JPS58201790A - Novel thiazoromophans and their preparations - Google Patents

Abstract

NEW MATERIAL:Compounds (salts) shown by the formula I (R1-R3 are H or methyl). EXAMPLE:5,9alpha-Dimethylthiazolo[5,4-f]morphan shown by the formula II. USE:An analgesic. PROCESS:2-Benzoyl-5-methyl-9-methylenethiazolo[5,4-f]morphan shown by the formula III (Bz is benzoyl) is hydrolyzed using H<+> of hydrochloric acid, etc. as a catalyst so that the benzoyl group is removed to give 5-methyl-9-methylenethiazolo[5,4-f]morphan. This compound is isolated, and hydrogenated in a solvent such as methanol, etc. using a catalyst such as Pd/C, etc. at relatively law pressure, to give the example compound shown by the formula II. If necessary, it is treated with a mixed solution of formaldehyde and formic acid, to give 2,5,9alpha-trimethylthiazolo[5,4-f]morphan shown by the formula IV.

Description

[Detailed description of the invention] This relates to a manufacturing method.

The excellent analgesic effect of morphine, an alkaloid in opium made from poppy seeds, has long been the focus of attention, but at the same time, the physical and mental dependence, such as addiction and overindulgence, seen with morphine has led to its use as a medicine. was severely restricted.

Conventionally, the complex structure of morphine has been simplified without losing its excellent analgesic effect, and it has been developed to reduce the addictive and addictive properties of morphine.
Attempts have been made to obtain non-addictive compounds, examples being benzoframe morphan, pyridomorphan, and chenomorphan nato.

The present inventors have conducted intensive studies to synthesize a compound having better pharmacological activity than these synthetic analgesics, and as a result, have succeeded in synthesizing a new theazolomorphan, and have arrived at the present invention.

The present invention is based on the general formula (wherein + Rt and R1 are hydrogen or methyl groups)
The present invention provides thiazolomorphans or salts thereof shown in the following.

The present invention also provides 2-penzoyl-5-methyl-9-methylenethiazolo[5,4-71 morphan (in the formula, Bz represents a benzoyl group) to be subjected to hydrolysis and hydrogenation reactions,
Theazolomorphans represented by the general formula (wherein R,

R, and R represent hydrogen or methyl group) or salts thereof.

The thiazolomorphans of the present invention and their salts (hereinafter referred to as the thiazolomorphans of the present invention) have excellent pharmacological (analgesic) effects and are useful as medicines.

The thiazolomorphans of the present invention include the compounds described below.

5,9α-dimethylthiazolo[5.4-t]morphan gives the following NMR spectrum (CDat,j).

δ: [184 (5H, d J = 7Hz) 1, 59
(3H, s) 1, 40 ~ 2.10 (3H, m) 1, 99 (
IH, s D, O e+cchan'ge) 2, 40
~N10 (4H, m) 537 (IH, ad
) Parent peak by mass spectrum l'') Ham/θ=208
It is.

Oxalate is a colorless prismatic crystal that decomposes at 222-223°C.

Also, 2,5.9α-rimethylthiazolo[5,4-z]mol 7
Anne gives the following NMR spectrum (0DO4,).

δ: α85 (5H, 6, J=7Hz) t37 (S
H,a) L59 (AH,5) 11L59 (IH,s) The parent peak (M+) according to the mass spectrum is ψ=222.

The hydrochloride salt is a colorless powder that decomposes at 224-227°C.

The stereoisomer 2,5.9β-trimethylthiazolo[5,4-t]morphan gives the following NMR spectrum.

δ: 1.24 (5H, d, , T=7H2) 1°33 (3H, s) 1.80~2.20 (4H, m) 2.34 (3H, s) 2.30~! L40 (4H9m) as7 (IH, 8) The parent peak (M+) by mass spectrum is m/e = 22
It is 2.

Oxalate Fi is a colorless prismatic crystal exhibiting a decomposition point of 228-250°C.

All of these thiazolomorphans of the present invention exhibit high analgesic activity, and in particular, 2.5.9α-trimethylthiazolo[5,4-71 morphan exhibits an analgesic activity more than twice that of codin.

The thiazolomorphans of the present invention are obtained by hydrolyzing 2-benzoyl-5-methyl-9-methylenethiazolo[:5.4-71morphane represented by the following formula (1), hydrogenating it, and optionally It can be easily produced by treatment with formaldehyde and formic acid. The hydrolysis, hydrogenation and optional treatment with formaldehyde and formic acid may be sequential in this order. Alternatively, hydrogenation may be performed first, followed by hydrolysis and treatment with formaldehyde and formic acid if necessary.

2-benzoyl-5-methyl-9-methylenethiazolo[5,4-/)morphan represented by general formula (1),
For example, when hydrolyzed using hydrogen ions as a catalyst, the benzoyl group is separated as shown in the following formula, resulting in 5-methyl-9-methylenethiazolo[5,4-71morphane.

This hydrolysis is performed using hydrochloric acid 1. It can be carried out using a conventional catalyst such as sulfuric acid in a conventional solvent such as an alcohol such as methanol or ethanol or a mixed solution of alcohol and water. The catalyst may be used in conventional amounts, ie usually in large excess relative to the methylenethiazolomorphane derivative.

The 5-methyl-9-methylenethiazolo[
:5.4-71 morphan is isolated by conventional methods and then purified by Pd/C in a conventional solvent such as methanol or ethanol.
By hydrogenating at relatively low pressure using a catalyst such as 9α-dimethylthiazolo[5,4-71morphan], selective hydrogenation can be performed. This reaction is as shown in the following equation.

The pressure of hydrogen is typically about 1 to about 50 atm, preferably about 3 to about 10 atm. The amount of catalyst used, the reaction temperature, etc. may be the conventional conditions for conventional hydrogenation reactions. The produced 5,9α-dimethylthiazolo[5,4-/]morphan can be isolated by conventional techniques such as distillation of the solvent and crystallization.

Thus obtained 9α-dimethylthiazolo[5,4-
By treating with a mixed solution of formaldehyde and formic acid, for example, formalin and formic acid, t''3 morphan can be easily converted to 2°5.9α-trimethylthiazolo[5,4-L/] according to the following formula. That's 7 moles.

This reaction is based on 5.9α-dimethylthiazolo[5,4-1
This process is easily carried out by heating 1 mole of 7 am with a mixed solution of formaldehyde and formic acid, for example under reflux. The reaction conditions may be those commonly used for methylating amines using a mixed bath solution of formaldehyde and formic acid. Since the mixed solution of formaldehyde and formic acid usually serves as a reaction solvent, it is advantageous to use it in large excess.

The generated 2,5.9α-trimethylthiazolo[5,4
-/) Morphan neutralizes and makes alkaline the reaction solution,
It can be easily isolated by conventional techniques such as extraction with organic solvents.

In the method of the present invention, when 2-benzoyl-5-methyl-9-methylenethiazolo[5,4-t]morphan is first hydrogenated and then subjected to hydrolysis, the reaction proceeds as shown in the following equation, -benzoyl-5,9α-dimethylthiazolo[5
,4-f''3morphant-2-benzoyl-5,9β-
Dimethylthiazolo[5,4-f]morphane is produced.

The hydrogenation reaction is carried out under elevated hydrogen pressures ranging from about 30 to about 100 atmospheres, preferably from about 40 to about 60 atmospheres. Other articles f! i- is the same as in the case of hydrogenation after hydrolysis as seen above. The mixture thus obtained was hydrolyzed in the same manner as in the case of 2-benzoyl-5-methyl-9-methylenethiazolo[5,4-7]morphan, and 5,9α-dimethylthiazolo[5,4- f, ]
morphan and 9β-dimethylthiazolo[5,,4-/
] A mixture with morphan is obtained. Both can be isolated by conventional separation means such as liquid bath chromatography. .

The thus obtained 5,9β-dimethylthiazolo[5゜4
1't] morphan and its mixture with 5,9α□-dimethylthiazolo['5.4-j]morphan, the aforementioned 5,9α-dimethylthiazolo('5. 4 =
t]Mole7a'' can be treated with formaldehyde and formic acid to obtain the corresponding 2-methyl forms.In this case, as shown in the following formula, λ5,9a
methylthiazolo to '-'; 5.4-]morpha.

A mixture of 45.9β-demethylthiazolo[5,4-17]morphane is obtained.

The mixture thus obtained can be separated into two components by conventional means such as liquid chromatography.

The 2-benzoyl-5-methyl-9-methylenethiazolo(s,4-f)morphan used as a starting material in the present invention can be easily synthesized from, for example, ethyl acrylate and methyl isopropyl ketone. dimethyl-
It can be prepared from 1,S-cyclohexanedione as follows.

That is, bromination of a diketone and reaction with thiourea in pyridine lead to a 2-aminothiazole derivative.

The resulting 2-aminothiazole derivative was led to tetraζ-droofquitabenzothiazole by Sandmeyer reaction and hydrogenation, cyanomethylated with Lion, ON, reduced with LiAjH4, and converted to 7-(2-aminoethyl) by Wagner-Meerpain rearrangement. )-4-7-sihydro-47-dimethylbenzothiazole is obtained.

Furthermore, this is reacted with bromine to perform bromination and ring closure, then reacted with potassium carbonate in methanol/chloroform to form aziridine, and reacted with nasal benzoyl etc. to form a thiazolo[5,4-11 morphan structure]. to form.

(陀:benzoyl group) Furthermore, in dimethyl sulfoxide, 1.8-
Diazabicyclo[5,4,Ol undecene-7 (DBU
) and t5-diazabicyclo[4,he〇]nonene (DB
2-benzoyl-5-methyl-9-
Methylenethiazolo[5,4-11 morphane can be prepared.

Raw material preparation example 2 - Synthesis of amino-4, 47-titrahydro 6,6-dimethyl-7-oxopenzothiazole 4,4-dimethyl-1,3-cyclohexane thione combined from ethyl acrylate and meliisopropyl ketone brominated 2-nibromo-4,4-9, methyl-1,3
-Cyclo, Hekin? On (, mp, 149.5~1
50.5℃l cape color prism crystal) 55. Of(α25m0
To this, 21% of (α25m0) of thiourea was added under ice-cooling and stirring, and 4
After stirring for an hour, all the thiourea dissolved. After standing at room temperature overnight, the reaction was completed by refluxing in argon for 1 hour. Concentrate it under reduced pressure to about 1 ml, add urine and collect the pale yellow prismatic crystals ('mp, 195-2 old degrees Celsius).
．． 2f (70% yield) to 2-amino-4, 6.7
-Tetrahydro-46-dimethyl-fuoxovezizotinazole was obtained.

By recrystallizing this from methanol, mp, 2
Colorless prism crystals at a temperature of 05 to 7°C were obtained.

Engineering R spectrum ν (Nujol):'5270,161
5crn-'.

M8”m/e:'196(M+) NMR,'δ(ODOj,): 1.18(6)i,a
) 1.95 (2H, t.

: r-6Hz) 2.80 (2H, t, J-6Hz) 124 (21 (, br s) ゛Elemental analysis 2 calculation value (C* H1! Nt OS ) f
s):055.08;)I &16;N1
4.27゛ capsule measurement (→:tj 55.37; H□
a98; N 14.044, Synthesis of 5.47-tetrahydro-46-dimethyl-fuoxobenzothiazole 2-amino-4,5,6,7-titrahydro6.6-
Dimethyl-7-oxopenzothiazole was subjected to Sandmeyer reaction to obtain 2-chloro-4,5,47-titrahydro-6,6-dimethyl-7-oxobenzothiazole. This 2-chloro-4,5,47-tetrahydro-
46-Simethyl-7-oxopenzothiazole 52.0
t (0.24 mol), ) ethylamine 3
4-(α25 mol) and 10% Pd-C! L5 f
was added to 260-ml ethanol and reduced with atmospheric hydrogen.

All of the catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, dried over magnesium sulfate, and then the solvent was distilled off to obtain a pale yellow oil.

When this is distilled under reduced pressure, bp is 85-95V0.50w
AiHg colorless solid 41.9f (yield 96%) was obtained, which was recrystallized from n-hexane, mp, 105
Colorless prismatic crystals at ~106°C were obtained.

IRν(C!HO1,): 1665cm'MSm/
e: 181 (M+) NMRδ (CDCl5): 1.24 (6H, s)2
．． 06 (2H, t, J=6H2) Engineering 12 (2H, t, J=6Hz) a95 (IH, s) Elemental analysis two calculated values (0, H,, N08X→:0 59.
64; H/i, 12: N 7.75 actual value (@:059.45; H6,10; N1
Synthesis of 12-benzoyl-5-methyl-9-methylenethiazolo[5,4-t]morphan under argon atmosphere for 300 min.
250 rd (rl, 39
mol) of 15% n-butyllithium hexane solution was added, and while stirring at -60°C or lower, 2 [15 m/(α59
A solution of 50 mol of acetonitrile dissolved in 50 mol of tetrahydrofuran was added dropwise over 15 minutes, and the mixture was further stirred at the same temperature for 1 hour to form a milky suspension.

This was added with 59.7 t of 4.5.6.7-titrahydro6.6-dimethyl-7-okinepenzothiazole (α3
A solution of 3 mol) dissolved in 10 mol of tetrahydrofuran was added dropwise at -70°C or less over 15 minutes.

After stirring at -70 to -80°C for 35 minutes, 200 d'li of water containing 23-acetic acid was added, and the resulting white precipitate was filtered, washed well with water and chloroform, and dried. Combine the filtrate and washing liquid, separate the organic layer, extract the aqueous phase with chloroform, combine the organic layer and chloroform layer, and chlorinate)
It was washed with an aqueous solution of IJum, dried over magnesium sulfate, and the solvent was distilled off. When the resulting a residue was combined with the nine-white precipitate obtained earlier and crystallized from ethyl acetate, mp was 174-5y.
) 7-Diathmethyl-4.5.4 as colorless prismatic crystals
59.3 f (yield: 81 f) of 7-titrahydro-7-hydroxy-6,6-dimethylbenzothiazole was obtained.

The mp of the recrystallized product of this product in ethyl acetate is 175.
It was ~6°C.

IRν (Nujol): 3200, 2225cm
-'Me m/e: 222(M+), 182(
M”-OHION)NMRδ(ODOj, :CD, 0
D=4:1):1.07(6H,s) 1.86(2H,t, J=5.5Hz)2.64(
IH, s) 2.75-5. OO (4H, m) a7o (1a, s) Elemental analysis two-calculated value' Cu N14 Nt O8) (Arrogant: C! 59.43; H&35: N
12.60 Actual value (Hook: 059.46: H6,
23; N 12.69 7-diazumythyl-4.5
．． 47-titrahydro-7-hydroxy-6,6-dimethylbenzothiazole 5αat<α14 mol)
The mixture was added to 1a58f of lithium aluminum hydride suspended in 500 of ether and added dropwise over 80 minutes under water cooling and stirring. After 2 hours, Rochelle salt bath solution was added to separate the organic layer, the aqueous layer was extracted with chloroform, and the chloroform layer was combined with the organic layer and extracted with sodium chloride.

The composition of 7-(2-aminoethyl)-4,5,6 was obtained by washing with an aqueous solution of 7-(2-aminoethyl)-4,5,6 and drying with anhydrous potassium carbonate.
, 7-titrahydro-7-hydroxy-6,6-dimethylbenzotheazole, a dark red oily proboscis 34. Of was obtained.

This was dissolved in 50% sulfuric acid, and in an argon stream,
React for 3 days in an oil bath at 115°C to 120°C, dilute with twice the amount of water to remove insoluble matter, make the filtrate alkaline with sodium hydroxide, extract with chloroform, and wash with a sodium chloride water bath. , dried over magnesium sulfate and distilled off the solvent to obtain 7-(2-aminoethyl)-4,7.
The oily substance of 7-dimethylbenzotheazole was distilled under reduced pressure to -Sihydro. bp, 1 (10-111℃ (α18
■ Hg) pale yellow clear fall product is 16.39 (yield: 58 cm)
Obtained.

Next, 4.1 td (7? mmol) of bromine was added to 200
- in chloroform and add h 24 f (5
0 mmol) of 7-(2-aminoethyl)-4,7-
Sihydro 6.7-dimethylbenzotheazole 40-
A solution dissolved in chloroform was added dropwise over 5 minutes while stirring under water cooling, and the mixture was further stirred under water cooling for 10 minutes, and then at room temperature for 1 hour. The solvent was concentrated under reduced pressure, and the residue was dissolved in ethanol and crystallized by adding acetone to give a pale yellow powder.
α-bromo4.5.5α,1a8α-tetrahydro-
5aα, 8a (Z-dimethyl-6H-thiazolo [翫4
-θ] indole trihydrobromide 1 (111f(
Yield: 75%). When the melting point was measured, it was 216-22
Decomposed at 0°C.

NMRδ(OFs 0OOH)”, 1.92 (A
M, s) 1.95 (3H, s) 2.55-100 (2H, ??+) 150-4.40 (4H, m) 5.04 (11, ad, J-5,5,10Hz
) 1αo6 (1n, a) Elemental analysis 2 calculations @ (01, Hl, N, SBr*2HBr
)(%): 0 29.42; H582;
N & 2491 iMV love) 2 0 29
．． 64; H3,58; N 409
5α-bromo4.5.5α,1a8α-tetrahydro-
5aα, 8aα-dimethyl-6■-thiairo[5,4
-8] Indole trihydrobromide 12.68f (2H
mmol) and potassium carbonate 15. Of (109mm
ol) in methanol-chloroform (1:1) for 100s
After stirring for 18 hours, water was added and extracted with chloroform, washed with water, dried over magnesium sulfate, and the solvent was distilled off to obtain 6.549 yellow solids.

This was confirmed to be a crosslinked aziridine type compound.

Furthermore, this crude product 'ii2. 80m7 of chloroform containing od of triethylamine! Nitokaji, this one
α08? (54 mmol) of sodium bromide/soil in 10
A solution of 9 baths dissolved in chloroform was added dropwise over 10 minutes while stirring on ice, and the mixture was further stirred at room temperature for 6 hours. Next 1
0% sodium carbonate aqueous solution 100 - Add all of it and stir overnight, then extract with chloroform and 1! After washing with dilute hydrochloric acid, water and drying over magnesium sulfate, the solvent was concentrated and the resulting yellow oil was purified by silica gel column chromatography.

Elution was first carried out with benzene and then with ethyl acetate, and the eluted portions of ethyl acetate 11 degrees 15% to 25% (7) were combined and crystallized from ethyl acetate-n-hexane to give a pale yellow prismatic group (rnp, 162 .5~164℃)
and 1, 9.94F of 2-pensoyl-9α-bromo-
9β-dimethylthiazolo[5,4-11 morphane was obtained (yield 90%).

Engineering Rν (Nujol): 1615a++-'Me
m/e: 392.390 (20%, 19%, M
)311 (100%, M-Br) NMRδ(ODO4)'', 1.60(AH,s)1
．． 99<2.08(5H,br s)7.41(5H,
5) a6s (1H, s) Elemental analysis two calculated values (o1@H1@N, 08Br
M@:05!1L25: H4,89: N 7.1
6 Actual measurement value (→: OS5.25; H5f16 i
N 6.97 2-benzoyl-9α-bromo-melon 9β-dimethylthiazolo [5,4-73 mol 7 am 4,10 f (1 (L5 mmol), DBU 5
．． After heating a mixture of 03f (1 mmol of 3N) and 10 tnt of dry dimethyl sulfoxide in an oil bath at 120±5°C in medium argon for 3 days, the dimethyl sulfoxide was distilled off under reduced pressure, water was added to the residue, and diluted hydrochloric acid was added. The mixture was made acidic, extracted with p-roform, washed with water, dried over magnesium sulfate, and the bath medium was distilled off.The resulting oil was subjected to column 1 chromatography on silica gel.

Ethyl acetate (15%) - benzene (ass) mixed bath solution (#) 154fc quantitative) 2-pensoyl-5-methyl-9-methylenethiazolo[5,4-f
] Obtained a morphan.

IRν(CIO7m): lS2Om-'Me
m/s: 510 (1.5%, M+), 295 (
88%, M”-OH, ) 105 (100%, co@
) Analysis calculation value by high-resolution mass spectrum (0, sHl, N, 013): 310.
1139 actual measurement value, 310. 11
15NMR' (CD C1@): t59 (
3L g ) 7.40 (5 Mr. 8) a65 (IH, s) Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 Synthesis of 5.9α-dimethylthiazolo[5,4-71morphan 2-benzoyl-5-methyl-9-methylenethiazolo(
5,4-z1morphan 318? (1α3 mmol) was dissolved in 40-molecular ethanol, added with 80-molar 6N hydrochloric acid, and refluxed for 21 hours. The ethanol was distilled off under reduced pressure. The remaining liquid was diluted with water, washed with ethyl acetate, and made alkaline with sodium carbonate. After extracting with chloroform, washing with water and drying with magnesium sulfate, the solvent was distilled off.
5-methyl-9-methylenethiazolo[5
,4-/, ]morphan was obtained.

Engineering Rν (OHOJ,): 5500,5075,1
655 (an""1M5m/e (20eV): 2
06 (6%, M”), 191 (100%) NMRδ(
ODC4, ): 1.55 (iH, θ)1, tS O
~1.80 (2H1m) 2.21 (IH, br, s).

2.70-2.85 (2H, m) 109 (, I H, dd, J=18.2Hz) 15
2 (I H, dd, J=18..6Hz)' 1
89 (IH, tXd, J=6.2Hz) 4:82 (
1'lH,8) 4.95(IH,5) a62(IH,s) The above 5-methyl-9-methylenethiazolo[5,4/]
Mol 77:/2.00 f, 5%P(1-00,5
1? After reducing the mixture of ethanol and ethanol at 4 atmospheres for 5.5 hours using Oskita Pearl's medium pressure reduction equipment, the catalyst was removed and the F solution was distilled off under reduced pressure.
A white solid of t was obtained. Column chromatography on silica gel was carried out, first with chloroform and then with methanol.
1.82t (yield 90t) of 5,9α from the 0t bath outlet
-dimethylthiazolo[5,4-71 morphane was obtained.

When oxalate is recrystallized from ethanol, the decomposition group 1i
Colorless prismatic crystals were obtained at 222-225°C, which gave the following elemental analysis values.

Calculated value (01, H,, N, 8.(C ring n) - (@:0
5233; H6iJ8; N 9.59
Actual value (@: csz39; H5,89;
N9.27 Example 2 Synthesis of 2,5.9α-trimethylthiazolo[5,4-z)morphan 5,9α-dimethylthiazolo[s,
a-t] Morphin 785■, 99% formic acid 30-
After refluxing a mixture of 35 and 35 tiformin 8 for 5 hours,
The reaction solution was concentrated under reduced pressure, the residual liquid was made alkaline with sodium carbonate, extracted with chloroform, washed with water, and dried over magnesium sulfate. The solvent was distilled off and the resulting pale yellow oil was transferred to an alumina column chromatograph. 7681 from the attachment part ""'-exit part and the dichloroform/benzene bath part
lv (yield: 92 g) of 2.5.9α-trimethylthiazolo[5°4-f]morphanke was obtained.

When hydrochloride is recrystallized from ethanol, the temperature is 224-227℃.
A colorless powder was obtained with a decomposition point of . The elemental analysis results were as follows.

Calculated value (C1, H,, N, 8・2H (J・+ato)
(Arrogant: 047.57; H&96; N 9.21
Actual value (@: 047.52; H6,
88; N 9.16 Example 3 Synthesis of 2,5.9β-trimethylthiazolo[5,4-71morphan 2-benzoyl-5-methyl-9-mefVnteazolo[
5,4-z]morphan&52F,1[1%F(1-0
1,18F and 150-ethanol were placed in an autoclave and hydrogenated at 50 atm and 50°C for 5 hours. Colorless oil t-20 obtained by soaking the catalyst in P and distilling off the F solution
- is dissolved in ethanoyl, 20-dihydrochloric acid 150- is added, refluxed for 2 days to hydrolyze, the reaction solution is made alkaline by a conventional method, extracted with ether, the ether layer is dried, and the ether is distilled off. A yellow clear autumn product of 1.86 f was obtained.

This crude amine was also subjected to the same treatment as in Example 2 and subjected to alumina column chromatography, and from the benzene eluate, 1.17 f (yield 46 g) of the target 2, 9
β-trimethylthiazolo[5,4-t]metalfanwo,
2.5.9α-trimethylthiazolo[5,4-t]morphan of α59f (yield 23%) was obtained from the ranibenzene-benzene/chlorophor A (1:1) eluate.

β-form Noshu [・ is 228 when recrystallized from ethanol
It was a colorless prismatic crystal that showed a decomposition point at ~2'30°C, and the elemental analysis values were as follows.

Calculated value (0,, H,, NtB・(coon)t) (proboscis: 0531; H6,45; N 11197 actual value (99: 053.67; H630; H9,
04 Example 4 Thiazolomorph analgesic activity Example 1
．． In order to understand the pharmacological action of the thiazolomorphans obtained in 2 and 3, the analgesic activity was measured using the Codin Society standard substance using the acetic acid writing method in mice. The results are shown in Table 1.

In the acetic acid writing method referred to herein, analgesic activity was evaluated as follows.

(Using ld-Y male mice, 20 minutes after subcutaneous administration of test drug and control drug [(L6% acetic acid saline (I11d
/10F) was administered intraperitoneally, and the number of writings that occurred 5 to 10 minutes after administration was counted, and when the number of writings was less than half that of the control group administered with physiological saline, it was determined that the analgesic effect was positive. .

Patent Applicant: Toyo Soda Kogyo Co., Ltd. Procedural Amendment August 11, 1980 Commissioner of the Patent Office Kazuo Wakasugi 1 Case Description 1984 Patent Application No. 084030 2 Name of Invention New thiazolomorphans and their Manufacturing method 6 Person making the amendment Telephone number (58515311 6 Detailed description of the invention column of the specification to be amended 7 Contents of the amendment (1) [5α-Bromo-45,5α , Sua8α-tetrahydro-5aα,8aα-dimethyl-6H-thiazolo(5,4
-e) indole trihydrobromide” and [5α-bromo4.5.5false7. a8α-tetrahydro-5aα, aaα-dimethyl-6H-thiazolo(5,4
-e) indole trihydrobromide” to [5α-bromo4.5.5a, 7. a 8a-tetrahydro-5aα, 8aα-dimethyl-6■-thiazolo[5,4-θ]indole trihydrobromide”.

Claims (1)

[Scope of Claims] (1) Thiazolomorphans or salts thereof represented by the general formula (wherein R1*R2 and R are hydrogen or methyl groups). (The thiazolomorphans or salts thereof according to claim 1, in which 21R, is hydrogen and R2 is a methyl group. (31R, is a methyl group, and R2 is hydrogen) Thiazolomorphans or salts thereof according to Range 1. 2-benzoyl-5-methyl-9-methylenethiazolo[5,4-13morphane (in the formula, Bz is
(representing a diyl group) is subjected to hydrolysis and hydrogenation reaction,
A method for producing thiazolomorphans represented by the general formula (wherein RIsR1 and R1 represent hydrogen or a methyl group) or salts thereof, which comprises treating with formaldehyde and formic acid as necessary. (5), R and R3 are hydrogen, each R2 is a methyl group, and after hydrolyzing 2-pensoyl-5-methyl-9-methylenethiazolo[5,4-13morphane, it is subjected to a hydrogenation reaction; The manufacturing method according to claim 4. f61 R1 is hydrogen, R7 and R3 are methyl groups, 2-benzoyl-5-methyl-9-methylenethiazolo[s,at]morphan is hydrolyzed, then subjected to hydrogenation reaction, and further formaldehyde 5. The manufacturing method according to claim 4, which comprises treating with formic acid and formic acid. (7) 2-benzoyl-5-methyl-9-methylenethiazolo[5,4-7) mol 7 am is hydrogenated and then hydrolyzed so that R1 and R3 are hydrogen and R1 is a methyl group. 5. The production method according to claim 4, for obtaining a mixture of thiazolomorphans and thiazolomorphans in which R8 is a methyl group and R3 and R1 are hydrogen. (8) 2-benzoyl-5-methyl-9-methylenethiazolo[5,4-13 morphane was hydrogenated and then hydrolyzed, further treated with formaldehyde and formic acid, and then RI
is hydrogen, R7 and R3 are methyl groups, thiazolomorphans, RI and R3 are methyl groups, and R1
5. The production method according to claim 4, which obtains a mixture with thiazolomorphans in which is hydrogen.