JPH072773A - New piperidine derivative and antiviral agent - Google Patents

Abstract

PURPOSE:To obtain a new compound useful as an anti-HIV agent, antiviral agent, etc., having low cell toxicity. CONSTITUTION:A compound of formula I (R<1> is H or protected guanidino; R<2> is alkyl, aryl or acyl; R<3> and R<4> are H, alkyl, aryl or acyl) such as 1- amidino-3-amino-2-methoxypiperidine. The compound of formula I is obtained by reducing a compound of formula III which is obtained by using a compound of formula II (Z is benzyloxycarbonyl) as a starting raw material, in a solvent such as methanol in the presence of a catalytic reduction catalyst such a palladium black in a hydrogen atmosphere.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel piperidine derivative which is expected as a drug such as an antiviral agent.

[0002]

2. Description of the Related Art At present, the drugs which are clinically used for the treatment of diseases caused by viruses include vidarabine (Ara-A), acyclovir (ACV), ganciclovir (GCV), which are effective against herpes virus. Also, H
Zidovudine (AZT), didanosine (DDI) and the like which are active against IV (AIDS-causing virus) are known.

[0003]

However, the application range of the above antiviral drugs is narrow, and the administration method is limited due to the effects of solubility, oral absorbability, metabolism and the like.
Many problems remain such as long-term administration is difficult due to side effects such as myelotoxicity. In particular, AZ, which is an AIDS treatment drug
T and DDI were found to induce delayed-type toxicity such as myositis, peripheral neuritis and acute pancreatitis after long-term administration,
It also has problems such as the emergence of resistant viruses.
Since AIDS is becoming a pandemic all over the world, development of new antiviral drugs, especially anti-AIDS drugs, is desired.

[0004]

The present invention is based on the general formula (1)

[0005]

[Chemical 4]

[Wherein R ¹ is a hydrogen atom or a protecting group for a guanidino group, R ² is an alkyl group, an aryl group or an acyl group, and R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, [Showing an aryl group or an acyl group]], a physiologically acceptable salt of these compounds and an antiviral agent containing the same as an active ingredient.

Examples of the protecting group for the guanidino group in R ¹ in the general formula (1) include a substituted or unsubstituted acyl group, a substituted or unsubstituted sulfonyl group, and a nitro group. Of these, the nitro group is preferred. Examples of the acyl group include those similar to R ² and R ³ described below, and examples of the sulfonyl group include substituted or unsubstituted arylsulfonyl groups such as p-toluenesulfonyl and benzenesulfonyl, and alkoxy such as methoxysulfonyl. Alkylsulfonyl groups such as sulfonyl groups and methanesulfonyl are mentioned.

In the general formula (1), examples of the acyl group represented by R ¹ , R ² and R ³ include acetyl group, butanoyl group, isopentanoyl group, octanoyl group and 3
-A linear or branched substituted or unsubstituted alkylcarbonyl group such as phenylpropanoyl group, a substituted or unsubstituted arylcarbonyl group such as benzoyl or p-methoxybenzoyl group, a benzyloxycarbonyl group, and a t-butoxycarbonyl group And substituted alkoxycarbonyl groups.

Examples of the alkyl group in the present invention include methyl group, butyl group, octyl group, octadecyl group, isoamyl group, benzyl group, p-methoxybenzyl group, 2
A substituted or unsubstituted linear or branched alkyl group such as a phenylethyl group, a substituted or unsubstituted cyclic alkyl group such as a cyclopentyl group or a cyclohexyl group, and the like, and R ² has 3 carbon atoms. Alkyl groups of 10 to 10 and lower alkyl groups of 1 to 6 carbon atoms for R ³ and R ⁴ are preferable. Examples of the aryl group include substituted or unsubstituted phenyl groups such as phenyl group and p-chlorophenyl group.

Examples of physiologically acceptable salts include mineral acid salts such as hydrochloric acid, sulfuric acid and nitric acid, and organic acid salts such as acetic acid, fumaric acid, maleic acid, tartaric acid and methanesulfonic acid.

Some specific examples of the compound represented by the general formula (1) are shown below. It should be noted that all stereoisomers, optically active forms, and racemates that exist for the compounds shown here are included. Among the optical isomers, the preferred one is (2S, 3
S) or (2R, 3S) body. Also, salt is not shown here.

1.1-amidino-3-amino-2-methoxypiperidine 2.1-amidino-3-amino-2-butoxypiperidine 3.1-amidino-3-amino-2- (t-butoxy)
Piperidine 4.1-amidino-3-amino-2-isopentyloxypiperidine 5.1-amidino-3-amino-2-octyloxypiperidine 6.1-amidino-3-amino-2- (2-phenylethoxy) Piperidine 7.1-amidino-3-amino-2-cyclohexyloxypiperidine 8.1-amidino-3-amino-2-phenoxypiperidine 9.1-amidino-3-amino-2-butanoyloxypiperidine 10.1- Amidino-3-amino-2- (3-phenylpropanoyloxy) piperidine

11.3-Acetylamino-1-amidino-2-methoxypiperidine 12.3-acetylamino-1-amidino-2-butoxypiperidine 13.3-acetylamino-1-amidino-2- (t-
Butoxy) piperidine 14.3-acetylamino-1-amidino-2-isopentyloxypiperidine 15.3-acetylamino-1-amidino-2-octyloxypiperidine 16.3-acetylamino-1-amidino-2- ( 2-
Phenylethoxy) piperidine 17.3-Acetylamino-1-amidino-2-cyclohexyloxypiperidine 18.3-Acetylamino-1-amidino-2-phenoxypiperidine 19.3-Acetylamino-1-amidino-2-butanoyl Oxypiperidine 20.3-acetylamino-1-amidino-2- (3-
Phenylpropanoyloxy) piperidine

21. 1-amidino-3-benzoylamino-2-methoxypiperidine 22.1-amidino-3-benzoylamino-2-butoxypiperidine 23.1-amidino-3-benzoylamino-2- (t
-Butoxy) piperidine 24.1-amidino-3-benzoylamino-2-isopentyloxypiperidine 25.1-amidino-3-benzoylamino-2-octyloxypiperidine 26.1-amidino-3-benzoylamino-2- (2
-Phenylethoxy) piperidine 27.1-amidino-3-benzoylamino-2-cyclohexyloxypiperidine 28.1-amidino-3-benzoylamino-2-phenoxypiperidine 29.1-amidino-3-benzoylamino-2-buta Noyloxypiperidine 30.1-amidino-3-benzoylamino-2- (3
-Phenylpropanoyloxy) piperidine

31.1-amidino-3-benzyloxycarbonylamino-2-methoxypiperidine 32.1-amidino-3-benzyloxycarbonylamino-2-butoxypiperidine 33.1-amidino-3-benzyloxycarbonylamino- 2- (t-butoxy) piperidine 34.1-amidino-3-benzyloxycarbonylamino-2-isopentyloxypiperidine 35.1-amidino-3-benzyloxycarbonylamino-2-octyloxypiperidine 36.1-amidino -3-Benzyloxycarbonylamino-2- (2-phenylethoxy) piperidine 37.1-amidino-3-benzyloxycarbonylamino-2-cyclohexyloxypiperidine 38.1-amidino-3-benzyloxycarbonylami No-2-phenoxypiperidine 39.1-amidino-3-benzyloxycarbonylamino-2-butanoyloxypiperidine 40.1-amidino-3-benzyloxycarbonylamino-2- (3-phenylpropanoyloxy) piperidine

41.1-amidino-3- (t-butoxycarbonylamino) -2-methoxypiperidine 42.1-amidino-3- (t-butoxycarbonylamino) -2-butoxypiperidine 43.1-amidino-3 -(T-Butoxycarbonylamino) -2- (t-butoxy) piperidine 44.1-amidino-3- (t-butoxycarbonylamino) -2-isopentyloxypiperidine 45.1-amidino-3- (t- Butoxycarbonylamino) -2-octyloxypiperidine 46.1-amidino-3- (t-butoxycarbonylamino) -2- (2-phenylethoxy) piperidine 47.1-amidino-3- (t-butoxycarbonylamino) -2-Cyclohexyloxypiperidine 48.1-amidino-3- (t-butoxy) Carbonylamino) -2-phenoxypiperidine 49.1-amidino-3- (t-butoxycarbonylamino) -2-butanoyloxypiperidine 50.1-amidino-3- (t-butoxycarbonylamino) -2- (3 -Phenylpropanoyloxy) piperidine

51.1-amidino-3-benzylamino-2-methoxypiperidine 52.1-amidino-3-benzylamino-2-butoxypiperidine 53.1-amidino-3-benzylamino-2- (t-
Butoxy) piperidine 54.1-amidino-3-benzylamino-2-isopentyloxypiperidine 55.1-amidino-3-benzylamino-2-octyloxypiperidine 56.1-amidino-3-benzylamino-2- ( 2-
Phenylethoxy) piperidine 57.1-amidino-3-benzylamino-2-cyclohexyloxypiperidine 58.1-amidino-3-benzylamino-2-phenoxypiperidine 59.1-amidino-3-benzylamino-2-butanoyl Oxypiperidine 60.1-amidino-3-benzylamino-2- (3-
Phenylpropanoyloxy) piperidine

61-amidino-3-dimethylamino-2-methoxypiperidine 62.1-amidino-3-dimethylamino-2-butoxypiperidine 63.1-amidino-3-dimethylamino-2- (t-
Butoxy) piperidine 64.1-amidino-3-dimethylamino-2-isopentyloxypiperidine 65.1-amidino-3-dimethylamino-2-octyloxypiperidine 66.1-amidino-3-dimethylamino-2- ( 2-
Phenylethoxy) piperidine 67.1-amidino-2-cyclohexyloxy-3-
Dimethylaminopiperidine 68.1-amidino-3-dimethylamino-2-phenoxypiperidine 69.1-amidino-3-dimethylamino-2-butanoyloxypiperidine 70.1-amidino-3-dimethylamino-2- (3 −
Phenylpropanoyloxy) piperidine

71. 3-Amino-1- (N-benzyloxycarbonylamidino) -2-methoxypiperidine 72.3-Amino-1- (N-benzyloxycarbonylamidino) -2-butoxypiperidine 73.3-amino -1- (N-benzyloxycarbonylamidino) -2- (t-butoxy) piperidine 74.3-amino-1- (N-benzyloxycarbonylamidino) -2-isopentyloxypiperidine 75.3-amino-1 -(N-benzyloxycarbonylamidino) -2-octyloxypiperidine 76.3-amino-1- (N-benzyloxycarbonylamidino) -2- (2-phenylethoxy) piperidine 77.3-amino-1- ( N-benzyloxycarbonylamidino) -2-cyclohexyloxypiperi 78.3-Amino-1- (N-benzyloxycarbonylamidino) -2-phenoxypiperidine 79.3-Amino-1- (N-benzyloxycarbonylamidino) -2-butanoyloxypiperidine 80.3-amino -1- (N-benzyloxycarbonylamidino) -2- (3-phenylpropanoyloxy) piperidine

81-Amino-2-methoxy-1-
(N-Nitroamidino) piperidine 82.3-Amino-2-butoxy-1- (N-nitroamidino) piperidine 83.3-Amino-2- (t-butoxy) -1- (N-
Nitroamidino) piperidine 84.3-Amino-2-isopentyloxy-1- (N
-Nitroamidino) piperidine 85.3-Amino-1- (N-nitroamidino) -2-
Octyloxypiperidine 86.3-amino-1- (N-nitroamidino) -2-
(2-Phenylethoxy) piperidine 87.3-Amino-2-cyclohexyloxy-1-
(N-Nitroamidino) piperidine 88.3-Amino-1- (N-nitroamidino) -2-
Phenoxypiperidine 89.3-Amino-2-butanoyloxy-1- (N-
Nitroamidino) piperidine 90.3-amino-1- (N-nitroamidino) -2-
(3-phenylpropanoyloxy) piperidine

91.3-amino-2-methoxy-1-
[N- (p-toluenesulfonyl) amidino] piperidine 92.3-amino-2-butoxy-1- [N- (p-toluenesulfonyl) amidino] piperidine 93.3-amino-2- (t-butoxy)- 1- [N-
(P-Toluenesulfonyl) amidino] piperidine 94.3-amino-2-isopentyloxy-1- [N
-(P-toluenesulfonyl) amidino] piperidine 95.3-amino-2-octyloxy-1- [N-
(P-Toluenesulfonyl) amidino] piperidine 96.3-amino-2- (2-phenylethoxy) -1
-[N- (p-toluenesulfonyl) amidino] piperidine 97.3-amino-2-cyclohexyloxy-1-
[N- (p-toluenesulfonyl) amidino] piperidine 98.3-amino-2-phenoxy-1- [N- (p-
Toluenesulfonyl) amidino] piperidine 99.3-amino-2-butanoyloxy-1- [N-
(P-Toluenesulfonyl) amidino] piperidine 100.3-Amino-2- (3-phenylpropanoyloxy) -1- [N- (p-toluenesulfonyl) amidino] piperidine

101. 3-Benzyloxycarbonylamino-2-methoxy-1- (N-nitroamidino) piperidine 102.3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine 103.3 -Benzyloxycarbonylamino-2-
(T-Butoxy) -1- (N-nitroamidino) piperidine 104.3-benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine 105.3-benzyloxycarbonylamino-1-
(N-nitroamidino) -2-octyloxypiperidine 106.3-benzyloxycarbonylamino-1-
(N-Nitroamidino) -2- (2-phenylethoxy) piperidine 107.3-Benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-nitroamidino) piperidine 108.3-Benzyloxycarbonylamino-1-
(N-Nitroamidino) -2-phenoxypiperidine 109.3-benzyloxycarbonylamino-2-butanoyloxy-1- (N-nitroamidino) piperidine 110.3-benzyloxycarbonylamino-1-
(N-nitroamidino) -2- (3-phenylpropanoyloxy) piperidine

111.1-amidino-3-butanoylamino-2-methoxypiperidine 112.1-amidino-3-butanoylamino-2-butoxypiperidine 113.1-amidino-3-butanoylamino-2-
(T-Butoxy) piperidine 114.1-amidino-3-butanoylamino-2-isopentyloxypiperidine 115.1-amidino-3-butanoylamino-2-octyloxypiperidine 116.1-amidino-3-buta Noylamino-2-
(2-Phenylethoxy) piperidine 117.1-amidino-3-butanoylamino-2-cyclohexyloxypiperidine 118.1-amidino-3-butanoylamino-2-phenoxypiperidine 119.1-amidino-3-butanoyl Amino-2-butanoyloxypiperidine 120.1-amidino-3-butanoylamino-2-
(3-phenylpropanoyloxy) piperidine

The compound of the present invention represented by the general formula (1) is, for example, a known compound (H. Khatri and
C. H. Stammer, J .; C. S. Chem. Co
mm. , 1979, 79), can be synthesized as shown in reaction formula (1).

[0025]

[Chemical 5]

[In the formula, Z represents a benzyloxycarbonyl group. R ² , R ³ and R ⁴ are R in the general formula (1).
² , the same as R ³ and R ⁴ ]

That is, the compound (B) is reacted with an alcohol in the presence of an acid catalyst and alkylated to obtain a compound represented by the general formula (1a) in which R ² is an alkyl group. Further, by acylating the compound (B), a compound represented by the general formula (1a) in which R ² is an acyl group is obtained. When the compound represented by the general formula (1a) is catalytically reduced, for example, the compound represented by the general formula (1b) or the general formula (1) is selected by selecting reaction conditions.
The compound represented by c) can be obtained. General formula (1
A compound represented by the general formula (1d) or a compound represented by the general formula (1e) is obtained by acylating or alkylating the compound represented by b) or the compound represented by the general formula (1c). Is obtained. General formula (1b)
The compound represented by the formula
A compound represented by c) or a compound represented by the general formula (1e) is obtained.

Examples of the acid catalyst in the alkylation for producing the compound represented by the general formula (1a) in which R ² is an alkyl group from the compound (B) include mineral acids such as hydrochloric acid and sulfuric acid, such as methanesulfone. Examples thereof include organic acids such as acids, trifluoromethanesulfonic acid, p-toluenesulfonic acid and camphorsulfonic acid, and Lewis acids such as boron trifluoride etherate, titanium tetrachloride and tin tetrachloride. The amount of the acid catalyst used is preferably 0.01 to 10 equivalents. The amount of alcohol used is preferably about 0.1 equivalent to a large excess (solvent amount).

Compounds (B) to R ² are acyl groups, compounds of general formula (1a), compounds of general formula (1b) to compounds of general formula (1d) and general formulas Acylation in producing the compound represented by the general formula (1e) from the compound represented by (1c) is achieved by, for example, treating with an acylating agent or treating with a combination of an acylating agent and a base. To be done. Examples of the acylating agent include acid halides such as acetyl chloride, benzoyl chloride, benzyloxycarbonyl chloride and t-butoxycarbonyl chloride, acetic anhydride, acid anhydrides such as di-t-butyldicarbonate, acetic acid and benzoic acid. Examples thereof include a combination of a carboxylic acid and a dehydration condensation agent such as dicyclohexylcarbodiimide (DCC). As the base, triethylamine, N-methylmorpholine, pyridine, 4-
Examples thereof include organic bases such as dimethylaminopyridine and inorganic bases such as sodium hydrogen carbonate, potassium carbonate and sodium hydroxide. The amount of the acylating agent used is preferably 0.1 to 10 equivalents, and the amount of the base is preferably 0 to a large excess (solvent amount).

When producing a compound represented by the general formula (1d) or a compound represented by the general formula (1e) from a compound represented by the general formula (1b) or a compound represented by the general formula (1c) Alkylation of is accomplished, for example, by treatment with an alkylating agent or a combination of alkylating agent and base. Examples of the alkylating agent include alkyl halides such as methyl iodide and benzyl bromide,
Examples include combinations of aldehydes such as formaldehyde and acetaldehyde and reducing agents such as sodium cyanoborohydride. Examples of the base include organic bases such as triethylamine, pyridine and 4-dimethylaminopyridine, and inorganic bases such as potassium carbonate and sodium hydroxide. The alkylating agent is preferably used in an amount of 0.1 to 10 equivalents, and the base is preferably used in an amount of 0 to a large excess (solvent amount).

Catalytic reduction in producing the compound represented by the general formula (1b) or the compound represented by the general formula (1c) from the compound represented by the general formula (1a) is carried out by, for example, methanol, acetic acid or the like. In a solvent of palladium black, 10
This can be achieved by stirring in a hydrogen atmosphere or while blowing a hydrogen gas in the presence of a catalytic reduction catalyst such as% palladium / carbon, 20% palladium hydroxide / carbon. For example, the compound represented by the general formula (1a) is obtained by stirring the compound represented by the general formula (1a) in methanol in the presence of palladium black while blowing hydrogen gas at room temperature to obtain the compound represented by the general formula (1a). The compound represented by the formula (1c) is obtained by stirring the compound represented by the formula in methanol in the presence of 20% palladium hydroxide / carbon at room temperature while blowing hydrogen gas.

A compound represented by the general formula (1c) or a compound represented by the general formula (1e) is produced from a compound represented by the general formula (1b) or a compound represented by the general formula (1d). The reduction in this case is achieved by the above-mentioned catalytic reduction or by treating with, for example, a reducing agent of titanium trichloride.

The compound (B) is synthesized from the compound (A), but the compound represented by the general formula (C) is used as a starting material instead of the compound (A), and is almost the same as the reaction formula (1). The compound represented by the general formula (1) can also be synthesized by performing the operation of. (Reaction formula (2)).

[0034]

[Chemical 6]

[0035] [wherein, R ^1, R ^2, R ³ and R ⁴ are the same as R ^1, R ^2, R ³ and R ⁴ in the general formula (1)]

[0036]

The compound of the present invention is found to have a strong antiviral effect from the following experimental examples.

[0037]

Experimental Example HIV (Human), which is a retrovirus
The effect on Immunodeficiency Virus) was tested by the following method. MT in 48-hole tray
-4 cells (approx. 50,000 cells / 0.5 ml), 50 μl of a solution containing a fixed amount of the compound of the present invention, and 37 ° C., 5%
(V / v) After culturing in a carbon dioxide incubator for 2 hours,
HI of 5.0 × 10 ⁴ to 1.0 × 10 ⁵ PFU / ml
After adding 50 μl of V and culturing for 4 days, a part of the culture solution was applied on a slide glass and fixed with acetone. Then, the expression of virus antigen was observed by the indirect fluorescent antibody method, and at a 50% effective concentration (EC50). Indicated. ) In addition, anti-human IgG labeled with sera from AIDS patients as the primary antibody of the fluorescent antibody method and FITC (fluorescein thiocyanate) as the secondary antibody
Was used.

Cell toxicity is 48
Approximately 50,000 MT-4 cells / 0.5 ml were placed in a hole tray, and 50 μl of a solution containing a fixed amount of the compound of the present invention was added,
After culturing at 37 ° C. in a 5% (v / v) carbon dioxide incubator for 4 days, the cell proliferation was observed under a microscope. The cell proliferation was equivalent to that of the control group (-), and the cell proliferation was slightly worse (±). In addition, a cell proliferation of about 50% as compared with the control group was designated as (+), and a cell in which the cells were almost dead was designated as (++).

The experimental results are shown in Table 1.

[Table 1]

When the compound of the present invention thus obtained is used as a drug such as an antiviral agent, it can be administered orally, intravenously or transdermally. The dose is usually 0.1-10000 mg / kg / day, though it varies depending on the symptoms, age and administration method of the patient to be administered. The compound of the present invention is administered in the form of a preparation prepared by mixing with a suitable pharmaceutical carrier. The form of the formulation is tablets,
Granules, fine granules, powders, capsules, injections, creams, suppositories, etc. are used. The amount of the active ingredient contained in the preparation is about 0.01% to 99%.

[0041]

EXAMPLES Next, the production of the compound of the present invention will be specifically described with reference to Examples.

Example 1 (2S, 3S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine [(2S, 3S) -Compound 102] and (2R, 3
S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine [(2
R, 3S) -Compound 102]

(3S) -3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
Piperidine [(3S) -Compound B] (6.32 g, 1
2.75 mmol) was dissolved in 80 ml of n-butanol and p-toluenesulfonic acid (400 mg, 2.5 mm
ol) is added. Heat to 60 ° C for 44 minutes, then air cool,
A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and then with saturated saline, and then dried over magnesium sulfate, and after filtration, the liquid is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; hexane-ethyl acetate = 1: 1, v / v) to obtain (2S, 3S) -3-benzyloxycarbonylamino-2-butoxy-1- (N.
-Nitroamidino) piperidine (0.44 g, 1.12
mmol, yield 8.8%) and (2R, 3S) -3-benzyloxycarbonylamino-2-butoxy-1- (N
-Nitroamidino) piperidine (1.83 g, 4.65
mmol, yield 36.5%).

[(2S, 3S) -Compound 102] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.9
1 (3H, t, J = 7.1Hz), 1.36 (2H,
m), 1.50-1.70 (5H, m), 2.17 (1
H, m), 3.19 (1H, m), 3.41 (2H,
m), 3.90 (1H, m), 4.10 (1H, br
m), 4.99 (1H, br), 5.09 (2H,
s), 5.53 (1H, d, J = 2.0 Hz), 7.2
6 (5H, s), 7.53 (2H, brs).

[(2R, 3S) -Compound 102] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.9
0 (3H, t, J = 7.2Hz), 1.27 (2H, q
td, J = 7.2, 7.2, 2.0 Hz), 1.52
(2H, m), 1.80 (4H, m), 3.10 (1
H, t, J = 13.0 Hz), 3.39 (1H, td,
J = 6.0, 9.2 Hz), 3.45 (1H, td, J
= 6.4, 9.2 Hz), 3.77 (2H, br),
5.05 (1H, brd, J = 9.2Hz), 5.10.
(2H, s), 5.55 (1H, brs), 7.36
(5H, s), 7.83 (2H, brs).

Example 2 (2R, 3R) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine [(2R, 3R) -Compound 102] and (2S, 3
R) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine [(2
S, 3R) -Compound 102]

(3S) -3-benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
Instead of piperidine [(3S) -Compound B] (3R)
-3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino) piperidine [(3R)
-Compound B] was used and synthesized in the same manner as in Example 1. NMR was consistent with the compound of Example 1.

Example 3 Preparation of (2S, 3S) -1-amidino-3-amino-2-butoxypiperidine [(2S, 3S) -Compound 2]

(2S, 3S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine (806.7 mg, 2.05 mmol)
Was dissolved in 20 ml of methanol, and 20% palladium hydroxide / carbon (173.4 mg) was added under a nitrogen atmosphere.
Stir vigorously for 8 hours and 10 minutes at room temperature while blowing in hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 50% methanol) (2S, 3
S) -1-amidino-3-amino-2-butoxypiperidine (142.8 mg, 0.67 mmol, yield 32.
7%). This 5.1 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.95 (3H, t, J = 7.2Hz), 1.
41 (2H, m), 1.61 (2H, m), 1.72-
1.92 (3H, m), 2.25 (1H, m), 3.3
6 (1H, m), 3.52 (2H, t, J = 6.0H
z), 3.66 (2H, brs), 5.58 (1H,
d, J = 2.2 Hz). Mass (FAB) m / z: 215 [M + H] ⁺ , 14
1 [M-BuO] ⁺ .

Example 4 Preparation of (2R, 3S) -1-amidino-3-amino-2-butoxypiperidine [(2R, 3S) -Compound 2]

(2R, 3S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine (520.1 mg, 1.32 mmol)
Was dissolved in methanol (20 ml), and 20% palladium hydroxide / carbon (130.0 mg) was added under a nitrogen atmosphere.
Stir vigorously for 5 hours and 35 minutes at room temperature while blowing in hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (eluted with 10% methanol) and (2R, 3S) -1-amidino-3-amino-2-butoxypiperidine (126.9m).
g, 0.59 mmol, yield 44.8%). 7.0 mg of this is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.96 (3H, t, J = 7.2Hz), 1.
43 (2H, m), 1.58-1.68 (3H, m),
1.84-2.20 (3H, m), 3.20 (1H, d
t, J = 2.4, 14.0 Hz), 3.46-3.58
(4H, m), 5.45 (1H, d, J = 3.3H
z). Mass (FAB) m / z: 215 [M + H] ⁺ , 14
1 [M-BuO] ⁺ .

Example 5 (2S, 3R) -1-amidino-3-amino-2-butoxypiperidine [(2S, 3R) -Compound 2] and (2
Production of R, 3R) -1-amidino-3-amino-2-butoxypiperidine [(2R, 3R) -Compound 2]

Instead of (2S, 3S) -3-benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine, (2S, 3R) -3-benzyloxycarbonylamino-2-butoxy- 1- (N
-Nitroamidino) piperidine or (2R, 3R)
Synthesis was performed in the same manner as in Example 3 except that -3-benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine was used. NMR was consistent with the compound of Example 3.

Example 6 (2S, 3S) -3-Benzyloxycarbonylamino-2- (t-butoxy) -1- (N-nitroamidino)
Piperidine [(2S, 3S) -Compound 103] and (2R, 3S) -3-Benzyloxycarbonylamino-2-tert-butoxy-1- (N-nitroamidino) piperidine [(2R, 3S) -Compound 103] Manufacturing of

(3S) -3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
Piperidine (700.2 mg, 2.08 mmol) was added to t
-Dissolved in butanol (1.96 ml), 4N hydrochloric acid-
Dioxane solution (100 μl, 0.42 mmol) is added. After stirring at room temperature for 1 hour and 20 minutes, phosphate buffer (0.1 M, pH 7.0) and ethyl acetate are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and saturated saline, then dried over magnesium sulfate, and the solution after filtration is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; hexane-ethyl acetate = 3: 2.
(2S, 3S) -3-benzyloxycarbonylamino-2- (t-butoxy) -1- (N-
Nitroamidino) piperidine (50.0 mg, 1.12
mmol, yield 5.8%) and (2R, 3S) -3-benzyloxycarbonylamino-2- (t-butoxy)-.
1- (N-nitroamidino) piperidine (224.4 m
g, 4.65 mmol, yield 27.4%).

[(2S, 3S) -Compound 103] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.5
7 (9H, s), 1.50-1.70 (3H, m),
2.22 (1H, m), 3.48 (1H, m), 3.6
7 (1H, m), 3.80 (1H, m), 5.09 (3
H, m), 5.77 (1H, brs), 7.36 (5
H, s), 7.65 (2H, brs).

[(2R, 3S) -Compound 103] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.1
7 (9H, s), 1.50-1.90 (4H, m),
3.32 (1H, dt, J = 2.7, 12.0Hz),
3.62 (2H, m), 4.87 (1H, d, J = 9.
0 Hz), 5.10 (2H, s), 5.65 (1H, b
r), 7.36 (5H, s), 7.78 (2H, br
s).

Example 7 (2R, 3S) -1-amidino-3-amino-2- (t
Preparation of -butoxy) piperidine [(2R, 3S) -Compound 3]

(2R, 3S) -3-Benzyloxycarbonylamino-2- (t-butoxy) -1- (N-nitroamidino) piperidine (220.0 mg, 0.56 m
mol) in methanol and 20% palladium hydroxide / carbon (50 mg) is added under a nitrogen atmosphere, and then the mixture is vigorously stirred for 15 hours and 25 minutes at room temperature while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol) (2R, 3S).
-1-Amidino-3-amino-2- (t-butoxy) piperidine (39.0 mg, 0.18 mmol, yield 3
2.1%). This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 1.30 (9H, s), 1.60-2.11
(4H, m), 3.30-3.70 (3H, m), 5.
64 (1H, d, J = 3.1 Hz). Mass (FAB) m / z: 215 [M + H] ⁺ .

Example 8 (2S, 3S) -3-Benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-nitroamidino) piperidine [(2S, 3S) -Compound 107] and (2R, 3S)- Preparation of 3-benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-nitroamidino) piperidine [(2R, 3S) -Compound 107]

(3S) -3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
Piperidine (813.3 mg, 1.82 mmol) was added to cyclohexanol (546.9 mg, 5.46 mmo).
1) and ethyl acetate, and concentrated under reduced pressure. 4 in the residue
Normal hydrochloric acid-dioxane solution (90 μl, 0.36 mmo
l) is added. After stirring for 35 minutes at room temperature, phosphate buffer (0.1 M, pH 7.0) and ethyl acetate are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and saturated saline, then dried over magnesium sulfate, and the solution after filtration is concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; hexane-ethyl acetate = 3:
2, v / v) and (2S, 3S) -3-benzyloxycarbonylamino-2-cyclohexyloxy-1
-(N-nitroamidino) piperidine (92.0 mg,
0.22 mmol, yield 12.1%) and (2R, 3S)
-3-Benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-nitroamidino) piperidine (239.8 mg, 0.57 mmol, yield 31.3
%).

[(2S, 3S) -Compound 107] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.2
0-2.30 (14H, m), 3.20-3.50 (2
H, m), 3.75-3.95 (2H, m), 5.03
(2H, s), 5.20 (1H, br), 5.73 (1
H, d, J = 2.1 Hz), 7.34 (5H, s),
7.75 (2H, brs).

[(2R, 3S) -Compound 107] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.1
0-1.90 (14H, m), 3.20 (1H, t, J
= 13.2 Hz), 3.37 (1 H, m), 3.76
(2H, m), 4.99 (1H, d, J = 8.8H
z), 5.10 (2H, s), 5.68 (1H, br
s), 7.36 (5H, s), 7.80 (2H, br)
s).

Example 9 Preparation of (2S, 3S) -1-amidino-3-amino-2-cyclohexyloxypiperidine [(2S, 3S) -Compound 7]

(2S, 3S) -3-Benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-
Nitroamidino) piperidine (90.0 mg, 0.21
(4 mmol) in methanol (4 ml), 20% palladium hydroxide / carbon (15 mg) is added under a nitrogen atmosphere, and the mixture is vigorously stirred at room temperature for 6 hours and 55 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol), (2
S, 3S) -1-amidino-3-amino-2-cyclohexyloxypiperidine (48.0 mg, 0.20 mm
ol, yield 95.2%). Take 4mg of this and 4
It is dissolved in a normal hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 1.20-1.64 (6H, m), 1.66-
2.04 (7H, m), 2.30 (1H, m), 3.2
0-3.70 (4H, m), 6.91 (1H, d, J =
2.3 Hz).

Example 10 Preparation of (2R, 3S) -1-amidino-3-amino-2-cyclohexyloxypiperidine [(2R, 3S) -Compound 7]

(2R, 3S) -3-benzyloxycarbonylamino-2-cyclohexyloxy-1- (N-
Nitroamidino) piperidine (228.0 mg, 0.5
(4 mmol) is dissolved in 6 ml of methanol, 20% palladium hydroxide / carbon (50 mg) is added under a nitrogen atmosphere, and the mixture is vigorously stirred at room temperature for 8 hours and 26 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol), (2
R, 3S) -1-amidino-3-amino-2-cyclohexyloxypiperidine (58.2 mg, 0.24 mm
ol, yield 44.4%). Take this 5mg, 4
It is dissolved in a normal hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 1.18-1.50 (4H, m), 1.52-
1.64 (2H, m), 1.66-2.12 (8H,
m), 3.24-3.44 (2H, m), 3.48-
3.64 (2H, m), 5.61 (1H, d, J = 2.
9 Hz).

Example 11 (2S, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2- (2-phenylethoxy) piperidine [(2S, 3S) -Compound 106]
And (2R, 3S) -3-benzyloxycarbonylamino-1- (N-nitroamidino) -2- (2-phenylethoxy) piperidine [(2R, 3S) -Compound 1
06]

(3S) -3-benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
2 piperidine (675.0 mg, 2.00 mmol)
-Phenylethanol (733.0 mg, 6.00 mm
ol) and methylene chloride, and concentrated under reduced pressure. 4N hydrochloric acid-dioxane solution (100 μl, 0.40
mmol) is added. After stirring at room temperature for 16 minutes, phosphate buffer (0.2 M, pH 7.0) and ethyl acetate are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and saturated saline, and then dried over sodium sulfate,
After filtration, concentrate under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; hexane-ethyl acetate = 2: 1,
(2S, 3S) -3-benzyloxycarbonylamino-1- (N-nitroamidino) -2-
(2-phenylethoxy) piperidine (99.6 mg,
0.23 mmol, yield 11.5%) and (2R, 3S)
-3-benzyloxycarbonylamino-1- (N-nitroamidino) -2- (2-phenylethoxy) piperidine (384.6 mg, 0.87 mmol, yield 43.
5%).

[(2S, 3S) -Compound 106] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.4
5-1.60 (3H, m), 2.10 (1H, m),
2.83 (1H, m), 2.87 (2H, t, J = 6.
6 Hz), 3.59 (1H, dd, J = 6.3, 8.5
Hz), 3.68 (1H, dd, J = 6.3, 9.0H
z), 3.78 (1H, m), 3.88 (1H, m),
4.92 (1H, br), 5.09 (2H, s), 5.
54 (1H, d, J = 2.6 Hz), 7.10-7.4
0 (12H, m).

[(2R, 3S) -Compound 106] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 1.5
0-1.90 (4H, m), 2.80 (1H, brt,
J = 13.0 Hz, 2.85 (2H, t, J = 6.3)
Hz), 3.57 (1H, brd, J = 13.0H
z), 3.60-3.75 (3H, m), 4.87 (1
H, brd, J = 9.5 Hz), 5.07 (2H,
s), 5.61 (1H, brs), 7.10-7.25.
(5H, m), 7.36 (5H, s), 7.69 (2
H, brs).

Example 12 (2S, 3S) -1-amidino-3-amino-2- (2
-Phenylethoxy) piperidine [(2S, 3S) -Compound 6]

(2S, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2- (2
-Phenylethoxy) piperidine (96.0 mg, 0.
(22 mmol) was dissolved in 5 ml of methanol, 20% palladium hydroxide / carbon (22.2 mg) was added under a nitrogen atmosphere, and then at room temperature for 6 hours 30 while blowing hydrogen gas.
Stir vigorously for a minute. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was made into HP-20 resin (water to 70
% Gradient methanol elution)
(2S, 3S) -1-amidino-3-amino-2- (2
-Phenylethoxy) piperidine (8.4 mg, 0.0
3 mmol, yield 13.6%). This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 1.50-1.90 (3H, m), 2.14
(1H, m), 2.92 (2H, t, J = 6.6H
z), 3.04 (1H, dt, J = 4.0, 12.0H
z), 3.48 (1H, m), 3.67 (2H, m),
3.76 (1H, m), 5.59 (1H, d, J = 2.
1 Hz), 7.15-7.35 (5H, m).

Example 13 (2R, 3S) -1-amidino-3-amino-2- (2
-Phenylethoxy) piperidine [(2R, 3S) -Compound 6]

(2R, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2- (2
-Phenylethoxy) piperidine (370.0 mg,
0.84 mmol) was dissolved in 6 ml of methanol, 20% palladium hydroxide / carbon (86 mg) was added under a nitrogen atmosphere, and then at room temperature for 7 hours 40 while blowing hydrogen gas.
Stir vigorously for a minute. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was made into HP-20 resin (60% from water).
% Gradient methanol elution)
(2R, 3S) -1-amidino-3-amino-2- (2
-Phenylethoxy) piperidine (77.8 mg, 0.
30 mmol, yield 35.7%) is obtained. This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 1.54-2.00 (4H, m), 2.85.
(1H, dt, J = 3.0, 12.4Hz), 2.97
(2H, t, J = 6.9 Hz), 3.35-3.40
(4H, m), 5.51 (1H, d, J = 2.6H
z), 7.15-7.35 (5H, m).

Example 14 (2S, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2-octyloxypiperidine [(2S, 3S) -Compound 105] and (2
R, 3S) -3-Benzyloxycarbonylamino-1
Preparation of-(N-nitroamidino) -2-octyloxypiperidine [(2R, 3S) -Compound 105]

(3S) -3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
N piperidine (700.1 mg, 2.08 mmol)
-Octanol (541.8 mg, 4.16 mmol)
And tetrahydrofuran, and concentrated under reduced pressure. 4N hydrochloric acid-dioxane solution (105 μl, 0.42
mmol) is added. After stirring for 1 hour and 20 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution and ethyl acetate are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent; hexane-ethyl acetate = 2:
1, v / v) and (2S, 3S) -3-benzyloxycarbonylamino-1- (N-nitroamidino)-
2-octyloxypiperidine (152.3 mg, 0.
34 mmol, yield 16.3%) and (2R, 3S) -3.
-Benzyloxycarbonylamino-1- (N-nitroamidino) -2-octyloxypiperidine (421.
4 mg, 0.94 mmol, yield 45.2%) are obtained.

[(2S, 3S) -Compound 105] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.8
8 (3H, t, J = 6.2Hz), 1.20-1.40
(10H, m), 1.50-1.85 (5H, m),
2.17 (1H, m), 3.18 (1H, m), 3.4
0 (2H, m), 3.89 (1H, m), 4.01 (1
H, m), 5.03 (1H, brm), 5.09 (2
H, s), 5.52 (1H, brd, J = 2.2H
z), 7.36 (5H, s), 7.57 (2H, br)
s).

[(2R, 3S) -Compound 105] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.8
8 (3H, t, J = 6.1Hz), 1.20-1.40
(10H, m), 1.50-1.90 (6H, m),
3.10 (1H, dt, J = 1.9, 13.0Hz),
3.41 (2H, m), 3.64-3.88 (2H,
m), 5.04 (1H, brd, J = 9.2Hz),
5.11 (2H, s), 5.52 (1H, brs),
7.37 (5H, s), 7.78 (2H, brs).

Example 15 Preparation of (2S, 3S) -1-amidino-3-amino-2-octyloxypiperidine [(2S, 3S) -Compound 5]

(2S, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2-octyloxypiperidine (150.0 mg, 0.33 mm
ol) is dissolved in 4 ml of methanol, and the solution is placed under a nitrogen atmosphere for 20 minutes.
% Palladium hydroxide / carbon (30.2 mg) was added, and the mixture was vigorously stirred at room temperature for 4 hours and 26 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 50% methanol), (2
S, 3S) -1-amidino-3-amino-2-octyloxypiperidine (30.3 mg, 0.11 mmol,
Yield 33.3%) is obtained. This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ OD)
δ: 0.90 (3H, t, J = 6.4Hz), 1.30 (1
0H, brs), 1.61 (2H, m), 1.74-
1.92 (3H, m), 2.25 (1H, m), 3.3
5 (1H, m), 3.46-3.60 (3H, m),
3.67 (1H, m), 5.60 (1H, brs). Mass (FAB) m / z: 271 [M + H] ⁺ , 14
1 [M-OctO] ⁺ (Base Peak).

Example 16 Preparation of (2R, 3S) -1-amidino-3-amino-2-octyloxypiperidine [(2R, 3S) -Compound 5]

(2R, 3S) -3-Benzyloxycarbonylamino-1- (N-nitroamidino) -2-octyloxypiperidine (409.0 mg, 0.91 mm
ol) is dissolved in 6 ml of methanol, and the solution is placed under a nitrogen atmosphere for 20
After adding% palladium hydroxide / carbon (80 mg), the mixture is vigorously stirred for 4 hours and 27 minutes at room temperature while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol) (2R, 3
S) -1-amidino-3-amino-2-octyloxypiperidine (77.8 mg, 0.29 mmol, yield 3)
1.9%). This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.90 (3H, t, J = 6.4Hz), 1.
30 (10H, brs), 1.60-1.76 (3H,
m), 1.84-2.02 (3H, m), 3.23 (1
H, dt, J = 1.0, 10.2 Hz), 3.51 (1
H, t, J = 6.5 Hz), 3.46-3.70 (3
H, m), 5.48 (1H, brs). Mass (FAB) m / z: 271 [M + H] ⁺ , 34
3 [M + H + 2HCl] ⁺ , 141 [M-OctO] ⁺
(Base Peak).

Example 17 (2S, 3S) -3-Benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine [(2S, 3S) -Compound 104] and (2R, 3S) Production of -3-benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine [(2R, 3S) -Compound 104]

(3S) -3-Benzyloxycarbonylamino-2-hydroxy-1- (N-nitroamidino)
Piperidine (700.1 mg, 2.08 mmol) was added to isopentyl alcohol (994.4 mg, 11.28 m).
mol) and ethyl acetate, and concentrated under reduced pressure. 4N hydrochloric acid-dioxane solution (70 μl, 0.28 m
mol) is added. After stirring for 59 minutes at room temperature, saturated aqueous sodium hydrogen carbonate solution and toluene are added and the mixture is vigorously stirred. The aqueous layer and the organic layer are separated, the organic layer is washed with water and saturated brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. Silica gel column chromatography of the residue
(Eluate; hexane-ethyl acetate = 8: 5, v / v), and subjected to (2S, 3S) -3-benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine (140 .2 mg, 0.34 mmo
l, yield 24.1%) and (2R, 3S) -3-benzyloxycarbonylamino-2-isopentyloxy-1.
-(N-nitroamidino) piperidine (275.5 m
g, 0.68 mmol, yield 48.2%).

[(2S, 3S) -Compound 104] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.8
8 (3H, t, J = 6.6Hz), 0.90 (3H,
t, J = 6.6 Hz), 1.47 (2H, m), 1.5
0-1.80 (4H, m), 2.18 (1H, m),
3.23 (1H, m), 3.38 (1H, dd, J =
6.6, 9.3 Hz), 3.50 (1H, dd, J =
7.0, 9.4 Hz), 3.89 (1H, m), 4.0
0 (1H, m), 4.98 (1H, br), 5.10
(2H, s), 5.53 (1H, brd, J = 2.5H
z), 7.36 (5H, s), 7.52 (2H, b
r).

[(2R, 3S) -Compound 104] ¹ H-NMR (200 MHz, CDCl ₃ ) δ: 0.8
8 (3H, t, J = 6.6Hz), 0.89 (3H,
t, J = 6.6 Hz), 1.47 (2H, m), 1.6
0-1.90 (5H, m), 3.09 (1H, dt, J
= 1.6, 12.3 Hz), 3.43 (1H, dt, J
= 9.4, 6.4 Hz), 3.48 (1H, dt, J =
9.4, 6.8Hz), 3.77 (2H, m), 5.0
3 (1H, d, J = 9.3 Hz), 5.10 (2H,
s), 5.54 (1H, m), 7.37 (5H, s),
7.78 (2H, brs).

Example 18 Preparation of (2S, 3S) -1-amidino-3-amino-2-isopentyloxypiperidine [(2S, 3S) -Compound 4]

(2S, 3S) -3-Benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine (140.0 mg, 0.34
mmol) in 6 ml of methanol, 20% palladium hydroxide / carbon (30 mg) is added under a nitrogen atmosphere, and the mixture is vigorously stirred at room temperature for 5 hours and 33 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to methanol), (2S, 3
S) -1-amidino-3-amino-2-isopentyloxypiperidine (41.4 mg, 0.18 mmol, yield 52.9%) is obtained. This 5 mg is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ OD)
δ: 0.93 (6H, dd, J = 1.4, 6.5H
z), 1.52 (2H, m), 1.62-1.98 (4
H, m), 2.26 (1H, m), 3.26-3.45.
(1H, m), 3.56 (2H, t, J = 6.5H
z), 3.64-3.72 (2H, m), 5.59 (1
H, d, J = 3.0 Hz).

Example 19 Preparation of (2R, 3S) -1-amidino-3-amino-2-isopentyloxypiperidine [(2R, 3S) -Compound 4]

(2R, 3S) -3-Benzyloxycarbonylamino-2-isopentyloxy-1- (N-nitroamidino) piperidine (255.0 mg, 0.63
(mmol) was dissolved in methanol (8 ml), 20% palladium hydroxide / carbon (45 mg) was added under a nitrogen atmosphere, and the mixture was vigorously stirred at room temperature for 6 hours and 50 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol), (2
R, 3S) -1-amidino-3-amino-2-isopentyloxypiperidine (62.6 mg, 0.27 mmo
1, yield 42.9%). 6 mg of this is taken, dissolved in a 4N hydrochloric acid-dioxane solution, and concentrated under reduced pressure to quantitatively obtain a hydrochloride.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.95 (6H, dd, J = 2.2, 6.4H
z), 1.57 (2H, m), 1.65-1.83 (2
H, m), 1.84-2.02 (3H, m), 3.23.
(1H, m), 3.55 (2H, t, J = 6.7H
z), 3.48-3.70 (2H, m), 5.46 (1
H, d, J = 2.9 Hz).

Example 20 (2S, 3S) -3-Amino-2-butoxy-1- (N
-Nitroamidino) piperidine [(2S, 3S) -Compound 82]

(2S, 3S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine (109.8 mg, 0.28 mmol)
Was dissolved in 3 ml of methanol, palladium black (21.5 mg) was added under a nitrogen atmosphere, and the mixture was vigorously stirred at room temperature for 1 hour and 23 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to methanol), (2S, 3S) -3-amino-2.
-Butoxy-1- (N-nitroamidino) piperidine (36.2 mg, 0.14 mmol, yield 50.0%)
To get

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.92 (3H, t, J = 7.1Hz),
1.20-2.20 (10H, m), 3.20 (1H,
dd, J = 4.3, 8.3 Hz), 3.35-3.70.
(4H, m), 5.08 (1H, d, J = 4.0H
z), 7.60-8.60 (2H, m).

Example 21 (2R, 3S) -3-Amino-2-butoxy-1- (N
-Nitroamidino) piperidine [(2R, 3S) -Compound 82]

(2R, 3S) -3-Benzyloxycarbonylamino-2-butoxy-1- (N-nitroamidino) piperidine (119.6 mg, 0.30 mmol)
Was dissolved in 6 ml of methanol, palladium black (30.0 mg) was added under a nitrogen atmosphere, and the mixture was vigorously stirred at room temperature for 83 minutes while blowing hydrogen gas. After completion of the reaction, the mixture is filtered through Celite, and the filtrate is concentrated under reduced pressure. HP-
20 resin (continuous gradient elution from water to 80% methanol) was used for purification and (2R, 3S) -3-amino-2.
-Butoxy-1- (N-nitroamidino) piperidine (44.1 mg, 0.17 mmol, yield 56.7%)
To get

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.92 (3H, t, J = 7.1 Hz) 1.
36 (2H, m), 1.45 to 1.85 (8H, m),
2.76 (1H, m), 3.13 (1H, dt, J =
1.2, 12.5 Hz), 3.35-3.55 (2H,
m), 3.74 (1H, m), 5.56 (1H, br
s). 7.60-9.00 (2H, br).

Example 22 (2S, 3S) -3-Acetylamino-1-amidino-
2-Butoxypiperidine [(2S, 3S) -Compound 1
2] production

(2S, 3S) -1-amidino-3-benzyloxycarbonylamino-2-butoxypiperidine (44.1 mg, 0.21 mmol) was dissolved in 2 ml of water, and triethylamine (30.4 mg, 0.30 mmo).
1) and 4-acetoxysulfonium methylsulfate (110.5 mg, 0.30 mmol) are added, and the mixture is stirred at room temperature for 28 hours. After the reaction is complete, dilute with water and add HP-
20 resin (continuous gradient elution from water to 30% methanol) and (2S, 3S) -3-acetylamino-1-amidino-2-butoxypiperidine (33.
4 mg, 0.13 mmol, yield 61.9%) is obtained.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.95 (3H, t, J = 7.2Hz), 1.
35-1.70 (6H, m), 1.80-2.20 (2
H, m), 1.99 (3H, s), 3.31 (1H,
m), 3.40-3.60 (3H, m), 4.15 (1
H, m), 5.10 (1H, d, J = 2.2 Hz).

Example 23 (2R, 3S) -3-Acetylamino-1-amidino-
Preparation of 2-butoxypiperidine [(2R, 3S) -Compound 12]

(2R, 3S) -1-amidino-3-benzyloxycarbonylamino-2-butoxypiperidine (44.0 mg, 0.21 mmol) was dissolved in 2 ml of water, and triethylamine (60.8 mg, 0.60 mmo).
1) and 4-acetoxysulfonium methylsulfate (220.1 mg, 0.60 mmol) are added and stirred overnight at room temperature. After the reaction was completed, it was diluted with water and HP-20
Resin (continuous gradient elution from water to 40% methanol)
Was purified using (2R, 3S) -3-acetylamino-1-amidino-2-butoxypiperidine (30.5 m
g, 0.12 mmol, yield 57.1%).

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.94 (3H, t, J = 7.2Hz) 1.3
0-2.00 (8H, m), 1.98 (3H, s),
3.21 (1H, dt, J = 3.0, 12.0Hz),
3.30-3.60 (3H, m), 3.90 (1H,
m), 5.10 (1H, d, J = 2.9 Hz).

Example 24 (2S, 3S) -1-amidino-2-butoxy-3-
(T-Butoxycarbonylamino) piperidine [(2
S, 3S) -Compound 42]

(2S, 3S) -1-amidino-3-amino-2-butoxypiperidine (32.0 mg, 0.15
mmol) was dissolved in water-dioxane (2 ml-0.5 ml) and sodium hydrogen carbonate (15.0 mg, 0.18) was added.
mmol), di-t-butyl carbonate (36.0 m
g, 0.16 mmol) was added, and the mixture was stirred at room temperature overnight.
After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue was treated with HP-20.
Resin (Continuous gradient elution from water to 90% methanol)
And purified with (2S, 3S) -1-amidino-2-
Butoxy-3- (t-butoxycarbonylamino) piperidine (40.4 mg, 0.14 mmol, yield 9
4.6%).

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.91 (3H, t, J = 7.2Hz),
1.45 (9H, s), 1.24-1.72 (7H,
m), 2.04 (1H, m), 3.15 (1H, dt,
J = 4.0, 12.0 Hz), 3.38-3.50 (2
H, m), 3.59 (1H, brd, J = 12.1H
z), 3.82 (1H, m), 4.93 (4H, b
r), 5.12 (1H, brs). MS (FAB) m / z: 315 [M + H] ⁺ (Base
Peak), 629 [2M + H] ⁺ , 241 [MB]
uO] ⁺ .

Example 25 (2R, 3S) -1-amidino-2-butoxy-3-
(T-Butoxycarbonylamino) piperidine [(2
R, 3S) -Compound 42]

(2R, 3S) -1-amidino-3-amino-2-butoxypiperidine (46.5 mg, 0.22)
mmol) was dissolved in 2 ml of water-0.5 ml of dioxane, and sodium hydrogen carbonate (22.0 mg, 0.26 mm)
ol), di-t-butyl carbonate (52.0 mg,
0.24 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was continuously extracted with methylene chloride, and the organic layer was concentrated under reduced pressure. The residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol), (2R, 3S) -1-amidino-2-butoxy-3- (t-butoxycarbonylamino) piperidine ( 38.6 mg, 0.12 mmol, yield 56.6%)
To get

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.93 (3H, t, J = 7.2Hz), 1.
45 (9H, s), 1.30-1.84 (8H, m),
3.01 (1H, dt, J = 2.8, 12.0Hz),
3.36-3.62 (4H, m), 5.14 (1H,
d, J = 3.0 Hz). MS (FAB) m / z: 315 [M + H] ⁺ (Base
Peak), 629 [2M + H] ⁺ .

Example 26 (2S, 3S) -1-amidino-3-benzyloxycarbonylamino-2-butoxypiperidine [(2S, 3
S) -Compound 32]

(2S, 3S) -1-amidino-3-amino-2-butoxypiperidine (30.8 mg, 0.14
mmol) was dissolved in 2 ml of water-1 ml of dioxane, and sodium hydrogen carbonate (15.0 mg, 0.18 mmo)
l), dibenzyl carbonate (45.0 mg, 0.1
6 mmol) was added and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, continuous extraction with methylene chloride was performed for 5.5 hours. The organic layer was concentrated under reduced pressure and the residue was purified using HP-20 resin (continuous gradient elution from water to 90% methanol), (2S, 3S) -1-amidino-3-benzyloxycarbonylamino-. 2-Butoxypiperidine (2
7.5 mg, 0.079 mmol, yield 48.7%)
To get

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.90 (3H, t, J = 7.2 Hz),
1.22-1.70 (7H, m), 2.06 (1H,
m), 3.09 (1H, dt, J = 4.2, 11.7H)
z), 3.40 (1H, dd, J = 6.2, 9.2H
z), 3.49 (1H, dd, J = 6.2, 9.3H
z), 3.43 (1H, m), 3.91 (1H, m),
4.30 (3H, br, exchangeable w
it D ₂ O), 5.09 (4H, brs, 1H w
as exchangeable withD ₂ O),
7.25-7.42 (5H, m). MS (FAB) m / z: 349 [M + H] ⁺ (Base
Peak), 697 [2M + H] ⁺ , 275 [MB]
uO] ⁺ .

Example 27 (2R, 3S) -1-amidino-3-benzyloxycarbonylamino-2-butoxypiperidine [(2R, 3
S) -Compound 32]

(2R, 3S) -1-amidino-3-amino-2-butoxypiperidine (34.7 mg, 0.16)
(mmol) was dissolved in 2 ml of water-1 ml of dioxane, and sodium hydrogen carbonate (16.0 mg, 0.19 mmo).
l), dibenzyl carbonate (51.0 mg, 0.1
8 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After completion of the reaction, the reaction mixture was diluted with water and washed with ether, and then purified using HP-20 resin (continuous concentration gradient elution from water to 90% methanol), (2R, 3S) -1-amidino-3-benzyl. Oxycarbonylamino-2-butoxypiperidine (29.8 mg, 0.062 mmol, yield 38.1)
%).

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.89 (3H, t, J = 7.1Hz),
1.22-1.82 (8H, m), 3.18 (1H, a
parent t, J = 11.0 Hz), 3.35.
(1H, dd, J = 6.3, 9.2 Hz), 3.42
(1H, dd, J = 9.3, 11.3Hz), 3.50
(1H, dd, J = 6.5, 9.3Hz), 3.57
(1H, d, J = 13.1 Hz), 3.75 (1H,
m), 5.03 (1H, d, J = 12.1 Hz), 5.
12 (1H, d, J = 12.1 Hz), 7.32-7.
36 (5H, m), 7.34 (4H, br). MS (FAB) m / z: 349 [M + H] ⁺ (Base
Peak), 697 [2M + H] ⁺ , 275 [MB]
uO] ⁺ .

Example 28 (2S, 3S) -1-amidino-3-benzoylamino-2-butoxypiperidine [(2S, 3S) -Compound 2
2] production

(2S, 3S) -1-amidino-3-amino-2-butoxypiperidine (45.6 mg, 0.21)
(mmol) is dissolved in 4 parts of hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain hydrochloride. This hydrochloride was dissolved in 0.5 ml of anhydrous pyridine under an argon atmosphere, and benzoyl chloride (24.7 μl, 0.21 mmo was added at 0 ° C.).
1) was added and stirred for 1 hour. After concentration under reduced pressure, the reaction mixture was diluted with water and the aqueous layer was washed with ether, and then purified using HP-20 resin (continuous concentration gradient elution from water to 90% methanol), (2S, 3S) -1-amidino- 3-benzoylamino-2-butoxypiperidine hydrochloride (47.7 mg,
0.15 mmol, yield 70.4%) is obtained.

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.97 (3H, t, J = 7.2Hz), 1.
38-1.56 (2H, m), 1.58-1.86 (4
H, m), 1.92-2.32 (2H, m), 3.38.
(1H, m), 3.51 (1H, dd, J = 3.6,
6.8 Hz), 3.57 (1H, dd, J = 3.6,
6.8 Hz), 3.65 (1 H, m), 4.33 (1
H, dd, J = 3.0, 6.2 Hz), 5.30 (1
H, d, J = 2.3 Hz), 7.41-7.60 (3
H, m), 7.76-7.82 (2H, m). MS (FAB) m / z: 319 [M + H] ⁺ (Base
Peak), 245 [M-BuO] ⁺ , 154.

Example 29 (2R, 3S) -1-amidino-3-benzoylamino-2-butoxypiperidine [(2R, 3S) -Compound 2
2] production

(2R, 3S) -1-amidino-3-amino-2-butoxypiperidine (44.0 mg, 0.21
(mmol) is dissolved in 4 parts of hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain hydrochloride. This hydrochloride salt was dissolved in 0.5 ml of anhydrous pyridine under an argon atmosphere, and benzoyl chloride (23.7 μl, 0.21 mmo) was added at 0 ° C.
1) was added and stirred for 1.5 hours. After concentration under reduced pressure, the residue was diluted with water and the aqueous layer was washed with ether, and then purified using HP-20 resin (continuous concentration gradient elution from water to 90% methanol), (2R, 3S) -1-amidino- 3-benzoylamino-2-butoxypiperidine hydrochloride (35.3 m
g, 0.11 mmol, yield 54.1%).

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.86 (3H, t, J = 7.2Hz),
1.22-1.40 (2H, m), 1.42-1.58
(2H, m), 1.76-2.00 (4H, m), 3.
22 (1H, m), 3.34 (1H, td, J = 7.
0, 10.0 Hz), 3.53 (1H, td, J = 7.
0, 10.0 Hz), 4.12 (1H, d, J = 13.
6Hz), 4.20 (1H, m), 5.43 (1H,
d, J = 2.9 Hz), 6.27 (1H, d, J = 9.
4Hz, exchangeable withD
₂ O), 7.28-7.42 (3H, m), 7.46-
7.56 (2H, m), 8.07 (4H, br, exc
changeable with D ₂ O). MS (FAB) m / z: 319 [M + H] ⁺ , 245
[M-BuO] ^<+> , 154 (Base Peak).

Example 30 (2S, 3S) -1-amidino-2-butoxy-3-butyrylaminopiperidine [(2S, 3S) -Compound 11
2] production

(2S, 3S) -1-amidino-3-amino-2-butoxypiperidine (42.0 mg, 0.20
(mmol) is dissolved in 4 parts of hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain hydrochloride. This hydrochloride was dissolved in 0.5 ml of anhydrous pyridine under an argon atmosphere, and butyryl chloride (24.0 μl, 0.22 m) was added at 0 ° C.
mol) was added and stirred for 1 hour. After concentration under reduced pressure, the residue was diluted with water and the aqueous layer was washed with ether, and then purified using HP-20 resin (continuous concentration gradient elution from water to 40% methanol), (2S, 3S) -1- Amidino-2-butoxy-3-butyrylaminopiperidine hydrochloride (26.9 m
g, 0.095 mmol, yield 48.2%).

¹ H-NMR (200 MHz, CD ₃ O
D) δ: 0.95 (6H, t, J = 7.4Hz), 1.
34-1.50 (2H, m), 1.52-1.72 (6
H, m), 1.90 (1H, m), 2.04-2.28.
(3H, m), 3.30 (1H, m), 3.45 (1
H, dd, J = 3.2, 7.0 Hz), 3.52 (1
H, dd, J = 3.2, 7.0 Hz), 3.55 (1
H, m), 4.12 (1H, dd, J = 2.9, 6.2)
Hz), 5.13 (1H, d, J = 2.6 Hz). MS (FAB) m / z: 285 [M + H] ⁺ , 211
[M-BuO] ^<+> , 154 (Base Peak).

Example 31 (2R, 3S) -1-amidino-2-butoxy-3-butyrylaminopiperidine [(2R, 3S) -Compound 11
2] production

(2R, 3S) -1-amidino-3-amino-2-butoxypiperidine (47.1 mg, 0.22)
(mmol) is dissolved in 4 parts of hydrochloric acid-dioxane solution and concentrated under reduced pressure to quantitatively obtain hydrochloride. This hydrochloride was dissolved in 0.5 ml of anhydrous pyridine under an argon atmosphere, and butyryl chloride (25.0 μl, 0.24 m) was added at 0 ° C.
mol) was added and stirred for 1 hour. After concentration under reduced pressure, the residue was diluted with water and the aqueous layer was washed with ether, and then purified using HP-20 resin (elution with a continuous concentration gradient from water to 40% methanol), (2R, 3S) -1-amidino- 2-Butoxy-3-butyrylaminopiperidine hydrochloride (36.2 m
g, 0.13 mmol, yield 58.0%).

¹ H-NMR (200 MHz, CDC
l ₃ ) δ: 0.92 (3H, t, J = 7.3Hz),
0.94 (3H, t, J = 7.2Hz), 1.30-
1.44 (2H, m), 1.48-1.64 (4H,
m), 1.70-1.90 (4H, m), 2.12 (2
H, dt, J = 3.6, 7.3 Hz), 3.18 (1
H, m), 3.42 (1H, dd, J = 6.8, 10.
2 Hz), 3.52 (1 H, dd, J = 7.6, 10.
2Hz), 3.93 (1H, d, J = 14.0Hz),
3.98 (1H, m), 5.30 (1H, d, J = 2.
9 Hz), 5.78 (1H, d, J = 9.0 Hz, ex
changeable withD ₂ O), 7.90
(4H, br, exchangeable with
D ₂ O). MS (FAB) m / z: 285 [M + H] ⁺ (Base
Peak), 211 [M-BuO] ⁺ , 169.

[0139]

As shown in Test Example 2, since the compound used in the present invention has an excellent anti-HIV activity and weak cytotoxicity, it is expected to be an antiviral drug including an anti-HIV drug.

Claims (3)

[Claims] 1. A compound represented by the general formula (1): [Wherein R ¹ is a hydrogen atom or a guanidino group protecting group, R ² is an alkyl group, an aryl group or an acyl group, and R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, an aryl group or [Showing an acyl group] and a physiologically acceptable salt of these compounds 2. A compound represented by the general formula (1): [Wherein R ¹ is a hydrogen atom or a guanidino group protecting group, R ² is an alkyl group, an aryl group or an acyl group, and R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, an aryl group or [Showing an acyl group], and a novel piperidine derivative represented by a physiologically acceptable salt of these compounds or an antiviral agent containing the physiologically acceptable salt thereof as an active ingredient 3. A compound represented by the general formula (1): [Wherein R ¹ is a hydrogen atom or a guanidino group protecting group, R ² is an alkyl group, an aryl group or an acyl group, and R ³ and R ⁴ are each independently a hydrogen atom, an alkyl group, an aryl group or [Showing an acyl group]] and an anti-AIDS virus agent containing a physiologically acceptable salt of these compounds as an active ingredient