JPS6097926A - Novel 4-hydroxy-2-cyclopentenone and its preparation - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to novel 4-hydroxy-2-cyclobenzonones and a method for producing the same.

More specifically, the present invention has excellent anticancer effects.

Glotaglandin, a novel 4-hi)'Ill with a human-like structure, has pharmacological effects such as antiviral and antibacterial effects.
The present invention relates to xy-2-cyc-μ penteno compounds and their production methods.

1-5- <Prior art> Prostaglandins are compounds that have unique biological activities such as inhibiting platelet-rich aggregation and lowering blood pressure, and have recently been used in the medical field as a treatment for peripheral circulatory system disorders. It is a useful natural product. Among the grosstaglandins, boostaglandin A is known as having a double bond in its cyclopentane ring; for example, grosstaglandin A.

is expected to be a drug with hypotensive effect (
E, J, Cor@y et al. 2 J, Amey, ehem, .
95.

6831 (1973)).

On the other hand, the potential of prostaglandin A as an antitumor agent has been reported because grosstaglandin AII strongly suppresses DNA synthesis (Bloehem, Bl.
ophys, Res, Cornn+un, 87°yc+
s, tc+7s; w, person, Turney et al. Prast
agrandinmRelat, Liplds, 2
, 365-8 (194i2)).

In addition, 1o-haloprostaglandin, which is represented by the following formula and has a hag atom at the 10th position in prostaglandin nomenclature, is known (USP 3755426), and its uses include bronchodilation and It has been suggested that it has a hypotensive effect.

On the other hand, in recent years, the booster tag glandin expressed by the following formula has been found in Okinawa corals (
Oklnawan sof t eoral m ft
am, 9 ulc
1iett, 23, t5171 (1982);
M. Kobayashi et al., Tetrahedro
ett, 23, 5331 (1982); Masanori Fukushima, Cancer and Chemotherapy, 1o, 1930 (198
3)).

Furthermore, Te1 growing on the bottom of a boat recently collected on Oahu.
A prostaglandin-related substance (bunagrandin) represented by the following formula has been isolated from Esto rilsei (see Monthly Yakuji 24, 4t(x9s2))
. However, its biological activity is unknown.

<Object of the Invention> The present inventors focused on this point, synthesized a prostaglandin analog or bunaglandin analog represented by the following formula as a new compound prostaglandin analog, and investigated its biological activity. Upon investigation, we discovered that it exhibited extremely strong cancer cell proliferation inhibitory activity and found that it was useful as a new type of pharmaceutical, leading to the present invention.

Therefore, the object of the present invention is to develop a novel 4-human hydroxyloxypropanase, which has a prostaglandin A-like structure, has excellent anticancer and antiviral effects, and has relatively low prostaglandin-like physiological activity. An object of the present invention is to provide 2-cyclobenzonones and a method for producing the same.

<Structure and Effects of the Invention The present invention relates to novel 4-hydroxy-2-cyclobentenones represented by the following formula [1] 9- and a method for producing the same.

In the above formula (1), the display? represents a single bond, triple bond or triple bond.

R1 is a hydrogen atom, substituted or unsubstituted, having 1 to 10 carbon atoms
represents a furkyl group or alkenyl group, or a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms.

10- As an unsubstituted C1-C10 (1') furkyl group,
For example, methyl, ethyl, n-propyl, improvil, n-butyl, 5ee-butyl, t-7'thyl, n
- Straight chain or branched furkyl groups such as -pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl and the like can be mentioned.

A substituent for such an unsubstituted alkyl group having 1 to 10 carbon atoms is -COOR' (where R4 represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a -equivalent cation).

), hydroxyl group.

Examples include a phenyl group or phenoxy group which may have a substituent, a furfoxy group having 1 to 6 carbon atoms, an acyloxy group having 1 to 7 carbon atoms, and a cycloalkyl group having 3 to B carbon atoms. It can have 1 to 3 such substituents, preferably 1.

R4 of such -〇〇〇〇R' is a hydrogen atom.

C1-1O alkyl group2. - Dental cations can be mentioned, and examples of the alkyl group having 1-P-10 carbon atoms include linear or branched alkyl groups as mentioned above.

- Equivalent cations include ammonium cations such as NH4'' I tetramethylammonium, monomethylammonium, dimethylammonium, trimethylammonium, benzylammonium, phenethyl ammonium, morpholinium cation, monoethanolammonium, piperidinium cation; Na'' ,
Alkali metal cations such as K+; 1/2Ca” 11
Divalent or trivalent metal cations such as /2Mg"H1/2Zn"I 1/3A/"+ can be mentioned.

Examples of the substituent of the phenyl group or phenoxy group which may have a substituent include a fluorine atom, a chlorine atom,
Hapgen atoms such as bromine atoms; methoxy, ethoxy, pupexy.

Alkoxy groups with 1 to 6 carbon atoms such as butoxy, trifluoromethoxy, dichloromethoxy; 1 to 6 carbon atoms such as methyllaethyl, propyl, butyl, trifluoromethyl, etc.
Examples include the alkyl group of No. 4.

Examples of the phenoxy group having 1 to 6 carbon atoms for R4 include methoxy, ethoxy, and h-p-boxy.

Preferred examples include isopropoxy, n-butoxy, chloromethoxy, dichloromethoxy, and trifluoromethoxy.

Examples of the 7-syloxy group having 1 to 7 carbon atoms include acetoxy, propionyloxy, n-butyryloxy, isobutyryloxy, n-valeryloxy, invaleryloxy, cabroyloxy, enantoyloxy, benzoyloxy, and the like. I can do it.

Examples of the cycloalkyl group having a foot prime number of 3 to 8 include t cyclopropyl, cyclopentyl, cyclohexyl, and the like.

When R1 represents a substituted or unsubstituted alkenyl group having 1 to 1 G of carbon atoms, examples of the unsubstituted alkenyl group having 1 to 10 carbon atoms include 13-ha2-7'abenyl, 1-7'lopenyl, , 3-7'tenyl, 4-pentenyl, 5-hexenyl and the like. As the substituent for such an unsubstituted alkenyl group having 1 to 10 carbon atoms, the above-mentioned unsubstituted alkenyl group having 1 to 1 carbon atoms may be used.
The same substituents as 0 can be mentioned.

When R1 represents a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, examples of the unsubstituted cycloalkyl group having 3 to B carbon atoms include cycloprovir, cyclopentyl, cyclohexyl, etc. can.

Examples of the substituent for the unsubstituted dichlorofurkyl group having 3 to 8 carbon atoms include the same substituents as for the above-mentioned unsubstituted alkyl group having 1 to 10 carbon atoms.

In the above formula (1), R1 represents a substituted or unsubstituted alkyl group having 1 to 10 carbon atoms or a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms. Examples of the unsubstituted alkyl group having 1 to 10 carbon atoms include methyl.

14- Ethyl, n-propyl) isopropyl) n-butyl-5
Examples include ee-butyl, 1-butyl, fl-pentyl, n-hexyl, 2-methyl-1-hexyl, 2-methyl-2-hexyl, n-heptyl, n-octyl, and the like. Examples of the substituent of such an unsubstituted furkyl group having 1 to 10 carbon atoms include -COOR'. .

Examples include a phenyl group or phenoxy group which may have a substituent, a furfoxy group having 1 to 6 carbon atoms, an acyloxy group having 1 to 7 carbon atoms, and a dichlorofurkyl group having 3 to 8 carbon atoms.

H40 in -COOR'° represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, or a -equivalent cation.

Examples of the furkyl group having 1 to 10 carbon atoms or the -equivalent group include those exemplified for R1. In addition, alkoxy groups having 1 to 6 carbon atoms, acyloxy groups having 1 to 7 carbon atoms, and phenyl groups that may have substituents are
In the case of the cycloalkyl group in 8, the same groups as those exemplified for R'' can be mentioned.

When R2 represents a substituted or unsubstituted cycloalkyl group having 3 to 8 carbon atoms, examples of the non-straight or substituted cycloalkyl group having 3 to 8 carbon atoms include cyclopentyl and cyclohexyl. Examples of the substituent for the unsubstituted cycloalkyl group having 3 to 8 carbon atoms include the same substituents as for the above-mentioned unsubstituted alkyl group having 1 to 10 carbon atoms.

The above formula [! ], 18 represents a hydrogen atom, a hydroxyl group or a protected hydroxyl group. The protecting group for the protected hydroxyl group is a C3-c7 acyl group.

M can include a tri(C,-C,)hydrocarbon-silyl group or a group that forms a 7-cetal bond with the oxygen atom of a hydroxyl group.

Examples of the C1-C77 sil group include 7cetyl, propionyl, n-butyryl, inbutyryl, n-valeryl, invaleryl, caproyl, enantoyl, benzoyl, and the like.

Among these, C1-C, aliphatic acyl groups such as 7-cetyl, n-butyryl or imbutyryl, caproyl or benzoyl are preferred.

Examples of the tri(C8-Ct) hydrocarbon silyl group include trimethylsilyl and triethylsilyl.

Tri(C1-C4) such as t-butyldimethylsilyl group
Preferred examples include alkylsilyl, diphenyl(01-C,)furkylsilyl groups such as t-7' tyldiphenylsilyl groups, and tribenzylsilyl groups.

An example of a group that forms an acetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-propyl, 2
-Ethoxy-2-propyl, (2-methoxyethoxy)
Mention may be made of the methyl, benzyloxi-17-dimethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 616-cymethyl-3-oxa-2-oxo-bicyclo(a,1.o)hex-4-yl group. .

Among these, 2-tetrahydropyranyl.

2-tetrahydrofuranyl, 1-ethoxyethyl, 2-
Methoxy-2-propyl, (2-methoxyethoxy)methyl or 6,6-dimethyl-3-oxa-2-oxo-
Bicyclo[3°1.0]hex-4-yl group is particularly preferred.

A and B are a hydrogen atom and B is a hydroxyl group, or A and B are bonded to each other to represent one bond. That is, the new 4- expressed by the above formula [1]
Hydroxy-2-cyclobentenones have a constant f of Atn
By i, 4-hydroxy-4-substituted-5-(1-hydroxyalkyl)-2-cyclobentenones represented by the following formula (da) 18- and the following formula [! b] represents 4-hydroxy-4-substituted-5-alkylidene-2-cyclobentenones.

In the above formula [+], (Im), (Ib), X
It represents a hydrogen atom or a norogen atom, and examples of the hydrogen atom include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom, with a chlorine atom and a bromine atom being preferred.

The novel 4-hydroxy-2-cyclobentenones of the present invention are particularly preferably compounds represented by the following formula [1']. In the above formula [11], R4 represents a hydrogen atom, a furkyl group having 1 to 1 o carbon atoms, or a one-equivalent cation.

These specific examples are the same as those described above.

Also R”, R”, A, B, X display,
? This is a book similar to the one mentioned above.

4-hydroxy- represented by the above formula m), (1')
Specific examples of 4-substituted-5-(1-hydroxyfurkyl)-2-cyclobentenones include the following.

(1) 4-Buty1-$-4-hydroxy-5-(]-Hytonyl-6-carboxyhexyl-2-cyclobentenone (2) 4-Hydroxy-4-octyl-5-(1-hydroxy-6- Carpoxyhexyl)-2-cyclobentenone (3) 44-hydroxy4-((tE)-1-octenyl)-5-(1-hydroxy-6-carboxyhexyl)-2-cyclobentenone (4) 44-hydroxy-4-((IK)-a-hydroxy-1-octenyl]-5-(1-hydroxy-6-
carboxyhexyl)-2-cyclobentenone (5) (1) to (4) 2-22 (6) (1)
2-boo superisomer of ~(4) (7) Methyl ester of (1) to (6) (8) Ethyl ester of (1) to (6) (
9) Ammonium salts α1(1) to (6) of (1) to (6)
Specific examples of the sodium salt of 6) and the 4-hydroxy-4-substituted-5-alkylidene-2-cyclobentenones represented by the above formula (lbL(:I')) include the following.

21-Al 4-hydroxy-4-butyl-5-(6-carboxyhexylidene)-2-cyclobentenone (6) 4-hydroxy-4-butyl-5-(6-carboxyhexylidene)-2 -cyclobentenone (to) 4-hydroxy-4-((I B)-1-octenyl)-S-(S-carboxyhexylidene)-2-
Cyclobentenone 044-Hydroxy-4-((IE)-a-hydroxy-1-octenyl)-s-(a-carboxyhexylidene)-2-cyclobentenone (to) 6■-a4-2-791 Body Q* (13) ~α Yuno 2-pro upper body αη CL,) ~α→ methyl ester light (b) ~0
Ethyl ester of 1 (11 (11) ~ ammonium salt of α (e) aη ~
The novel 4-human (koxy-2-cyclo22-lopentenone) of the present invention is produced by hydroxylating the starting material 2-cyclobentenone represented by the following formula (It). Manufactured.

The starting material (II) can be produced from 4-hydroxycyclobentenones, for example, by the methods shown in the following reaction schemes A to CK.

Evening tg ■OHC, R.

/ Buttoned.

As the hydroxidizing agent, t-butylhydron(-oxide) is preferably used.The amount used is preferably 1 to 40% per raw material (I); 0.1 to 100 mol, preferably 5 to 2025 to 24 mol.

The reaction is preferably carried out in the presence of a basic compound,
Examples of such basic compounds include methylamine, dimethylamine, ethylamine, diethylamine, triethylamine, dibutylamine, and diimpropylamine.

11 bases such as triinpropylamine, ethylamine, methylhexylamine, decylamine, dodecylamine, cyclopentylamine, dicyclohexylamine, benzylamine, dibenzylamine, α-7enethylamine, β-7enethylamine, ethylenedi7mine, diethylenetriamine, etc. Examples include amines, and triethylamine and diethylamine are preferably used.

The amount of the basic compound used is preferably the same as that of the raw material compound (It
) 0.1 to 30 equivalents, preferably 0.2 to 2%
．． 0 equivalents are used.

As a reaction solvent, aromatic hydrocarbons such as benzene, toluene, etc.; aliphatic hydrocarbons such as hexane, pentane petroleum ether, cyclohexane, etc.; ethers such as ether, tetrahydrofuran, dimethoxyethane, etc.; carbon chloride, chloroform,
pl-genated hydrocarbons such as dichloroethane, dichloroethane, tetrachloroethane, etc.; so-called aprotic polar solvents such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, etc. are used alone or in any combination thereof; The total is 1@~h.

The reaction temperature is preferably -20 to 100"C1%, preferably G"! It is in the range of θ to 60°C.

The reaction time varies depending on the raw material compounds and reagents 9 reaction solvent used, but is usually carried out in the range of 5 minutes to 3 days.

After completion of the reaction, the target compound can be purified and fractionated by conventional means, such as extraction, washing with water, drying, and pomatography.

The target compound can be subjected to a deprotection reaction when it has an intramolecular pressure protecting group.

When the protecting group is a group that forms an acetal bond with the oxygen atom of the hydroxyl group, the protecting group can be removed by, for example, acetic acid + p
) Using a pyridinium salt of luenesulfonic acid or a cation exchange resin as a catalyst, for example, water, tetrahydrofuran.

This reaction is suitably carried out using ethyl ether, dioxane, 7-setone, acetonitrile, etc. as a reaction solvent. The reaction is normally carried out at a temperature range of -78°C to +30°C for about 10 minutes to 3 days. Also, the protecting groups are great! J (C, ~C
1) In the case of hydrocarbon-silyl groups, for example acetic acid.

The reaction is carried out in the presence of tetrabutylammonium fluoride, cesium fluoride, etc. in a reaction solvent as described above at a similar temperature and for a similar period of time. In addition, when the protecting group is an acyl group, for example, in an aqueous solution or water-alcohol mixed solution of caustic soda, potassium hydroxide, calcium hydroxide, or a methanol or ethanol solution containing 1-lium methoxide, potassium methoxide, or sodium ethoxide. This can be carried out by hydrolysis.

If the target compound has an ester group, it can be subjected to hydrolysis, for example using an enzyme such as lipase,
The process is carried out in water or a solvent containing water at a temperature of 0° C. to +60° C. for about 1 minute to 24 hours.

When the target compound has a carboxyl group in its molecule, it can then be further subjected to a salt-forming reaction if necessary to obtain the corresponding carboxylate. The salt-forming reaction is known per se, and includes approximately the same amount of sodium hydroxide as the carboxylic acid.

Basic compounds such as potassium hydroxide and sodium carbonate,
Alternatively, it can be carried out by neutralizing with ammonia, trimethylamine, monoethanolamine, morpholine, etc. in a conventional manner.

or<LC Novel 4-hydroxy-2- of the above formula (1)
Schiff-pentynones are produced.

The novel 4-hydroxy-2-cyclo29-rointenones of the present invention are effective against %K L1210 leukemia cells at extremely low concentrations, e.g. 0.05 μm1/Ml (2-riC
x P -4-hydroxy-4-(1-octenyl)-
5-(s-methoxycarbonylhexylidene)-2-cyclobentenone) or 0.10 μm7/wrl
(4-hydroxy-4-(1-octenyl)-5-(6
-methoxycarbonylhexylidene)-2-cyclobentenone) exhibits a strong growth-inhibiting effect on cancer cells (L1210 leukemia cells) and is expected to be an anticancer agent.

Example 1 T-butyl hydroperoxide (1
After adding benzene (0,3i1), 4-(1-octenyl)-s-(s-methoxycarbonylhexylidene)-2- Cyclope-30-entenone (19,1IQ, 0.057 mmol
) was added to the benzene solution (0.3 mm), followed by triethylamine (9 to 1,21, 0.0114 mm).
ol) benzene solution (o, 1m), pd(ode)
, (1,3" fso, o o 57 rnmot) was added, and the ffi compound was heated at 50-60 °C with stirring.
45 minute diameter - butyl hydroperoxide (15111p
, 0.17 mmol) and continued heating.
After 0.5 hours, the reaction mixture (TLC shows that most of the starting material remains) was purified by column chromatography (StO,).

41 was subjected to ethyl acetate-hexane (1:4→1:1)) to obtain the target product 4-hydroxy-4-(t-:octenyl)-s-(6-medoxycarponylhexane).
; IR (CHCl5): 3600-3300
.

1735, 1?25, 1702, 1655, l
,, -1; 'HNMR (cocis) δ: 0.7
-1.0 (t, 3, J=6Hm.

CH,), 1.0-2.5 (m, 21, C
H,,OH) 3.65(s, a, ocn,)
, 5.50 (a, r, , r = ts
[z, C13 vinyl), 5.5o(at, I,, r
=16, 6.2 Hz, C14 vinyl), 6.2
2 (d.

I, J = 6 Hz, C10 vinyl), 6
．． 47 (dt.

I, J=7.5, 0.5 Hz, C7 vinyl)
17.10 (dd, I, J=6, 0.5
Hz, ctt vinyl); Mats (m/Z): 3
48 (yt”), aao, 316° Example 2 4-(1-octenyl)-s-(s-methoxycarbonylhexylidene)-2-cyclobentenone s Oxq
(0.15 mmol) was dissolved in 1 d of toluene, 28 μl (0.20 mmol) of triethylamine,
t-buty/L-human p-peroxide 6211v (0,
45 mmol) + palladium chloride 1 s! (0,
20rnmol) and cupric chloride amy (o,
o 1mmot) was added thereto, and the mixture was stirred at 70°C for 1.5 hours. Sodium thiosulfate aqueous solution was added, and extraction was performed with methane. Combine the organic layers and wash with saturated saline,
It was dried with anhydrous sodium sulfate. p overconcentrated diameter silica gel column chromatography (silica gel.

10! ! ; Elution solvent, Schift hexane: ethyl acetate = 5
:1→2:l), and the 4-human-oxy-4 of Example 1
-(1-octenyl)-5-(6-medoxycarponylhexylidene)-2-cyclobentenone 8■ (yield 15
h) was obtained.

Fruit decoration example 3 10a1! 1 Ct-butyl hydroperoxide (264, 0.2 mmol, 70 qb linear purity) was added to a test tube, and benzene (o, atd) was added.
PI Near-4-(1-octenyl)-3-(s33- monomethoxycarbonylhexylidene)-2-cyclobentenone (14,91R9t O*tf 4 mn+ol
) of benzene solution (o, am/) was added, followed by triethylamine (4iny, 0.04 mmot).
) benzene solution (o, id), pd(OAe)
, (4,s4.0.02 mmol) was added. The mixture is heated at 50-60°C under stirring. After 56.5 hours (during which time benzene was added little by little), the crude product was separated by column chromatography (Sin, I 5 +9 + ethyl acetate-hexane (1:S)).

Furthermore, thin layer chromatography (ethyl acetate/L, -heky(1-octenyl)-5-(6-medoxycarponylhexylidene)-2-cyclobentenone (1,02
, 7% yield).

R1: o, a1 (3:'r xane-ethyl acetate); IR (cncla): asoo-3300,
1725, 1660 wounds-”'H?JMR(C0CA',
) δ: o, s-x, o (t, a, J=6Hz, CH
l) t 1.1 2-6 (WL*21 +CH@+
34-0H)13.65(as3+0cH3)s5-”((1
+1, J = 15 I (z, C13 vinyl)
, s, as(dt.

1, J-15,6,2Hz, C14 vinyl).

6.68 (dt, l, J = 7.5, 0
．． 5 Hz, C7 vinyl), 7.14 (d, 1.J
=0.5Hz, C1l vinyl), Mats (m/Z
): 384: 382 (1:3), M+.

35- 164-

Claims (8)

[Claims] (1) A novel 4-hydroxybutane compound represented by the following formula [Natsu]. (2) In the above formula (1), ]111 is -C00
B' (here, R4 represents a hydrogen atom, a fulkyl group having 1 to 10 carbon atoms, or a -equivalent cation). Hydroxyl group, phenyl group or phenoxy group which may have a substituent, phenoxy group having 1 to 6 carbon atoms, carbon 141
A furkyl group or alkenyl group having 1 to 10 carbon atoms substituted with a 7-syloxy group having 1 to 7 carbon atoms or a cycloalkyl group having 3 to 8 carbon atoms: or a schiff-alkyl group having 3 to 8 carbon atoms. Novel 4-hydroxy-2-cyclopenzone compounds as described in Scope 1. (3) In the above formula CD, R2 is -COOR"(
Here, BaI2 represents a hydrogen atom, a C1-io7 alkyl group, or a -equivalent cation. ). Hydroxyl group, phenyl group or phenoxy group which may have a substituent, alkoxy group having 1 to 6 carbon atoms, 1 to 7 carbon atoms
an acyloxy group or an alkyl group having 1 to 10 carbon atoms substituted with a cycloalkyl group having 3 to 8 carbon atoms; or an alkyl group having 1 to 10 carbon atoms substituted with a dichlorofurkyl group having 3 to 8 carbon atoms;
0 alkyl group; or a cycloalkyl group having 3 to 8 carbon atoms.
Hydroxy-2-cyclobentenones. (4) Claim 18I that the novel 4-hydroxy-2-cyclobentenone is a compound f-4 represented by the following formula [1']
The novel 4P hydroxy-2-cyclobentenones described. (5) Claims 1 to 4, wherein in the above formula (1) and ['], X is a chlorine atom or an odor atom.
Novel 4-hydroxy-2-cyclopenkenones according to any one of the following items. (6) The following formula CD [in the formula ,Display;,2' I M”
I R” + R” + A * B + X 1 [
is the same as the above definition. ” A method for producing a novel 4-hydroxy-2-cyclobentenone. (7) t-Butylhydrobe as a hydroxidizing agent! Using a reoxidopalladium compound (Claim 6)
A method for producing novel 4-hydroxy-2-cyclobentenones as described in Section 1. (8) The novel method for producing 4-hydroxy-2-cyclopenteno 7 according to claim 7, wherein the palladium-based compound is radium acetate or palladium chloride.