JPS5965068A - 7,8-dehydroprostaglandin a, its preparation, and carcinostatic agent containing said compound as active component - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (R is H, 1-10C alkyl or one equivalent of cation; A is -CH2CH2-, -CH=CH-, or -CidenticalC-). EXAMPLE:(7E)-7,8-Dehydroprostaglandin A1. USE:A carcinostatic agent. Dose: 1mug-100mg of the active component per kg daily in 2-6 divided doses. PROCESS:A compound of formula I wherein R is R' is obtained by the dehydration reaction of 7,8-dihydroprostaglandin E of formula II (R' is H or 1-20C alkyl) with a dehydrating agent such as inorganic acid in a solvent at 0-80 deg.C for 10min-10hr. The compound can be converted to the carboxylic acid salt of formula I by neutralizing with KOH, Na2CO3, NH3, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides 718-dehydroprostaglandins A,
The present invention relates to a method for producing the same and an anticancer agent containing the same as an active ingredient. More specifically, the present invention has an excellent anticancer effect7,
Novel 7s such as 8-dehydroprostaglantin A,
．． The present invention relates to 8-dehydroprostaglandin AM, its production method, and an anticancer agent containing it as an active ingredient.

Prostaglandin is a compound that has unique biological activities such as platelet aggregation inhibiting action and depressant action, and is a useful natural product that has recently been used in the medical field as a peripheral circulation treatment drug. Among prostaglandins, prostaglandin A is known to have a double bond in its cyclopentane ring. For example, prostaglandin A is expected to be a drug that has a blood pressure lowering effect (E , J, Corey'+J, A
mer, Chem, Soc, +95.6831 (19
See 73). Irimoto synthesized a new 7,8-dehydroprostaglandin A derivative having a double bond at the 7-position as a prostaglandin A derivative, and investigated the pharmacological effects of such compounds, and found that they were excellent. The present invention was achieved by discovering that the novel 7,8-dehyde μbrostagrandeino A class is useful as an anticancer agent, as well as having anticancer effects.

That is, the present invention provides 7,8-dehydrobrostagrandein A represented by the formula (1)
, their production methods, and anticancer agents containing them as active ingredients.

In the 7,8-dehydroprostaglandin A of the above formula (1), R is a hydrogen atom, a furkyl group having 1 to 10 carbon atoms, or an -equivalent cation. Here carbon number 1~l
Examples of the furkyl group of O include methyl, ethyl, n-
Propyl.

1so-propyl, n-butyl, 5ec-butyl.

tert-7'tyl, l-pentyl, n-hexyl.

. -heftyl, n-octyl, n/nylIn-decyl, and the like. Among these, methyl,
Kosenru is preferred. - For example, as an equivalent cation,
Alkali metal carbions such as Na'', ni+; ''/
2 Ca", Z / 2 Mg" +1/ 2 Z
Divalent or trivalent gold 14 cations such as n'', s/3 A13+; NH4'', tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzyl heptanomonium, phenethyl ammonium, monoethanol ammonium,
Ammonium cations such as piperidiny and um cations/
Among these, especially sodium ions.

Anoheptinium ion is preferred.

In the above formula [1], A is -CH, -CH, -, -CH
=CH- or -〇miC-. Also, the above formula (1)
is expressed in /χ is for the oxo group at the 9th position (χ-0)
Represents a platform that coexists with cis (7Z) or transformer (7E), or any assignment of cis and transformer.

A specific example of such 7,8-dehydrobrostagrandeino A- is +11 (7K) -7,8-dehydope+7stagrandeino A-.

(21(7Z)-7,8-dehydroprostagranodei/A,.

(a+ (7E) -7,8-dehydrobrostagrandeino A1 (4) (7Z)-7,8-dehydrobrosta grandeino AI+ (5) (7E)-7,8-tehytrobrosta grandein A , methyl ester! (6) (7Z)-7,8-dehydroprostaglandin A, methyl ester.

(7) (7E) -7,8-dehydrobrostaglantin A! Methyl ester.

(81(7Z) -7,87 dehydroprostaglandin A, methyl ester.

5.6-dehydro form of the compound of 191 +31! Ql
5,6-dehydro form of the compound (4).

Sodium salt of the compound 0υ ('')! 0'lJ (
Sodium salt of compound 21.

1131 Sodium salt of the compound of +31.

(14 (Sodium salt of the 41 monster.

α! Ammonium salt of the compound 9il+.

11f9 (Ammonium salt of 21 compounds!071
(Ammonium salt of compound 31.

Examples include ammonium salts of compounds of No. 08 191.

The 7,8-dehydroprostaglandin A of the present invention is a 7,8-dehydroprostaglandin/din E represented by the following formula [■] Ho oti
It is necessary to subject the type to a dehydration reaction and mix it! It is produced by subjecting it to a salt-forming reaction depending on iK.

In the above formula (IID, [R' is a hydrogen atom or has 1 to 1 carbon atoms]
represents 10 alkyl groups. Examples of the alkyl group having a return prime number of 1 to 10 include the same a4kyl groups as described above.

The same applies to A and indication - as described above. 718-dehydrobrostaglandino E of the above formula] is represented by the following formula 7-hydroxyprostaglandino E HOo; This reaction is achieved by reacting the active compound with methanesulfonyl chloride and then eliminating the anchoring groups at the 11th and 15th positions.

] As a dehydrating agent used for dehydrating 2g self-formula (IIJ's 7.8-dehydroprustabran 1/E 11), for example, hydrochloric acid, hydrobromic acid, hydrofluoric acid, 1
) Inorganic acids such as acids; acetic acid, propionoic acid, beak, citric acid #1. Organic carboxylates such as maleic acid; methanesulfonic acid, ethanesulfonic acid, henzenosulfonic acid, p-
)M-organic sulfonic acids such as luenesulfonic acid, etc., and among them, non+sell is preferable. The amount of the dehydrating agent used is 7.8-dehydroprostagra/Din E.
It is preferably used in an amount of 0.5 to 50 equivalents, particularly preferably 1 to 10 equivalents. Reaction solvents include ethers such as tetrahydrofurano, dioxane, dimethoxyethane, and diethyl ether; alcohols such as methanol and ethanol; and monomers such as cy/methyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, acetonitrile, and water. Or it is used in a combination of these.

The reaction temperature is preferably θ~80゛C1, particularly preferably J
It ranges from O to 50-G.

The reaction time varies depending on the raw materials used, the dehydrating agent and the reaction solvent, but it is usually carried out in the range of 10 minutes to 10 days.
Preferably the range is between 20 minutes and 51-1.

In the dehydration reaction (・[ is the above formula (It
) 17) 7.8-dehydroprostaglandin E
Instead of using 7,8-dehydroprostaglandin E, the hydroxyl groups at positions 11 and 15 are retained with, for example, t-butyldimethylsilyl groups, and this is treated with dehydration such as hydrofluoric acid. It is also possible to perform a dehydration reaction at the 11th and 15th positions by carrying out a dehydration reaction with an agent, followed by a dehydration reaction to obtain the desired compound.

After the dehydration reaction, the target compound can be purified by a method such as silica gel column chromatography, silica gel thin J-chromatography, florisil column chromatography, or high performance liquid chromatography. , if the 1st position is a carboxyl group, then, if necessary, it can be subjected to an additional pressure salt formation reaction to yield the corresponding carboxylic acid salt. The salt-forming reaction is known per se, and involves approximately the same amount of sodium hydroxide, potassium hydroxide, and tricarboxylic acid.
The 7,8-dehydroprostate of the above formula (1) can be obtained by neutralizing with a basic compound such as sodium carbonate, or with ammonia, trimethyl 7-mino, monoethanolamine, morpholyph, etc., and then cooling. Grandin A is produced.

The 7,8-dehydroprostaglandin A of the present invention exhibits a strong anticancer effect, particularly in L1210 leukemia cells, with extremely low levels of itchiness, and is extremely useful as an anticancer agent.

The 7,8-dehydroprostaglandin AM of the present invention can be administered orally, intradermally, subcutaneously, or intracutaneously.

It can be administered parenterally, such as intravenously. For oral administration, 1. It can be a sJ-form preparation or a liquid preparation. Examples of solid preparations include chest preparations.

There are pills, tablets, granules, etc. Like this
In ll, one or more 7.8-dehydroprostaglandi''/A4A are mixed with e.g. sodium electrocarbonate, lucium carbonate, valene iodenbum, sucrose, manonitol, carboxymenal cellulose, etc. Preparation operations are carried out according to conventional methods.For solid preparations, lubricants such as Shio II, calcium stearate, magnesium stearate, and glycerin.

Sweeteners, stabilizers, preservatives, etc. may also be present.

Liquid preparations for oral administration include, for example, emulsions, solutions, suspensions, syrups, and elixirs. It can also be used as #I1% lubricant, turbidity adjuvant, resting agent, flavoring agent, aromatic agent, stabilizer, etc.

Liquid preparations can also be placed in capsules made of a dazzling substance such as gelatin.

For intrarectal administration, conventional suppositories such as gelatin soft capsules are used for K.

Examples of preparations for parenteral administration other than rectal administration include:
Examples include preparations for subcutaneous, intramuscular, and intravenous injection in the form of sterile aqueous or non-aqueous solutions, R cloudy agents, and emulsions.

Non-aqueous solutions and suspensions include, for example, bromelenoglycol,
Examples include polyethylene glyfur, olive oil, or injectable organic esters such as ethyl oleate. Such preparations may also contain preservatives, emulsifiers, dispersants, stabilizers, and the like. Furthermore, these nine preparations for injection can be made sterilized by appropriate treatment such as filtration through a bacteria-retaining filter, application of a sterilizing agent, or irradiation.

The 7,8-dehydroprostaglanobin A of the present invention can also be used by forming an inclusion compound with α, β, or r-cyclodextrin, methylated cyclodextrin, or the like.

The dosage of 7,8-dehydroprostaglandin A of the present invention depends on the condition of the subject receiving the administration.

Depends on age, gender 1 body weight, and route of administration, but usually 1
It can be administered in an amount of 9 units x 7 days in 1i1 to 100 ml/day. The dose 411 can be administered once or divided into several times, for example, 2 to 6 times.

As detailed above, according to the present invention, 7,8-dehydrobrostagrandein A, which is extremely useful for the treatment of cancer patients.
, a method for producing the same, and a cancer drug containing the same as an active ingredient.

The present invention will be explained in more detail below by way of examples.

(7E)-7, s-f hydroprostaglandin K 1
, 160 mg was dissolved in 3 ml of natrahydrofuran, 2 ml of 0.5N salt fli was added, and the mixture was stirred at room temperature for 4 days. A saturated saline solution was added and extracted with ethyl acetate. The ◎ and strainer layers were combined, washed with a saturated saline solution, and dried over anhydrous magnesium sulfate. After filtration and concentration, separation and purification with silica gel "I'LCK" resulted in (7E)-7,8-dehydroprostagra/
95 mg (yield 63%) of Jin AI was obtained.

TLC: RfO, 5g (developing solvent; hexanef7ton=1:2) IR (CHCj, solvent): 3650-2400.
1698°1646.967 (1-' NMR: δCDCl5.0.88 (t + 3H+
J=6.0Hz) 11.0~2.0(nl+1
4H) + 2.0”2.8 (m + 4H) +
3.4~4.6 (m+48), 5.1~6.9 (m
t2H), 6.34 (dd +IH, J””6.0
+ 2-4H1) + 6.111 (dd + IH
+ J=7.8 + 1.5Hz)+7.36(dd+
IH1J=6.0+2.7Hz) Example 2 (7K) -7,8-dehydroprostaglandi E
1,11.22 mg of 15-his-1-butyldimethylsilyl ether was mixed with 1 ml of acetonitrile and 4
7qb hydrogen fluoride #! It was poured into 50 μl of bath solution and stirred at room temperature for 20 minutes. After adding saturated aqueous sodium hydrogen solution, the pH was adjusted to 1 using oxalic acid. The organic layer was extracted with ethyl acetate, washed with saturated brine, and dried over anhydrous phosphorescent magisium. The mixture was purified in fractions by TLC on 1 lll hyperconcentrated temporary silica gel to obtain 14.7 mg (yield: 37 ml) of -7,8-tehydrobrostagranodine A.

Example 3 Measurement of anticancer activity Cancer cysts were 10%
Erum) was grown in RPMI 1640 medium. 7.8-Dehydroprostaglandi 7
A, is dissolved in 9<3s% ethanol and m+ before use.
Make sure the ethanol is at least 11 degrees or 0.1% F.
Added to Hj underground. 7.8-dehydroprostagra/
The medium containing Din A is Minboa th! I passed.

” Nodolol uses o,t% ethanol, 1
．． 1210 Nonon & Jll ill! Ikilx l
The cells were plated on a medium at a concentration of 100 g/ml and grown for 4 hours. The number of viable cells was determined by trypan blue staining. The results are shown in the table.

Example 4 Manufacture of tablets Tablets each having the same composition were manufactured.

(7E)-7,8-dehydroprostagra/din A,
10111g lactose
250 II @ potato starch 7Qll polyvinylpyrrolidone 101% magnesium stearate 5111 g (7E) -7,8-dehydroprostagra/din AI obtained in Example 1, lactose and potato starch were mixed,
The granules thus obtained were mixed with magnesium stearate, uniformly moistened with a 20% ethanol solution of polyvinylvinyl vinylide (J17), and then passed through a sieve.
0 compressed into tablets Patent applicant Teijin Ltd.

Claims (4)

[Claims] (1) 7,8 dehydrobrosta grandeino A group represented by the formula (1). (2) T! Self Formula (II) 7,8-dehydroprostaglandin E expressed as HO
[In the formula, the definitions of A and R are the same as above]. A method for producing 7,8-dehydrobrostagrandeino A represented by (3) Claim 2 in which the dehydration reaction is carried out using an inorganic acid
A method for producing 7,8-dehydroprostaglandin A as described in 2. (4) A study agent containing 7,8-dehydroprostaglanobin A represented by the above formula as a 1' active ingredient.