JPH0256462A - Retinoid analog and production thereof - Google Patents

Abstract

NEW MATERIAL:A trifluororetinoid analog expressed by formula I (R<1> is H or lower alkyl; R<2> is H, lower alkyl, fluoroalkyl, lower alkoxycarbonyl, hydroxycarbonyl, hydroxymethyl or formyl). EXAMPLE:9-(2,6,6-Triethyl-1-cyclohexene-1-yl)-7-methyl-1,1,1-trifluoro nona-2,4,6,8- tetraene. USE:A compound exhibiting antitumor activity. PREPARATION:beta-Ionylideneethyltriphenylphosphonium bromide is reacted with a fluoroaldehyde expressed by formula II in the presence of a base to provide the compound expressed by formula I.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to retinoid analogs, and more particularly to trifluororetinoid analogs having antitumor activity.

Although it is already known that retinoids and their analogs have antitumor effects, problems such as hepatotoxicity have also been pointed out.

In recent years, the search for non-natural retinoid derivatives has continued in order to improve these problems and to enhance efficacy [Cancer Research, Vol. 40, 3413 (1980)].

The present inventors have conducted extensive studies on various fluorine-containing retinoid analogs with the aim of searching for retinoid analogs that enhance antitumor effects while reducing side effects.

As a result, the general formula [I However, R1 is a hydrogen atom or a lower alkyl group, R2 is a hydrogen atom, lower alkyl group, or fluoroalkyl group, lower alkoxyca Rubonyl group, hydroxycarbonyl group, hydroxymethyl group, or Lumyl group.

The present invention, which has discovered that the trifluororetinoid analog represented by

In the present invention, the lower alkyl group represented by R1 is an alkyl group having 1 to 5 carbon atoms, and may be a straight-chain alkyl group or a branched alkyl group, such as a methyl group or an ethyl group. , n-propyl group, i-propyl group,
They are n-butyl group and n-pentyl group. When R2 is a lower alkyl group, this R2 is a lower alkyl group as represented by R1 above, and both may be the same or different. When R2 is a lower alkoxycarbonyl group, It is an alkoxycarbonyl group having 2 to 5 carbon atoms, such as a methyloxycarbonyl group, an ethyloxycarbonyl group, a propyloxycarbonyl group, a butyloxycarbonyl group, and the like.

Furthermore, when R2 is a fluoroalkyl group, the number of carbon atoms is 1 to
5. In particular, a fluoroalkyl group in which one to all hydrogen atoms of one to three alkyl groups are substituted with fluorine atoms is suitable. In addition, R2 may be a hydroxycarbonyl group, a hydroxymethyl group, or a formyl group.The compound of the present invention represented by the general formula [I] can be produced by, for example, the following reaction formula (A). It is obtained by

In the formula, RI and R2 are the same as shown above.

β-ionylideneethyltriphenylphosphonium bromide in the above formula is known [H, Pfander et al., He1
v. Chim, Acta, 53. lff77 (1980
) ].

In addition, the fluoroaldehyde shown in the above formula [ff] is
For example, R4 in formula 0 CB), which can be produced by the following formula (B), represents an alkyl group.

[111) [■] (It) In the compound [II[] in the above formula, when IIR" is a hydrogen atom and R3 is a methyl group [C, D, Poulter et al.
J,Am,Chem,Soc,,98.3376(19
76) ], and when both Rt and Ri are hydrogen atoms [Beilgtein.

2(4), 1509] is a known compound, and when R1 is a hydrogen atom and R3 is a trifluoromethyl group, it can be produced from hexafluoroacetone in the same manner as described in the above literature, and when R1 is a methyl group, When R3 is a hydrogen atom, it can be produced, for example, according to the following formula (C).

In the above formula (C), a conventional method can be used for the first step of methylation. That is, the methyl compound can be produced by reacting with sodium ethoxide, water, sodium chloride, lithium diisopropylamine or the like, and methyl iodide. For selective reduction of ester groups and carbonyl groups, reducing agents such as potassium borohydride, sodium borohydride, sodium cyanoborohydride, diborane, and borane-trialkylamine complexes can be used. For the dehydration step, a conventional method is used, that is, after converting the water-ugly group to a halogen atom, methanesulfonate, or p-toluenesulfonate, a base is present, and in the step of conversion to a leaving group &.

It can be converted into a β-unsaturated ester.

In reaction formula (B), a commonly used ester-to-alcohol reducing reagent can be used in the step of converting compound [ml to [IV]. For example, lithium aluminum hydride, bismethoxyethoxyaluminum hydride, etc. The reaction temperature at which lithium, lithium borohydride, aluminum hydride, etc. can be used is -1
A temperature range from 0.00°C to solvent reflux temperature can be used, but relatively low temperatures, i.e. 1.78°C, can be used to suppress side reactions.
As the reaction solvent, an ether solvent such as ether and tetrahydrofuran (THF) can be used.

In the step of oxidizing compound [] to [11], a commonly used oxidizing agent can be used. Namely, manganese dioxide, chromium dioxide, selenium dioxide, sulfuric acid, organic peroxide, dimethyl sulfoxide (DMSO), 0ppe
Nauer method, oxidizing agents such as nickel peroxide can be used, but due to the instability of the compound, it is necessary to carry out the reaction under as mild conditions as possible, and DMSO-oxalyl chloride triethylamine (Swern method) and other oxidizing agents can be used. An oxidation method using DMSO is preferred.

The reaction conditions used in reaction formula (A) are the so-called Wittig
Reaction conditions can be used. That is, after β-ionylidene ethyltriphenylphosphonium bromide is treated with a base to form a ylide, the reaction temperature for reacting it with the aldehyde shown in compound [1] is from -78°C to room temperature. .

The invention will be described in detail below, but is not limited to these Examples.

Example 1 Luorinona-2468-tetraene! DeRI
A solution of 10 g (60 mmol) of ethyl-4,4,4-trifluorocrotonate in which R2 is both water in anhydrous ether (10 ml) is prepared.

Lithium aluminum hydride cooled to -78@22.
3g (60mmol) of anhydrous ether (90l)
It was added dropwise to the suspension over 40 minutes. Methanol was added thereto, treated with hydrochloric acid at room temperature, and extracted with ether. By distillation, the objectives 4.4, 4. - 4.6 g of trifluorocrotyl alcohol was obtained (boiling point 1250C).

"H-NMR (CDCI3): 84.2-4.4 (layer,
211), 6.00 (d ■, J-15, 5Hz, IH)
, 6.6 (dm, J-15,5Hz, 111) A dichloromethane (85 ml) solution of 6.0 g (47,5 @ of) of chloride was cooled to -50°C to -60°C,
Dimethyl sulfoxide (DMO3) 8.6g (0,
10 mmo 1 ) in dichloromethane solution (16 ml)
was added dropwise over 15 minutes, and the mixture was further stirred for 15 minutes. 4.4.4-Trifluorocrotyl alcohol (4.6 g (36.5 mmol)) and dichloromethane (
:101) The solution was added dropwise over 40 minutes. 4 at the same temperature
After stirring for 0 minutes, add 24.0 g of triethylamine (0,2
4 mol) was added over 15 minutes after the completion of 0-4
15 minutes at 0℃.

The mixture was stirred at room temperature for 30 minutes, and 1N-HCl was added for post-treatment.

After extracting the water tank with dichloromethane, the organic layer was washed with saturated aqueous sodium bicarbonate and saturated brine. The solvent was distilled off to obtain a composition organism.

'N-NMR (CDC1i): δ6.5-6.8 (Otori, 2H), 9.85 (t, J-1, 11Hz, IH)
.

1.46 g (3 mmol) of β-ionylidene ethyltriphenylphosphonium bromide was suspended in tetrahydrofuran (THF) (10 ml), cooled to 0°C, and n-BuLi (1,6M hexane solution) 1.
88ml was added dropwise over 5 minutes and stirred for 30 minutes. A THF solution of 4,4,4-trifluorocrotonaldehyde prepared above was added and stirred for 15 minutes. Water was extracted with hexane and purified by column chromatography.

Low polar RfO, 7 hexane 210s'H-NM
R (CDCh): δ 1.04 (s, 6H), 1.2
-2.2(m+s(δ1.72)÷s(δ1.98)
, 12H), 5.6-7.2 (m, 7) 1).

Y'F-NMR (CDC, (: C11F standard) 63.3 ppp (t, J-8, 7 Hz).

Commercial rights RrO, 65 hexane, 70 servings)”H-
NMR (CDCIs): al, 04 (s, 6tl), 1
．． 2-2.2(m+s(81,72)+s(δ1,9
8), 12H), 5.6-7, 2(m, 71
1).

"F-NMR (CDCh, CG13F standard) Knee 65
．． 8ppm (t, J-10°2Hz).

Example 2 3-trifluoromethyl-2-butan-1-ol (C
, D., Poulter et al., J. Am., Ches+, So.
c, , 98° 3 cores 6 (197B)) 6g (4 pieces set o1), and the same operation as in Example 1 was performed to obtain 3-
Trifluoromethyl-2-buten-1-al (boiling point 65°C) Ig was obtained.

” H-NIIR (CDCI 3): δ6.50 (d
a, J-6,811z, IH), 10.22 (d, J
-6,8Hz, IH).

IR (neat film): 3030, 1700,
1355. as-' Aldehyde 27611 produced above
g (2,0 mol) and β-ion lideneethyltriphenylphosphonium bromide 1.1 g (2,0
The listed compound (E, Z mixture) 410B was obtained from 1.25 ml (2,0 mmol) of m-BuLi (1,6M hexane solution).

YiH-NMR (CDCI:I): δ1.04(s, 6
8), 1.4-2.2(m+s(61,72)+s(δ
1.91)+S(δ1.98), 1511), 6.
0-7.3 (m.

6H).

"F-NMR (CDCI+, CCI YuF standard) Knee 69
．． 0ppm (s, 2F).

−69, Lppm (s, IF).

IR (neat film): 2920, 164G, 1
585,1455.1:110゜1290 cm-' Example 3 A compound in which R2 is trifluoromethyl and one hydride! J '7 Mu (60%) 6.04g (
0.15 mmol) was washed with hexane and suspended in benzene (25 layers). After cooling to 0° C., a solution of 30 g (0.15 m servings) of triethylphosphonoacetate in benzene (37 ml) was added dropwise over 30 minutes, and the mixture was further stirred at room temperature for 30 minutes. 25g hexafluoroacetone
(0.15 g) in benzene (25 ml) at 10
Dilute hydrochloric acid was added to the reaction mixture, which was added over several minutes and stirred at room temperature for 30 minutes, and extracted with ether.

The solvent was removed by distillation, and a fraction containing β,β-bistrifluoromethylethyl acrylate (70 to 90%
°C) was obtained.

Ai'F-NMR (CDC12, CG13F standard) Knee 8
3. rJppmC5) - 0.81 g (,21*■ol) of lithium aluminum hydride was added to anhydrous ether (130
m1), and the above fraction was added at -78°C. 1
After 0 minutes, methanol was added while the temperature remained at -78°C, and after raising the temperature, the mixture was treated with dilute hydrochloric acid. Distilled fraction containing β,β-bistrifluoromethylacrylic alcohol (83-84°C)
I got it.

"F-NMR (CDC13, ClCl3F standard) Knee 8
2.9pp Maro (S).

The above fraction was oxidized in the same manner as in Example 1, and by distillation β, β
A fraction containing -bistrifluoromethylacrolein hydrate was obtained.

"F-NMR (CDC13, CG: 13F standard) Knee 7
6.0ppm(s).

Add 5 ml of concentrated sulfuric acid to the above fraction and 1 78 ml of the gas generated.
Stored in a trap at °C.

"F-NMR (CDCI+, CCIJ standard) Knee 83
．． 1pp wet (S).

The same operation as in Example 1 was carried out using the above-produced β,β-bistrifluoromethylacrolein (~11 of) and β-ionylideneethyltriphenylphosphonium bromide, and 15g of the listed compound (E, Z mixture) was obtained.

'H-NMR (CDCI 3): δ1.04 (s,
5)! ), 1.2-2.3(m+s (δ1.72)
◆S(δ1.96), 12H), 6.2-7.0(
m, , 6H).

"F-NMR (CDCh, (:C1*F standard) knee 59.8pp (d, J-10,7Hz), -60,0
ppm (d, J-10,7Hz).

Example 4 31.5 g of ethyl trifluoroacetoacetate (0,1711
ol) was added. Here, 10.6 ml of methyl iodide (
0.17 mol) was added thereto, heated to 100°C, and stirred for 30 minutes. After cooling to room temperature, it was distilled to obtain 20 g of methylated product.

'H-NMR (CDCI 3): δ 1.26 (t
, J-7, 211z, 31st place), 1.46 (d.

J=7.2Hz, 3H), 3.94(q, J-7,2
Hz, IH), 4.86 (q, J=7.2Hz, 2
H) - 19.8 g (0.1 mol) of the methylated product produced above
) in ethanol 2001, cooled to 0°C, and dissolved 1.9 g (0.05 mol) of sodium borohydride.
was added little by little. After 30 minutes, ethanol was distilled off, water was added, and the mixture was extracted with chloroform. By distillation, 13.6 g of hydroxyester was obtained.

IH-NMR ((:DCI,): δ1.30(t, J
-7.2Hz).

1.40 (d, J-7, 2Hz, 3H), 2.6-3.
0 (m, 0.878).

3.2-3.3 (+s, 0.13 8), 3.9-4.
5 (Otori+9 (δ4.26°J=7.2Hz)3N).

"F-NMR (CDCI+, (: Cl3F standard) knee 78.0 ppm (d, Jho 6.8Hz, 0.39F)
, -77.3ppm (d, J=6.!H1z), 2.
61F).

IR (neat film) 3450, 2980.1
730cm+-'Produced above+-Top Roxyester 1
3.6 g (68 ml) of dichloromethane (120 m
Dissolve in l).

47ml (0.34ml) of triethylamine was added and the mixture was cooled to 0°C. Here methanesulfonyl chloride 10
．． Add 5 ml (0,136 mol) and raise the temperature to room temperature to reduce the
Stirred for 24 hours. Ice-cooled saturated sodium bicarbonate solution was added, and the mixture was extracted with dichloromethane. After drying over anhydrous magnesium sulfate, the mixture was distilled to obtain 6.9 g of ethyl 2-methyl-4,4,4-)rifluorocrotonate (boiling point: 106°C).

"H-NMR (CDC1i): δ1.34 (t, J■
7.2Hz, 3H), 2.10(quint, J=1.
4HzjH), 4.32(q, J-7, 2Hz, 2H
), 6.76 (dq, J=1.4, 7.2Hz, 2H
).

"F-NMR (CDCI3.CC1zF standard) knee 59.2pp (shoes).

Lithium aluminum hydride 1. :18g (:16
．． 4 mmol) in ether (90 ml), -
α,β-unsaturated esters prepared above at 78°C 6.6
2 g (36.4 m) of ether solution were added.

After 15 minutes, methanol was added at -78°C, the temperature was raised, and the mixture was post-treated with dilute hydrochloric acid. Distill under reduced pressure and reduce the amount of solvent to 50+sl
This was used as it was in the next reaction.

The digit value of the product is H-NMR (CDCI+): δ1.82 (br s
, 311), 4.10 (m, 2H).

5.88 (Rin, 18).

1'F-NMR (CDC1ff, CC1ffF standard)
Knee 58.1ppm (dq, J-1, 3, 2, 4Hz)
.

A solution of 4.1 ml (47 ml) of oxalic acid chloride in dichloromethane (85 ml of sodium chloride) was added with DMSO6 at -50°C.
, 9 ml (102 mmol) of dichloromethane (lt
sl) solution was added over 10 minutes and stirred for 30 minutes at the same temperature. The above alcohol was diluted with dichloromethane (30 l), added dropwise over 30 minutes, and stirred for an additional 40 minutes.

22.6 ml of triethylamine was added thereto over 15 minutes, and after 20 minutes, the temperature was raised to room temperature, and after 30 minutes, room temperature was added for post-treatment. 0.18g of pure aldehyde (boiling point 64
°C) obtained.

"H-NMR ((:DC13): δ2.00 (layer, 3
8), 6.4-5.6 (m, IH).

9.63 (s, 1) 1).

"F-NMR ((:DC13, CchF standard) Knee 60
．． 3ppm (m).

The same operation as in Example 1 was carried out using 18 hg (1,: 1 mol) of α-methyl-β-trifluoromethylacrolein produced above and β-ionylidene triphenylphosphonium bromide to obtain 217 mg of the listed compound.
(EZ mixture) Wollj:.

"H-NMR (CDCI+): δ1.00 (s, 31
(), 1.04 (s, 3H), 1.4-2.2 (mis
(δ1.75,3H)+s(δL,80,3H)+s(
δf, 96, 1.5H) + s(δ2.OQ, l 5N
), tota 1ly21)1), 6.0-6
．． 6 (m, 68).

' gF- of a low polar compound (R, 0, 80, hexane)
NMR (CDCh, CG13F standard) knee 57.2
ppm (dt, J=81.2°5Hz) “F-NM” of highly polar compound (RrO, 70, hexane)
R (CDC1, CChF standard) knee 56.4 ppm (
d, J-9,:1tlz).

, Example 5 Mouse leukemia cells L 1210 were suspended in RPM Natsu 640 medium containing 10% tallow serum and kanamycin (50 μg/l), and the cell concentration was adjusted to 2 x 10'cells/plate! It was prepared as follows. Each formulation contains 0.2
It was adjusted to have a weight of 2.0.20 g/1. Take 0.5 mL of cell suspension and 0.5 mL of drug solution into 24-well microwell, adjust the final concentration to 0.1, 1.0, 10 g.
/plate, and cultured for 2 days at 37°C in 5% carbon dioxide. Cell proliferation was measured by Trivan blue staining, and the 50% growth inhibition concentration was determined.

Claims (2)

[Claims] (1) General formula▲ Numerical formulas, chemical formulas, tables, etc.▼...[I] However, R^1 is a hydrogen atom or a lower alkyl group, and R^2 is a hydrogen atom, a lower alkyl group, a fluoroalkyl group, a lower A trifluororetinoid analog represented by an alkoxycarbonyl group, hydroxycarbonyl group, hydroxymethyl group, or formyl group. (2) A general formula [characterized by reacting β-ionylideneethyltriphenylphosphonium bromide with a fluoroaldehyde represented by the following formula [II] in the presence of a base [
Production of a trifluororetinoid analog represented by [I]. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] However, R^1 is a hydrogen atom or a lower alkyl group, R^2 is a hydrogen atom, a lower alkyl group, a fluoroalkyl group, a lower alkoxycarbonyl group, Hydroxycarbonyl group, hydroxymethyl group, or formyl group. ▲There are mathematical formulas, chemical formulas, tables, etc.▼...[I] However, R^1 is a hydrogen atom or a lower alkyl group, R^3 is a hydrogen atom, a lower alkyl group, a fluoroalkyl group, a lower alkoxycarbonyl group, Hydroxycarbonyl group, hydroxymethyl group, or hydroxymethyl group with a protected hydroxyl group.