JP2000086601A - Ceramide derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new ceramide derivative having enzyme inhibitory action on sphingomyelinase, promoting action on the glucosylation of a ceramide, suppressive action on sphingosine-acyltransferase or the like, useful for an antidemential medicine, a dysmmesia improving agent, an antiinflammatory agent or the like as an enzyme inhibitor for ceramides. SOLUTION: This derivative is a compound expressed by formula I [R is H or a (halogenated)alkoxycarbonyl; (n) is 0 to 22] exhibiting a ceramide antagonism, for example, [2S,3R,4E]-2-acetylamino-1-amino-4-octadecene-3-ol. The compound of formula I is synthesized by using an azide compound of formula II (TBDMS is a t-butyl-dimethylsilyl) as a starting material.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel ceramide derivative and a salt thereof, more specifically, has a sphingomyelinase enzyme inhibitory action, a ceramide glucosylation promoting action, a sphingosine acyltransferase inhibitory action, a ceramide antagonistic action, and the like. As related enzyme inhibitors,
For example, the present invention relates to a ceramide derivative and a salt thereof useful as an anti-dementia drug, a memory disorder improving drug, an anti-inflammatory drug, and the like.

[0002]

2. Description of the Related Art Ceramide (N-acyl sphingosine)
Sphingolipids such as sphingomyelin and phosphocholine bound, and glycosphingolipids such as gangliosides having a complex structure in which a sugar chain is bound to sphingosine,
It is collectively called sphingolipid (sphingolipid). They are widely distributed as biomembrane components in the animal, plant and microbial communities.

The above gangliosides have hormonal activity,
Including the role of bacterial toxin as a receptor molecule, it has been shown to express nerve cell growth and differentiation promoting factor activity, and hydrophobic ceramide bound to the terminal of the ganglioside is capable of It is attracting attention as a factor controlling reactivity.

[0004] It is known that ceramide is increased into cells when cells are stimulated (stressed) by various physiologically active substances such as vitamins and cytokines. For this reason, ceramide is considered to be a factor mediating phenomena such as cell proliferation, differentiation, induction of apoptosis, and aging (Experimental Medicine, 1997, Vol. 15, No. 12, No. 14).
82-1487). The apoptosis is defined as DN
A means cell death as determined by fragmentation of A, cell morphological characteristics, activation of death protease, and the like.

More specifically, the following reports have been made on the action of ceramide on various cells.

(1) The addition of ceramide causes rapid apoptosis in many cell lines (Science, 1
993, 259, 1769-1771).

(2) The addition of ceramide stops cell cycle progression in some cell lines (Science,
1996, 274, 1855-1859).

(3) When human diploid fibroblasts enter the senescent stage, the amount of intracellular ceramide significantly increases (Biokimika Biophysica Actor, 793, 1984).
Vol. 79-83; Experimental Medicine, 1997, Vol. 15, 1
2, p. 1485).

(4) Ceramide induces the release of prostaglandin E2 and the transcription of interleukin-6, which mediate a systemic or local inflammatory response. Furthermore, it induces the expression of cyclooxygenase and phospholipase A2 (Experimental Medicine, 1997, Vol. 15, No. 12, 1482-148).
7).

(5) Ceramide induces apoptosis of rat midbrain or hippocampal neurons in the nervous system (Journal Neurochem, 1996, 66, 733).
~ 739; Journal Neuroscience, 199
7 years, 17: 2929-2938).

[0011] If the increase of ceramide having various actions as described above in a cell or its action can be suppressed, it is possible to suppress, for example, apoptosis, senescence, inflammation and the like caused by the ceramide. It is considered that a drug capable of suppressing the increase in the cell or its action is useful as an anti-dementia drug, a memory disorder improving drug, an anti-inflammatory drug and the like.

[0012]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel compound which can suppress the increase in the intracellular activity of ceramide having various physiological activities or the action thereof as described above. .

In view of the above-mentioned object, the present inventors, particularly in the course of research on the mechanism of action of increasing ceramide in cells, show that extracellular stimuli such as vitamins and cytokines cause neutral or acidic sphingomyelinase. Activate,
The fact that it promotes the production of ceramide by hydrolysis of sphingomyelin (Science, 1996, 27
4, 1855-1859; Endclinology, 1
995, 136, 4157-4160; Experimental Medicine, 1997, 15, 12, 1482-1487.
Focusing on (1), the present inventors have conceived that a compound having an activity of inhibiting the activity of sphingomyelinase can suppress the production of the ceramide.

Ceramide is metabolized by undergoing glucosylation in cells. Therefore, it was thought that if the glucosylation of ceramide could be promoted, the intracellular concentration of ceramide could be reduced. Furthermore, since ceramide increases its intracellular concentration by biosynthesis from its precursor sphingosine, it was considered that if this biosynthesis could be suppressed, the intracellular increase of ceramide could be suppressed. in addition,
It was thought that a compound having a chemical structure similar to that of ceramide, but not exhibiting the above-mentioned various actions of ceramide could be a competitive antagonist of ceramide (ceramide blocker).

Based on these ideas and the like, the present inventors have conducted further intensive studies, and as a result, have provided a novel compound having the following specific chemical structure which has a similar structure to ceramide and can be a blocker of the ceramide. Successfully, the present invention has been completed.

[0016]

According to the present invention, a novel ceramide derivative represented by the following general formula (1) and a salt thereof are provided.

[0017]

Embedded image

[Wherein, R represents an alkoxycarbonyl group which may be substituted with a hydrogen atom or a halogen atom.
n shows 0 or the integer of 1-22. ]

[0019]

BEST MODE FOR CARRYING OUT THE INVENTION In the ceramide derivative of the present invention represented by the above general formula (1), the halogen atom as a substituent of the alkoxycarbonyl group defined by R is
Examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom. Examples of the alkoxycarbonyl group that may have a halogen atom include, for example, unsubstituted carbon atoms having 1 to 6 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, tert-butoxycarbonyl, and hexyloxycarbonyl. , Preferably 1-3 alkoxycarbonyl groups, and fluoromethoxycarbonyl, chloromethoxycarbonyl, bromomethoxycarbonyl, iodomethoxycarbonyl, dichloromethoxycarbonyl,
Trichloromethoxycarbonyl, 1-chloroethoxycarbonyl, 2-chloroethoxycarbonyl, 1-fluoroethoxycarbonyl, 1,1-dichloroethoxycarbonyl, 1,2-dichloroethoxycarbonyl, 1,
1,1-trichloroethoxycarbonyl, 1,1,2-
An alkoxycarbonyl group having 1 to 6, preferably 1 to 3 carbon atoms, substituted by a halogen atom such as a trichloroethoxycarbonyl group can be exemplified.

N represents 0 or an integer of 1 to 22.

Among the compounds of the present invention represented by the above general formula (1), preferred are those wherein R is a hydrogen atom or a trichloroethoxycarbonyl group and n is 0, 4, 1
Ceramide derivatives having 6 and 22, more preferably n being 0, 16 and 22, and salts thereof can be exemplified.

Among the compounds of the present invention, particularly preferred specific examples include [2S, 3R, 4E] -2-acetylamino-1
-Amino-4-octadecene-3-ol, [2S, 3
R, 4E] -1-amino-2-octadecanoylamino-4-octadecene-3-ol, [2S, 3R, 4
E] -1-Amino-2-tetracosanoylamino-4-
Octadecene-3-ol, [2S, 3R, 4E] -2
-Acetylamino-1-trichloroethoxycarbonylamino-4-octadecene-3-ol, [2S, 3
R, 4E] -1-trichloroethoxycarbonylamino-2-octadecanoylamino-4-octadecene-3
A ceramide derivative selected from -ol and [2S, 3R, 4E] -1-trichloroethoxycarbonylamino-2-tetracosanoylamino-4-octadecene-3-ol, and salts thereof.

The ceramide derivative of the present invention is characterized by having an NHR group at the 1-position (R is the same as described above), as represented by the general formula (1). That is, the ceramide derivative of the present invention is clearly distinguished from the ceramide having a hydroxyl group at the 1-position (refer to JP-A-7-145117) in terms of the chemical structure at the 1-position substituent. The specific effect that ceramide acts as a blocker can be exhibited. However, the fact that the ceramide derivative having the NHR at the 1-position and its salt exerts the action of a ceramide as a blocker is, of course, described in Japanese Patent Application Laid-Open No. 7-145117, unless otherwise disclosed. There is no suggestion. The publication only teaches that the compound having a hydroxyl group at the 1-position is useful as a synthetic intermediate of ceramide or a homolog thereof.

The ceramide derivative of the present invention and a salt thereof have an inhibitory action on sphingomyelinase enzyme, an action of promoting glucosylation of ceramide, an action of inhibiting sphingosine acyltransferase, an action of ceramide antagonism, and the like, and are useful as ceramide-related enzyme inhibitors. is there. That is, they have an inhibitory action on cell proliferation caused by ceramide, an inhibitory action on cell apoptosis, differentiation, aging and the like, an inhibitory action on inflammation, etc., for example, an anti-dementia drug, a memory disorder improving drug, an anti-inflammatory drug. It is useful as such. In addition, if the compound of the present invention acts to inhibit the enzyme involved in the metabolic system of ceramide and increases the physiological amount of ceramide, the compound of the present invention is also applied as an anticancer agent for eliminating cancer cells on the principle of apoptosis. It is possible.

In particular, the compound of the present invention has a similar structure to ceramide, but has substantially no action of ceramide, and is effective as a ceramide blocker.

Hereinafter, the method for producing the ceramide derivative of the present invention will be described in detail. The derivative can be produced, for example, according to the method described in the following reaction schemes -1 and -2.

[0027]

Embedded image

In the above reaction schemes, the abbreviations for the substituents of each compound mean the following, respectively.
That is, TBDMS is a tert-butyl-dimethylsilyl group, Ph is a phenyl group, Ac is an acetyl group, NPh
th is the phthalimido-2-yl group, Tf ₂ O is trifluoroacetic anhydride, means respectively.

According to the above-mentioned reaction scheme 1, the target compound of the present invention can be easily and efficiently produced from the known azide compound (3) as a starting material by relatively simple steps and operations. . The azide compound (3) used as the starting material can be produced, for example, by the method described in Liebig Annarene Hemy (1988, pp. 663-667).

Azide compound (3) shown in Reaction Scheme 1.
To the compound (4) include 1) reduction of azide group, for example, reduction reaction using triphenylphosphine (Ph ₃ P), 2) protection of the formed amino group, for example, protection reaction using phthalic anhydride, and 3 ) Protection by esterification of the 1-hydroxyl group, for example, a protection reaction by esterification using an acid anhydride or an acid chloride.

The reduction of the azide group in the above 1) can be carried out using a reducing agent that does not reduce double bonds, such as sodium borohydride, lithium aluminum hydride, hydrogen sulfide and the like. In addition, this reduction reaction can be similarly carried out by, for example, catalytic reduction in the presence of a Lindlar catalyst or by a method using phosphines as a reaction reagent. The amount of the reducing agent to be used varies depending on the type of the reducing agent to be used and the reducing method, but can be appropriately selected usually from a range of about 1 to 10 molar equivalents of the theoretical amount.

As an example of the above step 1), a reaction scheme 1
The reduction reaction using triphenylphosphine exemplified in (1) can be carried out in an aromatic hydrocarbon solvent such as benzene, toluene and xylene. It is preferable that triphenylphosphine is generally used in an amount of about equimolar to 10 times, usually about 2 to 2.5 times, the mole of the azide compound (3). The reaction is usually carried out by stirring at room temperature to a temperature around the boiling point of the solvent used, preferably at about 40 to 60 ° C. for about 1 to 24 hours, usually about 12 hours.
After the reaction, a post-treatment is carried out by a conventional method, and the desired 2
A 2-amino derivative in which the azide group at the -position is reduced can be produced.

The amino group protection reaction of the above 2) can be advantageously carried out by forming a phthalimide group by reaction with phthalic anhydride. In the reaction using phthalic anhydride, the 2-amino derivative obtained in the above 1) is usually used as it is without isolating it from the reaction system, and the reaction mixture is concentrated. For example, it can be carried out by dissolving in methanol or the like, and adding phthalic anhydride to the solution in the presence of an organic basic compound such as triethylamine to cause a reaction. Here, the amount of the organic basic compound and the amount of phthalic anhydride to be used are respectively 1 to 5 times, usually 1 to 1.2 times the molar amount of the 2-amino derivative (or the starting material 12-azide compound) used as the starting material. It is suitably selected from a range of about twice the molar amount. This reaction is
Usually, it can be carried out at a temperature of about room temperature to about 60 ° C., preferably at a temperature of about room temperature to about the temperature for about 1 to 10 hours, and thus a desired 2-phthalimide derivative (5) can be obtained.

After completion of the above reaction, without isolating the product,
The reaction according to the following step 3) can be carried out as it is.

In the 3) esterification reaction (esterification reaction of the hydroxyl group at the 1-position), the reaction mixture obtained in the above 2) is concentrated under reduced pressure, dissolved in a suitable solvent such as pyridine, and then added with acetic anhydride or the like. It can be carried out by adding an acid anhydride and protecting the 1-position hydroxyl group with a corresponding protecting group such as an acetyl group. Here, the amount of the acid anhydride used is 1 to the starting compound.
It is sufficient to use about 10 to 10 moles, usually about 1.5 to 2 moles. The reaction conditions are about 0 to 100 ° C.,
Preferably, stirring conditions of about 60 to 80 ° C. and about 1 hour can be adopted.

In the reaction scheme 1, the above 3)
Acetylation using acetic anhydride is shown as a representative example of the esterification of

As described above, the desired compound (4) can be isolated and obtained. The resulting compound (4) can then be converted to compound (5) by hydrolyzing it. This hydrolysis reaction can follow the usual hydrolysis reaction of an ester. For example, in a suitable solvent, DBU (1,
8-diazabicyclo [5,4,0] undecene-7),
Organic basic compounds such as triethylamine and pyridine; inorganic basic compounds such as potassium carbonate, sodium carbonate, sodium hydroxide and potassium hydroxide; alkali metal salts of organic acids such as sodium acetate and potassium acetate; sodium methylate; The reaction can be carried out in the presence of a basic compound such as an alkali metal alcoholate such as tert-butoxy potassium. Here, as the solvent, water, alcohols, ethers such as dioxane and tetrahydrofuran, halogenated hydrocarbons such as chloroform and methylene chloride, mixed solvents thereof and the like, preferably methylene chloride / methanol (1: 1) mixture Solvents can be exemplified. The amounts of the basic compound and sodium methylate used are usually selected from the range of about 0.1 to 10 times the molar amount and about 0.01 to 0.1 times the molar amount of the raw material compound, respectively. It is. The hydrolysis reaction is completed at a temperature of usually 0 to 80 ° C., preferably 0 ° C. or near it, for about 1 to 24 hours, usually about 8 hours.

The compound (5) thus obtained is usually subjected to the next step without isolation, ie, the reaction of converting the 1-hydroxyl group to an azido group. The reaction includes: 1) a step of deriving a 1-hydroxyl group to an easily removable ester such as trifluoroacetic acid ester, methanesulfonic acid ester (mesylate), and balatoluenesulfonic acid ester (tosylate); and 2) the elimination. It can be carried out by a step of easily converting the 1-position ester residue to an azide using an azide.

In the above step 1), the compound (5) is dissolved in, for example, a pyridine / methylene chloride (1:20) mixed solvent or the like, and trifluoromethanesulfonic anhydride (Tf
₂ O), methanesulfonic acid chloride, palladium toluenesulfonic acid chloride and the like are added in an amount of about 1 to 5 moles, preferably about 1.1 to 1.3 moles, based on the amount of the starting compound. It is performed by stirring at a temperature of about -10 ° C or less for about several tens minutes to several hours. As the reaction solvent, other than the above, for example, a basic solvent such as pyridine, picoline, lutidine, triethylamine and the like and a mixed solvent of these with another non-polar solvent can be used. After completion of the reaction, the product can be subjected to subsequent steps without isolation. In addition, in reaction process formula-1, the case where trifluoroacetic anhydride is used is shown typically.

In the step 2) following the above, the ester derivative obtained above is azide-ized using an azide. The azide used here is a metal salt of hydrogen azide (HN ₃ ). For example, sodium azide (N
aN ₃ ), potassium azide, lithium azide, copper azide, mercury azide and the like. Such an azide is generally inferior in solubility, and is usually used in a large excess of several times to several tens times the theoretical amount, preferably about 4 to 5 times the molar amount. The reaction is usually performed in a suitable solvent such as dimethylformamide (DMF), and the solvent used in the previous esterification step may remain in the reaction system. The reaction temperature and time are usually about 100 to 120 ° C. and several hours to several tens of hours when the ester derivative used as a raw material is mesylate and tosylate, and usually used when the ester derivative is trifluoroacetate. The temperature is preferably from room temperature or lower to about −10 ° C. and several hours to about ten hours. Reaction process formula-1
When the trifluoroacetic acid ester exemplified in (1) is dissolved in DMF and sodium azide is used, stirring at room temperature for 2 hours is preferable. Here, sodium azide is suitably used in a molar ratio of 1 to 10 times the amount of the starting compound.

After the reaction, a post-treatment is carried out according to a conventional method, and the target compound (6) (azide derivative) can be produced in good yield by purifying it by column chromatography or the like.

Subsequent to the above, the reaction for obtaining the compound (7) from the compound (6) is a reaction for removing the protecting group for the 2-position amino group. The reaction is typically carried out, for example, by dissolving compound (6) in ethanol and then adding hydrazine monohydrate (NH ₂ NH ₂ H ₂ O) to the solution 30 to 50 times that of compound (6). It can be carried out by adding a large excess amount of about a molar amount and stirring with heating. The heating conditions are not particularly limited, but generally may be about 70 to 90 ° C. Thus, the desired compound (7) having a free amino group at the 2-position can be obtained by decomposing the phthalimide group which is a protecting group for the 2-position amino group.

[0043]

Embedded image

(Wherein R, n, TBDMS and Ph are the same as described above). According to the reaction scheme 2, first, the 2-position amino group of the compound (7) obtained in the reaction scheme 1 is Compound (8) can be obtained by the acylation reaction. This reaction can be performed according to a general method for amidating amines. The method includes (1) an acid anhydride method, (2) a mixed acid anhydride method, (3) a method using an acid halide, and (4) a carboxylic acid or the like in the presence of a condensing agent such as carbodiimides. And (5) a method of activating carboxylic acids.

More specifically, for example, in the case of producing the compound (8) in which n = 0, that is, in the case of a reaction for forming acetylamide, the reaction is carried out by stirring acetic anhydride in pyridine at room temperature. Can be easily implemented.
In the case of producing a compound in which n is 1 to 22, a fatty acid having a carbon number corresponding to the n (a saturated linear fatty acid having 2 to 23 carbon atoms, for example, propionic acid, butyric acid, capric acid, lauric acid, Using myristic acid, palmisic acid, stearic acid, lignoceric acid, etc., for example, stearic acid (octadecanoic acid) when n is 16, and lignoceric acid (tetracosanoic acid) when n is 22; Carbodiimides such as 1-ethyl-3-
(3′-dimethylaminopropyl) carbodiimide (W
The reaction may be performed in the presence of a condensing agent such as SC). The conditions for these reactions are not particularly different from those of the corresponding known amidation reactions. The details are as shown in Examples below.

Thus, the obtained compound (8) can then be subjected to elimination of its protecting group (TBDMS) to give the desired compound (9) in which the 3-position is a hydroxyl group. For the elimination reaction of this protective group, for example, a weak acid such as acetic acid, trifluoroacetic acid, formic acid, or tetrafluoroboric acid, a low concentration of a mineral acid, or an aprotic strong acid can be used. Particularly advantageously, the elimination reaction is, for example, IR120B (H +)
It can be carried out using a strongly acidic cation exchange resin such as (manufactured by Organo).

The reaction using the ion-exchange resin is carried out, for example, by mixing the compound (8) with the ion-exchange resin, and adding water and stirring the mixture at room temperature or, if necessary, with heating. it can. The reaction time can be determined appropriately according to the type of acid used and the reaction temperature. Usually, it is good to set it to several minutes to several hours. After completion of the reaction, a post-treatment is carried out according to a conventional method, and the product is purified by column chromatography, recrystallization, or the like, so that the desired ceramide or a homolog thereof can be obtained in high yield.

The resulting compound (9) is then converted to the compound (1a) of the present invention having a free amino group at the 1-position by reducing the azide group at the 1-position using triphenylphosphine (PPh ₃ ). it can.

This reaction can be carried out under the same conditions as in the method for reducing the 2-position azide derivative of compound (3) shown in the above reaction scheme 1. As the reducing agent used, for example, a reducing agent which does not reduce a double bond such as sodium borohydride, lithium aluminum hydride, hydrogen sulfide and the like is preferable. This reaction can also be carried out by catalytic reduction in the presence of a Lindlar catalyst, and can also be carried out by a method using phosphines as a reaction reagent. The amount of the reducing agent used is usually selected from the range of about 1 to 10 molar equivalents of the theoretical amount, and the reaction conditions vary depending on the type of the reducing agent to be used and the reduction method, and can be determined as appropriate. For example, when using triphenylphosphine as a reducing agent, triphenylphosphine is used in an equimolar to 10-fold molar amount, usually 1.5-2.5-fold molar amount with respect to the raw material compound, and benzene,
In an aromatic hydrocarbon solvent such as toluene or xylene or a mixed solvent thereof with water, the temperature is usually from about room temperature to about the boiling point of the solvent used, preferably from about 40 to 70 ° C.
The reaction is completed by stirring for about 5 hours. After completion of the reaction, a desired 1-amino derivative can be obtained by performing a post-treatment according to a conventional method and purifying by column chromatography or the like.

In the present compound (1b) having a substituent R at the 1-position, the 1-position obtained above has a free amino group (R
= H) of the compound of the present invention (1a) in a suitable solvent,
It can be produced by reacting a suitable acylating agent in the presence of an organic basic catalyst. Examples of the solvent used here include dichloromethane and the like. Examples of the organic basic catalyst include diisopropylethylamine, dichloromethane pyridine, picoline, lutidine, triethylamine and the like. It is generally preferred that these compounds are used in an amount of about 2 to 2.5 times the molar amount of the starting compound. Examples of the acylating agent include an appropriate one which gives the above R group, for example, an alkyl chloroformate derivative such as trichloroethyl chloroformate. These acylating agents are usually preferably used in an amount of about 1.2 to 1.7 times the molar amount of the starting compound. The reaction can be carried out in the same manner as a usual acylation reaction of this kind, for example, at a temperature of about 10 to 30 ° C. for 2 to 4 hours. Completion of the reaction can usually be confirmed by thin layer chromatography (TLC).

The ceramide derivative of the present invention can be a pharmaceutically acceptable acid addition salt. Acids capable of forming such acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and the like, and organic acids such as oxalic acid, fumaric acid, maleic acid, tartaric acid, citric acid, benzoic acid and p-toluene. Sulfonic acid and the like can be exemplified. The acid addition salt forming reaction using such an acid can be carried out according to a commonly used conventional method.

The target compound obtained by the method shown in the above reaction scheme can be easily isolated and purified by usual separation means. Examples of the means include partition chromatography, preparative thin-layer chromatography, recrystallization, and solvent extraction.

The compound of the present invention obtained as described above has an optically active form as shown by the general formula (1). The derivatives of the present invention naturally include the symmetric and cis forms of such optically active forms.

The present invention also provides a pharmaceutical composition comprising a ceramide derivative represented by the above general formula (1) or a pharmaceutically acceptable salt thereof as an active ingredient, and a pharmaceutically acceptable carrier. To provide.

The pharmaceutical composition of the present invention is usually made into a general pharmaceutical preparation using a pharmaceutical carrier together with the above-mentioned active ingredient compound. Examples of the pharmaceutical carrier include diluents or excipients such as a filler, a bulking agent, a binder, a humectant, a disintegrant, a surfactant, and a lubricant which are usually used depending on the use form of the pharmaceutical. These can be appropriately selected and used depending on the dosage unit form of the obtained preparation.

The administration route of the pharmaceutical composition of the present invention is desirably intravenous injection, but oral administration is also possible, and the pharmaceutical composition can be prepared in a dosage unit form according to the administration route. Representative examples are tablets, pills, powders, powders, fat solutions, suspensions, granules, capsules, suppositories, injections (solutions, suspensions, etc.),
Liposomes, ointments and the like can be mentioned.

In the case of molding into a tablet form, the above-mentioned preparation carriers include excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, potassium phosphate and the like.
Water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, methylcellulose, binders such as polyvinylpyrrolidone, sodium carboxymethylcellulose, calcium carboxymethylcellulose, low-substituted hydroxypropylcellulose, dried Disintegrants such as starch, sodium alginate, agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, surfactants such as polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, and monoglyceride stearate; sucrose, stearin, cocoa butter; Disintegration inhibitors such as hydrogenated oil, quaternary ammonium bases, absorption enhancers such as sodium lauryl sulfate, glycerin, starch and the like Moisturizers, starch, lactose, kaolin, bentonite, adsorbent such as colloidal silicic acid, purified talc, stearates, boric acid powder, a lubricant such as polyethylene glycol can be used.

Further, the tablets can be made into tablets coated with a usual coating, if necessary, such as sugar-coated tablets, gelatin-encapsulated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets.

In the case of molding into a pill form, as a preparation carrier, for example, glucose, lactose, starch, cocoa butter,
Excipients such as hardened vegetable oil, kaolin and talc, gum arabic powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran and agar can be used.

For shaping in the form of suppositories, for example, polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used as pharmaceutical carriers. Capsules are prepared by mixing the active ingredient compound of the present invention with the various pharmaceutical carriers exemplified above and filling the mixture into hard gelatin capsules, soft capsules and the like according to a conventional method.

When the pharmaceutical composition of the present invention is prepared as an injection, such as a liquid, emulsion or suspension, it is preferable that the composition is sterilized and isotonic with blood. Is, for example, water, ethyl alcohol,
Macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters and the like can be used. In this case, a sufficient amount of salt, glucose or glycerin to adjust the isotonic solution may be contained in the drug of the present invention, and ordinary solubilizers, buffers, soothing agents and the like are added. May be.

Further, the drug of the present invention may contain a coloring agent, a preservative, a fragrance, a flavoring agent, a sweetening agent, and other pharmaceuticals as necessary.

The amount of the ceramide derivative represented by the general formula (1) and its salt (active ingredient compound) to be contained in the pharmaceutical composition of the present invention is not particularly limited and may be appropriately selected from a wide range. It is preferable that about 1 to 70% by weight be contained in the composition.

The administration method of the above pharmaceutical composition is not particularly limited, and is determined according to various preparation forms, age, sex and other conditions of the patient, degree of disease, and the like. For example, tablets, pills, solutions, suspensions, emulsions, granules, and capsules are orally administered, and injections are administered intravenously, alone or as a mixture with ordinary replenishers such as glucose and amino acids. Intramuscularly, intradermally, subcutaneously or intraperitoneally, and suppositories may be administered rectally alone.

The dose of the above pharmaceutical composition is appropriately selected depending on the usage, age, sex and other conditions of the patient, degree of the disease and the like. Usually, the amount of the active ingredient is about 1 to 3 per day per adult.
The dosage is preferably about 000 mg, and the preparation can be administered once a day or divided into 2 to 4 times.

[0066]

EXAMPLES In order to explain the present invention in more detail, Production Examples of the starting compounds for producing the compounds of the present invention will be given as Reference Examples, and then Production Examples of the compounds of the present invention will be given as Examples. In addition, the compound number in each example was made to correspond with the compound number shown by each formula shown in reaction process formula-1 and -2.

[0067]

Reference Example 1 Production of [2S, 3R, 4E] -1-O-acetyl-3-O-tert-butyldimethylsilyl-2-phthalimido-4-octadecene-1,3-diol (4) 3R, 4E] -2-Azido-3-O-tert-butyldimethylsilyl-4-octadecene-1,3-diol (3) (100 mg) was dissolved in benzene / water (4: 1) mixed solvent (3 ml). To this, 119 mg of triphenylphosphine was added, and the mixture was stirred at 55 ° C. for 12 hours. The concentrate obtained by concentration under reduced pressure was dissolved in 5 ml of methanol,
32 μl of triethylamine and 33.7 mg of phthalic anhydride
After stirring at room temperature for 2 hours, the mixture was concentrated under reduced pressure. Further, the obtained concentrate was dissolved in 2 ml of pyridine, and 0.5 ml of acetic anhydride was added thereto, followed by stirring at 80 ° C. for 12 hours. After extraction with chloroform, the organic layer was washed with an aqueous solution of sodium carbonate, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.

The syrup thus obtained was subjected to silica gel column chromatography (silica gel: BW-300,
Purified with Fuji Silysia Chemical Ltd., eluent: ethyl acetate / n-hexane = 1/60) to give the desired compound (4) 1
34 mg (96% yield) were obtained.

This had the following physical properties.

[Α] _D = + 0.29 ° (c = 2.72, CHCl ₃ ) Note that the above and the following optical rotation measurements were performed at 25 ° C.

IRνmax (film) (cm ⁻¹ ): 1720,
1740 (phthalimide) 2850, 2900 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
27,0.088 (2s, 6H, Si ( CH 3) 2) 0.
_{740-1.317 (m, 34H, -CH 2} CH 3) 1.
627-1.838 (m, 2H, H-6, 6 ') 1.9.
44 (s, 3H ', CO CH 3) 4.349-4.40
7 (2t, 1H, H-2) 4.630-4.728
(M, 3H, H-1, 1 ', H-2) 5.257 (d
d, 1H, J4,5 = 15.3 Hz, H-4) 5.475
-5.530 (m, 1H, H-5) 7.712-7.8
13 (m, 4H, phthalimide)

[0072]

Reference Example 2 Production of [2S, 3R, 4E] -3-O-tert-butyldimethylsilyl-2-phthalimido-4-octadecene-1,3-diol (5) [2S, 3R, 4E] -1 -O-acetyl-3-O-te
45 mg of rt-butyldimethylsilyl-2-phthalimido-4-octadecene-1,3-diol (4) was dissolved in 10 ml of a mixed solvent of methylene chloride / methanol (1: 1), and 1 drop of sodium methoxide was added thereto. In addition, 0
Stirred at C for 8 hours. The reaction mixture was extracted with chloroform, and the organic layer was washed successively with 2N hydrochloric acid, an aqueous sodium carbonate solution and water, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to silica gel column chromatography ( The eluate was purified with ethyl acetate / n-hexane = 1/10) to give the desired compound (5) in 92%.
mg (74% yield).

This had the following physical properties.

[Α] _D = + 9.11 ° (c = 1.58, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1700 (phthalimide) 2
850, 2900 (CH) 3500 (OH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
33,0.101 (2s, 6H, Si ( CH 3) 2) 0.
_{858-1.317 (m, 34H, -CH 2} CH 3) 1.
680-1.816 (m, 2H, H-6, 6 ') 4.0
88-4.146 (m, 2H, H-1, 1 ') 4.26
3-4.303 (m, 1H, H-2) 4.710 (t,
1H, H-3) 5.299 (dd, 1H, J4,5 = 1)
5.3Hz, H-4) 5.407-5.465 (m, 1
H, H-5) 7.711-7.800 (m, 4H, phth)
alimide)

[0075]

Reference Example 3 [2S, 3R, 4E] -1-azido-3-
O-tert-butyldimethylsilyl-2-phthalimide-
Preparation of 4-octadecene-3-ol (6) [2S, 3R, 4E] -3-O-tert-butyldimethylsilyl-2-phthalimido-4-octadecene-1,3
-1.2 g of diol (5) was dissolved in 10 ml of a pyridine / methylene chloride (1:20) mixed solvent under a nitrogen stream, and 0.4 ml of trifluoroacetic anhydride was added thereto.
Stir at -15 ° C for 15 minutes. After completion of the reaction, 15 ml of dimethylformamide and 0.6 g of sodium triazide were added to the reaction mixture, the mixture was stirred at room temperature for 2 hours, extracted with ethyl acetate, and the organic layer was extracted with 2N hydrochloric acid, aqueous sodium carbonate solution,
Washed sequentially with water. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting syrup was subjected to silica gel column chromatography (eluent: ethyl acetate / n-
Purification with hexane = 1/100) afforded 146 mg of the desired compound (6) (75% yield).

This had the following physical properties.

[Α] _D = −22.94 ° (c = 0.68, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1700, 1760 (phth
alimide) 2100 (azide) 2700, 2900 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
00,0.056 (2s, 6H, Si ( CH 3) 2) 0.
_{826-1.279 (m, 34H, -CH 2} CH 3) 1.
687-1.816 (m, 2H, H-6, 6 ') 3.8
10 (dd, 1H, H-1 ′) 4.046 (t, 1H,
H-1) 4.247-4.310 (m, 1H, H-2)
4.576 (t, 1H, H-3) 5.206-5.26
5 (dd, 1H, J4,5 = 15.3 Hz, H-4)
416-5.488 (m, 1H, H-5) 7.708-
7.791 (m, 4H, phthalimide)

[0078]

Reference Example 4 [2S, 3R, 4E] -2-amino-1-
Preparation of azido-3-O-tert-butyldimethylsilyl-4-octadecene-3-ol (7) [2S, 3R, 4E] -1-azido-3-O-tert-butyldimethylsilyl-2-phthalimide- 95 mg of 4-octadecene-3-ol (6) was added to 8 m of ethanol.
hydrazine monohydrate 0.3m
and stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction mixture was extracted with chloroform, and the organic layer was washed with an aqueous sodium carbonate solution. The extract was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting syrup was purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/10) to give the desired compound ( 7) (48 mg, yield 59%) was obtained.

This had the following physical properties.

[Α] _D = −1.87 ° (c = 0.96, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 2900, 2950 (CH)
3350, 3450 (amine) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
00,0.040 (2s, 6H, Si ( CH 3) 2) 0.
_{841-0.957 (m, 9H, CH 3} ) 1.236
_{(S, 22H, -CH 2 -} ) 1.994-2.047
(M, 2H, H-6,6 ') 2.764-2.807
(M, 1H, H-2) 3.273-3.322 (m, 1
H, H-1) 3.434-3.475 (m, 1H, H-
1 ') 3.919 (t, 1H, H-3) 5.311-
5.347 (m, 1H, H-4) 5.592-5.66
6 (m, 1H, H-5)

[0081]

Reference Example 5 Production of [2S, 3R, 4E] -2-acetylamino-1-azido-3-O-tert-butyldimethylsilyl-4-octadecene-3-ol (8) (n = 0) [ 2S, 3R, 4E] -2-Amino-1-azido-3-
O-tert-butyldimethylsilyl-4-octadecene-
270 mg of 3-ol (7) was dissolved in 2 ml of pyridine, 1 ml of acetic anhydride was added thereto, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, azeotroped with toluene, and the resulting syrup was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/1).
Purification in 5) gave the desired compound (8) (n = 0) in 2
20 mg (74% yield) was obtained.

This had the following physical properties.

[Α] _D = + 5.42 ° (c = 0.7, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1560, 1660 (NHA
c) 2100 (azide) 2850, 2950 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
08,0.100 (m, 6H, Si ( CH 3) 2) 0.8
_{34-1.054 (m, 9H, CH 3} ) 1.255-
_{1.460 (m, 22H, -CH 2} -) 1.966-
_{2.051 (m, 5H, CH 3} , H-6,6 ') 3.4
40-3.571 (m, 2H, H-1, 1 ') 4.00
7-4.069 (m, 1H, H-2) 4.143-4.
185 (m, 1H, H-3) 5.333-5.389
(Dd, 1H, J4,5 = 15.3 Hz, H-4) 5.5
90-5.698 (m, 1H, H-5)

[0084]

Reference Example 6 [2S, 3R, 4E] -1-azide-2-
Octadecanoylamino-3-O-tert-butyldimethylsilyl-4-octadecene-3-ol (8) (n =
16) Preparation of [2S, 3R, 4E] -2-amino-1-azido-3-
O-tert-butyldimethylsilyl-4-octadecene-
153 mg of 3-ol (7) was added to methylene chloride 10m.
and added with triethylamine to adjust the pH to 1
After adjusting to 0, 0.5 g of stearic acid and 0.3 g of 1-ethyl-3- (3′-dimethylaminopropyl) carbodiimide (WSC) were added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with chloroform, and the extract was washed with water. After dehydration with anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure, and the concentrated solution was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/4).
0) to give 141 mg of the desired compound (8b)
(57% yield).

This had the following physical properties.

[Α] _D = + 3.54 ° (c = 2.82, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1539, 1645 (amid
e) 2100 (azide) 2850,2920 ( -CH 2 CH 3) 330
4 (NH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
00,0.099 (m, 6H, Si ( CH 3) 2) 0.8
_{66-0.938 (m, 15H, 2CH 3} , SiC (C
_{H 3) 3) 1.255 (s} , 50H, -CH 2 -) 1.5
_{74 (m, 2H, NHCOCH 2} CH 2 -) 1.998-
2.040 (m, 2H, H-6, 6 ') 2.122-
2.209 (m, 2H, NHCO CH 2 -) 3.467
-3.568 (m, 2H, H-1, 1 ') 4.020-
4.068 (m, 1H, H-2) 4.159 (t, 1
H, H-3) 5.339 (dd, 1H, J4,5 = 15.
3551, H-4) 5.551 (d, 1H, JNH, H-2 =
8.925 Hz, H-5) 5.551-5.672
(M, 1H, H-5)

[0087]

Reference Example 7 [2S, 3R, 4E] -1-azide-2-
Tetracosanoylamino-3-O-tert-butyldimethylsilyl-4-octadecene-3-ol (8) (n =
22) Preparation of [2S, 3R, 4E] -2-amino-1-azide-3-
O-tert-butyldimethylsilyl-4-octadecene-
350 mg of 3-ol (7) was added to methylene chloride 10 m
and added with triethylamine to adjust the pH to 1
After adjusting to 0, 1.0 g of lignoceric acid and WSC
0.6 g was added, and the mixture was stirred at room temperature for 12 hours. After completion of the reaction, the mixture was extracted with chloroform, and the organic layer was washed with water. After dehydration with anhydrous sodium sulfate and filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: chloroform / n-hexane = 1/1) to give the desired compound (8) 208 mg of (n = 22)
(43% yield).

This had the following physical properties.

[Α] _D = + 0.28 ° (c = 4.16, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1543, 1651 (amid
e) 2108 (azide) 2851,2957 ( -CH 2 CH 3) 328
4 (NH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.0
07, 0.107 (m, 6H, Si ( CH ₃ ) ₂ ) 0.7
_{46-1.059 (m, 15H, 2CH 3} , SiC (C
_{H 3) 3) 1.105-1.325 (m} , 62H, -CH
_{2 -) 1.592-1.680 (m, 2H} , NHCOC
H ₂ CH ₂ − ) 2.000−2.054 (m, 2H, H−)
6,6 ') 2.139-2.188 (m, 2H, NHC
_{O CH 2 -) 3.443-3.577 (m} , 2H, H-
1,1 ') 4.033-4.069 (m, 1H, H-
2) 4.168 (t, 1H, H-3) 5.340-5.
396 (dd, 1H, J4,5 = 15.3 Hz, H-4)
5.524 (d, 1H, JNH, H-2 = 8.789, H-
5) 5.627-5.700 (m, 1H, H-5)

[0090]

Reference Example 8 [2S, 3R, 4E] -2-acetylamino-1-azido-4-octadecene-3-ol (9)
Preparation of (n = 0) [2S, 3R, 4E] -2-Acetylamino-1-azido-3-O-tert-butyldimethylsilyl-4-octadecene-3-ol (8) (n = 0) 225 mg.
It was dissolved in 10 ml of methanol, and a strongly acidic cation exchange resin IR-120 (H +) (manufactured by Organo) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained concentrate was purified by silica gel column chromatography (eluent: chloroform) to obtain 128 mg (yield) of the desired compound (9) (n = 0). Rate 66%).

This had the following physical properties.

[Α] _D = + 10.39 ° (c = 0.26, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1545, 1656 (NHA
c) 2109 (azide) 3296 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.8
_{62-0.896 (m, 3H, CH 3} ) 1.257-
_{1.380 (m, 22H, -CH 2} -) 2.022-
2.077 (m, 5H, NHC ( O) CH 3, H-6,
6 ') 3.477-3.659 (m, 2H, H-1,
1 ') 4.029-4.086 (m, 1H, H-2)
4.184-4.212 (m, 1H, H-3) 5.43
0-5.485 (dd, 1H, J4.5 = 15.3 Hz,
H-4) 5.731-5.805 (m, 1H, H-5)
6.079 (d, 1H, JNH, 2 = 8.422, NH)

[0093]

Reference Example 9 [2S, 3R, 4E] -1-azide-2-
Preparation of octadecanoylamino-4-octadecene-3-ol (9) (n = 16) [2S, 3R, 4E] -1-azido-2-octadecanoylamino-3-O-tert-butyldimethylsilyl -4
14 of octadecene-3-ol (8) (n = 16)
0 mg was dissolved in 10 ml of methanol, and a strongly acidic cation exchange resin IR-120 (H +) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction mixture is filtered and washed, the filtrate and the washing liquid are combined, concentrated under reduced pressure, and the concentrated liquid is purified by silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1/10) to obtain the desired compound. Compound (9)
95 mg (yield 80%) of (n = 16) was obtained.

This had the following physical properties.

[Α] _D = + 30.31 ° (c = 1.9, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1542, 1646 (amid
e) 2103 (azide) 2851, 2920 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.8
_{62-0.920 (m, 6H, 2CH 3} ) 1.286
_{(M, 50H, -CH 2 -} ) 1.587-1.642
(M, 2H, NHC (O ) CH 2 CH 2 -) 2.019
(Dd, 2H, H-6, 6 ') 2.184-2.222
(M, 2H, NHC (O ) CH 2 -) 3.481-3.
636 (m, 2H, H-1, 1 ') 4.028-4.0
84 (m, 1H, H-2) 4.181 (m, 1H, H-
3) 5.428-5.483 (m, 1H, H-4) 5.
729-5.914 (m, 1H, H-5) 5.914
(D, 1H, JNH, 2 = 8.056, NH)

[0096]

Reference Example 10 [2S, 3R, 4E] -1-azide-2
Preparation of -Tetracosanoylamino-4-octadecene-3-ol (9) (n = 22) [2S, 3R, 4E] -1-azido-2-tetracosanoylamino-3-O-tert-butyldimethyl Cyril-4
20 of octadecene-3-ol (8) (n = 22)
0 mg was dissolved in 10 ml of methanol, and ion-exchange resin IR-120 (H +) was added thereto, followed by stirring at room temperature for 3 hours. After completion of the reaction, the reaction solution is filtered and washed, the filtrate and the washing solution are combined, concentrated under reduced pressure, and the concentrated solution is subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1).
/ 10) to give the desired compound (9) (n = 2
2) (92 mg, yield 54%) was obtained.

This had the following physical properties.

[Α] _D = + 1.30 ° (c = 1.84, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1560, 1660 (NHA
c) 2100 (azide) 2850, 2900 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.8
_{62-0.939 (m, 3H, CH 3} ) 1.120-
_{1.442 (m, 62H, -CH 2} -) 1.589-
1.643 (m, 2H, NHC ( O) CH 2 CH 2 -)
2.022-2.075 (m, 2H, H-6, 6 ')
2.184-2.242 (m, 2H, NHC (O) CH
₂ − ) 3.509−3.644 (m, 2H, H−1,
1 ') 4.025-4.068 (m, 1H, H-2)
4.081-4.219 (m, 1H, H-3) 5.43
0-5.485 (dd, 1H, J = 15.3 Hz, H-
4) 5.749-5.787 (m, 1H, H-5) 5.
804-5.845 (d, 1H, JNH, 2 = 8.056
NH).

[0099]

Example 1 [2S, 3R, 4E] -2-acetylamino-1-amino-4-octadecene-3-ol (1
a) Preparation of (n = 0) 30 mg of [2S, 3R, 4E] -2-acetylamino-1-azido-4-octadecene-3-ol (9) (n = 0) was added to benzene / water (4). : 1) 1.6m mixed solvent
l, and triphenylphosphine 400 mg
Was added and stirred at 55 ° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the obtained concentrated liquid was subjected to silica gel column chromatography (eluent: chloroform / methanol = 5/5).
Purification was performed in 1) to obtain 21 mg (yield: 75%) of a desired compound (1a) (n = 0).

This had the following physical properties.

[Α] _D = −9.04 ° (c = 0.42, CHCl ₃ ) IRνmax (film) (cm ⁻¹ ): 1560, 1660 (NHA
c) 2850, 2950 (CH) 3300 (amino) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.8
_{63-0.897 (m, 3H, CH 3} ) 1.258-
_{1.371 (m, 22H, -CH 2} -) 2.065
(T, 5H, NHC (O ) CH 3, H-6,6 ') 3.
034 (s, 2H, H-1, 1 ') 3.851 (s, 1
H, H-2) 4.200 (s, 1H, H-3) 5.47
2-5.525 (dd, 1H, J4,5 = 15.0 Hz,
H-4) 5.735-5.804 (m, 1H, H-5)

[0102]

Example 2 [2S, 3R, 4E] -1-amino-2-
Preparation of octadecanoylamino-4-octadecen-3-ol (1a) (n = 16) [2S, 3R, 4E] -1-azido-2-octadecanoylamino-4-octadecene-3-ol (9 ) (N
= 16) was dissolved in 1.6 ml of a mixed solvent of benzene / water (4: 1), 45 mg of triphenylphosphine was added thereto, and the mixture was stirred at 50 ° C for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (silica gel W-300 (manufactured by Fuji Silysia Chemical Ltd.), eluent: chloroform / methanol = 10/1).
The desired compound (1a) (n = 16) was purified by 2
8 mg (58% yield) was obtained.

This had the following physical properties.

IRνmax (KBr) (cm ⁻¹ ): 1550,1
640 (amido) 2850, 2920, 2950 (CH) 32
80 (NH ₂ , OH) ¹ H-NMR (500 MHz, CDCl ₃ ): δ: 1.2
_{6-1.30 (m, 50H, -CH 2} -) 1.59-
_{1.62 (m, 2H, NHCOCH 2} CH 2 -) 1.01
−2.06 (m, 2H, H-6, 6 ′) 2.16 (t,
_{2H, NHCO CH 2 -) 2.83-2.94} (m, 2
H, H-1, 1 ') 3.36 (m, 1H, H-2) 3.
82-3.85 (m, 1H, H-3) 5.42-5.4
6 (dd, 1H, J3,4 = 6.636 Hz, J4,5 = 1
5.332 Hz, H-4) 5.71-5.77 (m, 1
H, H-5) 5.94 as (d, 1H, NH) Elemental analysis _{(C 36 H 72 N 2 O} 2 (564.98)): Calculated: C: 76.53, H: 12.84 , N: 4.96 Found: C: 76.29, H: 12.70, N: 4.79.

[0105]

Example 3 [2S, 3R, 4E] -1-amino-2-
Preparation of tetracosanoylamino-4-octadecene-3-ol (1a) (n = 22) [2S, 3R, 4E] -1-azido-2-tetracosanoylamino-4-octadecene-3-ol (9 ) (N
= 22) was dissolved in 6 ml of a benzene / water (4: 1) mixed solvent, and triphenylphosphine 39 was added thereto.
The mixture was stirred at 50 ° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: chloroform / methanol = 10/1) to obtain the desired compound (1a) (n = 22).
mg (77% yield).

This had the following physical properties.

[Α] _D = -10.0 ° (c = 0.2, CHCl ₃ ) IRνmax (KBr) (cm ⁻¹ ): 1550, 1640 (amid
o) 2850, 2920, 2950 (CH) 3280 (NH ₂ , OH) ¹ H-NMR (500 MHz, CDCl ₃ ): δ: 0.8
8 (t, 6H, 2Me) 1.26-1.30 (m, 62
H, —CH ₂ —) 1.59-1.62 (m, 2H, NH
COCH ₂ CH ₂ − ) 1.01 to 2.06 (m, 2H, H
−6, 6 ′) 2.16 (t, 2H, NHCO CH ₂ − )
2.83-2.94 (m, 2H, H-1, 1 ') 3.3
6 (m, 1H, H-2) 3.82-3.85 (m, 1
H, H-3) 5.42-5.46 (dd, 1H, J3,4)
= 6.636 Hz, J4,5 = 15.332 Hz, H-
4) 5.71-5.77 (m, 1H, H-5) 5.94
(D, 1H, NH) Elemental analysis (as C ₄₂ H ₈₄ N ₂ O ₂ (649.14)): Calculated: C: 77.71, H: 13.04, N: 4.32 Actual: C: 77.57, H: 12.90, N: 4.29.

[0108]

Example 4 Preparation of [2S, 3R, 4E] -2-acetylamino-1-trichloroethoxycarbonylamino-4-octadecene-3-ol (1b) (n = 0) [2S, 3R, 4E]- 2-acetylamino-1-amino-4-octadecene-3-ol (1a) (n = 0)
Was dissolved in 2 ml of methylene chloride, and 17 μl of diisopropylethylamine was added thereto.
2,2-trichloroethyl chloroformate 10 μl
Was added and stirred at room temperature for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: chloroform / methanol = 40/1) to obtain 15 mg of the desired compound (1b) (n = 0).
(53% yield).

This had the following physical properties.

[Α] _D = −3.33 ° (c = 0.30, CHCl ₃ ) IRν max (film) (cm ⁻¹ ): 800 (CCl ₃ ) 1540,
1640 (NHAc) 2850, 2900 (CH) ¹ H-NMR (400 MHz, CDCl ₃ ): δ: 0.8
_{29-0.897 (m, 3H, CH 3} ) 1.256-
_{1.497 (m, 22H, -CH 2} -) 1.954-
2.076 (t, 5H, NHC ( O) CH 3, H-6,
6 ') 3.413-3.513 (m, 2H, H-1,
1 ') 4.029-4.088 (m, 1H, H-2)
4.202 (s, 1H, H-3) 4.673-4.80
1 (m, 2H, NHC ( O) CH 2 CCl 3) 5.466
−5.520 (dd, 1H, J4,5 = 15.0 Hz, H
-4) 5.556 (m, 1H, NH C (O) CH 2 CC
l ₃ ) 5.734-5.806 (m, 1H, H-5)
6.077 (d, JNH = 8.056 Hz, 1H, NH C
OCH ₃ )

[0111]

Example 5 [2S, 3R, 4E] -1-Trichloroethoxycarbonylamino-2-octadecanoylamino-4-octadecene-3-ol (1b) (n = 16)
Preparation of [2S, 3R, 4E] -1-amido-2-octadecanoylamino-4-octadecene-3-ol (1a)
24 mg of (n = 16) was dissolved in 5 ml of methylene chloride, 15 μl of diisopropylethylamine was added thereto, and 9 μl of 2,2,2-trichloroethyl chloroformate was further added thereto, followed by stirring at 25 ° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated liquid was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 /
Purification in 3) to give the desired compound (1b) (n = 16)
Was obtained (yield 16%).

This had the following physical properties.

IRνmax (KBr) (cm ⁻¹ ): 1549,1
648 (amido) 2856, 2920, 2951 (CH) 32
85 (NH, OH) ¹ H-NMR (500 MHz, CDCl ₃ ): δ: 0.8
8 (t, 6H, 2Me) 1.25-1.29 (m, 48
H, —CH ₂ —) 1.59-1.62 (m, 4H, NH
_{COCH 2 CH 2, H-7,7} ') 2.01-2.06
(M, 2H, H-6, 6 ') 2.16-2.19 (m, 2H, H-6, 6')
2H, NHCO CH _2- ) 3.40-3.50 (m, 2
H, H-1, 1 ') 4.04-4.08 (m, 1H, H
-2) 4.18 (m, 1H, H-3) 4.68-4.7
5 (m, 2H, NHC ( O) O CH 2 CCl 3) 5.46
-5.50 (m, 2H, NH C (O) OCH 2, H-
4) 5.73-5.79 (m, 1H, H-5) 6.01
_{(D, 1H, NH COCH 2} , JNH = 8.0Hz) Elemental analysis (as _{C 39 H 73 Cl 3 N 2} O 4 (740.38)): Calculated: C: 63.27, H: 9 . 94, N: 3.78 Found: C: 63.15, H: 9.66, N: 3.53.

[0114]

Example 6 [2S, 3R, 4E] -1-Trichloroethoxycarbonylamino-2-tetracosanoylamino-4-octadecene-3-ol (1b) (n = 22)
Preparation of [2S, 3R, 4E] -1-amino-2-tetracosanoylamino-4-octadecene-3-ol (1a)
18 mg of (n = 22) was dissolved in 5 ml of methylene chloride, 10 μl of diisopropylethylamine was added, 6 μl of 2,2,2-trichloroethyl chloroformate was further added, and the mixture was stirred at 25 ° C. for 3 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the concentrated liquid was subjected to silica gel column chromatography (eluent: ethyl acetate / n-hexane = 1 /
Purify in 3) to give the desired compound (1b) (n = 22)
Was obtained (yield 76%).

This had the following physical properties.

[Α] _D = + 3.5 ° (c = 0.34, CHCl ₃ ) IRνmax (KBr) (cm ⁻¹ ): 1549, 1648 (amid
o) 2856, 2920, 2951 (CH) 3285 (NH, OH) ¹ H-NMR (500 MHz, CDCl ₃ ): δ: 1.2
_{5-1.29 (m, 60H, -CH 2} -) 1.57-
_{1.63 (m, 4H, NHCOCH 2} CH 2, H-7,
7 ') 2.02-2.06 (m, 2H, H-6, 6')
_{2.16-2.19 (m, 2H, NHCOCH 2} -)
3.40-3.50 (m, 2H, H-1, 1 ') 4.0
4-4.08 (m, 1H, H-2) 4.18 (m, 1
H, H-3) 4.68-4.75 (m, 2H, NHC
_{(O) CH 2 CCl 3)} 5.46-5.50 (dd, 1
H, H-4, J4,5 = 15.3 Hz, J3,4 = 6.5H
z) 5.56-5.58 (m, 1H, NH C (O) OC
_{H 2) 5.73-5.79 (m, 1H} , H-5) 6.0
6 (d, 1H, NH COCH 2, JNH = 7.8Hz) Elemental analysis (as _{C 45 H 85 Cl 3 N 2} O 4 (824.54)): Calculated: C: 65.55, H: 10 .39, N: 3.40 Found: C: 65.30, H: 10.20, N: 3.36.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI theme coat ゛ (Reference) A61K 31/221 A61K 31/22 601

Claims (4)

[Claims] 1. A compound of the general formula [In the formula, R represents an alkoxycarbonyl group which may be substituted with a hydrogen atom or a halogen atom. n is 0 or 1
Represents an integer of ~ 22. Or a salt thereof. 2. The ceramide derivative or a salt thereof according to claim 1, wherein in the general formula (1), R is a hydrogen atom or a trichloroethoxycarbonyl group, and n is 0, 4, 16, and 22. 3. In the general formula (1), R represents a hydrogen atom or a trichloroethoxycarbonyl group and n represents 0, 16 and 22.
The ceramide derivative according to claim 1 or a salt thereof. [4] [2S, 3R, 4E] -2-acetylamino-1-amino-4-octadecene-3-ol, [2
S, 3R, 4E] -1-amino-2-octadecanoylamino-4-octadecene-3-ol, [2S, 3
R, 4E] -1-amino-2-tetracosanoylamino-4-octadecene-3-ol, [2S, 3R, 4
E] -2-acetylamino-1-trichloroethoxycarbonylamino-4-octadecene-3-ol, [2
S, 3R, 4E] -1-Trichloroethoxycarbonylamino-2-octadecanoylamino-4-octadecene-3-ol and [2S, 3R, 4E] -1-trichloroethoxycarbonylamino-2-tetracosanoylamino The ceramide derivative or a salt thereof according to claim 1, which is selected from -4-octadecene-3-ol.