JP2003506332A - Bisplatinum complex active for oral administration - Google Patents

Abstract

(57) Abstract: A compound represented by the formula (I), wherein X is a halogen (chlorine, bromine, iodine), n and m are integers of 2 to 8, p is 1, 2, a is _{-B -, - B- (CH 2} ) r -B -, - B- (CH 2) r -B- (CH 2) z -B- (r and z is selected from the group consisting of 2-8 in a), B is the formula -NR- (R is a group capable of changing into a hydrogen atom under physiological conditions, provided that C ₁ -C ₄ alkyl group or an acyl group and t Q- ^p is an anion selected from the group consisting of chloride, bromide, iodide, nitrate, sulfate, hydrogen sulfate and perchlorate. Disclose. [Formula 1]

Description

Detailed Description of the Invention

The present invention relates to a novel platinum complex having antitumor activity when orally administered.

Oral administration of pharmaceuticals has a number of advantages over other commonly used routes of administration, such as intravenous or subcutaneous administration. First, it is easier for patients, who are often unwilling to treat with injectable formulations, because the administration by injection is inherently incompatible. Another significant advantage of oral administration is the patient's own ability to self-medicate, whereas in the case of injectable formulations, one must resort to a trained specialist.

Very few platinum complexes, similar to cisplatin described in the literature, show antitumor activity when administered orally. Carboplatin, JM-216
And AMD-473 (the latter being described in EP 727430A, 1996). However, these compounds are less effective against tumors that are either cisplatin intrinsic or acquired resistant.

The polynuclear platinum complexes disclosed in US Pat. No. 5,744,497 have an interesting antitumor activity profile because they are active against tumors with cisplatin intrinsic or acquired resistance. (G. Pratesin et al., Br. J. Cancer, 1999, August, 80.
: 12, 1912-9; P. Perego et al., Mol. Pharmacol., 55,528-534, 1999). However, this complex is less effective when administered by the oral route. In some cases, this limits its use.

WO 98/03519 and “American Cancer Research Society Bulletin” Vol. 39, Abstract 109
6 discloses platinum (II) binuclear complexes in which natural polyamines such as spermine and spermidine and their synthetic homologs bridge two monofunctional platinum spheres (Spheres). The most potent complexes in vitro are characterized by the presence of one or two secondary amino groups in the spacer bridging the two platinum atoms. Introducing a t-butoxycarbonyl group onto the amino group results in a significant reduction of in vitro cytotoxic activity and in vivo antitumor activity.

It is now surprisingly possible to obtain a binuclear platinum complex having antitumor activity and absorbed by the oral route by introducing a spacer having a suitable functional group on the secondary nitrogen atom. all right.

[0007]   The compound of the present invention has the following general formula (I):

[0008]

[Chemical 1]

[In the formula, X is halogen (chlorine, bromine, iodine, etc.), n and m are integers of 2 to 8, p is 1 and 2, and A is -B- and -B-. _{(CH 2) r -B -,} - B- (CH 2) r -B- (CH 2) Z -B
-(Where r and z are 2-8), and B is of the formula -NR- (
In the formula, R is a group that can be converted into a hydrogen atom under physiological conditions, provided that it is different from a C ₁ -C ₄ alkyl group or an acyl group, and a t-butoxycarbonyl group). And Q- ^p is an anion selected from the group consisting of chloride, bromide, iodide, nitrate, sulfate, acid sulfate or perchlorate.

[0010]   Examples of groups R are 1) formula

[0011]

[Chemical 2]

[0012] (In the formula, R₁, R₂And R₁May be the same or different, hydrogen, C₁~ C _Four Alkyl group, C_Five~ C₆Cycloalkyl groups, optionally one or more
C₁~ C_FourAlkyl group, C₁~ C_FourDepending on the alkoxy group, halogen and hydroxy group
Optionally substituted phenyl group, or C₇~ C_TenIs an aralkyl group,
Or R₁, R₂And R₃Is a D-type or L-type α-amino acid residue, and R_aIs
C₁~ C₆An alkyl group, preferably a t-butyl group),   2) Formula R_FourCO- [In the formula, R_FourIs hydrogen, C₃~ C₈A cycloalkyl group, preferably C_Five~ C₆Cycloa
Rukyl group, optionally C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group, hydroxy group,
Nitro group, cyano group, phenyl group substituted by halogen, alkyl C₁~
C₂Interrupted by phenyl, ethyloxy, or 1 to 4 oxygen atoms
(However, -O-CH₂Excluding --O-acetal group) C₃~ C₈Is an alkyl group
Or R_FourIs a saturated or unsaturated fatty acid residue or hexose or pent
Is a residue of sucrose],   3) Expression

[0013]

[Chemical 3]

A group represented by: 4) Formula —CO—O—R ₅ [In the formula, R ₅ is a C _{1 to} C ₁₈ alkyl group (excluding t-butyl group), a C _{3 to} C ₁₈ alkenyl group, and benzyl. Group or one or more hydroxy group at the phenyl group, C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, nitro group, cyano group, acetoxy group, C ₁ -C ₃ alkylaminocarbonyl Oxy group, benzyl group substituted by C ₁ -C ₃ alkoxycarbonyloxy group, residue of hexose or pentose sugar, formula

[0015]

[Chemical 4]

A group represented by the formula (wherein R _g is a methyl group or a phenyl group), or a group

[0017]

[Chemical 5]

(Wherein R ₆ is hydrogen or a C ₁ -C ₄ alkyl group, and w is an integer of 1-6)], a group represented by the formula 5):

[0019]

[Chemical 6]

A group represented by the formula (wherein R _g has the above-mentioned meaning), 6) Formula

[0021]

[Chemical 7]

A group represented by the formula: wherein R ₆ and R ₇ are the same or different and are hydrogen or a C ₁ -C ₄ alkyl group;

[0023]

[Chemical 8]

(Wherein R ₈ is hydrogen or a C ₁ -C ₄ alkyl group), 8) Formula

[0025]

[Chemical 9]

(Wherein R ₉ is hydrogen or a C ₁ -C ₄ alkyl group, and R ₁₀ is a C ₁ -C ₄ alkyl group), 9) Formula

[0027]

[Chemical 10]

(Wherein R ₁₁ and R ₁₂ are the same or different and each is hydrogen, a C ₁ -C ₄ alkyl group, or a phenyl group),

[0029]

[Chemical 11]

A group represented by the formula: wherein R _b is a C ₁ -C ₆ alkyl group, preferably a methyl group, 11) Formula (C), (D) or (E)

[0031]

[Chemical 12]

Wherein R _b has the above meaning and R _c , R _d , R _e , and R _f are the same or different and are H, CH ₃ or OCH _3. Base, formula 12)

[0033]

[Chemical 13]

[0034] A group represented by   13) Expression

[0035]

[Chemical 14]

[0036] [Where Z is C₂~ C_FourAlkylene groups, cycloalkylene groups, optionally substituted fluorine
Is an enylene group, T is an oxygen atom, -NH- or -NR₁₄Group (in the formula, R ₁₄ Is C₁~ C_FourIs an alkyl group), Y represents a bond or is an oxygen atom, NH or the above-N-R₁₄The base, R₁₃Is C₁~ C_FourAlkyl group, C_Five~ C₆Cycloalkyl group, phenyl group, optionally C ₁ ~ C₃Alkyl group, C₁~ C₃Alkoxy group, nitro group, cyano group, hydroxy group
Is a phenyl group substituted by].

Examples of C ₁ -C ₄ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl and t-butyl groups. Examples of C ₅ -C ₆ cycloalkyl groups are cyclopentyl and cyclohexyl groups. Examples of optionally substituted phenyl groups include phenyl, 4-methylphenyl,
2,4-dimethoxyphenyl group, 4-methoxyphenyl group, 4-nitrophenyl group, 3-chlorophenyl group, 4-hydroxyphenyl group, 3,5-dimethoxy-
There are a 4-hydroxyphenyl group, a 3-cyanophenyl group, a 2-hydroxyphenyl group and a 2-carboxyphenyl group.

Examples of the aralkyl group include a benzyl group and a phenethyl group. Q is preferably nitrate. The groups R _{1 to} R ₃ are preferably hydrogen or alkyl groups. R ₄ is preferably an alkyl group interrupted by an oxygen atom such as a polyoxyethylene group, or a residue of a saturated or unsaturated fatty acid. R ₅ is preferably methyl group, i-butyl group, n-hexyl group, benzyl group, p
-Nitrobenzyl group, 4-acetyloxybenzyl group, 4-methylaminocarbonyloxybenzyl group, 4-methoxycarbonyloxybenzyl group. R ₆ and R ₇ are preferably hydrogen, methyl group, t-butyl group or isopropyl group.

R _c , R _d , R _e and R _f of the group of formula (D) are preferably hydrogen or a methyl group, and most preferably at least one of R _c and R _f is a methyl group. Z is preferably an ethylene group, a 1,2-cyclohexenyl group or a 3,4-butenyl group. T and Y are preferably oxygen atoms, and R ₁₃ is preferably a C ₁ -C ₄ alkyl group or a phenyl group.

The compound represented by the formula (I) has the formula (II) NH ₂ — (CH ₂ ) _n —A— (CH ₂ ) _m —NH ₂ (II) An intermediate represented by the formula (III
)

[0041]

[Chemical 15]

(Wherein X has the above-mentioned meaning and (O) DMF is a dimethylformamide molecule coordinated to a platinum atom) and a platinum complex represented by the following formula: , U.S. Pat. No. 5,749,497, by reacting under similar conditions.

The compound represented by the formula (III) is obtained by reacting a complex of the formula trans-Pt (NH ₃ ) ₂ X ₂ (where X has the above-mentioned meaning) in dimethylformamide with the presence of an equimolar amount of silver nitrate. By reacting below, it can manufacture in situ. Usually, the obtained complex represented by the formula (III) is not recovered but directly reacted with the compound represented by the formula (II).

[0044]   The compound of formula (II) is prepared from the corresponding polyamine in which R is hydrogen by   The mino group is selectively protected, and then a suitable R-G group (where R has the meaning given above).   G is a suitable reactive group such as a halogen atom, 4-nitrophenyl group, mesyl   A leaving group such as a group, a tosyl group or an activated carbonyl group)   It can be produced by functionalizing the amino group.

The protecting group for the primary amino group is of course stable under the reaction conditions used for the functionalization of the secondary amino group, and at the same time is selected such that it is cleaved under selected conditions without removing the group R. To be done. For example, when the group R is base sensitive, applicable protecting groups are t-butoxycarbonyl groups or benzylidene derivatives which can be removed by treatment under mildly acidic conditions. On the other hand, when the group R is sensitive to both acids and bases, suitable protecting groups are phthalimide or bromocarbobutyloxycarbonyl groups, which can be removed under neutral conditions, or other groups. Finally, when the group R is acid sensitive, a suitable protecting group is a trifluoroacetyl group or a similar acyl derivative which can be removed by basic hydrolysis.

An example of a synthetic reaction for producing the intermediate amine represented by the formula (II) is as follows. Indicated by. Reaction formula 1:

[0047]

[Chemical 16]

A compound of formula (IV) (wherein Z ′ is a protecting group) is replaced by a compound of formula (V) wherein Z ′ has the meaning given above, Hal is a halogen atom, or mesylate or tosylate, Sulfonic acid ester).

On the other hand, the compound of formula (II) (wherein A is a —B— (CH ₂ ) _r —B— group) can be prepared, for example, according to the following reaction scheme 2:

[0050]

[Chemical 17]

It can be produced by reacting a diamine (VI) with a compound of the above formula (V).

Suitable reaction conditions for introducing the R groups of the above formulas are described, for example, in the following references: For groups 4) and 5) J. Med chem., 27,713-717, 1984; chem., phar
m, Bull.32.2241-2248. For group 6), j. Med. Chem. 31, 318-322, 1988. Regarding Group 7), Synthesis 9. 824-827, 1987. For group 10), see J. Org. Chem. 41, 2029-2031, 1976; Chem. Pharm. Bu.
ll. 32, 2241-2248; Cancer Chemotherapy Rep 59, 679-683. For the group 11), see J. Am. Chem. Soc. 9175-9182, 1972; J. Org. Chem. 5
4, 3303-3310, 1989; Chem. Pharm. Bull. 47, 90-95, 1999. For base 12), see Nucleic Acid Res, Vol. 22, Issue 15, 3119-3123, 19
94. For group 13), PCT / US97 / 03640.

A compound of formula (I) prepared as described above may optionally further be subjected to saltification, separation of enantiomers when at least one asymmetric center is present, according to conventional methods, Conversion of the R group to another group R takes place.

The intermediates of formula (II) are new and are therefore another object of the invention. The compounds of the present invention can be treated with cis-platinum or when administered to humans or animals with tumors resistant to cis-platinum at doses of 0.1 mg to 1.2 mg / m ² body surface. , Can induce the regression of such tumors.

More generally, the compounds of the invention can be used to treat the similar pathological conditions in which cisplatin is used. This may be tumor treatment, radiation sensitization or enhancement
[Douple et al., Cis-platin Current Status and Developments, And. AW Presta
Ngle et al., Academic Press, 125 (1980); Douple et al., Platinum Metals Res., 29; 1
18 (1985)], and the treatment of parasitic diseases such as African sleeping sickness [Farrell et al., Biochem.
Pharmacol., 33, 961 (1984)]. Accordingly, another object of this invention is a pharmaceutical composition containing a therapeutically effective amount of at least one compound of formula (I) in admixture with conventional carriers and excipients.

The effective dose of the compound of the present invention is determined by a specialized clinician according to a conventional method.
Dosages used for animals of various species and sizes and for humans (mg
/ Body surface m ² ) is the relationship with Freireth et al .: Quantitative Comparison of To
xicity of Anticancer Agents in Mouse, Rat, Hamster, Dog, Monkey and Man,
Cancer Chemother. Rep., 50. N. 4, 219-244 (1986). However, patients are admitted with a dose regimen of 0.
A complex dose of 1-200 mg / kg body weight will be received. The treatment regimen may be modified as is well known to specialist clinicians depending on the type of tumor to be treated and the condition of the patient.

The compounds of the present invention can be administered by parenteral or oral routes. Pharmaceutical compositions for parenteral administration include sterile saline, or sterile powders for solution extemporaneous formulations, as well as oily formulations for intramuscular (im) or intraperitoneal (ip) administration, described below.

The compounds of the present invention optionally contain sodium chloride in a suitable concentration (0.1-0.
It is preferably administered as a sterilized aqueous solution containing 9%). This solution is preferably administered by the intravenous (iv) or intraarterial (ia) route, although other modes of administration are possible in special cases.

Pharmaceutical compositions useful for oral administration include, for example, syrup or similar liquid forms and solid forms such as tablets, capsules and the like.

The pharmaceutical composition of the present invention is described in Remington's Pharmaceutical Sciences Handbook, XV
Manufactured by conventional methods as described in Edition II, Ed., Mack Pub., NY, USA.

Sometimes the platinum complexes of the invention are administered in combination with one or more agents that either enhance antitumor activity or reduce the undesired side effects that may be associated with treatment with the platinum complex. Is advantageous. For example, the platinum complexes of the present invention are disclosed in British Patent 2,174,905 and US Patent 4,871,528.
Can be co-administered with reduced glutathione as disclosed in US Pat.

Furthermore, the platinum complexes of the invention can be advantageously administered in combination with other platinum complexes having antitumor activity. Therefore, a further object of the present invention is a pharmaceutical composition containing at least one compound of formula (I) in combination with a platinum complex having antitumor activity.

A further object of the present invention is the manufacture of a pharmaceutical composition for treating a mammal having a tumor that can be treated with cis-platinum or is resistant to cis-platinum. ) Is used.

[0064]   The invention is explained in more detail by the following examples.

Examples Production Example 1 1,12-Bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (methoxycarbonyl) dodecane 1,12 in dry THF (12 mol) at room temperature - bis (trifluoroacetamido) -4,9-Jiazadodekan [N ^1, N ¹² - bis - trifluoroacetyl spermine] (0.544g, 1.379mmol) to a solution containing K ₂ CO ₃ (0.4
20 g, 3.03 mmol) are added. After that, methyl chloroformate (0.34
ml, 4.4 mmol) is carefully poured into it. The reaction is slightly exothermic. After about 5 hours, TLC (CH ₂ Cl ₂ / MeOH / NH ₄ OH = 9: 1: 0.4, r
f = 0.8) reveals the completion of the reaction.

This mixture was poured into H ₂ O (15 ml) and t-butyl methyl ether (3 × 3
0 ml). The extracts are combined, washed with saturated NaCl, dried over Na ₂ SO ₄ and concentrated under vacuum to give 650 mg (97% yield).

¹ H-NMR (DMSO-d ₆ ): 1.4 (bs, 4H), 1.7 (g, 4H)
, 3.15 (m, 12H), 3.6 (s, 6H), 9.35 (bt, 2H, N H COCF 3).

Production Example 2 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-
Bis (n-hexyloxycarbonyl) dodecane in dry CH ₂ Cl ₂ (18 ml) 1,12-bis (trifluoroacetamido) -4,9-diazadodecane- [N ¹ , N ¹² -bis-trifluoroacetylspermine ] (0.789 g, 2 mmol) was cooled to 5 ° C., triethylamine (TEA: 0.3 ml, 2.2 mmol) was added, then CH ₂ Cl ₂ 1.
N-Hexyl chloroformate (0.36 ml, 2.2 mmol) dissolved in 5 ml is added. The white suspension obtained is stirred overnight until the starting product is completely burned out. (TLC: CH ₂ Cl ₂ / MeOH / NH ₄ OH = 9: 1: 0.4, r = 0
． 9). The mixture is poured into water (40 ml) and extracted with CH ₂ Cl ₂ (2 x 50 ml). The combined extracts are washed with water, dried over Na ₂ SO ₄ and concentrated under vacuum to give 585 mg (45% yield) of a clear oil which tends to solidify.

¹ H-NMR (DMSO-d ₆ ): 0.85 (bt, 6H), 1.25 (bs,
12H), 1.4 (bs, 4H), 1.5 (bq, 4H), 1.7 (bq, 4H)
), 3.15 (m, 12H) , 4.0 (t, 4H), 9.4 (m, 2H, N H C
OCF ₃ ).

Production Example 3 1,8-Bis (trifluoroacetylamino) -4-aza-4 (p-nitrobenzyloxycarbonyl) octane 1,8-Bis (trifluoroacetamido) -4 in dry THF (20 ml) −
A solution containing azaoctane (0.5 g, 1.48 mmol) was added with K ₂ CO ₃ (0.225
g, 1.63 mol), then 4-nitrobenzyl chloroformate (0.362 g, 1.63 mmol) dissolved in 3 ml of THF is added dropwise keeping the temperature at 25 ° C. The reaction is completed after 2 hours (TLC: CHCl ₃ / MeOH = 8: 2).
, Rf = 0.5). The mixture is concentrated under vacuum to a small volume, 20 ml of water
Dissolve in and extract with AcOEt (2 x 20 ml). The combined extracts are washed first with water, then with saturated NaCl, dried over Na ₂ SO ₄ and concentrated under vacuum to give 0.72 g (94%) of a clear oil.

¹ H-NMR (DMSO-d ₆ ): 1.5 (bs, 4H), 1.75 (m, 2H
), 3.25 (bq, 8H), 5.2 (s, 2H), 7.6 (d, 2H), 8.
25 (d, 2H), 9.4 (m, 2H, N H COCF 3).

Production Example 4 1,8-Bis (trifluoroacetylamino) -4-aza-4- (benzyloxycarbonyl) octane 1,8-bis (trifluoroacetamido) -4-in dry THF (20 ml)
To a solution containing azaoctane (0.5 g, 1.48 ml), K ₂ CO ₃ (0.225 g,
1.63 mmol) is added, and then benzyl chloroformate (0.24 g, 1.63 mmol) dissolved in 3 ml of THF is added dropwise thereto while keeping the temperature at 25 ° C. The reaction is slightly exothermic (temperature rises from 20 ° C to 25 ° C). 1
After a lapse of time, the reaction is completed (TLC: CHCl ₃ / MeOH = 8: 2, rf = 0.
5). The mixture is concentrated under vacuum to a small volume, dissolved in 20 ml of water,
Extract with cOEt (2 x 50 ml). The combined extracts were washed first with water, then with saturated NaCl, dried over Na ₂ SO ₄ and concentrated under vacuum,
0.74 g (96%) of a clear oil is obtained. The product is purified by column chromatography (SiO ₂ , 230 mesh, eluent CHCl ₃ / MeOH = 9: 1) to give 0.58 g of pure clear oil by TLC.

¹ H-NMR (DMSO-d ₆ ): 1.4 (bs, 4H), 1.75 (m, 2H
), 3.25 (m, 8H), 5.0 (s, 2H), 7.25 to 7.5 (m, 5H)
, Ph), 9.4 (m, 2H, N H COCF 3).

Preparative Example 5 1,8-Bis (trifluoroacetylamino) -4-aza-4- (p-nitrobenzenesulfonyl) octane 1,8-bis (trifluoroacetamido) -4-in dry THF (10 ml)
To a solution containing azaoctane (0.5 g, 1.48 ml), K ₂ CO ₃ (0.225 g,
1.63 mmol), then p-nitrobenzenesulfonyl chloride (0.4 g, 1.63 mm) dissolved in 3 ml THF, keeping the temperature at 25 ° C.
ol) is dropped therein. The reaction is complete after 3 hours (TLC: CHCl ₃ /
MeOH = 8: 2, rf = 0.7). The mixture is concentrated under vacuum to a small volume, dissolved in 20 ml of water and extracted with AcOEt (2 x 50 ml). The combined extracts are washed first with water, then with saturated NaCl, dried over Na ₂ SO ₄ and concentrated under vacuum to give 0.8 g of a clear oil which tends to solidify. Et ₂ O
Crystallization yields 0.435 (56%) of a white solid, mp 109-111 ° C.

¹ H-NMR (DMSO-d ₆ ): 1.5 (bs, 4H), 1.75 (q, 2H
), 3.15 (bt, 8H), 8.05 (d, 2H), 8.4 (d, 2H), 9
． 4 (m, 2H, N H COCF 3).

Production Example 6 1,8-Bis (trifluoroacetylamino) -4-aza-4-oleyloctane 1,8-bis (trifluoroacetamido) -4-in dry THF (20 ml)
Azaokutan (0.5g, was added K ₂ CO ₃ containing 1.48 mmol (0.225 g
, 1.63 mmol), then 3 ml of THF, keeping the temperature at 25 ° C.
Oleyl chloride (0.495 g, 1.63 mmol) dissolved in was added dropwise therein. The reaction is completed after one night (TLC: CHCl ₃ / MeOH = 8: 2,
rf = 0.9). The mixture was poured into 50 ml of water and AcOEt (2 x 20 ml).
Extract with. The combined extracts were washed first with water, then with saturated NaCl,
Dry over a ₂ SO ₄ and concentrate under vacuum. The oily product obtained is chromatographed (SiO ₂ , 230 mesh, eluent CHCl ₃ / MeOH = 9: 1),
TLC gives 0.41 g (46%) of pure clear oil.

Production Example 7 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-
Bis (i-butyloxycarbonyl) dodecane 1,12-bis (trifluoroacetamido) -4 in dry THF (35 ml)
, 9-diazadodecane [N ¹ , N ¹² -bis-trifluoroacetylspermine]
(1 g, 2.5 mmol) in a solution at 25 ° C. containing triethylamine (TEA: 0.
35 ml, 5 mmol), then dissolved in chloroform 5 ml THF i-.
Butyl (0.76 g, 5.6 mmol) is added. The resulting white suspension is stirred overnight until complete disappearance of the starting product (TLC: CH ₂ Cl ₂ / MeOH /
_{NH 4 OH = 9: 1:} 0.4, rf = 0.9). The mixture is poured into water (80 ml) and extracted with CH ₂ Cl ₂ (3 x 50 ml). Wash the combined extracts with water,
Dry over Na ₂ SO ₄ and concentrate under vacuum to give 1.4 g of a clear extract (95% yield).
) Get.

¹ H-NMR (DMSO-d ₆ ): 0.85 (d, 12H), 1.4 (bs, 4)
H, 1.7 (bt, 4H) , 1.8 (m, 2H, C H - (CH 3) 2), 3.15
(M, 12H), 3.75 ( d, 4H, C H 2 -O), 9.4 (m, 2H, N H
COCF ₃ ).

Preparation 8 Starting from the corresponding α, ω-bis (trifluoroacetylamino) -n (, m)-(bis) azaalkane by a method similar to that described in Preparations 1-9,
The following compounds are produced:

1,16-bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (methoxycarbonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (methoxycarbonyl) hexadecane, 1,8-bis (trifluoroacetylamino) -3,6-diaza-3,6-bis (methoxycarbonyl) octane, 1,16-bis (trifluoroacetylamino) -8 -Aza-8-methoxycarbonylhexadecane, 1,13-bis (trifluoroacetylamino) -7-aza-7-methoxycarbonyltridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5 Methoxycarbonylundecane, 1,8-bis (trifluoroacetylamino) -3-aza-3-methoxycarbonyloxane, 1,8-bis (trifluoroacetylamino) -4-aza-4-methoxycarbonyloctane, 1, 5-bis (trifluoroacetylamino) -3-aza-3-methoxycarbo Nylpentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (n-hexyloxycarbonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (n-hexyloxycarbonyl) hexadecane, 1,8-bis (trifluoroacetylamino) -3,6-diaza-3,6-bis (n-hexyloxycarbonyl) octane, 1,16-bis (tri Fluoroacetylamino) -8-aza-8- (n-hexyloxycarbonyl) hexadecane, 1,13-bis (trifluoroacetylamino) -7-aza-7- (n-hexyloxycarbonyl) tridecane, 1,11 -Bis (trifluoroacetylamino) -5-aza-5- (n-hexyloxycarbonyl) undecane, 1,8-bis (trifluoroacetylamino) -3-aza-3- (n-hexyloxycarbonyl) octane , 1,8-bis (trifluoroacetylamino) -4-aza-4- (n-hexyloxycal Nyl) octane, 1,5-bis (trifluoroacetylamino) -3-aza-3- (n-hexyloxycarbonyl) pentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza-6 , 11
-Bis (p-nitrobenzyloxycarbonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (p-nitrobenzyloxycarbonylaza) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (p-nitrobenzyloxycarbonyl) dodecane, 1,8- Bis (trifluoroacetylamino) -3,6-diaza-3,6-bis (p-nitrobenzyloxycarbonyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8- (p- Nitrobenzyloxycarbonyl) hexadecane, 1,13-bis (trifluoroacetylamino) -7-aza-7- (p-nitrobenzyloxycarbonyl) tridecane, 1,11-bis (trifluoroacetylamino) -5-aza -5- (p-nitrobenzyloxycarbonyl) undecane, 1,8-bis (trifluoro Cetylamino) -3-aza-3- (p-nitrobenzyloxycarbonyl) octane, 1,5-bis (trifluoroacetylamino) -3-aza-3- (p-nitrobenzyloxycarbonyl) pentane, 1,16 -Bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (p-nitrobenzenesulfonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (p-nitrobenzenesulfonyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (p-nitrobenzenesulfonyl) dodecane, 1,8-bis (trifluoroacetyl) Amino) -3,6-diaza-3,6-bis (p-nitrobenzenesulfonyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8- (p-nitrobenzenesulfonyl) hexadecane, 1, 13-bis (trifluoroacetylamino) -7-aza-7- (p-nitrobenzenesulfonyl) tridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5- (p-nitrobenzenesulfonyl) undecane, 1,8-bis (trifluoroacetylamino) -3-aza-3- (p-ni) Robenzenesulfonyl) octane, 1,5-bis (trifluoroacetylamino) -3-aza-3- (p-nitrobenzenesulfonyl) pentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza- 6,11
-Bis (benzyloxycarbonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (benzyloxycarbonyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (benzyloxycarbonyl) dodecane, 1,8-bis (trifluoroacetylamino) -3,6-Diaza-3,6-bis (benzyloxycarbonyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8-benzyloxycarbonylhexadecane, 1,13-bis (trifluoro) Acetylamino) -7-aza-7-benzyloxycarbonyltridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5-benzyloxycarbonylundecane, 1,8-bis (trifluoroacetylamino) -3-aza-3-benzyloxycarbonyl octane, 1,5-bi Sus (trifluoroacetylamino) -3-aza-3-benzyloxycarbonylpentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (p-nitrobenzenesulfonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (p-nitrobenzenesulfonyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (p-nitrobenzenesulfonyl) dodecane, 1,8-bis (trifluoroacetyl) Amino) -3,6-diaza-3,6-bis (p-nitrobenzenesulfonyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8- (p-nitrobenzenesulfonyl) hexadecane, 1, 13-bis (trifluoroacetylamino) -7-aza-7- (p-nitrobenzenesulfonyl) tridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5- (p-nitrobenzenesulfonyl) undecane, 1,8-bis (trifluoroacetylamino) -3-aza-3- (p-ni) Robenzenesulfonyl) octane, 1,5-bis (trifluoroacetylamino) -3-aza-3- (p-nitrobenzenesulfonyl) pentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza- 6,11
-Bis (i-butyloxycarbonyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (i-butyloxycarbonyl) hexadecane, 1,8-bis (trifluoroacetylamino) -3,6-diaza-3,6-bis (i-butyloxycarbonyl) octane, 1,16-bis (tri Fluoroacetylamino) -8-aza-8- (i-butyloxycarbonyl) hexadecane, 1,13-bis (trifluoroacetylamino) -7-aza-7- (i-butyloxycarbonyl) tridecane, 1,11 -Bis (trifluoroacetylamino) -5-aza-5- (i-butyloxycarbonyl) undecane, 1,8-bis (trifluoroacetylamino) -3-aza-3- (i-butyloxycarbonyl) octane 1,8-bis (trifluoroacetylamino) -4-aza-4- (i-butyloxycarbonyl) octane, 1,5-bis (trifluoroacetylamino) -3-aza-3- (i-butyloxycarbonyl) pentane, 1,16-bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (α- [1,4,7,10-Tetraoxaundecanyl] acetyl) dodecane, 1,8-bis (trifluoroacetylamino) -4-aza-4- (α- [1,4
, 7,10-Tetraoxaundecanyl] acetyl) octane, 1,16-bis (trifluoroacetylamino) -6,11-diaza-6,11
-Bis (oleyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (oleyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (oleyl) dodecane, 1,8-bis (trifluoroacetylamino) -3,6 -Diaza-3,6-bis (oleyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8-oleylhexadecane, 1,13-bis (trifluoroacetylamino) -7-aza- 7-oleyltridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5-oleylundecane, 1,8-bis (trifluoroacetylamino) -3-aza-3-oleyloctane, 1, 5-bis (trifluoroacetylamino) -3-aza-3-oleylpentane, 1,16-bis (trifluoroacetylamino) 6,11-diaza -6,11
-Bis (stearyl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (stearyl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (stearyl) dodecane, 1,8-bis (trifluoroacetylamino) -3,6 -Diaza-3,6-bis (stearyl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8-stearylhexadecane, 1,13-bis (trifluoroacetylamino) -7-aza- 7-stearyl tridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5-stearyl undecane, 1,8-bis (trifluoroacetylamino) -3-aza-3-stearyl octane, 1, 5-bis (trifluoroacetylamino) -3-aza-3-stearylpentane, 1,16-bis (trifluoro Sechiruamino) -6,11-diaza -6,11
-Bis (palmityl) hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (palmityl) hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (palmityl) dodecane, 1,8-bis (trifluoroacetylamino) -3,6 -Diaza-3,6-bis (palmityl) octane, 1,16-bis (trifluoroacetylamino) -8-aza-8-palmitylhexadecane, 1,13-bis (trifluoroacetylamino) -7-aza -7-palmityl tridecane, 1,11-bis (trifluoroacetylamino) -5-aza-5-palmitylundecane, 1,8-bis (trifluoroacetylamino) -3-aza-3-palmityl Octane, 1,5-bis (trifluoroacetylamino) -3-aza-3-palmitylpentane, 1,16-bis (trifluoro Sechiruamino) -6,11-diaza -6,11
-Bis (α-1- [1,4,7,10-tetraoxaundecanyl] acetyl)
Hexadecane, 1,16-bis (trifluoroacetylamino) -7,10-diaza-7,10
-Bis (α-1- [1,4,7,10-tetraoxaundecanyl] acetyl)
Hexadecane, 1,12-bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (α-1- [1,4,7,10-tetraoxaundecanyl] acetyl) dodecane, 1 , 8-Bis (trifluoroacetylamino) -4-aza-4- (α- [1,4
, 7,10-Tetraoxaundecanyl] acetyl) octane.

Production Example 9 1,12-Diamino-4,9-diaza-4,9-bis (methoxycarbonyl)
Dodecane 0.2 N NaOH (14.5 ml, 2.2 mmol) was added to 1,12-bis (
Trifluoroacetylamino) -4,9-diaza-4,9-bis (methoxycarbonyl) dodecane (0.64 g, 1.315 mmol) was added dropwise to a methanol solution (15 ml) cooled to 10 ° C over 30 minutes. The mixture is stirred overnight at 25 ° C. then concentrated under vacuum to remove MeOH. The aqueous phase is CHCl ₃ / Me
Extract with OH (20: 1, 3 × 30 ml), dry the combined extracts over Na ₂ SO ₄ and concentrate to dryness under vacuum to give 0.403 g (96%) of a clear oil. .

¹ H-NMR (D ₂ O): 1.35 (bs, 4H), 1.5 (q, 4H), 2.
4 (t, 4H), 3.15 (m, 8H), 3.55 (s, 6H).

Production Example 10 1,12-Diamino-4,9-diaza-4,9-bis (n-hexyloxycarbonyl) dodecane 0.2N NaOH (9.9 ml, 2.2 mmol) was added to 1,12- 30 minutes in a methanol solution (15 ml) containing bis (trifluoroacetylamino) -4,9-diaza-4,9-bis (n-hexyloxycarbonyl) dodecane (0.584 g, 0.897 mmol) cooled to 10 ° C. Drop by. This mixture at 25 ° C
Stir overnight at rt and then concentrate under vacuum to remove MeOH. Then the aqueous phase is CH
Extraction with Cl ₃ / MeOH (20: 1, 3 × 10 ml) and drying of the combined extracts over Na ₂ SO ₄ and concentration under vacuum to dryness gave a clear oil.
39 g (95%) are obtained.

¹ H-NMR (DMSO-d ₆ ): 0.85 (t, 6H), 1.25 (bs, 1)
2H), 1.4 to 1.6 (m, 12H, +2 NH ₂ ), 2.5 (bt, 4H)
3.15 (bq, 8H), 3.95 (t, 4H).

Production Example 11 1,8-Diamino-4-aza-4- (p-nitrobenzyloxycarbonyl)
Octane 1,8-bis (trifluoroacetylamino) -4-aza-4- (p-nitrobenzyloxycarbonyl) octane (0.7 g, 1.35 mmol) was added to MeO.
Dissolve in H (15 ml) and cool the solution to 0 ° C. 0.2N NaOH (1
5 ml, 2.98 mmol) is added dropwise in 30 minutes and then left overnight to raise the temperature. Most of the MeOH was removed under vacuum, then the aqueous phase was washed with CHCl ₃ / MeOH (
20: 1, 3 × 15 ml). The combined extracts are dried over Na ₂ SO ₄ and concentrated under vacuum to dryness. Column chromatography (SiO ₂ , 23
0 mesh, eluent CHCl ₃ / MeOH / NH ₄ OH = 45: 50: 5) gives 0.28 g (64%) of colorless oil.

¹ H-NMR (DMSO-d6 + D ₂₀ ): 1.25 (m, 2H), 1.5 (m
4H), 2.4 (m, 4H), 3.25 (m, 4H), 5.15 (s, 2H).
, 7.6 (d, 2H), 8.25 (d, 2H).

Production Example 12 1,8 Diamino-4-aza-4-benzyloxycarbonyloctane 1,8-bis (trifluoroacetylamino) -4-aza-4- (benzyloxycarbonyl) octane (0.58 g, 1.23 mmol) in MeOH (13
． 5 ml) and the solution is cooled to 0 ° C. 0.2N NaOH (13.
5 ml, l. 27 mmol) in 30 minutes and then left overnight to raise the temperature. Most of the MeOH was distilled off under reduced pressure, then the aqueous phase was washed with CHCl ₃ / MeOH
Extract with (20: 1, 3 × 50 ml). The combined extracts were dried over Na ₂ SO ₄ and concentrated under vacuum to dryness, yielding 0.27 g (79%) of a pale yellow oil.
%).

¹ H-NMR (DMSO-d ₆ ): 1.25 (bq, 2H), 1.5 (m, 2H
), 2.5 (m, 4H), 5.05 (s, 2H), 7.25 to 7.5 (m, 5H)
, Ph).

Production Example 13 1,8 Diamino-4-aza-4- (p-nitrobenzenesulfonyl) octane 1,8-bis (trifluoroacetylamino) -4-aza-4- (p-nitrobenzenesulfonyl) octane ( 0.451 g, 0.8 mmol) in MeOH (
9 ml) and the solution is cooled to 0 ° C. 0.2N NaOH (8.8m
1, 1.77 mmol) in 30 minutes and then left overnight to raise the temperature. M
The OH was concentrated under reduced pressure, then the aqueous phase was washed with CHCl ₃ / MeOH (20: 1, 2 ×).
20 ml). The combined extracts are dried over Na ₂ SO ₄ and concentrated under vacuum to dryness to give 0.24 g (90%) of an oil.

¹ H-NMR (DMSO-d ₆ ): 1.25 (q, 2H), 1.5 (m, 4H)
, 2.5 (m, 4H + 2NH ₂ ), 3.15 (m, 4H), 8.05 (d, 2H
), 8.4 (d, 2H).

Production Example 14 1,8 Diamino-4-aza-4-oleyloctane 1,8-bis (trifluoroacetylamino) -4-aza-4-oleyloctane (0.40 g, 0.68 mmol) in MeOH Dissolve in (15 ml) and cool the solution to 0 ° C. 0.2 N NaOH (15 ml, 1.49 mmol) is added dropwise in 30 minutes and then left overnight to raise the temperature. Most of ^- MeOH was removed under reduced pressure, then the aqueous phase CHCl ₃ / MeOH: extract with (20 1,10 × 20ml). The combined extracts are dried over Na ₂ SO ₄ and concentrated under vacuum to dryness to give 0.25 g (89%) of product as an oil.

Production Example 15 1,12-Diamino-4,9-diaza-4,9-bis- (i-butyloxycarbonyl) dodecane 0.2N NaOH (27 ml, 5.35 mmol) was added to 1,12-bis (. Trifluoroacetylamino) -4,9-diaza-4,9-bis (i-butyloxycarbonyl) dodecane (1.45 g, 2.43 mmol) was added dropwise to a methanol solution (45 ml) cooled to 10 ° C over 30 minutes. To do. After stirring overnight at 25 ° C., the mixture is concentrated under vacuum to remove MeOH. The aqueous phase is then added to CHCl ₃ / M
Extraction with MeOH (20: 1, 3 × 10 ml) and drying of the combined extracts over Na ₂ SO ₄ and concentration under vacuum to dryness gave 1 g (99%) of product as a clear oil. It is obtained as a thing.

¹ H-NMR (DMSO-d ₆ ): 0.9 (d, 12H), 1.35 to 1.6 (
_{m, 8H + 2NH 2),} 1.85 (m, 2H, CH- (CH 3) 2), 3.2 (m
, 8H), 3.75 (d, 4H, C H 2 O).

Preparation 16 The following compounds are prepared by a method similar to that described in Preparations 10 to 15, starting from the appropriate bistrifluoroacetamide described in Preparation 9.

1,16-diamino-6,11-diaza-6,11-bis (methoxycarbonyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (methoxycarbonyl) hexadecane, 1 , 8-diamino-3,6-diaza-3,6-bis (methoxycarbonyl) octane, 1,16-diamino-8-aza-8-methoxycarbonylhexadecane, 1,13-diamino-7-aza-7- Methoxycarbonyltridecane, 1,11-diamino-5-aza-5-methoxycarbonylundecane, 1,8-diamino-3-aza-3-methoxycarbonyloctane, 1,8-diamino-4-aza-4-methoxy Carbonyl octane, 1,5-diamino-3-aza-3-methoxycarbonylpentane, 1,16-diamino- 6,11-diaza-6,11-bis (n-hexyloxycarbonyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (n-hexyloxycarbonyl) hexadecane, 1,8- Diamino-3,6-diaza-3,6-bis (n-hexyloxycarbonyl) octane, 1,16-diamino-8-aza-8- (n-hexyloxycarbonyl) hexadecane, 1,13-diamino-7 -Aza-7- (n-hexyloxycarbonyl) tridecane, 1,11-diamino-5-aza-5- (n-hexyloxycarbonyl) undecane, 1,8-diamino-3-aza-3- (n- Hexyloxycarbonyl) octane, 1,8-diamino-4-aza-4- (n-hexyloxycarbonyl) octane, 1,5-dia No-3-aza-3- (n-hexyloxycarbonyl) pentane, 1,16-diamino-6,11-diaza-6,11-bis (p-nitrobenzyloxycarbonyl) hexadecane, 1,16-diamino- 7,10-diaza-7,10-bis (p-nitrobenzyloxycarbonyl) hexadecane, 1,12-diamino-4,9-diaza-4,9-bis (p-nitrobenzyloxycarbonyl) dodecane, 1, 8-diamino-3,6-diaza-3,6-bis (p-nitrobenzyloxycarbonyl) octane 1,16-diamino-8-aza-8- (p-nitrobenzyloxycarbonyl) hexadecane 1,13 -Diamino-7-aza-7- (p-nitrobenzyloxycarbonyl) tridecane, 1,11-diamino-5-aza-5 (P- nitrobenzyloxycarbonyl) undecane, 1,8-diamino-3-aza-3- (p- nitrobenzyloxycarbonyl)
Octane, 1,5-diamino-3-aza-3- (p-nitrobenzyloxycarbonyl)
Pentane, 1,16-diamino-6,11-diaza-6,11-bis (benzyloxycarbonyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (benzyloxycarbonyl) hexadecane, 1,12-diamino-4,9-diaza-4,9-bis (benzyloxycarbonyl) dodecane, 1,8-diamino-3,6-diaza-3,6-bis (benzyloxycarbonyl) octane, 1, 16-diamino-8-aza-8-benzyloxycarbonylhexadecane, 1,13-diamino-7-aza-7-benzyloxycarbonyltridecane, 1,11-diamino-5-aza-5-benzyloxycarbonylundecane, 1,8-diamino-3-aza-3-benzyloxycarbonyloctane, 1,5-diami -3-Aza-3-benzyloxycarbonylpentane, 1,16-diamino-6,11-diaza-6,11-bis (p-nitrobenzenesulfonyl) hexadecane, 1,16-diamino-7,10-diaza-7 , 10-bis (p-nitrobenzenesulfonyl) hexadecane, 1,12-diamino-4,9-diaza-4,9-bis (p-nitrobenzenesulfonyl) dodecane, 1,9-diamino-3,6-diaza-3 , 6-bis (p-nitrobenzenesulfonyl) octane, 1,16-diamino-8-aza-8- (p-nitrobenzenesulfonyl) hexadecane, 1,13-diamino-7-aza-7- (p-nitrobenzenesulfonyl) Tridecane, 1,11-diamino-5-aza-5- (p-nitrobenzenesulfonyl) undecane, 1,8-Diamino-3-aza-3- (p-nitrobenzenesulfonyl) octane, 1,5-diamino-3-aza-3- (p-nitrobenzenesulfonyl) pentane, 1,16-diamino-6,11- Diaza-6,11-bis (oleyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (oleyl) hexadecane, 1,12-diamino-4,9-diaza-4,9- Bis (oleyl) dodecane, 1,8-diamino-3,6-diaza-3,6-bis (oleyl) octane, 1,16-diamino-8-aza-8-oleylhexadecane, 1,13-diamino-7 -Aza-7-oleyltridecane, 1,11-diamino-5-aza-5-oleylundecane, 1,8-diamino-3-aza-3-oleyloctane, 1, 5-diamino-3-aza-3-oleylpentane, 1,16-diamino-6,11-diaza-6,11-bis (i-butyloxycarbonyl) hexadecane, 1,16-diamino-7,10-diaza -7,10-bis (i-butyloxycarbonyl) hexadecane, 1,8-diamino-3,6-diaza-3,6-bis (i-butyloxycarbonyl) octane, 1,16-diamino-8-aza -8- (i-Butyloxycarbonyl) hexadecane, 1,13-diamino-7-aza-7- (i-butyloxycarbonyl) tridecane, 1,11-diamino-5-aza-5- (i-butyloxy) Carbonyl) undecane, 1,8-diamino-3-aza-3- (i-butyloxycarbonyl) octane, 1,8-diamino-4-aza-4- ( -Butyloxycarbonyl) octane, 1,5-diamino-3-aza-3- (i-butyloxycarbonyl) pentane, 1,16-diamino-6,11-diaza-6,11-bis (α-1-) [1,4
, 7,10-Tetraoxaundecanyl] acetyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (α-1- [1,4
, 7,10-Tetraoxaundecanyl] acetyl) hexadecane, 1,12-diamino-4,9-diaza-4,6-bis (α-1- [1,4,7]
, 10-Tetraoxaundecanyl] acetyl) dodecane, 1,8-Diamino-4-aza-4- (α-1- [1,4,7,10-tetraoxaundecanyl] acetyl) octane, 1 , 16-Diamino-6,11-diaza-6,11-bis (stearyl) hexadecane, 1,16-diamino-7,10-diaza-7,10-bis (stearyl) hexadecane, 1,12-diamino-4 , 9-diaza-4,9-bis (stearyl) dodecane, 1,8-diamino-3,6-diaza-3,6-bis (stearyl) octane, 1,16-diamino-8-aza-8-stearyl Hexadecane, 1,13-Diamino-7-aza-7-stearyltridecane, 1,11-Diamino-5-aza-5-stearylundecane, 1,8-Diamino-3-aza 3-stearyloctane, 1,5-diamino-3-aza-3-stearylpentane, 1,16-diamino-6,11-diaza-6,11-bis (palmityl) hexadecane, 1,16-diamino-7, 10-diaza-7,10-bis (palmityl) hexadecane, 1,12-diamino-4,9-diaza-4,9-bis (palmityl) dodecane, 1,8-diamino-3,6-diaza-3, 6-bis (palmityl) octane, 1,16-diamino-8-aza-8-palmitylhexadecane, 1,13-diamino-7-aza-7-palmityltridecane, 1,11-diamino-5-aza -5-palmitylundecane, 1,8-diamino-3-aza-3-palmityloctane, 1,5-diamino-3-aza-3-palmitylpentane.

Example 1 Bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (methoxycarbonyl) dodecane] dinitrate trans-diamine Dichloroplatinum (II) (0.705g, 2.35mmol)
) Was dissolved in dry DMF (70 ml), then in DMF (5ml) AgNO ₃ ^- (
0.399 g, 2.35 mmol) is added, and the resulting mixture is protected from light and stirred at 20 ° C. for 20 hours. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to -20 ° C. Then 1,12-diamino-4 in 10 ml DMF
, 9-diaza-4,9-bis (methoxycarbonyl) dotecan (0.35 g, 1
． A solution containing 114 mmol) is added dropwise thereto and then (about 40 minutes), the resulting mixture is stirred at -20 ° C for 1 hour and at 25 ° C for 3 hours. It is then concentrated under vacuum to a volume of about 5 ml under vacuum and diluted with acetone (30 ml). The gray precipitate formed is stirred overnight, then filtered and dried under vacuum (2 hours at 35 ° C.,
25 ° C overnight). The solid obtained is dissolved in MeOH / H ₂ O (10: 1, 165 ml). Next, activated carbon Norit A (100 ml) was added, and the mixture was stirred for 35 minutes and then filtered off. The clear filtrate is concentrated under vacuum to a volume of about 5 ml, then M
OH (30 ml) is added and the mixture is left to crystallize for 2 hours. The precipitated solid is filtered and dried under vacuum (35 ° C. for 2 hours, 25 ° C. overnight) to give 0.6 g (55%) of the desired product.

¹ H-NMR (D ₂ O): 1.6 (bs, 4H), 1.9 (m, 4H), 2.7
5 (bt, 4H), 3.25-3.5 (m, 8H), 3.75 (s, 6H).

Example 2 Bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (n-hexyloxycarbonyl) dodecane]
Dinitrate trans-diaminedichloroplatinum (II) (0.524 g, 1.747 mmo
1) was dissolved in dry DMF (52 ml) and then AgNO ₃ (in DMF (3 ml)).
0.296 g, 1.747 mmol) is added and the resulting mixture is stirred for 20 hours at 20 ° C., protected from light. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to -18 ° C. Then 1,12-diamino-in 10 ml DMF
4,9-diaza-4,9-bis (n-hexyloxycarbonyl) dodecane (0
． A solution containing 38 g, 0.828 mmol) is added dropwise thereto, and then (about 40 minutes) the resulting mixture is stirred at -20 ° C for 1 hour and at 25 ° C for 3 hours. The pale yellow solution is then concentrated under vacuum to a volume of about 5 ml and diluted with MeOH (15 ml).
The gray precipitate formed was stirred for 2 hours, then filtered and dried under vacuum (2 ° C at 35 ° C).
Time, 25 ° C overnight). The resulting solid _{(0.49g) MeOH-H 2 O} (
2: 1, 75 ml) and heat to 35 ° C. Activated carbon Norit A (10
0 mg), then stir for 35 minutes, then filter off. The clear filtrate is concentrated under vacuum until crystallization begins and then left to crystallize at 10 ° C. for 3 hours.
The precipitated solid is filtered and dried under vacuum (2 hours at 35 ° C., overnight at 25 ° C.) to give 0.33 g (67%) of product.

Example 3 Bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-Aza-4- (benzyloxycarbonyl) octane] dinite trans-diaminedichloroplatinum (II) (0.725 g, 2.415 mmo
l) was dissolved in dry DMF (75 ml) and then AgNO _{3 in} DMF (10 ml).
A solution containing (0.410 g, 2.416 mmol) is added and the resulting mixture is protected from light and stirred at 20 ° C. for 20 hours. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to -18 ° C. Next, 1,8-diamino-4-aza-4- (
A solution of benzyloxycarbonyl) octane (0.27 g, 0.966 mmol) in DMF (10 ml) was added dropwise thereto, after which (about 40 minutes) the resulting mixture was added at -18 ° C for 1 hour at 25 ° C. Stir for 3 hours. The pale yellow solution is then concentrated under vacuum to a volume of about 3 ml and diluted with H ₂ O (15 ml). The gray precipitate formed is stirred for 3 hours, then filtered and dried under vacuum (2 hours at 35 ° C., overnight at 25 ° C.). The obtained solid (0.2 g) was added to DMF / H ₂ O (2: 1, 35 ml).
Dissolve in and heat to 35 ° C. Activated carbon Norit A (100 mg) was added,
Then stir for 35 minutes and filter off. The clear filtrate is concentrated under vacuum until crystallization begins and then left to crystallize at 10 ° C. for 3 hours. The precipitated solid was filtered and dried under vacuum (35 ° C. for 2 hours, 25 ° C. overnight) to give the product 0.
06 g are obtained.

Example 4 Bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (i-butyloxycarbonyl) dodecane] dinite Trans-diaminedichloroplatinum (II) (0.750 g, 2.5 mmol)
Was dissolved in dry DMF (78 ml), then AgNO ₃ (0 ml) in DMF (10 ml).
． 424 g, 2.5 mmol) containing solution was added and the resulting mixture was protected from light by 2
Stir for 20 hours at 0 ° C. The precipitated AgCl is filtered off and the clear yellow filtrate is cooled to -18 ° C. Next, 1,12-diamino-4,9-bis (i-butyloxycarbonyl) dodecane (0.402 g, 1 mmol) in DMF (10
ml) solution was added dropwise thereto, after which (about 40 minutes) the resulting mixture was added to -18
Stir at 1 ° C for 1 hour and at 25 ° C for 3 hours. The pale yellow solution is then concentrated under vacuum to a volume of about 3 ml and diluted with H ₂ O (15 ml). 3 gray precipitates formed
Stir for an hour, then filter and dry under vacuum (2 hours at 35 ° C., overnight at 25 ° C.) to give 0.14 g (14%) product.

Example 5 The following compounds are prepared by a method similar to that described in Examples 1 to 4, starting from the corresponding diamine:

Bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis (methoxycarbonyl) hexadecane] dinitrate, bis [trans-diamine Chloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (methoxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ -[1,8-diamino-
3,6-diaza-3,6-bis (methoxycarbonyl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8- (methoxy Carbonyl) hexadecane] dinitrate, bis [trans-diamine chloroplatinum (II)]-μ- [1,13-diamino-7-aza-7- (methoxycarbonyl) tridecane] dinitrate, bis [trans-diamine Chloroplatinum (II)]-μ- [1,11-diamino-5-aza-5- (methoxycarbonyl) undecane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,8 -Diamino-
3-aza-3- (methoxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (methoxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-aza-3- (methoxycarbonyl) pentane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis (n) -Hexyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (n-hexyloxycarbonyl) Hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
3,6-diaza-3,6-bis (n-hexyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8 -(N-hexyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,13-diamino-7-aza-7- (n-hexyloxycarbonyl) tridecane] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,11-diamino-5-aza-5- (n-hexyloxycarbonyl) undecane] dinitrate, bis [trans-diaminechloro] Platinum (II)]-μ- [1,8-diamino-
3-aza-3- (n-hexyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (n-hexyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-aza-3- (n-hexyloxycarbonyl) pentane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11- Bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7, 10-diaza-7,10-bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [ 1,12-diamino-4,9-diaza-4,9-bis (α- [1,4,7,10-tetraoxaundecanyl] acetyl) dodecane] dinitrate, bis [trans- Diamine chloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (α- [1,4,7,10-tetraundecanyl] acetyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,16- Diamino-6,11-diaza-6,11-bis (oleyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7 , 10-bis (oleyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (oleyl) dodecane] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (oleyl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis (p- Nitrobenzenesulfonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (p-nitrobenzenesulfonyl) hexadecane] di Nitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (p-nitrobenzenesulfonyl) dodecane]
Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (p-nitrobenzenesulfonyl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis (Benzoyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (benzyloxycarbonyl) hexadecane] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (benzyloxycarbonyl) dodecane] dinitrate, bis [trans -Diamine chloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (benzyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
3,6-diaza-3,6-bis (benzyloxycarbonyl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8- ( Benzyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,13-diamino-7-aza-7- (benzyloxycarbonyl) tridecane] dinite, bis [ Trans-diamine chloroplatinum (II)]-μ- [1,11-diamino-5-aza-5- (benzyloxycarbonyl) undecane] dinitrate, bis [trans-diamine chloroplatinum (II)]-μ- [1,8-diamino-
3-aza-3- (benzyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-aza-3- (benzyloxycarbonyl) pentane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis ( i-Butyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (i-butyloxycarbonyl) ) Hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
3,6-diaza-3,6-bis (i-butyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8 -(I-Butyloxycarbonyl) hexadecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,13-diamino-7-aza-7- (i-butyloxycarbonyl) tridecane] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,11-diamino-5-aza-5- (i-butyloxycarbonyl) undecane] dinitrate, bis [trans-diaminechloro] Platinum (II)]-μ- [1,8-diamino-
3-aza-3- (i-butyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
4-aza-4- (i-butyloxycarbonyl) octane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-aza-3- (i-butyloxycarbonyl) pentane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11- Bis (stearyl) hexadecane] dinite, Bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (stearyl) hexadecane] dinite , Bis [trans-diaminechloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (stearyl) dodecane] dinitrate, bis [trans-diaminechloroplatinum ( II)]-μ- [1,8-diamino-
3,6-diaza-3,6-bis (stearyl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8-stearylhexadecane] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,13-diamino-7-aza-7-stearyltridecane] dinitrate, bis [trans-diaminechloroplatinum (II)] -[Mu]-[1,11-diamino-5-aza-5-stearylundecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-[mu]-[1,8-diamino-
3-aza-3-stearyloctane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-aza-3-stearylpentane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-6,11-diaza-6,11-bis (palmityl) hexadecane] Dinitrate, bis [trans-diamine chloroplatinum (II)]-μ- [1,16-diamino-7,10-diaza-7,10-bis (palmityl) hexadecane] dinitrate, bis [trans-diamine Chloroplatinum (II)]-μ- [1,12-diamino-4,9-diaza-4,9-bis (palmityl) dodecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-
3,6-diaza-3,6-bis (palmityl) octane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,16-diamino-8-aza-8-palmitylhexadecane ] Dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,13-diamino-7-aza-7-palmityltridecane] dinitrate, bis [trans-diaminechloroplatinum (II) )]-Μ- [1,11-Diamino-5-aza-5-palmitylundecane] dinitrate, bis [trans-diaminechloroplatinum (II)]-μ- [1,8-diamino-]
3-aza-3-palmityloctane] dinite, bis [trans-diaminechloroplatinum (II)]-μ- [1,5-diamino-
3-Aza-3-palmitylpentane] dinitrate.

─────────────────────────────────────────────────── ─── Continued front page    (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, I T, LU, MC, NL, PT, SE), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, K E, LS, MW, MZ, SD, SL, SZ, TZ, UG , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE, AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, C A, CH, CN, CR, CU, CZ, DE, DK, DM , DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, K E, KG, KP, KR, KZ, LC, LK, LR, LS , LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, R U, SD, SE, SG, SI, SK, SL, TJ, TM , TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Spinelli Silvano             Italy, 110, Eye-20052 Mon             The, Via G. Bee. Stut             Ki F term (reference) 4C086 AA01 AA03 HA10 HA28 MA01                       MA04 NA14 ZB26                 4H050 AA01 AB28 WB14 WB22

Claims (9)

[Claims] 1. Formula (I): [In the formula, X is halogen (chlorine, bromine, iodine, etc.), n and m are integers of 2 to 8, p is 1 and 2, A is -B-, -B- (CH _{2 ) r -B -, - B- (} CH 2) r -B- (CH 2) z -B
-(R and z are 2-8), B is of the formula -NR-, wherein R is a group that can be converted to a hydrogen atom under physiological conditions, provided that C _1- A group represented by a C ₄ alkyl group or an acyl group and a t-butoxycarbonyl group), and Q- ^p is chloride, bromide, iodide, nitrate, sulfate, acid sulfate or Which is an anion selected from the group consisting of perchlorates]. 2. R is 1) [Chemical 2] (In the formula, R₁, R₁And R₃Are the same or different and are hydrogen, C₁~ C_FourAl
Kill group, C_Five~ C₆A cycloalkyl group, optionally one or more C₁~ C_FourAl
Kill group, C₁~ C_FourFluorine substituted by an alkoxy group, halogen, or hydroxy group
Phenyl group or C₇~ C_TenAn aralkyl group or R₁, R₂And R₃Is
A D-type or L-type α-amino acid residue, and R_aIs C₁~ C₆Alkyl group, preferred
Or a t-butyl group),   2) Formula R_FourCO- [In the formula, R_FourIs hydrogen, C₃~ C₈A cycloalkyl group, preferably C_Five~ C₆Cycloa
Rukyl group, optionally C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy group, hydroxy group,
Nitro group, cyano group, phenyl group substituted by halogen, alkyl C₁~
C₂-Interrupted by phenyl, ethyloxy or 1 to 4 oxygen atoms
(However, -O-CH₂Excluding --O-acetal group) C₃~ C₈Is an alkyl group
Or R_FourIs a saturated or unsaturated fatty acid residue or hexose or pen
Is a residue of tose sugar],   3) Expression [Chemical 3] Group represented by   4) Formula-CO-OR_Five [In the formula, R_FiveIs C₁~ C₁₈Alkyl group (excluding t-butyl group), C₃~ C₁₈Arche
One or more hydroxy groups at the nyl, benzyl, or phenyl groups.
Shi group, C₁~ C_FourAlkyl group, C₁~ C_FourAlkoxy, nitro, cyano, ace
Toxy group, C₁~ C₃Alkylaminocarbonyloxy group, C₁~ C₃Alkoxyca
Benzyl group, hexose or pentose substituted by rubonyloxy group
Sugar residue, formula [Chemical 4]     (In the formula, Rg is a methyl group or a phenyl group), or a group [Chemical 5] (In the formula, R₆Is hydrogen or C₁~ C_FourIt is an alkyl group, and w is an integer of 1 to 6.
A group represented by], a group represented by   5) formula [Chemical 6] (In the formula, R_gIs a methyl group or a phenyl group),   6) Expression [Chemical 7] (In the formula, R₆And R₇Are the same or different and are hydrogen or C₁~ C_FourArchi
A group represented by   7) Expression [Chemical 8] (In the formula, R₈Is hydrogen or C₁~ C_FourA group represented by an alkyl group),   8) Expression [Chemical 9] (In the formula, R₉Is hydrogen or C₁~ C_FourAn alkyl group, R_TenIs C₁~ C_FourAlkyl
A group represented by),   9) Expression [Chemical 10] (In the formula, R₁₁And R₁₂Are the same or different and are hydrogen, C₁~ C_FourAlkyl
Group is a phenyl group) A group represented by   Formula 10) [Chemical 11] (In the formula, R₆Is an alkyl group, preferably a methyl group),   11) Formula (C), (D) or (E) [Chemical 12] (In the formula, R_bHas the above meaning, R_c, R_d, R_e, And R_fAre the same or different
And H, CH₃Or OCH₃Is a group represented by   12) formula [Chemical 13] A group represented by   13) Expression [Chemical 14] [Wherein Z is C₂~ C_FourAlkylene groups, cycloalkylene groups, optionally substituted fluorine
Is an enylene group, T is an oxygen atom or -NH- or -N-R₁₄Group (in the formula, R₁₄Is C₁~ C_FourArchi
Is a ru basis), Y represents a bond or an oxygen atom NH or the above-N-R₁₄The base, R₁₃Is C₁~ C_FourAlkyl group, C_Five~ C₆Cycloalkyl group, phenyl group, optionally C ₁ ~ C₃Alkyl group, C₁~ C₃Alkoxy group, nitro group, cyano group, hydroxy group
A phenyl group substituted by], The compound of claim 1 selected from the group consisting of: 3. The compound according to claim 2, wherein R _{1 to} R ₃ are hydrogen or an alkyl group. 4. R ₄ is an alkyl group interrupted by an oxygen atom selected from a polyoxyethylene group, or a saturated or unsaturated fatty acid residue or a hexose or pentose sugar residue. Compound. 5. R ₅ is a methyl group, i-butyl group, n-hexyl group, benzyl group, p-nitrobenzyl group, 4-acetyloxybenzyl group, 4-methylaminocarbonyloxybenzyl group, 4-methoxycarbonyl group. The compound according to claim 2, which is an oxybenzyl group. 6. The compound according to claim 2, wherein R ₆ and R ₇ are hydrogen, methyl group, t-butyl group and isopropyl group. 7. A pharmaceutical composition containing the compound according to claim 1 as an active ingredient in admixture with a suitable carrier. 8. A composition according to claim 7 in the form of a combined preparation for sequential or co-administration, containing a synergistic anti-tumor agent in addition to the compounds of claims 1-6.
The composition according to. 9. Use of a compound according to claims 1 to 6 for the manufacture of an antitumor agent.