JPS5849395A - Novel nitrosourea compound - Google Patents

Abstract

NEW MATERIAL:A compound of formulaI[Ac is acetyl; R1 is H, alkyl or alkoxyl; R2 is H or (hydroxy)alkyl; R3 is H or (halogeno)alkyl; n is 0 or an integer 1-5]. EXAMPLE:2-[N'-(2-Chloroethyl)-N'-nitrosocarbamoyl]aminoethyl-2-acetami do-2- deoxy-beta-D-glucopyranoside. USE:An antitumor agent. PROCESS:An N-acetylglucosamine of formula II as a starting raw material is reacted with chloroform and then refluxed with an N-(benzyloxycarbonyl)aminoethanol, etc. of formula III (Z is protecting group of the amino group) under heating to give a compound of formula IV, which is then reduced with a reducing agent, e.g. sodium methoxide, to remove the protecting group Z of the amino group. The resultant product is then reacted with p-nitrophenyl N-(2-chloroethyl)- N-nitrosocarbamate in a solvent in the presence of an acid binder and tetrahydrofuran (THF) under shielded light at room temperature.

Description

[Detailed description of the invention] The present invention relates to novel nitrosourea compounds.

Although certain nitrosourea compounds are known to have antitumor activity, there is a need for compounds with excellent pharmacological activity. The inventor has proposed the general formula I) in which A6 represents acetyl, R1 represents hydrogen, alkyl or alkoxy, R2 represents hydrogen, alkyl or hydroxyalkyl, and R3 represents hydrogen, alkyl or halogenoalkyl. , n is an integer of 0 or 1 to 5) has been found to have excellent antitumor activity, and the present invention has been completed.

It is an object of the present invention to provide novel ditronic compounds having antitumor activity. Compounds provided by the present invention have the formula (I) (wherein, R1, R2
, R3 and n have the meanings given above)=
) is a lonurea compound [hereinafter referred to as compound (1)].

The alkyl shown in the general formula means an alkyl having 1 to 5 carbon atoms, including methyl, ethyl, propyl, n-butyl, 10
-butyl, t-butyl, n-propyl, and 1so-propyl are exemplified. The moiety in alkyl, hydroxyalkyl, or ISOgenoalkyl corresponds to the definition of alkyl above.

Compound (I) of the present invention may be a stereoisomer or a racemate thereof.

The compound of the present invention is produced by the following steps.

HONHAe (Compound (t)) N-acetylglucosamine [Compound (I)] [Compound (4)] [Compound (I)] (In the above process formula, Ae% R1, R2, R3 and n have the same meanings as above) .2 indicates a protecting group for an amino group.) Each step will be explained in detail below.

Step (1) Production of compound (1[) Compound (Ill) is a known compound, for example, N-
Can be easily produced from acetylglucosamine (Org
.

8yn, 0o11.1-5 volume 4s (1966))
, Reference Example 1 shows a manufacturing example thereof.

``Co''A Production of Compound (V) After stirring Compound (B) in a suitable solvent such as anhydrous benzene at 50 to 70°C in the presence of mercuric cyanide and a drying agent (such as anhydrous calcium sulfate), Compound (1) is added and heated to reflux at 80-90°C.

The reaction mixture is filtered, washed with saturated brine and water, dried over anhydrous sodium sulfate, separated from P, and concentrated to give a generally syrupy residue. This is recrystallized from a solvent such as ethanol, ethyl acetate, hexane, etc. to obtain compound (V').

The compound (IV) used in the reaction is a compound represented by the general formula (1) (wherein R1, R2, and n have the same meanings as above), in which the hydrogen of the amino group or the substituted 72 group is replaced with a protecting group for the amino group. Obtained by preserving eel.

As a protecting group for the amino group, benzylox7carbonyl,
Examples include t-butoxycarbonyl and tosyl. Introduction of these protecting groups can be easily carried out by applying known techniques in the field of organic synthetic chemistry. ◎ Compound (IV) into which a benzyloxycarbonyl group is introduced, which is used in the examples of the present invention, is For example, it can be obtained by adding an alcohol amine that softens the target compound (IV) to a solution of cyclized benzyloxycarbonyl, and then adding sodium carbonate for reaction. Production examples of compound (5) used in Examples are shown in Reference Examples 2 and 3 below.

It is obtained by reducing Compound ff) produced by Korigumi Compound FF) under relatively weak conditions. For example, compound ff+ may be reacted in a solvent such as methanol or ethanol in the presence of a reducing agent such as sodium methoxide. Compound (2) is obtained by neutralizing the reaction mixture, filtering and concentrating.

Futamise Compound (A) is obtained by removing the protective group of the aino group of the compound (S) obtained in the production step (3) of Compound (S). a<
The group may be removed by any suitable known means depending on the type of protecting group. For example, when the protecting group is benzyloxycarbonyl, the reaction may be carried out in a hydrogen stream in the presence of a reducing agent such as palladium black in a solvent such as methanol. The reaction is completed in 10-30 hours under pressure of 1-a KyS. When the catalyst is separated from the P and the P solution is concentrated, an oily compound (a) is obtained. This can be used as a starting material for the next step (5) without purification.

Step (5) The product obtained in step (4) for producing compound (T) and p-nitrophenyl N-
(2-chloroethyl)-N-nitrosocarbamate is reacted with tetrahydrofuran in a suitable solvent such as methane in the presence of an acid binder such as triethylamine at room temperature under transparent light to form the compound (2-chloroethyl)-N-nitrosocarbamate. 11
is obtained.

After the reaction, the reaction mixture is concentrated under reduced pressure to obtain an oil. Purification of this oil can be carried out, for example, by dissolving it in methanol, adding an excess of isopropyl ether, discharging it, removing the supernatant, treating the residue with silica gel column chromatography, concentrating the eluate, and dissolving it in an appropriate manner. This is done by recrystallizing from a solvent.

Measurement of antitumor activity (mouse) The antitumor activity of the nitrosourea compound of the present invention was measured as follows.

10 abscess cells of L 1210 were administered intraperitoneally to 5 mice per group. Test compounds were given on days 1, 2 and 3 of the administration phase! ! Administer your own dose and learn the number of survivors after 60 days.
IL8 (%) was determined. The following compound is Example 1'5
1 is described in 2.

The method for producing the compound of the present invention will be explained below with reference to Examples.

Example 1 Compound (V-a) 30011F obtained in Reference Example 4 was added to 5
- dissolved in methanol of 0. 18.0 d of IN sodium methoxide methanol solution was added dropwise while cooling, and after returning to room temperature, the mixture was stirred for 1 hour. A 4-ion exchange resin IR-120 (H+) was added to neutralize the mixture, and after P was removed from the resin, the mixture was concentrated under reduced pressure to obtain a white crystalline residue.

Thin layer chromatography [hereinafter referred to as TLC, developing solvent chloroform/methanol = 4/1 (v/v
) gives Rt = 0.39.

The obtained crystals were dissolved in 10-methanol, 4-4 radium black was added, and the mixture was exposed to light for 18 hours under a hydrogen pressure of 2.7 kp/z. After separating the catalyst, the P liquid was depressurized. Concentrate to obtain an oily residue.

Dissolve the nuclear oily residue in methanol of 5-34111
Triethylane (F) was added, and while stirring while shielding from light, a tetrahydrofuran solution 5- containing compound 55319 (5-) was added dropwise over 15 minutes, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure to obtain a pale yellow oily residue. This was dissolved in a small amount of methanol, inglovir ether was added, and the mixture was placed in a freezer for about 16 hours. The supernatant was decanted, the oily residue was dissolved in chloroform-ethanol (8:1 v/v) (supplied), and subjected to silica glu column chromatography (Wako Glu C-20).
0,211f) and am form-meth/-ol (
4,: 1 v/v) 100 df elute the target product. The eluate was washed with Sat under reduced pressure, and the oily residue was crystallized with acetone-ethyl acetate mixed solvent and washed with ethyl acetate for 12 hours.
3. White crystals of compound (1-a) are obtained.

Compound (I-!L): 2-CN'-(2-chloroethyl)-Nl-nitronecarbamoyl)aminoethyl-2-acedoaodo-2-deoxy-β-D-glucopyranoside Yield: 53.44 m, p, : 112°C (decomposition) [α] also 3 knees 21.8° (0 = 0.5 methanol) Elemental analysis value (%): C,, H,, N, 08C4, -g
Calculated value as cH, 5COOC, HIS C: 40
．． 6B, H: 6.15. N: 12.65. C
1: 8.01 actual value C: 41.27+H: 5.98
．． N: 12.18sCt: 8°0OKBr −+.

Engineering R-axm 344(1-:(28(1,1725
, 1650, 15302] 485 Example 2 The compound obtained in Reference Example 5 (
The same method as in Example 1 was repeated except for using V-b, V-Q, V-4-cross Ve), and the target compound (I-1), t-c, and -d-Make ■-θ) is obtained.

Compound (T-1+'l: 3-(N'-12-chloroethyl)-Nl-nitronecarbamoyl]aminopropyl-2-acetamido-2-deoxy-β-D-glucopyranoside Yield: 56.3 coefficient m, 1), : 105°C (decomposition) [α]♂: -21,5" (Q = 0.5, methanol) elemental analysis value part) 2014H2,08N4C4・-C
H, COOC2H5 calculated value C: 42.06. I(
: 6.40. N: ]2.26. C1: 7.
76 Actual value C: 41.71. H:6.16. N:10
．． 33. CtNia, 18IRuKBrffi-1: 3
430-3260.1720.1650.1520゜l
LX Compound (x-c): 2-(N-(2-chloroethyl)-
N'-nitronecarbamoyl]aminozolobyl-2-acetamido-2-deoxy-β-D-glucopyranoside Yield: 46.3 Coefficient m, p: 137°C (decomposition) [α] also 3: 23.1' r c = 0.5, methanol) Elemental analysis value part): C1, H75N, C1
Total value as Owa: C: 42.35. H: 6.
:(5, N: 14.12. C1: 8.95 actual measurement 1
71 C:42.04. H:6.21. N: 13.9
8. Ct: 9.011R2KB"cm-': 34
20-3280.1720.1650.1530°ax 490 Compound (1-d): 5-(N'-(2-chloroethyl)
-N'-nitronecarbamoyl]aminopentyl-2
-acetamido-2-deoxy-β-D-glucopyranoside Yield: 55.7 min, p: 103°C (decomposition) [α) fi3: -22,2 (Q = 0.5, methanol) Elemental analysis Seikai): C engineering, 1 (2, DI, CtO,
Calculated value as C:4:1.57. I(:fi, 63.
tJ:12.71. C2: 8.06 Actual value c: 43
．． 21. H: 6.75. N: 12.50. C4:
8.12 engineering R2m, 3420-3260.1720
．． 1650.1530゜ax 485 Compound (t-e) 26-('N'-(2-chloroethyl)N/-nitroncarnomoyl]amino-1-hexyl-2-acetamido-2-deoxy-β- D-glucopyranoside yield: 63.8m, p: 11°C (decomposed) [α]mo': -22,o (c = o, s, methanol) Elemental analysis value r*): C Yuwa H31N , ClO
Calculated value as 3 C: 44.86. T(:6.86.N
:12.32. C/, Near, 81 Actual value C: 44.6
0. H:6.62. N:12. OO, C1: 8.03 engineering RλKBrcm-”: 3440-3260.172
0.1650.1530°m &
0L) to acetate chloride 22.6m (317.8mm
ot) and stirred at room temperature for 767 hours. After adding and mixing 50-chloroform, the mixture was poured into ice water with stirring. The chloroform layer was washed and neutralized with 50% of a saturated sodium bicarbonate solution, and then dehydrated with anhydrous sodium sulfate. Then, it was filtered, and the F solution was concentrated under reduced pressure at a temperature below 1°C.
When the temperature reaches the 〇-position, 50% of ether is added, and after discharging at room temperature for 1 day, it is left in the apparatus for 1 day and filtered. The residue was washed with ether and dried under reduced pressure to give the compound m s, 22t as pale yellow crystals.
(yield 74.24). m, T), 123-1
2'5°C, - Reference Example 2 30% toluene solution 3 of hensyl chloride
Sewage 5- and monoethanolamine (compound ■-IL) 2n wt (33,1mmot
) into the mixture. Add 5 tons of sodium carbonate to this over 15 minutes, and stir at room temperature for about 16 hours. 15 wt of chloroform is added to the reaction solution K, and the chloroform layer is washed with water (10 m+/X3) and dried over anhydrous sodium sulfate. After filtration with
A yield of 99.9 h) is obtained.

m, p, : 57-59°C Elemental analysis value (@: Calculated value as CxoHxaNO3 C: 61.52. H: 6,71. N: 7
゜1B actual measurement value C: 62.07, I(: 6.7
2. N: 6.87 Reference Example 3 The same method as in Reference Example 2 was carried out to obtain ■-b, C5Δ, θ having the physical properties of lower manure.

Compound (■-b): 3-(pencyloxy7cargenyl)
Amino-1-7" Lonoyanol Yield: 97.6% m, T), : 4R-50'C Elemental analysis value (@: Calculated value as C1 U H1, No3 C
: 63.14. ) (: 7.23. N: 6.
69 Actual value C: 63.37. H: 7.23.
N: 6.46 Compound (rv-c): 2-(pencyloxycarvinyl)amino-1-glopanol Yield: 95.5 cm, 1): 68-70°C Elemental analysis value (arrogant): Calculated as C4□”1flN03*
c: 63.14. H: 7.23. N:
6.69 Actual value C: 63.12. H: 7.1
9. N: 6.53 compounds (IT-cl 5-(
(pencyloxycarvinyl)amino-1,,2 ethanol Yield: R7,8 m, 1): 44-45°C Elemental analysis value: 1: Calculated value as C1, H19NO, C: 65.80. H: LO7, N: 5.90
Actual l1lQ value C: 65.90. T(: 7.97
．． N: 6.02 Compound (IV-@1) 6-(pen-soloxycarmonyl)amino-1-hexanol Yield: 76.7%゛m,p,: 83-84'C Elemental analysis f%IC Calculated value as Yu4H211J05
C: 56.91, H: 8.42. N: 5
．． 57 Actual measurement value C: 67.19. H: 8.27. N
: 5.34 Gold 4 Shelf IA Compound obtained in Reference Example 2 (TV-a) 1. ost
6. Dissolve in 120 parts of anhydrous benzene. Of cyanide second mizusen and 12. Add anhydrous calcium sulfate of
Stir between the regions with ω”CK and add 1.989F compound ■
was added and heated under reflux for about 16 hours at 90"C. The reaction mixture was filtered, and the solution was washed with chloroform, then with saturated brine 5n+a/X2 and water 50WtIX4, and then with anhydrous sodium sulfate for 1 hour. dry.

After the mixture is filtered through r, the liquid f is concentrated under reduced pressure to obtain a pale yellow syrup-like substance. The crude crystals 2.3 obtained by crystallizing this from ethanol are re-crystallized from ethanol to give 1.9Of white crystals of 2-(benzyloxycarbonylaminoethyl-2-acetamido-3,4,6-) -acetyl-2-deoxy-β-D-glucopyranoside (compound V-a) is obtained.

Yield 67.3 Physical properties of compound v-a.

m, p, : 170-171°C [α] Heat: ': -15,0' (c = 1.o, chloroform) Elemental analysis value (qb): C24H3,N,0
0, calculated as ill C: 54.96. H:
6.11, N: 5.34 Actual value C: 5.1
．． 82. H: 6.19. N: 5.14-b,
By repeating the same method as in Reference Example 4 except for using ■-C, ■-tl or mV-8, a compound V-
b, V-c, V-1 or ye.

Compound e (v-b) + 3-(benzyloxycarbinyl)aminopropyl-2-acetamide: (,4,6
-) Cou 0-acetyl-2-deoxy-β-D-glucopyranoside Yield: 59.4q6 m,p, : 149-151°C [αKita 3: -7,o (c=1.o, chloroform) Elemental analysis value (俤) 2〇25H340□□ and 1-calculated value C: 55.76, H: 6.36. N:
5.20 Actual value C: 56.04. H: 6,
30. N: 5.03 Compound (V-a): 2-(
benzyloxycarbinyl) aonoderopyru-2-acedo-2-do 3.4.6-tri〇-acetyl-2-deoxyβ-D-glucopyranoside yield 40 m, 1): 169-171°C [α] also 3: - 16'C (C= 1. ('l, chloroform) elemental analysis value (to) l: Cp5Ha4Ns+
O], calculated values C: 55.76, H: 6.36.
N: 5.20 Actual measurement IC: 55.63.
H: 6.2Fl, N: 5.14 Compound V-d
: 5-(Benzyloxycarbinyl)amino 4-thyl-2-acetamide: 1.4.6-tri〇-acetyl-2-deoxy-β-D-glucopyranoside Yield: 25.5% 111.1), : 140~ 142”C [α] also:'
Kony ° (C = 1.0, chloroform) elemental analysis value (correspondence) "2'FH58N2011 calculated value C: 57.2
4. E: 6.76, N: 4.94 actual day C: 57.32. I(: 6.66 N:
4.82 Compound v-e: 6-(benzyloxycarvinyl)aminehexyl-2-acetamide-3,4
, 6-tri〇-acetyl-2-deoxy-β-D-glucopyranoside deprivation: 60.61! I1. p, : 113~116°C [α几7, -8
(c == 1.0% chloroform) Elemental analysis value (@
: CzeHa. N, 0yu.

Claims (1)

[Claims] (1) General formula (1) (wherein A6 represents acetyl, R1 represents hydrogen, alkyl or alkoxy, R2 represents hydrogen, alkyl or hydroxyalkyl, R3 represents hydrogen, alkyl or halogenoalkyl , 0 or an integer from 1 to 5).