JPH045264A - Ethanolamine derivative and production thereof - Google Patents

Abstract

NEW MATERIAL:An ethanolamine derivative expressed by formula I or salt of said derivative (ring A is crosslinked cyclic hydrocarbon substitutable with cycloalkane or hydroxy methyl; R<1> is alkyl, alkenyl, saturated aliphatic acyl or unsaturated fatty acyl). EXAMPLE:1-(palitoylamino)cyclopentyl methanol. USE:Useful as preventive and remedy of various diseases having high selectivity and strong inhibiting activity against protein kinase C. For instance, useful as an anti-cancer agent, anti-inflammation agent, platelet aggregation-inhibitor, antihypertensive agent, immunomodulation agent and further as cerebral activator. PREPARATION:For instance, a compound expressed by formula II(ring B is cycloalkane; R<2> is ester residue) is reduced by using a reducing agent, or a compound expressed by formula II (ring C is crosslinked cyclic hydrocarbon; R<31> is H, etc.) is reduced to afford the aimed compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to an ethanolamine derivative and a method for producing the same. More specifically, the present invention relates to an ethanolamine derivative having a protein kinase C inhibitory effect and a method for producing the same.

[Prior art/issues to be solved by the invention] Protein kinase C, together with calcium, plays a central role in the communication between cells, and plays a role in the regulation of a variety of biological phenomena [
Y, N15hlzuka.

5science, 233.305-312 (198
6) and Yasumi Nishizuka, Science, 57 (3), 132-
See page 140 (1987)]. Therefore, protein kinase C inhibitors are expected to be used as preventive and therapeutic agents for various diseases, and are also useful for elucidating the mechanisms of diseases in which protein kinase C is involved.

Staurosporine, dibucaine, tetracaine, neomycin, gentamicin, tobramycin, trifloperazine, chloropromacine, polymyxin B, etc. have been reported as protein kinase C inhibitors.
These have problems such as low inhibitory activity, cytotoxicity, and also have protein kinase A inhibitory activity.

The object of the present invention is to provide a novel compound with a high protein kinase C inhibitory activity, which has a completely different structure from conventional products.

[Means for Solving the Problems] The present invention has the general formula (I): (wherein, the ring is a bridged cyclic hydrocarbon which may be substituted with a cycloalkane or hydroxymethyl group, R1 is an alkyl group, The present invention provides an ethanolamine derivative represented by an alkenyl group, a saturated aliphatic acyl group, or an unsaturated aliphatic acyl group, or a salt thereof.

The present invention further provides a general formula N: (wherein ring B represents a cycloalkane, R1 represents an alkyl group, alkenyl group, saturated aliphatic acyl group or unsaturated aliphatic acyl group, and R2 represents an ester residue). An ethanolamine derivative represented by the general formula (Ia) (wherein, ring B and R1 are the same as above), which is characterized by reducing the compound obtained by using a reducing agent and, if necessary, converting the product into a salt. Or provide a method for producing the salt.

The present invention further provides a general formula (VD: (wherein, ring C is a bridged cyclic hydrocarbon, Bi2 represents a hydrogen atom or -CO2R'(R' is an ester residue),
General formula (Ib) characterized in that the compound represented by R1 and R2 are the same as above is reduced using a reducing agent and the product is converted into a salt if necessary: (wherein R3 is a hydrogen atom or hydroxymethyl group, and ring C and R1 are the same as above).

[Function and Examples] In the general formula (I), examples of the cycloalkane as ring A include cycloalkanes having 5 to 6 carbon atoms. Examples of the bridged cyclic hydrocarbon as ring A include two-ring hydrocarbons having 7 to 8 carbon atoms. This bridged cyclic hydrocarbon may be substituted with a hydroxymethyl group.

Preferred examples of Ring A include cyclopentylidene.

Examples of the alkyl group having 10 to 20 carbon atoms represented by R1 include decanyl group, undecanyl group, dodecanyl group, tridecanyl group, tetradecanyl group, pentadecanyl group, cetyl group, heptadecanyl group, octadecanyl group, nonadecanyl group, eicosanyl group, etc. It will be done. Number of carbon l
Examples of the O-20 alkenyl group include geranyl group and oleyl group. Examples of the saturated aliphatic acyl group having 10 to 20 carbon atoms include decanoyl group, undecanoyl group, lauroyl group, myristoyl group, pentadecanoyl group, valmitoyl group, heptadecanoyl group, and stearoyl group. Examples of the unsaturated aliphatic acyl group having 10 to 20 carbon atoms include undecenoyl group and oleoyl group.

Further, among the compounds (I) of the present invention, those in which R1 is an alkyl group or an alkenyl group can form a salt by acid treatment in a conventional manner.

Examples of the salt include inorganic acid salts such as hydrochloride, hydrobromide, and sulfate, and organic acid salts such as paratoluenesulfonate and maleate.

Preferred examples of the compound (I) of the present invention are shown in Table 1.

[See the following margins] The compounds of the present invention have high selectivity and strong inhibitory activity against protein kinase C, and are useful as preventive and therapeutic agents for various diseases.

In other words, protein kinase C is likely to be a target of oncogenic promoters and is involved in cell proliferation through the activation of growth factors. Therefore, protein kinase C can be used as an anticancer agent to stimulate the release and secretion of various cellular components, such as catecholamines, hormones, and acetylcholine. It is an anti-inflammatory agent and platelet aggregation inhibitor because it is involved in the secretion of dopamine, serotonin, arachidonic acid, lysosomal enzymes, histamine, and thromboxane. It is an antihypertensive agent because it is involved in the contraction of vascular smooth muscle, and it is effective for immune system cells. (T lymphocytes, B lymphocytes)
It is used as an immunomodulatory agent because it is involved in the activation of the brain and seabird pyramidal neurons, and as a brain stimulant because it may be related to synaptic plasticity and learning/memory since the brain and seabird pyramidal neurons are strengthened over a long period of time by this enzyme. It is useful as

It can also be used as a reagent to elucidate the mechanism of action of drugs in diseases involving protein kinase C and disease mechanisms in pathological models.

Compound [11] of the present invention can be produced, for example, by the following method.

(1) First method A compound in which ring A is a cycloalkane in general formula (1) can be produced by the following method.

First step (la) (wherein, X represents a halogen atom, and rings B1R1 and R2 are the same as above).

The first step can be carried out under conventional acylation and alkylation reaction conditions.

In the case of the acylation reaction, compound (I[) is first reacted with an acid halide circle as an acylating agent in the presence of a base in a suitable solvent.

Examples of the solvent used here include water, tetrahydrofuran (TIP), acetonitrile,
Examples include aprotic organic solvents such as dichloromethane. As the base, for example, Na HCOs, Na
Examples include alkali metal carbonates such as 2CO3, bicarbonates, and trialkylamines (alkyl groups having 1 to 4 carbon atoms) such as triethylamine and tripropylamine.

Preferred solvent-base systems include water-NaHCO3, tetrahydrofuran-triethylamine, acetonitrile-triethylamine, dichloromethane-triethylamine, etc. In the case of an aprotic organic solvent-trialkylamine, an acylation promoter such as 4-dimethylaminopyridine is used as a catalyst. By using a sufficient amount, the reaction can proceed rapidly. In general formula 1, when R1 is an acyl group, X is a chlorine atom, a bromine atom, or the like. Further, as the ester residue in compound (1), any commonly used ester residue can be used, and for example, substituted or unsubstituted alkyl groups can be suitably used. A base is a compound (
1[) 1.1 to 2.0 times equivalent, preferably 1.2
~1.5 equivalents are added. An acid halide circle is a compound (1
1.0 to 2.0 times equivalent of ), preferably 1.2 to 1
．． Five equivalents are added. The reaction is carried out at θ°C to the boiling point of the solvent, preferably 0 to 30°C, particularly preferably 0 to 10°C,
It is carried out for 0.5 to 20 hours, preferably 1 to 2 hours.

In the case of alkylation, compound (II) is reacted with an alkyl or alkenyl halide circle as an alkylating agent in a suitable solvent or in the absence of a solvent in the presence of a base. Examples of the solvent used here include aprotic solvents such as hexamethylphosphoric triamide (IMPA), dimethylformamide (DMF), acetone, and dimethyl sulfoxide (DMSO). Examples of the base include K2CO3.

As a solvent/base system, HMPA-, 2C03, DMF
-2CO3, acetone-2CO3, DMSO-2
C03 and the like are preferred. In general formula 1, when R1 is an alkyl group or an alkenyl group, X is a chlorine atom, a bromine atom, an iodine atom, or the like. The base is added in an amount of 1.2 to 2 times, preferably 1.2 to 1.5 times the equivalent of compound [n). The alkyl or alkenyl halide is 1.2 to 2 times the weight equivalent or 1.2 times the amount of the compound.
~1.5 equivalents are added. The reaction is carried out at a temperature of 0 to 100°C, preferably 50 to 100°C, particularly preferably 70 to 80°C.
℃ for 10-24 hours.

In the second step, the compound N obtained in the first step is
is reduced using a reducing agent in a suitable solvent. Examples of the solvent used here include ether solvents such as THF, dioxane, and diethyl ether, preferably THF and diethyl ether. As a reducing agent, Li/VH<, B2)+6, LIB)+4,
Ca(BN2)2, NaB)14-CHJOH, preferably Li/VHa, Ca(BN2)2, NaBH4-C
One example is HxOH. The reducing agent is 1.5 to 2 of compound ■
．． Five equivalents are added. The reaction is carried out at 10-25°C, preferably 20-25°C, for Go-180 minutes.

(21 Second Method) Compounds in which the ring is a bridged cyclic hydrocarbon in general formula (1) can be produced by the method described above.

First step (Ib) (wherein, ring C5RI R2R3R'' and X are the same as above).

The reaction conditions of the first step and the second step are the same as those of the first step and the second step of the method for producing a compound in which ring A is a cycloalkane in general formula (1).

In addition, compounds in which a double bond exists in ring C in compound (1b) can be prepared using a conventional method of catalytic hydrogenation, for example,
A compound in which the double bond in ring C is reduced to a single bond by hydrogenation in the presence of palladium-carbon, palladium black, etc.
b).

Incidentally, among the raw material compounds M mentioned above, a compound in which ring C is norbornane or norbornene can be obtained using the Diels-Alder reaction as follows.

[Margin below] (In the formula, R5 represents an alkyl group, and R2R3+ and R4 are the same as above).

The Diels-Alder reaction can be carried out by a known method [Horiyo et al., Tetrahedron Letters, Vol. 21, pp. 4101-4104 (1980) and JP-A-54-109957. See official bulletin].

Refer to R - Shrimping in the case of CO2R4 is handled by Deals.
This can be carried out by dissolving the compound (Vlla) obtained by the Alder reaction in a suitable solvent and reacting with a base. Examples of the solvent used here include methanol, ethanol, THP, DMP, and dioxane. Examples of the base include sodium methoxide, potassium t-butoxide, and 1,8-diazabicyclo[5,4,0]-7-undecene (DBU). The base is 0.2 to 0.5 of the compound (Vlla)
Double equivalents are added.

The reaction is carried out at θ°C to the boiling point of the solvent, preferably 10 to 20°C, for 10 to 24 hours. At this time, the solvent-base system is preferably methanol-sodium methoxide, and when methanol is used as the solvent, the reaction proceeds suitably under heating and reflux conditions.

The solvent used in the subsequent deacylation reaction is, for example, CH2C12, CHCIIIs, preferably CH
2C12 is mentioned. The deacylation reaction is, for example,
This is done by using the Meerbein reagent. The deacylating agent is a compound (Vlla)
or m1lb) in an amount of 1.1 to 1.2 times equivalent.

This reaction is carried out at 10-20°C, preferably at room temperature, for 2-4 hours.

In addition, norbornene compounds (Va) and (Vb) are reduced in the same manner as when ring C has a double bond in compound (Ib) to form norbornane compound (Vc).
and (Vd).

The present invention will be explained in more detail below using Examples, but the present invention is not limited to these Examples.

Example 1 Production of 1-(balmitoylamino)cyclobentylmethanol (1) 2.5 g of -aminocyclopentanecarboxylic acid methyl ester was dissolved in 20 ml of THF, and triethylamine 4, 45 ml and 4 -Add 1 g of dimethylaminopyridine O. While stirring under water cooling, 4.37 g of valmitoyl chloride was added over 5 minutes, and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the residue was extracted with ethyl acetate, washed with water, and then dried. The solution was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-hexane to obtain 4.1 g of 1-(balmitoylamino)cyclopentanecarboxylic acid methyl ester as colorless needle-like crystals (mpnia a to 74°C).

IR (Nujol) (Country-1): 3300.1735.
1640, NMR (CDC#3) δ: 0.
7-2.5 (shoes, 39H), 3.67 (s, 3H)
, 5.95 (br s, 1H) (2) 3.83 g of 1-(balmitoylamino)cyclopentanecarboxylic acid methyl ester obtained in (1) above was dissolved in THF (20 ml
) dissolves in This solution is added to lithium aluminum hydride (379 mg) suspended in THF (lom+) while stirring under water cooling. After stirring at the same temperature for 30 minutes, water (0.38 ml) and 15% NaOH aqueous solution (0.38 ml) were added.
m1) and water (0.38 m1 x 3) were added in order to stop the reaction. After filtering out insoluble matter, the liquid is concentrated to dryness. The remaining crystals are recrystallized from ethyl acetate-hexane to obtain 3.0 g of 1-(balmitoylamino)cyclopentylmethanol as colorless needles (mpia 8-77°C).

Example 2 Production of 1-(balmitoylamino)cyclohexylmethanol (1) 1.1 g of -aminocyclohexanecarboxylic acid methyl ester and 2.02 g of balmitoyl chloride were reacted in the same manner as in Example 1 (1). , 1-(balmitoylamino)cyclohexanecarboxylic acid methyl ester is recrystallized from petroleum ether to obtain 2.7 g as colorless needles.

(2) 2 g of 1-(valmitoylamino)cyclohexanecarboxylic acid methyl ester obtained in (1) above was treated in the same manner as in Example 1-(2) to obtain the desired product l-(valmitoylamino). Cyclohexylmethanol was recrystallized from isopropyl ether, resulting in 1.4g of colorless needle crystals.
(mp: 61-62°C).

NMR (CDCA' δ: 0.8~1, 0 (m
, 3H), 1.1-2.0(s, 38H) 2.
1-2.3 (m, 2H), 3.59 (d, 2H), 4.
93 (t, LH), 5.38 (br s, IH) MS (i/e): 36G (M-1) Example 3 Production of 2-endo-cetylamino-5-norbornene-2-methanol (1) 1.05 g of 2-endo-acetamido-5-norbornene-2-carboxylic acid methyl ester was added to CH2C
Dissolve in 1220ml and add EtxO・BF4 (
triethyloxonium tetrafluoroborate)2.
Add 29 g and stir at room temperature for 2 hours. The reaction solution is cooled with ice, and the reaction is stopped by adding aqueous sodium bicarbonate and stirring for 30 minutes. The organic layer was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (CHCI!3:acetone-5:1) to obtain 2-endo-amino-5-norbornene-2.
- Carboxylic acid methyl ester as pale yellow syrup 0
．． Obtain 55g.

NMR (CDCl2) δ: 0.8-1.1 (s, IH)
, 1.2~1.8(m, 214>, 1.59(s, 2
B), 2.8-3.1 (s, 2H), 3.7111 (
s, 3H), 6.1~6゜3(s, LH), 6.4~1
3.8 (m, LH) MS (m/e) + 167 (
M") (2) Dissolve 0.84 g of 2-endo-amino-5-norbornene-2-carboxylic acid methyl ester obtained in (1) above in 1 ml of HMPA, and add 1.9 g of cetyl bromide and 1 ml of potassium carbonate. .03 g was added and stirred at room temperature for 4 days. Ethyl acetate was added to the reaction solution, washed with water, and dried. After concentration under reduced pressure, the residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate).
2-endo-cetylamino-5
1.3 g of -norbornene-2-carboxylic acid methyl ester are obtained as a colorless syrup.

(3) 2-endo-cetylamino-5-norbornene-2-carboxylic acid methyl ester 2 obtained in (2) above
．． 0 g was reacted in the same manner as in Example 1-[2), and the product was treated with hydrogen chloride-methanol in acetone to give 2-endo-cetylamino-5-norbornene-2-methanol hydrochloride as colorless crystals. Obtain 48g (Practice: 1
37-139°C).

NHR(CDCIs + DMSO-d6 + D2
0) δ: 0.9-1.0 (s, 3H), 1.1-
1.9 (Peng, 34H), 2.6-3.1 (m, 4
H), 5.9-6.1 (Oboro, LH), 6.3-6.
5 (m, lH) MS (m/e): 383 (Freebase ")
Example 4 Production of 2-endo-balmitoylamino-5-norbornene-2-methanol (1) 2-endo-amino-5-norbornene-2-
1.5 g of carboxylic acid methyl ester and 2.5 g of balmitoyl chloride were reacted in the same manner as in Example 1-[1) to obtain 2-endo-balmitoylamino-5-norbornene-2-carboxylic acid methyl ester 2. Obtain .8g (
mpnia 3-74°C).

('23 41 g of 2-endo-balmitoylamino-5-norbornene-2-carboxylic acid methyl ester obtained in (1) above was reacted in the same manner as in Example t-(2),
Obtain 3.1 g of 2-endo-balmitoylamino-5-norbornene-2-methanol as colorless needles (s
p: 94-96°C).

NMR (CD(J3)δ: 0.75-1.0(m
, 3H), 1.0-1.8 (w, 2.9H), 1.9-
2.2 (m, 3H), 2.85 (br s, IH), 3
．． 32 (br s, IH), 3.80 (d, 2H), 5
．． 03 (t, IH), 5.4-5.6 (s, IH), 5
．． 9-6.1 (i, LH), 6.2-6.4 (ei, I
H) MS (m/e): 377 (M”) Example 5 Production of 2-endo-cetylamino-2-exo-3-exo-bis(hydroxymethyl)-5-norbornene (1) 2-endo-acetamide 11.5 g of -2-exo-3-exo-bis(methoxycarbonyl)-5-norbornene was treated in the same manner as in Example 3-[1), and
-endo-amino-2-exo-3-exo-bis(
5.2 g of methoxycarbonyl)-5-norbornene are obtained as syrup.

(2-2-endo-amino-2- obtained in (1) above)
exo-3-exo-bis(methoxycarbonyl)-5
- 5.2 g of norbornene and 8.6 g of cetyl bromide
was reacted in the same manner as in Example 3-(z) to give 2-endo-cetylamino-2-exo-3-exo-bis(methoxycarbonyl)-5-norbornene as colorless crystals.
．． Get 5g.

(3) 2-endo-cetylamino- obtained in the above (2)
2-exo-3-exo-bis(methoxycarbonyl)
5.5 g of -5-norbornene was treated in the same manner as in Example 3-(3) to obtain colorless 2-endo-cetylamino-2-exo-3-exo-bis(hydroxymethyl)-5-norbornene hydrochloride. Obtain 4.1 g as needle crystals (s
p: 154-155°C).

NMR (CDCI3 + DMSO-d6 + D20
) δ: 0.7-1.0 (comic, 3H), 1.0-2.
0 (m, 29H), 2.5-3.0 (m, 4H),
3.4-4.2 (■, 4H), 5.9-6.1 (Ten, I
B), 6.4-6.6 (Zen, lH) MS (1/e)
: 393 (Freebase') Example 6 2-endo-valmitoylamino-2-exo-3-
Production of exo-bis(hydroxymethyl)-5-norbornene (1) 2-endo-amino-2-exo-3-exobis(methoxycarbonyl)-5-norbornene 2.6
Example 1-(
1) to obtain 4.1 g of 2-endo-balmitoylamino-2-exo-3-exo-bis(methoxycarbonyl)-5-norbornene as colorless crystals.
(19288-89°C).

('2JExample 1-
(Processed in the same manner as '2J, 2-endo-balmitoylamino-2-exo-3-exo-bis(hydroxymethyl)-5-norbornene was converted into colorless needles at 2.1
g (mp: 90-91"C).

NMR (CD (J s”) δ: 0.8 to 1.0 (m, 3
H), 1.1-1.9 (+a, 29B), 2.0-2.
2(m, 2H), 2.55(br s, It(),
3.23 (br s, lH), 3.5-4.1 (g
+, 4H), 4.0 to 4.4 (br, IH),
5.0-5.2 (m, LH), 5.77 (s, LH
) 6.0-6.2 (m, lH), 6.3-6.5 (m
, LH) MS (m/e): 407 (M”)
Example 7 2-endo-oleoylamino-5-norbornene
-Production of 2-methanol (1) 2-endo-amino-5-norbornene-2-
0.5 g of carboxylic acid methyl ester and 0.9 g of oleoyl chloride were treated in the same manner as in Example 1-(1) to obtain 2-
endo-oleoylamino-5-norbornene-2-
The carboxylic acid methyl ester is obtained as a colorless syrup.

(2) 1.1 g of 2-endo-oleoylamino-5-norbornene-2-carboxylic acid methyl ester obtained in (1) above was treated in the same manner as in Example 1-[21, and
-Endo-oleoylamino-5-norbornene 2-
0.9 g of methanol is obtained as a colorless syrup.

Example 8 Production of 2-endo-cetylaminonorbornane-2-methanol 0.15 g of 2-endo-cetylamino-5-norbornene 2-methanol was dissolved in 10 ml of methanol, and 1
Add 0.1 g of 0% palladium-carbon. 2 of the mixture
A reduction reaction is carried out for 3 hours at room temperature in a hydrogen stream at atmospheric pressure. Insoluble matter is removed from the reaction solution, and the furnace solution is dried under reduced pressure. By adding hexane to the residue and crystallizing it, 2-endo-cetylaminonorbornane-2-methanol O,
1 g is obtained (llfl 119-126°C).

Reference Example 1 (1) 2-acetamidofumaric acid dimethyl ester 55.
6g of carbon tetrachloride was dissolved in 400ml of carbon tetrachloride, 25.1g of aluminum chloride was added to the solution, and 14g of cyclopentadiene was dissolved in 400ml of carbon tetrachloride.
Divide 0 ml into 4 portions and add over 3 hours.

After stirring the mixture overnight at room temperature, the solvent was removed under reduced pressure. The residue was triturated twice with 400 ml of ethyl acetate, and the solution was separated by decantation. The solutions are combined, washed and dried, and then the solvent is distilled off.

The residue was purified with a silica gel column [solvent: chloroform-acetone (roll)] and recrystallized from ethyl acetate-〇-hexane to give 2-endo-acetamido-2-exo-3-endo-bis(methoxycarbonyl)- Obtain 18.4 g of 5-norbornene as colorless needle crystals (mp:
97-99°C).

NMR (CDC# s>δ: 1.4-2.1 (s+, 3
H), 1.89 (s, 3H), 3.111 (br s,
IH), 3.44 (d, J-3Hz, IH) 3.
H and 3.76 (2s, 6H), 6.2-6.5 (s
, 2H), 7.09 (br s, IH) MS (1/e): 287 (M") (2) Said (
2-endo-acetamide 2-exo-3 obtained in 1)
-Endo-bis(methoxycarbonyl)-5-norbornene 0.53 g was dissolved in 20 ml of methanol, and IN
Add 0.5 ml of sodium methoxide and stir at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified with a silica gel column [solvent: chloroformacetone (5:1)] and recrystallized from ethyl acetate to give 2-endo-acetamido-2-exo-3-exo-bis(methoxy) 0.28g of (carbonyl)-5-norbornene as colorless needle crystals
(-p: 170-171'c).

NMR (CDCl2) δ: 1.7-1.9 (m, IN
), 1.91(S, 31(), 2.3-2.6(m, 2
H), 3.00 (br s, IH), 3.67 and 3
．． 69 (2s, 6H), 3.84 (br s, In),
6.1-6.3 (m, IH), 6.3-6.5 (m, L
H), 6.26 (s, LH) MS (m/e): 267 (M”) The protein kinase C inhibitory activity of the compounds of the present invention was investigated by the method described [Zoku Biochemistry Experiment Course, Vol. 7 ( top), 3
See pages 28-332].

(Preparation of Crude Enzyme Solution) After decapitating a rat (male, 150-200 g), the brain was quickly taken out and mixed with 6 times the amount of buffer A (2501N sucrose, 105M EGTA, 2mM EDTA,
1mM PMSF.

The mixture was homogenized using 20 sM Tris/HCf% pH 7,5) and centrifuged at 100OOOX g for 60 minutes to obtain a supernatant.

Cholera Buff Y-B (10+sM 2-mercaptoethanol, 1 sM EGTA, 205M T
Fast protein liquid chromatography (FPLC) Mono equilibrated with rls/IC & pH 7,5)
Q column (Monodispersion e
xchanger Q■) (HR10/10), and linear gradient end (11near
gradient) elution was performed to prepare a partially purified protein kinase C fraction.

(Preparation of liposomes) Phosphatidylserine (ps) solution (5 g/ml CH
CI s) 25 μI was placed in a test tube, air-dried with N2 gas, and then 20 mW Tris/HC# (pH 7,5)
Liposomes were prepared by adding 1 ml of the solution, stirring thoroughly, and further applying ultrasonication. Liposomes were prepared by pre-mixing the test compound in a PS solution, and inhibition or activation of the enzyme was measured.

(Measurement of activity) Phosphorylated active histone aqueous solution (2 mg/ml), (CH3C00
)2 Mg aqueous solution (25PM), PS liposome solution (125Mg/ml), CaCl2 aqueous solution (0,65
PM) and 30 Pg of crude enzyme solution (1sM E containing TA) were mixed, incubated at 37°C for 5 minutes, and then incubated with 10 u C17-32P-AT.
The reaction was started by adding 20Pg of a 0.25mM ATP solution containing P. After reaction at 37℃ for 10 minutes, 25% TCA
The reaction was stopped by adding 3 ml, and the acid-insoluble protein was filtered through a membrane filter (0.45 ta, made of nitrocellulose).
collected by. After washing this with 25% TCA, the radioactivity of 32P incorporated into the protein was measured to determine the 50% inhibitory concentration (Ic5o).

The results of the experiment are shown in Table 2.

[Margin below] Table 2 [Effects of the Invention] The ethanolamine derivative of the present invention is useful as a protein kinase C inhibitor that is expected to be applied to the treatment and prevention of various diseases. Further, according to the production method of the present invention, the compound of the present invention can be produced in an economically and industrially advantageous manner.

Claims (1)

[Claims] 1. General formula (I): ▲Mathematical formulas, chemical formulas, tables, etc.▼(I) (In the formula, ring A is a bridged cyclic carbonized compound which may be substituted with a cycloalkane or hydroxymethyl group. An ethanolamine derivative or a salt thereof, represented by hydrogen, R^1 represents an alkyl group, an alkenyl group, a saturated aliphatic acyl group, or an unsaturated aliphatic acyl group. 2. The ethanolamine derivative or salt thereof according to claim 1, wherein ring A is a cyclopentylidene group or a cyclohexylidene group. 3 Ring A is ▲There is a mathematical formula, chemical formula, table, etc.▼, ▲There is a mathematical formula, chemical formula, table, etc.▼, ▲There is a mathematical formula, chemical formula, table, etc.▼ or ▲There is a mathematical formula, chemical formula, table, etc.▼ The ethanolamine derivative or its salt according to claim 1. 4 R^1 is an alkyl group having 10 to 20 carbon atoms, an alkenyl group having 10 to 20 carbon atoms, a saturated aliphatic acyl group having 10 to 20 carbon atoms, or an unsaturated aliphatic acyl group having 10 to 20 carbon atoms. The ethanolamine derivative or salt thereof according to claim 1, 2 or 3. 5 General formula (IV): ▲Mathematical formulas, chemical formulas, tables, etc.▼(IV) (In the formula, ring B is a cycloalkane, R^1 is an alkyl group,
A compound represented by an alkenyl group, a saturated aliphatic acyl group, or an unsaturated aliphatic acyl group (R^2 represents an ester residue) is reduced using a reducing agent, and if necessary, the product is converted into a salt. Featured general formula (Ia): ▲Mathematical formula, chemical formula, table, etc.▼(Ia) Method for producing the ethanolamine derivative or its salt represented by (in the formula, ring B and R^1 are the same as above) . 6 General formula (VI): ▲Mathematical formulas, chemical formulas, tables, etc.▼(VI) (In the formula, ring C is a bridged cyclic hydrocarbon, R^1 is an alkyl group, alkenyl group, saturated aliphatic acyl group, or Saturated aliphatic acyl group, R^2 is an ester residue, R^3^1 is a hydrogen atom or -CO_2R^4 (R^4 is an ester residue)
) is reduced using a reducing agent,
General formula (
I b): ▲There are mathematical formulas, chemical formulas, tables, etc.▼ (I b) Ethanol represented by (In the formula, R^3 represents a hydrogen atom or a hydroxymethyl group, and Ring C and R^1 are the same as above) A method for producing amine derivatives or their salts.