtained.

These results show that the compound according to the present invention exhibits an effect of increasing cerebral blood flow superior to that of the control substance, Hanoiperine, and has no effect on blood pressure or heart rate.

Table 1 Pharmacological test example 2 Acute toxicity A group of 6 male DD mice weighing 15 to 189
Acute toxicity (LD5o) after oral administration of various compounds to each group
When the values were determined, the results shown in Table 2 below were obtained. These results show that the compound according to the present invention has low toxicity and is therefore superior in safety when compared with conventional related drugs.

Table 2 Procedural amendment (voluntary) January 1980//'' Japan Patent Office Commissioner Manabu Shiga 1, Indication of case % Application No. 152926/1982 2, Name of invention Ebrunamonin oxime derivative and its salt and its presentation method 3, and its relationship to the case of the person making the amendment Patent applicant: 55 Higashi Sotobori-cho, Higashi-ku, Nagoya City, Ltd. Representative: Shinji Suzuki 4, Tamayo Chemical Research Institute, Agent: 105 Toranomon, Minato-ku, Tokyo Column 6 of Detailed Description of the Invention in Specification No. 1-11 @ No. 7, content of amendment “Production Example 3 (3α, 160-Ebrunamonine-〇-[2-(N,N
-dimethylamino)ethyl]oxime 7.00 liters (22.6 mmol) of (3α,16α)-epurnamonine oxime obtained by the method described in Preparation Example 1 was suspended in 112 grams of dry dimethylformamide. The gas phase was replaced with argon, and 2.49 f (62° 2 mmol) of 60 thihydrogen (hysodium) was added under ice cooling, and the mixture was stirred for 10 minutes and further stirred at room temperature for 2 hours. Chloride hydrochloride 4.89t (33,9
Mi! 7 mol) and stirred for 10 minutes, and further stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 80 cm of water and 100 fnt of dichloromethane were added and dissolved, the dichloromethane layer was separated, and the aqueous layer was extracted 4 times with dichloromethane.
The combined extracts were dried over anhydrous sodium sulfate, concentrated under reduced pressure,
Desired compound as a brown oil upon condensation 11. I got Of. The compound 6 was separated and purified using column Chromadog 2F (silica gel, chloroform:methanolation = 40:1).
．． 54F was obtained. Next, the hydrochloride was converted into a hydrochloride with a 34.4% hydrochloric acid solution in ethanol, and then recrystallized from a mixed solvent of ethanol and ether to obtain 5.5Of the dihydrochloride of the desired compound as colorless needle crystals.

Yield: Quantitative MA8S spectrum (Le's): 3s, ONMR
Spectrum (CDC15) δppm: 8.5 8.2 (
IHXm%, Ar-H) 7-5 7-1 (3Hs, m5
Ar-H)4-25 (2Hs t % J = 6
-OH1% -C1j 2-0-N =)3.82
(IH, wide S, C, g-H) 3.7 0.8
(18H, m, -CH2-)2.73 (2H,
t, J=6.0Hz, -C)12-N(CH3)2
)1.33 (6H,%s, -N(cH5)2)
0.92 (3H, t, J=7a5Hz) -C
) 13) Dihydrochloride melting point 182-194℃ (decomposed) (ethanol/Zukunori I, PT Yumej Colorless crystal theory C57.49, H7.76, N11.66 actual measurement
C57,38, H7,74, N11.67 Production Example 4 (3α, 16α)-Ebrunamonin〇-(2-(1-
7.00 f (22.6 mm!j mol) of (3α,16α)-epurnamonine oxime obtained (by the method described in Preparation Example 1) of (pyrrolidinyl)ethyl]oxime was suspended in 112 m of dry dimethylformamide, and The phase was replaced with argon, and sodium 60thihydride 2°49fC62 was added under water cooling.
, 2 mmol) and stirred for 10 minutes, and further stirred at room temperature for 2 hours. Cooled on ice again, added 5.77 r (33.9 mmol) of pyrrolidylethyl chloride hydrochloride, stirred for 10 minutes, and after rooming, separated the dichloromethane layer, extracted the aqueous layer three times with dichloromethane, and extracted the combined extracts. was separated and purified using anhydrous sulfuric acid (silica gel, n-hexane-thylnitriethylamine = 6:4!l) to obtain 8.58 ft of the compound as a yellow oil. That 7.5O
Dissolve r in 20° of ethanol, dropwise add 4.60 f of 34°4 solution of hydrochloric acid in ethanol, evaporate the solvent under reduced pressure, and recrystallize from a mixed solvent of ethanol and ether to obtain the colorless dihydrochloride of the desired compound. Obtained 6.35F as needle-like crystals ◎ Yield: 94 cm MASS spectrum (''/e): 406 NMR spectrum (CDC25) δppm: 8-4 8-2 (I
H% 111. 'Ar-H) 7.5 7.0 (3H
,m, Ar-H)4.28 (2HXt,
J=J, Q)Iz, -C)12-0-N=)4.0-
0.7 (18HXm, -CH2-)3-85
(IH% wide s% C3α-H) 2.87 (2H
St,, J=6.0Hz, mouth>-CH2→O,93(3
H, t, J=7.5)1z, -C)I3) Dihydrochloride Melting point 183-189℃ (decomposition) (ethanol/ether) Colorless crystal elemental analysis C25H31INqO"2HCt*H20 theory C60,39, H7,70 , N11.20 actual measurement C60
,39,H7',79,N11.20 Production Example 5 (3α, 16α)-epurnamonin〇-(2-(4~
(2-Methoxyphenyl)-1-piperazinyl[ethyl]oxime 6.48 f (21,0 mmol) of (3α, 16α) engineered brunamonin oxime obtained by the method described in Production Example 1)
Dry 78 ydKm of dimethylformamide and add 60 ydKm of sodium thihydride 1.47f under ice cooling in a stream of argon.
(36.8 mmol°) was added and stirred at room temperature for 4 hours. Next, 8.02f of 1-(2-chloroethyl)-4-(2-methoxyphenyl)-1-piperazine was distilled off. Then column chromatography (silica gel,
Separation and purification with ethyl acetate:n-hexane=1:1) gave the desired compound 11.11 as a yellow oil. This oil was subjected to column chromatography (silica gel, ether: n-hexane: triethylamine = 1:1:
0.05), the obtained oil was dissolved in ethanol to obtain a hydrochloric acid solution in ethanol, and then recrystallized from a mixed solvent of methanol and ether to give colorless needle-shaped crystals of 8.719 I got it.

Yield: Quantitative MASS spectrum (''/e): 5z7NMR spectrum # (CDC15) δppm: 8.44 8.13 (I
HXm, Ar-H)7.51-6.59 (7H,m
, Ar-H)4.28 (2H,t, J=
5.5Hz, -CH2-0-N=)3.77
(3H,S, -0CR8)3.38 0-64 (
28HXm%-CH3-1-CH3)0.89
(3HXt.
84 actual measurement C59,20, B7.01, N11
．． 00 Production Example 6 (3α, 16α)-x7′lunamonine〇-(2-hydroxy-3-(4-(2-methoxyphenyl)-1-piperazinyl]propyl]oxime Obtained by the method described in Production Example 1 ( 3α, 16α)-epurnamonine oxime 8.0Or < 25.9 mi!
j mol) Suspended in completely dry dimethylformamide, the gas phase was replaced with argon, and 1 mol of 60'% sodium hydride was added under water cooling.
．． 24F (31.0 mmol) was added and stirred at room temperature for 2 hours. The solvent was distilled off under reduced pressure, 100 ml of water and 150 wj of dichloromethane were added and dissolved, the dichloromethane layer was separated, and the aqueous layer was extracted twice with dichloromethane.
The combined extracts were dried over anhydrous sulfuric acid and the solvent was distilled off under reduced pressure. Column chromatography (
Silica gel, riQQform: /fi/-le=40
: 1) A brown starch syrup-like (3α, 16α)-epurnamonin-0-(2
, 3-epoxypropyl) oxime to 9.514 (10
0chi) obtained.

This (3α, 16α)-epurnamonin-(2,
3□Epoxyprovir) oxime 8.0Of (21,
9 mmol) and 1-(2-methoxyphenyl)bibet2
5.059 (26.3 mmol) of gin was dissolved in 100 - of n-butanol, the gas phase was replaced with argon, and the mixture was heated on an oil bath for 1 hour.
Refluxed for an hour. The solvent was removed under reduced pressure. Next, the product was separated and purified by column chromatography (described above) to obtain 11.1F of the desired compound as a yellow oil. Of this, 9.502 was dissolved in 50% of ethanol, and 6.00 t (56.5 mmol) of 34.4 hydrochloric acid in ethanol was added dropwise under water cooling to obtain a hydrochloride salt.The solvent was distilled off under reduced pressure, and the mixture was dissolved in methanol. Recrystallization from a mixed solvent of ether gave 7.20 r of the hydrochloride of the desired compound as a white powder.

Yield: 91 cm MASS spectrum (m/e): 557 NMR spectrum (CDCjs) δppm: 8.5 8.2 (1B
, m, Ar-H)7;5-6.7(7H,mXAr
-H) 4゜5-4.0 (3B, wide S, -CH2-0
-N= ,Cuα-H)3.80 (3H,S,
-0CH5)3.7 0.8 (26H,m, -CH
2-1C3a -H)0,93 (3H,t,
J=7.0Hz, -CH5) dihydrochloride Melting point 171-181℃ (decomposition) White powder elemental analysis: Cs5H*3N+03.3HC2.-H2
O theory C57, 10,) 17.12, N10.09 actual measurement C57°00. ) 16.95, N10.07 J procedural amendment (spontaneous) Date of February 1985 Manabu Shiga, Commissioner of the Patent Office, Indication of the case - Japanese Patent Application No. 12926-1988 2, Name of invention Ebru Namonin oxime derivatives and their salts and their manufacturing method 6, and their relationship to the case of the person making the amendment Patent applicant: 35 Higashimatotobori-cho, Higashi-ku, Nagoya City, Tamaryo Chemical Laboratory Co., Ltd. Representative: Shinji Suzuki 4, Agent: 105 Tokyo S Minato-ku Toranomon 1-11-7 Column 6 of the detailed description of the invention, Contents of amendment +1 + Page 24 of the specification (Pharmacology test example 1) is deleted and replaced with Add the following.

r Pharmacological Test Example 1 Cerebral Blood Flow Increasing Effect Male and female mongrel dogs anesthetized with Nembutal were used as experimental animals, and vertebral artery blood flow was measured using an electromagnetic blood flow meter. For administration, each drug was made into a 10 thiascorbic acid solution, and 1.0 kg/kg was administered.
It was performed at a ratio of eLof i,a.

The increase in blood flow was 9 times as shown in Table 1 below.

These results revealed that the compound according to the present invention has an effect of increasing cerebral blood flow comparable to or superior to that of vinpocetine.

Table 1 +21 The following amendments are made in the procedural amendment dated November 19, 1959.

1. On page 3, line 11, r8,5-8,2J is r8.
, 47-8.2 DJ.

2. Go to the 12th line and stop s-7, 1J as r 7 ,
' Corrected to 50-7.10J.

3. In the same line 15, rs, 7-0.8J is rs, 6
Correct it to 7-0.683.

4. On the same line 17, rl, 55 J is r2.55J.
and correct it.

5. r8.4-8.2 in the 18th line of the 5th Sada.
Corrected as El, 52-8.15J.

6, r7.5-7. on line 19. OJ is corrected to "7°57-7, OOJ.

7. In the 1st line of the 6th car, replace "r4.0-0.7 J" with "4
．． Corrected to 08-0.73J.

8. The 4th line says "2.7-2.5". r2.73
Corrected to -2.25J.

9, r 1 , 9-1, . 6 Correct "J" to i"1.97-1.60J.

10. Formula in the 1st line of the 7th Sada %formula% and correct it.

11, page 8, line 9 says "4.28" r4,31
Correct it with J.

12. Correct r5#77J in the 10th line to r181J.

13. In the same line 11, rs, 3sJ is written as r5,55
Correct it with J.

14. In the same line 12, [J=5.5H2, J]
Correct as J=7.0HzJ.

15, page 10, line 18, "rs, s-s, 2" is corrected to F8.48-8', 17J.

16. The 19th line of the same line says r7.5-6,7J.
Corrected to 56-6.63J.

17, V4.5-4. on the 20th line. OJ and “wide S”
and r4.46-4. OOJ and rmJ
r3. (Corrected to 55-0.75J.

19. Add ``r(methanol/ethanol)'' after ``(bunfold)'' in the 5th line.

Procedural amendment September 27, 1985

Claims (4)

[Claims] (1) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (In the formula, R is a hydrogen atom, an alkyl group, an alkoxyalkyl group, an oxiranyl alkyl group, or a group ▲ Numerical formula, chemical formula,
There are tables, etc. ▼ or ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼. R_1 and R_2 are hydrogen atoms, carbon numbers 1 to
4 means an alkyl group, an aryl group, an aralkyl group,
or R_1 and R_2 together with adjacent nitrogen atoms mean an unsubstituted or substituted heterocyclic group, and n means an integer of 2 or 3) and acid addition salts thereof. . (2) Formula ▲ Numerical formulas, chemical formulas, tables, etc. ▼ (II) Ebrunamonine thione shown in formula (II) is reacted with hydroxylamine hydrochloride in an organic solvent and in the presence of an alkali metal carbonate, and as needed. A method for producing a novel eburnamonine oxime and its acid addition salt shown by the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I-a), which is characterized by being converted into an acid addition salt. (3) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The formula obtained by reacting eburnamonine thione with hydroxylamine hydrochloride in an organic solvent and in the presence of an alkali metal carbonate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I-a) React the ebrunamonin oxime shown in (I-a) with an alkali metal hydride in an anhydrous organic solvent, and the resulting ebrunamonin oxime alkali metal salt and the formula R^ oX (III) (In the formula, R^o means an alkyl group, an alkoxyalkyl group, an oxiranyl alkyl group, or a group ▲ There are numerical formulas, chemical formulas, tables, etc. ▼, X means a halogen atom, R_1 and R_
2 means a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group, an aralkyl group, or R_1 and R_2 together together with the adjacent nitrogen atom mean an unsubstituted or substituted heterocyclic group, and n is 2 or an integer of 3) in an anhydrous organic solvent and, if necessary, converted into an acid addition salt. There are formulas, chemical formulas, tables, etc. I-b) (wherein R^o has the above-mentioned meaning) A method for producing a novel eburnamonine oxime derivative and its acid addition salt. (4) Formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The formula obtained by reacting eburnamonine thione with hydroxylamine hydrochloride in an organic solvent and in the presence of an alkali metal carbonate. ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I-a) React the ebrunamonin oxime shown in (I-a) with an alkali metal hydride in an anhydrous organic solvent, and the obtained eburnamonin oxime alkali metal salt and formula▲Math. , chemical formulas, tables, etc. ▼ (IV) (X in the formula means a halogen atom) is reacted with the compound shown in an anhydrous organic solvent, and then the formula ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ ( V) (In the formula, R_1 and R_2 mean a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an aryl group, an aralkyl group, or
_1 and R_2 together mean an unsubstituted or substituted heterocyclic group together with the adjacent nitrogen atom) and optionally converted into an acid addition salt, There are chemical formulas, tables, etc. ▼ (I-c) A method for producing a novel eburnamonine oxime derivative and its acid addition salt represented by (in the formula, R_1 and R_2 have the above-mentioned meanings).