JPH07267903A - Fluorine-containing compound having anti-hiv activity - Google Patents

Abstract

PURPOSE:To obtain a new fluorine-containing compound having anti-HIV activity and useful as a new therapeutic medicine for AIDS functioning as a HIV protease inhibitor. CONSTITUTION:A fluorine-containing compound is pressed by formula I (R<1> 18 a 1-12C straight-chain or a branched alkyl; R<2> is a 1-10C straight-chain or a branched alkoxy or 1 or 2-substituted amino), e.g. ethyl 2,2-difluoro-12- methyl-3-oxotridecanoate of formula II. Another fluorine-containing compound is expressed by formula III (R<3> is H, a 1-5C straight chain, a branched acyl, an arylsulfonyl or a l-5C straight-chain alkylsulfonyl), e.g. ethyl 2,2-difluoro-3- hydroxy-12-methyltridecanonate of formula IV. The compound of formula I is obtained by reducing a new compound of formula V (R<2>' is R<2>, etc.) using Dess-Martin reagent. A compound of formula V in the compound of formula III is obtained by reacting an aldehyde of the formula, R<1>-CHO with a bromodifluoroacetic acid ester of formula VI.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to fluorine-containing compounds having anti-HIV activity.

[0002]

2. Description of the Related Art With the global spread of AIDS, there is a strong demand for the development of effective anti-AIDS drugs. Nevertheless, AIDS is a slow virus infectious disease caused by HIV (human immunodeficiency virus), which is the easiest to make a mutant strain, and thus its development is extremely difficult. However, recently, the life cycle of this virus has been clarified, and accordingly, many studies have been conducted to inhibit the growth of HIV at any stage of the life cycle.

One of such studies is the development of HIV protease inhibitors (Yoshiaki Kiso,
Others, BIOINDUSTRY, Vol.18, No.10, P38,
1991). HIV protease has a function of converting a precursor protein produced from host cell DNA into which information from the HIV virus is incorporated into various functional proteins, and the amino acid structure of its substrate cleavage site is Xaa-Pr.
Since it is o, it has been clarified that it is an aspartyl protease to which the digestive enzyme pepsin, the enzyme renin involved in blood pressure preparation, and the like belong.

Many studies have already been conducted on aspartyl protease, and the mechanism of cleaving its substrate has been clarified. Chemical formula 3 shows the cutting mechanism. As shown in Chemical formula 3, it is believed that two aspartic acid residues catalytically act and undergo a tetrahedral transition state to cleave the substrate. From such knowledge of aspartyl protease, it is considered that HIV protease also cleaves the substrate by a similar mechanism.

[0005]

[Chemical 3]

Pepstatin A, which is a typical inhibitor of aspartyl protease, is considered to exert its inhibitory action by mimicking this tetrahedral transition state. Therefore, it is considered that HIV protease is also inhibited by the compound that mimics this tetrahedral transition state. Research focusing on this point has been carried out, and several HIV protease inhibitors have been obtained.

[0007]

However, the HIV protease inhibitors obtained thus far are not sufficient in terms of activity expression and side effects in vivo.

The present invention has been made in view of the above circumstances, and the present invention is to provide a fluorine-containing compound which functions as an HIV protease inhibitor.

[0009]

The present inventor has found that the fluorine-containing compound shown in Chemical formula 4 has anti-HIV activity.

[0010]

[Chemical 4]

Here, as R ¹ in Chemical formula 4, a linear or branched alkyl group having 1 to 12 carbon atoms is preferable, and a linear or branched alkyl group having 8 to 12 carbon atoms is particularly preferable. R ² is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, or a 1- or 2-substituted amino group, more preferably a 1- or 2-substituted amino group, and among them, a group derived from an essential amino acid is preferable.

The present inventor has also found that the fluorine-containing compound shown in Chemical formula 5 has anti-HIV activity.

[0013]

[Chemical 5]

Here, as R ¹ in Chemical formula 5, a linear or branched alkyl group having 1 to 12 carbon atoms is preferable, and a linear or branched alkyl group having 8 to 12 carbon atoms is particularly preferable. R ² is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, or a 1- or 2-substituted amino group, more preferably a 1- or 2-substituted amino group, and particularly preferably a group derived from an essential amino acid. R ³ is hydrogen,
A linear or branched acyl group having 1 to 5 carbon atoms, an arylsulfonyl group, or a linear alkylsulfonyl group having 1 to 5 carbon atoms is preferable.

Of the fluorine-containing compounds shown in Chemical formula 5,
In the case where R ³ is hydrogen and R ² is an alkoxy group as shown in, a bromodifluoroacetic acid ester containing an alkyl group R ² ′ shown in Chemical formula 7 is added to an aldehyde having an alkyl group R ¹ shown in Chemical formula 6. It can be produced by reacting. The "OR ² '" group of Chemical formula 8 is the "R ² " of Chemical formula 5
It is a base.

[0016]

[Chemical 6]

[0017]

[Chemical 7]

[0018]

[Chemical 8]

The --OR ² 'group shown in Chemical formula 8 is further reacted by a well-known method, for example, ammonia, or a mono- or di-substituted amine without solvent or in a solvent such as benzene, toluene, xylene, chloroform and dichloromethane. Thus, it can be converted into an amino group or a mono- or di-substituted amino group. Further, the hydrogen atom of the hydroxyl group in Chemical formula 8 can be determined by a well-known method, for example, the corresponding acyl halide or acid anhydride or sulfonic acid halide, pyridine,
By reacting in the presence of a base such as triethylamine, it can be converted into an acyl group or a sulfonyl group.

The fluorine-containing compound shown in Chemical formula 4 can be obtained by reducing the compound of Chemical formula 8 using a Dess-Martin reagent.

[0021]

From a number of findings on aspartyl protease, it is considered that the fluorine-containing compound of the present invention mimics a tetrahedral transition state as shown in Chemical formula 9. That is, as shown in Chemical formula 9, it is considered that the two aspartic acid residues catalytically act and the substrate is cleaved via the tetrahedral transition state. At the time of this hydrolysis reaction, since the electronegativity of fluorine bonded to the carbon adjacent to the carbonyl carbon is very large, it is considered that the hydrolysis of this fluorine-containing compound is promoted.

[0022]

[Chemical 9]

[0023]

EXAMPLES The present invention will be described based on examples.

Example 1 Ethyl 2,2-difluoro-3-hydroxy-12-
Synthesis of Methyltridecanoate (Chemical Formula 10) A fluorine-containing compound having a structural formula shown in the Chemical Formula 10 was synthesized as follows.

[0025]

[Chemical 10]

(A) Synthesis of 8-tetrahydroxypyranyloxy-1-octanol (Chemical formula 11)

[0027]

[Chemical 11]

1,8-octanediol (25 g, 17
1.2 mmol) and Al ₂ (SO ₄ ) ₃ catalyst (578
mg, 0.856 mmol) was added to 155 ml of anhydrous octane, and dihydropyran (17.2 ml, -78 ° C) was added.
188.1 mmol) was added dropwise under an argon atmosphere.
The reaction was stirred overnight. The reaction is saturated with NaHCO 3.
_{3) It} was stopped with an aqueous solution, extraction was performed with ether, and the aqueous layer was further extracted with ether. These ether layers were combined and dried using MgSO ₄ , and ether was collected under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 40/60) to obtain the alcohol of Chemical formula 11 in a yield of 49% (1
9.1 g, 83.0 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum and IR spectrum of this alcohol were as follows. ¹ H-NMR (δ) 1.15-2.00 (18H, m), 3.32-3.97 (7H, m), 4.57 (1H, dd, J = 4.
72,3.08Hz) ¹³ C-NMR (δ) 19.70, 25.51, 25.70, 26.18, 29.36, 29.43, 29.73, 3
0.79, 32.78, 62.35, 62.98, 67.66, 98.85; IR (neat) (ν) 3425, 1140, 1120, 1080, 1035.

(B) Synthesis of 8-tetrahydroxypyranyloxy-1-octanal (Chemical Formula 12)

[0031]

[Chemical 12]

Oxalyl chloride (2.99 ml, 34.4)
mmol) in anhydrous dichloromethane (70 ml),
Dimethyl sulfoxide (4.88 ml, 68.8 mmol) was added dropwise at -78 ° C under an argon atmosphere. Next, a solution of the alcohol of Chemical formula 11 (3.4 g, 17 mmol) in dichloromethane (100 ml) was added at the same temperature,
Then, it stirred for 25 minutes. Next, at the same temperature, trimethylamine (23.8 ml, 172 mmol) was added and stirred for 15 minutes. A saturated NH ₄ Cl aqueous solution was added to the reaction solution to stop the reaction. The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined and dried with MgSO ₄ and the dichloromethane was removed under reduced pressure. The residual oil was purified by silica gel column chromatography (ethyl acetate / hexane = 25/75),
Obtained in a yield of 0% (3.52 g, 15.4 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, and IR spectrum of this aldehyde were as follows. ¹ H-NMR (δ) 1.22-1.95 (16H, m), 2.43 (2H, td, J = 7.18, 1.84Hz), 3.32
-3.56 (2H, m), 3.66-3.93 (2H, m), 4.57 (1H, dd, J = 4.40,
2.74Hz), 9.77 (1H, t, J = 1.84Hz) ¹³ C-NMR (δ) 19.73, 22.04, 25.52, 26.06, 29.11, 29.20, 29.68, 3
0.80, 43.89, 62.38, 67.56, 98.87, 202.80 IR (neat) (ν) 1720, 1140, 1120, 1075, 1030.

(C) 1- (2-methylpropyl) -8-
Synthesis of tetrahydroxypyranyloxy-1-octanol

[0035]

[Chemical 13]

The aldehyde of formula 12 (5.3 g, 23.2
A solution of isobutylmagnesium bromide (34.8 mmol) in ether (17.4 ml) was added dropwise to a solution of (mmol) in anhydrous ether (116 ml) at 0 ° C. under an argon atmosphere, followed by stirring for 30 minutes. A saturated NH ₄ Cl aqueous solution was added to the reaction solution to stop the reaction.

The ether layer was separated, the aqueous layer was extracted with ether, the ether layers were combined, dried over MgSO ₄ and the ether removed under reduced pressure. The residual oil was purified by silica gel column chromatography (ethyl acetate / hexane = 25/75) to obtain the alcohol of Chemical formula 13 in a yield of 76% (5.04 g, 17.6 m).
mol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum and IR spectrum of this alcohol are as follows. ¹ H-NMR (δ) 0.91 (3H, d, J = 6.56Hz), 0.92 (3H, d, J = 6.68Hz), 1.13-1.9
0 (21H, m), 3.33-3.94 (6H, m), 4.54-4.62 (1H, m) ¹³ C-NMR (δ) 19.71, 22.09, 23.53, 24.65, 25.52, 25.57, 26.20, 2
9.46, 29.64, 29.74, 30.80, 38.08, 46.84, 62.35, 6
7.66, 69.95, 98.85 IR (neat) (ν) 3450, 1140, 1120, 1080, 1040.

(D) 1- (2-methylpropyl) -8-
Synthesis of tetrahydroxypyranyloxy-1-octanyl methanesulfonate (Chemical formula 14)

[0040]

[Chemical 14]

Alcohol of Chemical formula 13 (10.9 g, 38.
To a solution of 1 mmol) in anhydrous dichloromethane (190 ml) was added N, N-diisopropylethylamine (19.9 m).
1, 114.3 mmol) was added dropwise at 0 ° C. under an argon atmosphere. Next, methanesulfonyl chloride (9.
24 ml, 114.3 mmol) was added at the same temperature and then stirring was continued for 1 hour. Water was added to this reaction solution to stop the reaction. The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined and dried with MgSO ₄ and the dichloromethane was removed under reduced pressure. The remaining oil was subjected to silica gel column chromatography (ethyl acetate / hexane = 20/8).
0) to give the sulfonate compound of
Obtained in a yield of% (13.1 g, 36.0 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum and IR spectrum of this sulfonate compound were as follows. ¹ H-NMR (δ) 0.94 (3H, d, J = 6.40Hz), 0.95 (3H, d, J = 6.60Hz), 1.17-1.9
0 (21H, m), 2.99 (3H, s), 3.32-3.57 (2H, m), 3.67-3.93 (2
H, m), 4.54-4.61 (1H, m), 4.72-4.87 (1H, m) ¹³ C-NMR (δ) 19.75, 22.19, 22.94, 24.50, 24.79, 25.53, 26.17, 2
9.31, 29.37, 29.72, 30.82, 35.05, 38.85, 43.57, 6
2.41, 67.62, 82.74, 98.91 IR (neat) (ν) 1355, 1180, 1035, 905.

(E) Synthesis of 10-methylundecanol tetrahydroxypyranyl ether (Chemical formula 15)

[0044]

[Chemical 15]

Lithium aluminum hydride (18 mg,
0.467 mmol) anhydrous tetrahydrofuran (3 m
l) Into the solution of
g, 0.467 mmol) was added under an argon atmosphere. The reaction was then stirred at 80 ° C. for 3 hours, after which it was added to a frozen saturated aqueous NH ₄ Cl solution.

The tetrahydrofuran layer was separated, the aqueous layer was extracted with ether, and the ether layers were combined and combined with MgS.
Dry with O ₄ and remove the ether under reduced pressure.
The remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 10/90),
The ether of Chemical formula 15 was obtained in a yield of 97% (122 mg,
0.452 mmol).

¹ H-NMR spectrum of this ether,
^{The 13} C-NMR spectrum and IR spectrum were as follows. ¹ H-NMR (δ) 0.91 (6H, d, J = 6.56Hz), 1.03-1.93 (23H, m), 3.31-3.58 (2
H, m), 3.64-3.94 (2H, m), 4.58 (1H, dd, J = 4.32, 2.66Hz) ¹³ C-NMR (δ) 19.72, 22.67, 25.53, 26.26, 27.42, 27.98, 29.52, 2
9.63, 29.67, 29.78, 29.93, 30.81, 39.07, 62.35, 6
7.72, 98.85 IR (neat) (ν) 1470, 1140, 1120, 1080, 1040.

(F) Synthesis of 10-methylundecanol

[0049]

[Chemical 16]

The ether of Chemical formula 14 (3.0 g, 11.1 m
mol) in ethanol (56 ml), pyridinium p-toluenesulfonate (279 mg, 1.11).
mmol) was added. Next, this reaction liquid was stirred at 60 ° C. for 8 hours, and then ethanol was removed under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80), and
6 alcohol was obtained in 98% yield (2.02 g, 1
0.9 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum and IR spectrum of this alcohol were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.58Hz), 1.05-1.67 (17H, m), 2.18 (1H, br.
s), 3.64 (2H, t, J = 6.62Hz) ¹³ C-NMR (δ) 22.68, 25.77, 27.42, 28.00, 29.47, 29.65, 29.94, 3
2.85, 39.07, 63.13 IR (neat) (ν) 3325, 1470, 1380, 1365, 1060.

(G) Synthesis of 10-methylundecanal

[0053]

[Chemical 17]

Oxalyl chloride (4.28 ml, 49.2)
mmol) in anhydrous dichloromethane (60 ml),
Dimethyl sulfoxide (6.99 ml, 98.4 mmol) was added dropwise at -78 ° C under an argon atmosphere. Then, a solution of the alcohol of Chemical formula 16 (4 mmol) in dichloromethane (60 ml) was added at the same temperature, followed by stirring for 25 minutes. Next, at the same temperature, trimethylamine (3
(4.3 ml, 246 mmol) was added and the mixture was stirred for 1 hour. A saturated NH ₄ Cl aqueous solution was added to the reaction solution to stop the reaction. The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined and dried with MgSO ₄ and the dichloromethane was removed under reduced pressure. The residual oil was purified by silica gel column chromatography (ethyl acetate / hexane = 10/90) to obtain the aldehyde of Chemical formula 17 in 99% yield (4.48 g, 24.3 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum and IR spectrum of this aldehyde were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.56Hz), 1.03-1.62 (15H, m), 2.42 (2H, td,
J = 7.18, 1.90Hz), 9.77 (1H, t, J = 1.90Hz) ¹³ C-NMR (δ) 22.12, 22.67, 27.38, 27.98, 29.20, 29.38, 29.48, 2
9.85, 39.04, 43.95, 202.96 IR (neat) (ν) 1730, 1470, 1385, 1370, 1175.

(F) Ethyl 2,2-difluoro-3-
Hydroxy-12-methyl tridecanoate (Chemical formula 10)
To a solution of the aldehyde of formula 17 (1.1 g, 5.98 mmol) and zinc (586 mg, 8.97 mmol) in anhydrous tetrahydrofuran (30 ml) was added ethyl bromodifluoroacetate (1.15 ml, 8.97 mmol) at room temperature. added. Next, this reaction solution was stirred for 2.5 hours, and then a 1N HCl aqueous solution was added to stop the reaction. The tetrahydrofuran layer was separated, the aqueous layer was extracted with dichloromethane, the organic layers were combined and dried with MgSO ₄ , and the solvent was removed under reduced pressure. The residual oil was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80) to obtain the fluorine-containing compound of Chemical formula 10 in a yield of 91% (1.68 g, 5.45 m).
mol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.54Hz), 1.07-1.74 (20H, m), 1.37 (3H, t, J
= 7.14Hz), 1.91-2.09 (1H, br s), 3.90-4.16 (1H, m), 4.3
6 (2H, q, J = 7.14Hz) ¹³ C-NMR (δ) 13.96, 22.67, 25.23, 27.41, 27.99, 29.17-29.26 (m),
29.34, 29.50, 29.61, 29.91, 39.06, 63.04, 71.81 (d
d, J = 27.04, 24.82Hz), 114.72 (dd, J = 255.00, 252.95H
z), 163.76 (t, J = 30.85Hz) ¹⁹ F-NMR (δ) -123.51 (dd, J = 265.50, 15.25Hz), -116.15 (dd, J = 265.5)
0, 7.63Hz) IR (neat) (ν) 3450, 1760, 1470, 1375, 1315, 1220, 1100.

Example 2 Synthesis of Ethyl 2,2-difluoro-12-methyl-3-oxotridecanoate (Chemical Formula 18) A fluorine-containing compound having the structural formula shown in Chemical Formula 18 was synthesized as follows. .

[0059]

[Chemical 18]

Alcohol shown in Chemical formula 10 (1.1 g, 3.
To a solution of 57 mmol) anhydrous dichloromethane (36 ml), Dess-Martin reagent (2.27 g, 5.
36 mmol) was added at room temperature under an argon atmosphere.
The reaction was then stirred for 30 minutes and then saturated NaH
The reaction was stopped by adding a CO ₃ aqueous solution and a saturated Na ₂ S ₂ O ₃ aqueous solution. The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined and dried with MgSO ₄ , and the solvent was removed under reduced pressure. The residual oil was purified by silica gel column chromatography (ethyl acetate / hexane = 10/90) to obtain the fluorine-containing compound of Chemical formula 18 in a yield of 92% (1.01 g, 3.30 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.56Hz), 1.07-1.74 (18H, m), 1.35 (3H, t, J
= 7.14Hz), 2.73 (2H, tt, J = 7.14, 1.04Hz), 4.37 (2H, q, J =
7.14 Hz); ¹³ C-NMR (δ) 13.88, 22.55, 22.70, 27.49, 28.07, 28.91, 29.37, 2
9.55, 29.94, 36.69, 39.13, 63.73, 108.33 (t, J = 262.1
5Hz), 161.54 (t, J = 30.05Hz), 197.53 (t, J = 27.70Hz) ¹⁹ F-NMR (δ) -115.00 IR (neat) (ν) 1780, 1745, 1470, 1375, 1315, 1210, 1140, 1020.

Example 3 Synthesis of N ′-(2,2-difluoro-12-methyl-3-oxotridecanoyl) nornicotine (Chemical Formula 19) A fluorine-containing compound having the structural formula shown in Chemical Formula 19 was prepared as follows. It was synthesized in this way.

[0063]

[Chemical 19]

The ester shown in Chemical formula 18 (306 mg, 1 m
mol) and dl-nornicotine (0.304 ml,
2.2 mmol) was stirred overnight without solvent. The reaction mixture was subjected to silica gel column chromatography (ethyl acetate /
Hexane = 70/30) to obtain the fluorine-containing compound of Chemical formula 19 in a yield of 76% (309 mg, 0.7).
57 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.59Hz), 1.00-2.13 (18H, m), 2.26-2.46 (1
H, m), 2.53-2.73 (2H, m), 3.65-3.98 (2H, m), 5.20 (1H, dd,
J = 7.86, 4.18Hz), 7.12-7.32 (1H, m), 7.33-7.50 (1H, m),
8.36-8.55 (2H, m) ¹³ C-NMR (δ) 22.59, 22.66, 24.30, 27.36, 27.94, 28.82, 29.29, 2
9.43, 29.82, 33.23, 37.30, 39.01, 47.49 (t, J = 5.26H
z), 60.43, 110.15 (t, J = 265.45Hz), 123.47, 133.09, 1
37.09, 147.38, 148.49, 160.20 (t, J = 27.80Hz), 198.29
(t, J = 27.10Hz) ¹⁹ F-NMR (δ) -113.57 (d, J = 282.29Hz), -112.38 (d, J = 282.29Hz) IR (neat) (ν) 1750, 1660, 1435, 1100 , 710.

Example 4 N '-(2,2-difluoro-3-hydroxy-12-
Synthesis of Methyltridecanoyl) Nornicotine (Chemical Formula 20) A fluorine-containing compound having a structural formula shown in Chemical Formula 20 was synthesized as follows.

[0067]

[Chemical 20]

The amide of Chemical formula 19 (204 mg, 0.5 mm
ol) in a solution of absolute ethanol (5 ml) at -78 ° C,
Sodium borohydride (7 mg,
0.19 mmol) was added and stirred for 1 hour. next,
The reaction was stopped by adding saturated aqueous NH ₄ Cl solution to the reaction solution, and the solvent was removed under reduced pressure. The remaining oil was diluted with dichloromethane, the dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane. The dichloromethane layers were combined and dried with MgSO ₄ and the dichloromethane was removed under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate) to obtain the fluorine-containing compound of Chemical formula 20 in a yield of 98% (201
mg, 0.49 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.58Hz), 1.04-2.13 (20H, m), 2.27-2.47 (1
H, m), 3.38 (1H, br s), 3.96-4.18 (3H, m), 5.15-5.26 (1
H, m), 7.20-7.31 (1H, m), 7.36-7.50 (1H, m), 8.41-8.55
(2H, m) ¹³ C-NMR (δ) 22.66, 24.33, 25.36-25.54 (m), 27.39, 27.94, 28.45,
29.42, 29.51, 29.62, 29.88, 33.21, 39.02, 47.60-4
8.21 (m), 60.34, 60.41, 70.69-71.83 (m), 110.97-121.
69 (m), 123.50, 133.24, 133.29, 137.57, 137.52, 14
7.23, 148.01, 148.20, 162.48-163.67 (m) ¹⁹ F-NMR (δ) -124.08 (dd, J = 289.92, 18.31Hz), -122.57 (dd, J = 285.3
5, 18.32Hz), -112.30 (dd, J = 286.87, 4.57Hz), -111.32
(dd, J = 286.37, 3.05Hz) IR (neat) (ν) 3200, 1650, 1470, 1425, 1095, 1050, 710.

Example 5 Synthesis of 2,2-difluoro-3-hydroxy-12-methyltridecanol (Formula 21) A fluorine-containing alcohol having the structural formula shown in Formula 21 was synthesized as follows.

[0071]

[Chemical 21]

The amide of Chemical formula 19 (675 mg, 1.14 m
mol) in absolute ethanol (14 ml) at room temperature under argon atmosphere under sodium borohydride (80
(mg, 2.12 mmol) was added and stirred for 1 hour.
Then the solvent was removed under reduced pressure. The remaining oil was diluted with ether and the reaction was stopped by adding saturated NH ₄ Cl aqueous solution. Then the ether layer was separated and the aqueous layer was extracted with ether. Combine these ether layers to MgS
Dry with O ₄ and remove the ether under reduced pressure.
The remaining oil was purified by silica gel column chromatography (ethyl acetate), and the fluorine-containing compound of Chemical formula 21 was obtained in a yield of 46% (177 mg, 0.643 mmo).
l) and the fluorine-containing compound of Chemical formula 20 were obtained in a yield of 35% (200 mg, 0.488 mmol).

¹ H-NMR of the fluorine-containing compound of Chemical formula 21
The spectrum and ¹⁹ F-NMR spectrum were as follows. ¹ H-NMR (δ) 0.86 (6H, d, J = 6.54Hz), 1.07-1.83 (17H, m), 1.93-2.18 (2
H, m), 3.81-4.06 (3H, m) ¹⁹ F-NMR (δ) -124.89 (ddt, J = 257.78, 16.02, 1069Hz), -118.38 (ddd
d, J = 258.64, 19.08, 12.97, 6.11Hz).

Example 6 Synthesis of ethyl 2,2-difluoro-3-hydroxyoctanoate (Chemical Formula 22)

[0075]

[Chemical formula 22]

Caproaldehyde (2.40 ml, 20 m
mol) and zinc (1.96 g, 30 mmol) in anhydrous tetrahydrofuran (100 ml) was added ethyl bromodifluoroacetate (3.84 ml, 30 mmol) at room temperature. Next, this reaction solution was stirred for 1 hour, and then a 1N HCl aqueous solution was added to stop the reaction. The tetrahydrofuran layer was separated, the aqueous layer was extracted with dichloromethane, the organic layers were combined and dried with MgSO ₄ , and the solvent was removed under reduced pressure. The remaining oil was refined using a Kugel distiller at 120 ° C and 5 mmHg,
The fluorine-containing compound of Chemical formula 22 was obtained in a yield of 93% (4.
14 g, 18.5 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.83-0.98 (3H, m), 1.16-1.74 (9H, m), 1.37 (3H, t, J = 7.14
Hz), 1.97 (1H, br s), 3.93-4.13 (1H, m), 4.36 (2H, q, J =
7.14Hz) ¹³ C-NMR (δ) 13.95, 14.01, 22.51, 24.92, 29.14 (dd, J = 3.00, 1.63
Hz), 31.51, 63.12, 71.77 (dd, J = 27.25, 24.96Hz), 11
4.80 (dd, J = 256.64, 254.30Hz), 163.91 (dd, J = 32.84, 3
1.12Hz) ¹⁹ F-NMR (δ) -123.65 (dd, J = 263.98, 13.73Hz), -116.22 (dd, J = 263.9)
8, 7.63Hz) IR (neat) (ν) 3450, 1760, 1470, 1380, 1310, 1095.

(Example 7) Synthesis of ethyl 2,2-difluoro-3-oxo-octanoate (Chemical Formula 23) A fluorine-containing compound having a structural formula shown in Chemical Formula 23 was synthesized as follows.

[0079]

[Chemical formula 23]

Alcohol shown in Chemical formula 22 (1.0 g, 4.
To a solution of 46 mmol) anhydrous dichloromethane (23 ml), Dess-Martin reagent (2.84 g, 6.
69 mmol) was added at room temperature under argon atmosphere.
The reaction was then allowed to stir for 2 hours and then saturated N 2
The reaction was stopped by adding an aqueous solution of aHCO ₃ and a saturated aqueous solution of Na ₂ S ₂ O ₃ . The dichloromethane layer was separated, the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined and dried with MgSO ₄ , and the solvent was removed under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80) to obtain the fluorine-containing compound of Chemical formula 23 in a yield of 87% (861 mg, 3.88 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.82-1.01 (3H, m), 1.21-1.50 (7H, m), 1.36 (3H, t, J = 7.14
Hz), 1.56-1.78 (2H, m), 2.74 (2H, tt, J = 7.14, 1.18Hz),
4.38 (2H, q, J = 7.14Hz) ¹³ C-NMR (δ) 13.86, 22.16, 22.33, 30.96, 36.61, 63.71, 108.25
(t, J = 262.55Hz), 161.48 (t, J = 30.65Hz), 197.55 (t, J = 2
9.35 Hz) ¹⁹ F-NMR (δ) -115.04 IR (neat) (ν) 1780, 1745, 1470, 1370, 1310, 1200, 1140, 1015.

(Example 8) N '-(2,2-difluoro-3-oxo-octyl)
Synthesis of Nornicotine (Chemical Formula 24) A fluorine-containing compound having a structural formula shown in Chemical Formula 24 was synthesized as follows.

[0083]

[Chemical formula 24]

The ester shown in Chemical formula 23 (870 mg, 3.
92 mmol) and dl-nornicotine (1.19 m)
(l, 8.62 mmol) was stirred overnight without solvent. The reaction mixture was purified by silica gel column chromatography (ethyl acetate), and the fluorine-containing compound of Chemical formula 24 was purified by
Obtained in% yield (901 mg, 2.78 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.879 (3H, t, J = 6.68Hz), 1.17-1.48 (4H, m), 1.50-1.74 (2
H, m), 1.80-2.22 (3H, m), 2.29-2.50 (2H, m), 2.69 (2H, tt,
J = 7.10, 1.24Hz), 3.84-4.06 (2H, m), 5.20 (1H, dd, J = 7.7
8, 3.94Hz), 7.23-7.37 (1H, m), 7.41-7.56 (1H, m), 8.43
-8.61 (2H, m) ¹³ C-NMR (δ) 13.85, 22.25, 22.33, 24.31, 30.95, 33.24, 37.32, 4
7.50 (t, J = 5.36Hz), 60.43, 110.15 (t, J = 265.25Hz), 12
3.47, 133.03, 136.97, 147.44, 148.63, 160.27 (t, J = 2
7.8Hz), 198.44 (t, J = 27.2Hz) ¹⁹ F-NMR (δ) -113.72 (d, J = 282.29Hz), -112.52 (d, J = 280.76Hz) IR (neat) (ν) 1750, 1670, 1430, 1120, 715.

(Example 9) N '-(2,2-difluoro-3-hydroxy-12-
Synthesis of Methyltridecanoyl) nornicotine (Chemical Formula 25) A fluorine-containing compound having the structural formula shown in Chemical Formula 25 was synthesized as follows.

[0087]

[Chemical 25]

The amide of Chemical formula 24 (162 mg, 0.5 mm
ol) in anhydrous ethanol (5 ml) at 78 ° C. under argon atmosphere, sodium borohydride (7 mg,
0.19 mmol) was added and stirred for 1 hour. next,
The reaction was stopped by adding saturated aqueous NH ₄ Cl solution to the reaction solution, and the solvent was removed under reduced pressure. The remaining oil was diluted with dichloromethane, the dichloromethane layer was separated, and the aqueous layer was extracted with dichloromethane. The dichloromethane layers were combined and dried with MgSO ₄ and the dichloromethane was removed under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate) to obtain the fluorine-containing compound of Chemical formula 25 in a yield of 98% (161
mg, 0.49 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.73-1.00 (3H, m), 1.08-2.13 (11H, m), 2.24-2.48 (1H,
m), 3.39 (1H, br s), 3.92-4.18 (3H, m), 5.14-5.28 (1H,
m), 7.23-7.34 (1H, m), 7.38-7.55 (1H, m), 8.40-8.62 (2
H, m) ¹³ C-NMR (δ) 14.02, 22.51, 24.27, 24.37, 25.05, 25.11, 28.21-2
9.00 (m), 31.56, 33.21, 47.58-48.48 (m), 60.36, 60.4
3, 70.50-71.86 (m), 111.07-121.76 (m), 123.54, 133.3
6, 133.44, 137.68, 147.18, 147.90, 148.10, 162.50-
163.76 (m) ¹⁹ F-NMR (δ) -124.18 (dd, J = 289.92, 19.83Hz), -122.67 (dd, J = 285.3)
4, 19.83Hz), -112.34 (dd, J = 286.87, 4.57Hz), -111.38
(dd, J = 288.40, 3.05Hz) IR (neat) (ν) 3400, 3160, 1660, 1430, 1115, 1090, 715.

(Example 10) Synthesis of N '-(2,2-difluoro-3-t-butylcarbonyloxy-octyl) nornicotine (Chemical Formula 26) A fluorine-containing compound having a structural formula shown in Chemical Formula 26 was prepared as follows. Was synthesized.

[0091]

[Chemical formula 26]

The ester of Chemical formula 22 (1.0 g, 4.46 m)
(mol) was dissolved in 23 ml of an ethanol solution of potassium hydroxide (1N), and the mixture was stirred overnight at room temperature. The solvent was distilled off from the reaction solution under reduced pressure, the residue was acidified by adding a 3N hydrochloric acid aqueous solution, and diluted with ethyl acetate. The ethyl acetate layer was separated, the aqueous layer was extracted with ethyl acetate, the ethyl acetate layers were combined and dried with MgSO _4, and the ethyl acetate was removed under reduced pressure.

The remaining crystals were mixed with anhydrous tetrahydrofuran (2
3 ml) and N, N-diisopropylethylamine (3.1 ml, 17.8 mmol) was added at -78.
C., and was added dropwise under an argon atmosphere. Next, trimethylacetyl chloride (1.21 ml, 9.81 mmol)
Was added at the same temperature and then stirring was continued for 30 minutes at room temperature. Next, nornicotine was added at 0 ° C., stirring was continued at room temperature for 2 hours, and then water was added to the reaction solution to stop the reaction. The organic layers were separated, the aqueous layer was extracted with ethyl acetate, the organic layers were combined and dried with MgSO ₄ ,
The solvent was removed under reduced pressure. The remaining oil was purified by silica gel column chromatography (ethyl acetate),
The amide compound of Chemical formula 26 was obtained in a yield of 45% (808 m
g, 2.00 mmol).

The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of this amide compound were as follows. ¹ H-NMR (δ) 0.86-0.91 (3H, m), 1.13-1.40 (14H, m), 1.52-1.70 (3H,
m), 1.84-2.08 (3H, m), 2.32-2.41 (1H, m), 3.95-4.13 (3
H, m), 5.17-5.26 (1H, m), 7.24-7.31 (1H, m), 7.46-7.52
(1H, m), 8.46-8.58 (2H, m) ¹⁹ F-NMR (δ) -124.00 (dd, J = 289.92, 19.83Hz), -122.77 (dd, J = 285.3
4, 19.84Hz), -112.17 (dd, J = 283.82, 3.05Hz), -111.37
(dd, J = 289.92, 3.05Hz).

(Example 11) Synthesis of N '-(2,2-difluoro-3-acetyloxy-octyl) nornicotine (Chemical formula 27) A fluorine-containing compound having the structural formula shown in the chemical formula 27 was synthesized as follows. did.

[0096]

[Chemical 27]

Alcohol of Chemical formula 22 (1.0 g, 4.46
mmol) in 12 ml of anhydrous dichloromethane,
4-Dimethylaminopyridine (54mg, 0.446m
mol) and acetic anhydride (0.629 ml, 6.69 mm)
ol) was added at room temperature under an argon atmosphere. 2 reaction solutions
After stirring at room temperature for an hour, saturated NaHCO ₃ aqueous solution was added to terminate the reaction, and ether was added. Separate the organic layer, extract the aqueous layer with ether, combine the organic layers, and
Dried with SO ₄ . The solvent was distilled off under reduced pressure, and the remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 10/90),
The fluorine-containing compound of 7 was obtained in 100% yield (1.1
8 g, 4.46 mmol).

The ¹ H-NMR spectrum, ¹³ C-NMR spectrum, ¹⁹ F-NMR spectrum and IR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.83-0.97 (3H, t, J = 6.44Hz), 1.23-1.80 (11H, m), 1.34 (3
H, t, J = 7.12Hz), 2.13 (3H, s), 4.32 (2H, q, J = 7.12Hz), 5.
29-5.47 (1H, m) ¹³ C-NMR (δ) 13.92, 20.58, 22.36, 24.53, 27.24 (dd, J = 1.72, 3.09H
z), 31.32, 63.18, 71.24 (dd, J = 24.42, 28.97Hz), 113.
23 (dd, J = 252.5, 255.6Hz), 162.74 (t, J = 57.6), 169.65 ¹⁹ F-NMR (δ) -118.68 (dd, J = 233.2, 13.76Hz), -112.35 (dd, J = 263.05 ,
9.64Hz) IR (neat) (ν) 1760, 1370, 1310, 1225.

Example 12 Synthesis of N ′-(2,2-difluoro-3-methanesulfonyloxy-octyl) nornicotine (Chemical Formula 28) A fluorine-containing compound having the structural formula shown in the Chemical Formula 28 was prepared as follows. Synthesized.

[0100]

[Chemical 28]

Alcohol of Chemical formula 22 (500 mg, 2.2
3 mmol) was dissolved in 10 ml of anhydrous dichloromethane and triethylamine (0.622 ml, 4.46 mm) was added.
ol) at 0 ° C. under an argon atmosphere and then at the same temperature methanesulfonyl chloride (0.259 ml,
3.35 mmol) was added. After stirring the reaction solution for 5 hours, water was added to terminate the reaction. The organic layers were separated, the aqueous layer was extracted with dichloromethane and the organic layers were combined and dried with MgSO ₄ . The solvent was distilled off under reduced pressure, and the remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 20/80) to obtain the fluorine-containing compound of Chemical formula 28 in a yield of 95% (640 mg, 2 .12 mmol).

The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.84-0.98 (3H, m), 0.87 (9H, s), 1.20-1.84 (11H, m), 1.3
8 (3H, t, J = 7.12Hz), 3.11 (3H, s), 4.38 (2H, q, J = 7.12Hz),
4.95-5.12 (1H, m) ¹⁹ F-NMR (δ) -116.04 (dd, J = 263.98, 12.21Hz), -115.12 (dd, J = 263.9
8, 9.15Hz).

Example 13 Synthesis of N ′-(2,2-difluoro-3-t-butyldimethylsilyloxy-octyl) nornicotine (Chemical Formula 29) A fluorine-containing compound having the structural formula shown in the Chemical Formula 29 was prepared as follows. It was synthesized in this way.

[0104]

[Chemical 29]

The alcohol of Chemical formula 22 (975 mg, 4.3
5 mmol) of anhydrous N, N-dimethylformamide 2
Dissolve in ml, imidazole (335 mg, 5.22 m
mol) and t-butyldimethylsilyl chloride were added at room temperature under an argon atmosphere, and the reaction solution was stirred for 2 days. Then, a saturated NaHCO ₃ aqueous solution was added to terminate the reaction. The organic layers were separated, the aqueous layer was extracted with hexane and the organic layers were combined and dried with MgSO ₄ . The solvent was distilled off under reduced pressure, and the remaining oil was purified by silica gel column chromatography (ethyl acetate / hexane = 5/95) to obtain the fluorine-containing compound of Chemical formula 29 in a yield of 95% (1.39 g , 4.11mmo
l).

The ¹ H-NMR spectrum and ¹⁹ F-NMR spectrum of this fluorine-containing compound were as follows. ¹ H-NMR (δ) 0.08 (6H, s), 0.83-0.94 (12H, m), 1.18-1.69 (11H, m), 1.
35 (3H, t, J = 7.22Hz), 3.92-4.18 (1H, m), 4.30 (2H, ddq, J =
14.2, 7.22, 1.72Hz) ¹⁹ F-NMR (δ) -117.07 (dd, J = 254.82, 9.15Hz),-114.31 (dd, J = 254.82,
12.21Hz).

When the anti-HIV activity of the fluorine-containing compounds of Examples 1 to 13 above was evaluated, it was found to have anti-HIV activity.

[0108]

The fluorine-containing compound of the present invention is an anti-HIV compound.
It was found to have activity. Therefore, according to the present invention,
Fluorine-containing compounds that function as HIV protease inhibitors are provided, opening the way as new therapeutic agents for AIDS.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication C07C 69/734 Z 9279-4H 235/04 7106-4H 235/80 7106-4H 309/64 7419- 4H 309/72 7419-4H C07D 401/04 207

Claims (2)

[Claims] 1. A fluorine-containing compound represented by Chemical formula 1. [Chemical 1] (In Chemical Formula ¹ , R ¹ represents a linear or branched alkyl group having 1 to 12 carbon atoms, and R ² represents a linear or branched alkoxy group having 1 to 10 carbon atoms, or a 1- or 2-substituted amino group. .) 2. A fluorine-containing compound represented by Chemical formula 2. [Chemical 2] (In Chemical Formula 2, R ¹ represents a linear or branched alkyl group having 1 to 12 carbon atoms, and R ² represents a linear or branched alkoxy group having 1 to 10 carbon atoms, an amino group, or a 1 or 2 substituted group. Represents an amino group, and R ³ represents hydrogen, a linear or branched acyl group having 1 to 5 carbon atoms, an arylsulfonyl group, or a linear alkylsulfonyl group having 1 to 5 carbon atoms.)