GB2028795A - Novel nitrosourea compounds and process for preparing the same - Google Patents

Novel nitrosourea compounds and process for preparing the same Download PDF

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GB2028795A
GB2028795A GB7834564A GB7834564A GB2028795A GB 2028795 A GB2028795 A GB 2028795A GB 7834564 A GB7834564 A GB 7834564A GB 7834564 A GB7834564 A GB 7834564A GB 2028795 A GB2028795 A GB 2028795A
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glucopyranosyl
aldo
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hexopyranosyl
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Tanabe Seiyaku Co Ltd
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Priority to GB7834564A priority Critical patent/GB2028795A/en
Priority to US06/066,421 priority patent/US4241053A/en
Priority to NL7906191A priority patent/NL7906191A/en
Priority to JP54105184A priority patent/JPS6055077B2/en
Priority to DE2933663A priority patent/DE2933663C2/en
Priority to IT25246/79A priority patent/IT1193213B/en
Priority to CA000334307A priority patent/CA1121347A/en
Priority to FR7921268A priority patent/FR2434174A1/en
Priority to ES483636A priority patent/ES483636A1/en
Priority to AT0568979A priority patent/AT368517B/en
Priority to GB7929525A priority patent/GB2031875B/en
Priority to CH773279A priority patent/CH640867A5/en
Priority to BE0/196867A priority patent/BE878412A/en
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia

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Abstract

Nitrosourea compounds of the general formula: <IMAGE> wherein R<1> is hydrogen, alkyl of one or two carbon atoms, alkoxy of one or two carbon atoms or alkoxymethyl of two or three carbon atoms, R<2> is alkoxy of one or two carbon atoms or alkoxymethoxy of two or three carbon atoms. R<3> is aldo-pentofuranosyl, aldo- pentopyranosyl, aldo-hexopyranosyl or O-aldo-hexopyranosyl-(-1-@4)-aldo- hexopyranosyl and n is an integer of one or two, which may be prepared by nitrosation of a compound of the general formula: <IMAGE> wherein R<1>, R<2>, R<3> and n have the meanings given above. These nitrosourea compounds are useful as anti- tumor or anti-leukemic agents.

Description

SPECIFICATION Novel nitrosourea compounds and process for preparing the same This invention relates to novel nitrosourea compounds and a process for preparing the same. More particularly, it relates to a compound of the general formula:
wherein R1 is hydrogen, alkyl of one or two carbon atoms, alkoxy of one or two carbon atoms or alkoxymethyl of two or three carbon atoms, R2 is alkoxy of one or two carbon atoms or alkoxymethoxy of two or three carbon atoms, R3 is aldo-pentofuranosyl, aldo-pentopyranosyl, aldo-hexopyranosyl or O-aldo-hexopyranosyl-(1 < 4)-aldo-hexopyranosyl, and n is an integer of one or two.
It is known that (N'-chloroethyl-N'-nitrosocarbamoyl)-amino derivatives of monosaccharides are prepared by nitrosation of (N'-chloroethylcarbamoyl)amino-monosaccharides with an alkali metal nitrite such as sodium nitrite (Japanese Patent Application Nos. 31 131/1975, 90266/1974 and 124319/1974which were laid open to the public under Nos. 108043/1976, 26876/1976 and 52128/1976, respectively). These patents also disclose that 1 -(2-chloroethyl )-1 -nitroso-3-D-man nopyranosylu rea and 1 -(2-chloroethyl)-1 -n itroso-3-D- glucopyranosylurea (the latter compound being hereinafter referred to as "GANU") increase the life span of mice implanted intraperitoneally with the tumor cells of lymphoid leukemia L-1210.Further, it is known that (N'-chloroethyl-N'-nitrosocarbamoyl)amino derivatives of disaccharides such as 1 -(2-chloroethyl)-1 -nitroso- 3-D-lactosylurea and 1 -(2-chloroethyl)-1 -nitroso-3-D-maltosylurea are prepared from the corresponding (N'-chloroethylcarbamoyl)-amino-disaccharides in the same manner as above and show anti-tumor activity against leukemic cells (Japanese Patent Application No. 64073/1975 which was laid open to the public under No.141815/1976).
We have now found that the nitrosourea compound [I] of the present invention shows potent anti-tumor or anti-leukemic activity with low toxicity and is useful to inhibit the growth of malignant tumor cells in warm-blooded animals. For example, when the anti-tumor effects upon leukemia is estimated by administering such drugs intraperitoneallyto tumor cell-inoculated mice (i.e., mice implanted with tumor cells of Leukemia L-1 210) for five consecutive days, 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxyethyl)-3-L- arabinopyranosylurea at the daily dose of 0.85 mg/kg or 1-(2-chloroethyl)-1 -nitroso-3-(2-ethoxyethyl)-3-[O-a- D-glucopyranosyl-(1 > 4)-D-glucopyranosyl]-urea at the daily dose of 1.6 mg/kg shows an increase of about 30 % in the average life span of said mice. Moreover, the nitrosourea compound [I] of the invention has low toxicity and shows great safety for use as an anti-tumor agent.For example, when the therapeutic index is estimated by the ratio of the optimal dose (the daily dose at which the maximum increase in the life span of tumor cell-inoculated mice occurs) to ILS30 (the minimum daily dose which shows 30 % increase in the life span of said mice) in case of Leukemia L-1210, said therapeutic indexes of 1-(2-chloroethyl)-1-nitroso-3-(2- methoxyethyl )-3-L-arabi nopyranosylu rea and 1 -(2-ch loroethyl )-1 -nitroso-3-(2-ethoxyethyl ) 3-[O-a-D- glucopyranosyl-(1 > 4)-D-glucopyranosyl]urea may be more than 7 times greater than that of GANG. The compound [I] may also be characterized by a high therapeutic index estimated in terms of ratio of Max.D (the maximum dose which shows 100 % inhibition for the growth of Ehrlich ascites tumor in mice without causing the death of said mice) to M.E.D. (the minimum effective dose which shows 100 % inhibition for the growth of said ascites tumor). For example, said therapeutic indexes (Max.D/M.E.D.) of 1 -(2-chloroethyl)-1 - nitroso-3-(2-methoxyethyl )-3-L-ara binopyranosyl urea, 1 -(2-chloroethyl )-1 -nitroso-3-(2-ethoxyethyl )-3-[O-a D-gIucopyranosyl-(14)-D-gIucopyranosyl]urea and 1 -(2-chlo roethyl )-1 -nitroso-3-(3-ethoxypropyl )-3-[O-a- D-glucopyranosyl-(144)-D-glucopyranosyl]urea are 2 to 4 times greater than that of GANU. The compound [I] of the invention may further show low bone marrow toxicity.
In the above-mentioned formula [I], representative examples of the group R1 include hydrogen; alkyl such as methyl and ethyl; alkoxy such as methoxy and ethoxy; and alkoxymethyl such as methoxymethyl and ethoxymethyl. On the other hand, representative examples of the group R2 include alkoxy such as methoxy and ethoxy; and alkoxymethoxy such as methoxymethoxy and ethoxymethoxy.Further, representative examples of the group R3 include aldo-pentofuranosyl such as D-ribofuranosyl and D-deoxyribofuranosyl; aldo-pentopyranosyl such as L-arabinopyranosyl and D-xylopyranosyl; aldo-hexopyranosyl such as D-glucopyranosyl, D-galactopyranosyl, D-mannopyranosyl, L-rhamnopyranosyl, D-fucopyranosyl and Dtalopyranosyl; and O-aldo-hexopyranosyl-(1 < 4)-aldo-hexopyranosyl such as O-a-D-glucopyranosyl-(1e4)- D-g lucopyranosyl(= D-maltosyl) and O-frD-galactopyranosyl-( 14)-D-gIucopyranosyI (-D-lactosyl).Among the compounds of the invention, a preferred subgenus includes the compound of the formula [I] in which R3 is D-aldo-pentofuranosyl, D- or L-aldo-pentopyranosyl, D- or L-aldo-hexopyranosyl and O-D-aldo hexopyranosyl-(1 < 4)-D-aldo-hexopyranosyl. Another preferred subgenus are the compounds of the formula [I] in which R1 is hydrogen, R2 is alkoxy of one or two carbon atoms, and R3 is D-ribofuranosyl, L-arabinopyranosyl, D-xylopyranosyl, D-mannopyranosyl, D-galactopyranosyl, D-glucopyranosyl or O-a-D glucopyranosyl-(1 < 4)-D-glucopyranosyl. A further preferred subgenus of the invention are the compounds of the formula [I] in which R1 is hydrogen, R2 is methoxy or ethoxy, and R3 is L-arabinopyranosyl, D-xylopyranosyl, D-galactopyranosyl or O-a-D-glucopyranosyl-(1o4)-D-glucopyranosyl. Further, a most preferred subgenus of the invention or the compounds of the formuia [I] in which R1 is hydrogen, R2 is methoxy or ethoxy, R3 is L-arabinopyranosyl or O-a-D-glucopyranosyl-(1 < 4)-D-glucopyranosyl, and n is one.
According to the present invention, the nitrosourea compound [I] may be prepared for example by nitrosation of a compound having the general formula:
wherein R1, R2, R3 and n are the same as defined above.
The starting compound [II] is readily obtained. For example, it can be prepared by condensing a primary amine of the formula:
wherein R1, R2 and n are the same as defined above, with a compound of the formula: R3-OH (wherein R3 is the same as defined above) at about 20 to 80"C in an inert solvent (e.g., methanol, ethanol) to give a secondary amine of the formula:
wherein R1, R2, R3 and n are the same as defined above, and then condensing said secondary amine with 2-chloroethyl isocyanate at 0 to 30"C in a suitable solvent (e.g., tetrahydrofuran, methanol, ethanol).
The nitrosation of the invention is accomplished by contacting the compound [II] with nitrous acid, nitrogen trioxide or nitrogen tetroxide in a suitable inert solvent. The reaction is preferably carried out at a temperature of -20" to 20"C, especially at about 0" to about 5"C. Examples of suitable solvents are water, tetrahydrofuran, methylene chloride, ethyl acetate, acetic acid, and formic acid.When free nitrous acid is prepared by reacting an alkali metal salt of nitrous acid (e.g., sodium nitrite, potassium nitrite) or a lower alkyl ester thereof (e.g., butyl nitrite, amyl nitrite) with a mineral or organic acid (e.g., hydrochloric acid, sulfuric acid, formic acid, or acetic acid), it is preferred that said free nitrous acid is employed for the subsequent nitrosation reaction immediately after preparation thereof. On the other hand, when nitrogen trioxide or nitrogen tetroxide is employed in the invention, it is preferred to carry out the nitrosation reaction by dissolving the starting compound [II] in the inert solvent and then introducing gaseous nitrogen trioxide or tetroxide thereto in the presence or absence of an acid acceptor. Sodium bicarbonate, sodium carbonate, potassium carbonate, sodium acetate, potassium acetate are examples of suitable acid acceptors.When the nitrosation reaction is completed, the compound [I] of the invention is readily recovered from the reaction mixture and may be, if required, further purified by silica gel chromatography.
The nitrosourea compound [I] thus obtained shows potent anti-tumor activity against various tumor cells such as for example Ehrlich carcinoma, Sarcoma 180, Leukemia L-1210, Lewis lung carcinoma,Yoshida sarcoma and Rat ascites hepatoma. It may be useful to prolong the survival time of warm-blooded animals afflicted with said tumors and/or minimize the growth of said tumors in said animals. It may also be employed for therapy of malignant lymphoma, leukemia, stomach tumor, hepatoma and other malignant tumors. The nitrosourea compound [I] can be used for pharmaceutical use in the form of a pharmaceutical preparation suitable for either oral or parenteral administration. The compound [I] may also be used in conjunction or admixture with a pharmaceutical excipient. The excipient selected should be the one which does not react with the compound [I].Suitable excipients include, for example, gelatin, lactose, glucose, sodium chloride, starch, magnesium stearate, talcum or vegetable oil. Other known medicinal excipients may be employed. The pharmaceutical preparation may be a solid dosage form such as for example a tablet, a coated tablet, a pill or a capsule; or a liquid dosage form such as for example a solution, a suspension or an emulsion. Further, the compound [i] may be employed for example in the form of an injection or suppository when administered parenterally. The pharmaceutical preparation may be sterilized and/or may contain auxiliaries such as for example preserving and stabilizing agents. The dose of the compound (I) for pharmaceutical use depends on route of administration; the age, weight and condition of the patients; and the particular disease to be treated.
Practical and presently-preferred embodiments of the present invention are illustratively shown in the following Examples.
Example 1 (1) A mixture of 3.8 g of D-ribose, 3.8 g of 2-methoxyethylamine and 5 ml of methanol is heated at 50 to 55"C for 15 minutes under stirring. The reaction mixture is condensed to dryness under reduced pressure.
The residue is washed with ether. Then, the residue is dissolved in 40 ml of methanol, and a solution of 3.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofu ran is added dropwise thereto at 0 to 5 C. Said mixture is stirred at the same temperature for one hour. After the reaction, said mixture is condensed under reduced pressure. The residue thus obtained is washed with ether, whereby 7.0 g of 1-(2-chloroethyl)-3-(2methoxyethyl)-3-D-ribofuranosylurea are obtained as colorless caramel.
IRum (cm -1):3320,1630,1540,1110 max.
NMR(D2O)b: 3.40(s, OCH3) (2) 3.1 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-D-ribofuranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is stirred at the same temperature for 10 minutes. Then, 10 ml of methanol and 3 ml of water are added to the mixture, and said mixture is stirred vigorously at 0 - 5 C for 10 minutes. The mixture is dried and filtered. The filtrate is condensed under reduced pressure.The residue obtained is purified by silica gel chromatography (Solvent: ethyl acetate - chloroform - methanol (5: 2 1)), whereby 2.2 g of 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxyethyl)-3-D-ribofuranosylurea are obtained as yellow oil.
IR#liquid (cm-1): 3425, 1710, 1080, 1050, 1020 max.
NMR(D2O)6: 3.36 (s, 3H, OCH3) 4.24 (t, 2H, -N(NO)-CH2CH2CI) r) -21.9 (C=1.1, in methanol) rCI]Y6 Example 2 (1) A mixture of 3.0 g of L-arabinose, 2.3 g of 2-methoxyethylamine and 10 ml of methanol is heated at 60 to 65"C for 20 minutes under stirring. The reaction mixture is condensed to dryness under reduced pressure. The residue is washed with ether. Then, the residue is dissolved in 40 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise thereto at 0 to 5"C. Said mixture is stirred at the same temperature for one hour. After the reaction, the mixture is condensed under reduced pressure.The residue obtained is dissolved in 20 ml of formic acid, said solution is allowed to stand at room temperature for 15 minutes, and 150 ml of a mixture of ether and hexane (3:1) are added thereto. The resultant oil is washed with ether, whereby 5.5 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)3-L-arabinopyranosylurea are obtained as pale light brown caramel.
IR io (Registered Trade Mark) (cm-1): 3350, 1640, 1540, 1090 NMR(D2O)6: 3.35(s, 3H, OCH3) 4.90(d, 1 H, C1-H) (2) 3.1 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-L-arabinopyranosylurea are dissolved in a mixture of 60 ml of tetrahydrofuran and 60 ml of methylene chloride, and 15 g of sodium carbonate anhydrate are added thereto. 5 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. Then, the mixture is treated in the same manner as described in Example 1-(2), whereby 2.4 g of 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxyethyl)-3-L-arabinopyranosylurea are obtained as yellow caramel.
lRCHCl 3(cm-1): 3420, 1695, 1080 max.
NMR(D2O)b: 3.35(s, 3H, OCH3) 4.20(t, 2H, -N(NO)-CH2CH2Cl) 4.90(d, 1 H, C1-H) [&alpha;]D25 +45.5 (C=1.5, in methanol) Example 3 (1) 3.8 g of D-xylose, 3.8 g of 2-methoxyethylamine and 3.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 2-(1). The crude product (light brown caramel) thus obtained is purified by silica gel chromatography (Solvent: ethyl acetate - chloroform - methanol (5 : 2:1)), whereby 6.1 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-D-xylopyranosylurea are obtained as colorless caramel.
lR Nujol (cm1 ):3350,1640,1540,1110,1040 max.
NMR(D2O)6: 3.35(s, 3H, OCH3), 5.0(d, 1 H, C1-H) (2) 3.1 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-D-xylopyranosylurea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 2-(2), whereby 2.5 g of 1-(2-chloroethyl)-1-nitroso-3 (2-methoxyethyl)-3-D-xylopyranosylurea are obtained as yellow caramel.
IRVCHC13(cm-'): 3410,1695,1105,1080 NMR(CDC13)6: 3.35(s, OCH3) 28 [a]D +4.9 (C=1.2, in methanol) Example 4 (1) 3.6 g of D-mannose, 2.6 g of 2-methoxyethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 1 -(1), whereby 6.5 g of 1 -(2-chloroethyl)-3-(2-methoxyethyl)-3-Dmannopyranosylurea are obtained as colorless caramel.
|R# Nujol (cm-1): 3320,1630,1550,1110,1060 max.
NMR(D2O)6: 3.40(s, OCH3) (2) 3.4 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-D-mannopyranosylurea are dissolved in a mixture of 40 ml of tetrahydrofuran and 10 ml of acetic acid, and 17 g of sodium acetate anhydrate are added thereto. 6 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is further stirred at the same temperature for 10 minutes. 70 ml of hexane are added to the reaction mixture, and said mixture is filtered. The filtrate is condensed under reduced pressure. A mixture of 200 ml of hexane and 4 ml of methanol is added to the residue. After the resultant oil is washed with ether, said oil is dissolved in 50 ml of ethyl acetate. 10 ml of water are added to the ethyl acetate solution, and the mixture is shaken. Then, the ethyl acetate layer is collected therefrom, dried and evaporated under reduced pressure.
1.7 g of 1-(2-chloroethyl)-1-nitroso-3-(2-methoxyethyl)-3-D-mannopyranosylurea is thereby obtained as pale yellow caramel.
IRUCH Cl3(cm1): 3370, 1695, 1090, 1070 max.
NMR(D2O)6: 3.30(s, OCH3) 27 [&alpha;]D27 +20.O (C=1.5, in methanol) Example 5 (1) 3.6 g of D-galactose, 1.8 g of 2-methoxyethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 2-(1), whereby 6.5 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-Dgalactopyranosylurea are obtained as pale light brown caramel.
|R# Nujol (cm-1): 3350, 1630, 1545, 1110, 1060 max.
NMR(D2O)6: 3.35(s, OCH3) (2) 3.4 g of 1-(2-chloroethyl)-3-(2-methoxyethyl)-3-D-galactopyranosylurea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 2-(2), whereby 2.7 g of 1-(2-chloroethyl)-1 nitroso-3-(2-methoxyethyl)-3-D-galactopyranosyiurea are obtained as pale yellow caramel.
|R#CHClmax 3(cm-1)=3350,1700,1080 max.
NMR(d6-DMSO-D2O)6: 3.26(s, 3H, OCH3) 4.82(d, 1 H, C1-H) 20 [a] D +9.2 (C=1.1, in methanol) Example 6 (1) 3.6 g of D-galactose, 2.5 g of 3-methoxy-n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 3-(1), whereby 5.1 g of 1 -(2-chloroethyl)-3-(3-methoxyn-propyl)-3-D-galactopyranosylurea are obtained as colorless caramel.
Nujol (cm-1): 3330, 1630, 1540, 1050 max.
NMR(D2O)6: 1.75 - 2.15(m, 2H, -CH2CH2CH2-) 3.35(s, 3H, OCH3) (2) 3.6 g of 1-(2-chloroethyl)-3-(3-methoxy-n-prnpyl)-3-D-galactopyranosylurea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 2-(2), whereby 2.8 g of 1 -(2-chloroethyl )-1 -nitroso-3-(3-methoxy-n-propyl )-3-D-galacto pyranosyl u rea are obtained as pale yellow caramel.
|R# CHClmax 3(cm-1): 3380, 1700, 1080 max.
NMR(D2O)b: 1.80 - 2.25(m, 2H, -CH2CH2CH2-) 3.35(s, 3H, OCH3) 4.20(t, 2H, -N(NO)-CH2CH2CI) 20 [a] D +15.5 (C=1.3, in methanol) Example 7 (1) 3.6 g of D-galactose, 3.5 g of 2,2-diethoxyethylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 1-(1 ), whereby 7.2 g of 1-(2-chloroethyl)-3-(2,2-diethoxyethyl)-3 D-galactopyranosylurea are obtained as colorless caramel.
IR Nujol (cm-1): 3370,1635,1545, 1110, 1070 max.
NMR(D2O)6: 1.06(t, OCH2CH3) (2) 4.0 g of 1-(2-chloroethyl)-3-(2,2-diethoxyethyl)-3-D-galactopyranosylurea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 2-(2), whereby 1.5 g of 1 -(2-chloroethyl)-1 - nitroso-3-(2,2-diethoxyethyl )-3-D-ga lactopyranosylurea is obtained as pale yellow caramel.
|R#CHClmax3(cm-1):3400,1700,1120,1070 max.
NMR(d6-DMSO)6: 1 .08(t, 6H, OCH2CH3) 4.80(d, 1 H, C1-H) [a]D -3.4 (C=1.4, in methanol) Example 8 (1) 3.6 g of D-glucose, 2.7 g of 3-methoxy-n-propylamine and 3.0 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 3-(1), whereby 6.5 g of 1-(2-chloroethyl)-3-(3-methoxy-n- propyl)-3-D-glucopyranosylurea are obtained as colorless caramel.
IRu Nujol(cm-1): 3350,1640,1530,1110, 1070,1020 max.
NMR(D2O)6: 1.70- 2.20(m, 2H, -CH2CH2CH2-) 3.30(s, 3H, OCH3) 5.00(d, 1 H, C1-H) (2) 3.6 g of 1-(2-chloroethyl)-3-(3-methoxy-n-propyl)3-D-glucopyranosylurea and 5 g of nitrogen tetroxide gas are treated in the same manner as described in Example 2-(2), whereby 2.7 g of 1 -(2-chloroethyl)-1 -nitroso-3-(3-methoxy-n-propyl)-3-D-glucopyranosylurea are obtained as yellow caramel.
|R#CHClmax 3(cm-1): 3400, 1695, 1070 max.
NMR(D20)6: 1.75- 2.30(m, 2H,-CH2CH2CH2-) 3.35(s, 3H, OCH3) 4.20(t, 2H, -N(NO)-CH2CH2CI) 5.0(d, lH, C1-H) 28 [a] D + 9.8 (C=1.2, in methanol) Example 9 (1) A mixture of 7.2 g of D-maltose monohydrate, 2.3 g of 2-methoxyethylamine and 15 ml of methanol are heated at 60 to 65 C for 40 minutes after stirring. The reaction mixture is condensed to dryness under reduced pressure. The residue is washed with ether. Then, the residue is dissolved in 50 ml of methanol, and a solution of 2.5 g of 2-chloroethyl isocyanate in 10 ml of tetrahydrofuran is added dropwise thereto at 0 to 5 C. Said mixture is stirred at room temperature for one hour.After the reaction, the mixture is condensed under reduced pressure. The residue thus obtained is washed with ether, whereby 8.5 g of 1-(2-chioroethyl)- 3-(2-methoxyethyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-3-(2- methoxyethyl)-3-D-maltosylurea) are obtained as colorless powder.
(cm1): 3350,1630,1540, 1070, 1025 max.
NMR(D2O)6: 3.35(s, OCH3) (2) 5.0 g of 1 -(2-chloroethyl)-3-(2-methoxyethyl)-3-[O-&alpha;-D-g I ucopyranosyl-(1e4)-D-gl ucopyranosyl] urea are dissolved in a mixture of 150 ml of tetrahydrofuran and 20 ml of acetic acid, and 20 g of sodium acetate anhydrate are added thereto. 8 g of nitrogen tetroxide gas are introduced into the mixture for 10 minutes under ice-cooling and stirring. The mixture is further stirred at the same temperature for 20 minutes. 200 ml of n-hexane are added to the reaction mixture. Insoluble materials are removed by filtration.Then, the filtrate is condensed. 200 ml of a mixture of ether and methanol (40:1) are added to the residue, and the resultant oil is purified by silica gel chromatography (Solvent: ethyl acetate - chloroform - methanol (2:1:1)), whereby 2.9 g 1 -(2-ch loroethyl )-1 -nitroso-3-(2-methoxyethyl )-3-[O-a-D-gl ucopyranosyl-(1 < 4)-D- glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxyethyl)-3-D-maltosylurea) are obtained as pale yellow powder.
M.p. 52 C (decomp.) lRv Nujol (cm-1): 3350, 1695, 1070, 1025 max.
NMR(D2O)b: 3.38(s, OCH3) 32 [a] D +54.2'(C=1.2, in methanol) Example 10 (1) 7.2 g of D-maltose monohydrate, 2.7 g of 3-methoxy-n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-( 1), whereby 9.0 g of 1 -(2-chloroethyl)3-(3-methoxy-n-propyl )-3-[O-a-D-g lucopyranosyl-( 14)-D-g l ucopyranosyl]u rea (i.e., 1 -(2-chloroethyl )-3-(3methoxy-n-propyl)-3-D-maltosylurea) are obtained as colorless powder.
|R#Nujol(cm-1): 3350, 1635, 1540,1070,1030 max.
NMR(D2O)5: 1.75 - 2.1 5(m, 2H, -CH2CH2CH2-) 3.30(s, 3H, OCH3) (2) 5.2g of 1 -(2-chlorethyl)-3-(3-methoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D- glucopyranosyl]urea and 8 g of nitrogen tetroxide gas are treated in the same manner as described in Example 9-(2), whereby 3.0 g of 1-(2-chloroethyl)-1-nitroso-3-(3-methoxy-n-propyl)-3-[O-a-D- glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-1 -nitroso-3-(3-methoxy-n-propyl)-3-Dmaltosylurea) are obtained as pale yellow powder.
M.p.70 - 74 C(decomp.) IRumai 3350, 1700, 1070, 1030 max.
NMR(D20)0: 1.85 - 2.25(m, 2H, -CH2CH2CH2-) 3.30(s, 3H, OCH3) 25 [a] D +62.4'(C=1.6, in methanol) Example 11 (1) 7.2 g of D-maltose monohydrate, 2.8g of 2-ethoxyethylamine and 2.5 9 of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-(1), whereby 8.9 g of 1 -(2-chloroethyl)-3-(2 ethoxyethyl)-3-[O-&alpha;-D-gIucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-3-(2- ethoxyethyl)-3-D-maltosylurea) are obtained as colorless powder.
3340, 3340,1640,1555,1070,1025 max.
NMR(D2O)6: 1.20(t, OCH2CH3) (2) 5.2 g of 1 -(2-chloroethyl)-3-(2-ethoxyethyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea and 8 g of nitrogen tetroxide gas are treated in the same manner as described in Example 9-(2), whereby 3.2 g of 1-(2-chloroethyl)-1-nitroso-3-(2-ethoxyethyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl-urea (i.e., 1 -(2-chloroethyl )-1 -nitroso-3-(2-ethoxyethyl)-3-D-maltosylurea) are obtained as pale yellow powder.
M.p. 58 C(decomp.) lRii Nujol (cm-1): 3380, 1710, 1070, 1030 max.
NMR(D2O)ô: 1.21(t, OCH2CH3) 27 [&alpha;]D27 +52.0 (C=1.0, in methanol) Example 12 (1) 7.2 g of D-maltose monohydrate, 3.0 g of 3-ethoxy-n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-(1), whereby 8.5 g of 1 -(2-chioroethyl)- 3-(3-ethoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-3-(3- ethoxy-n-propyl)-3-D-maitosylurea) are obtained as colorless powder.
IRUNUIOI (cm-1): 3350, 1630, 1540, 1070, 1025 max.
NMR(D2O)ô: 1 .20(t, 3H, OCH2CH3) 1.65-2.15(m, 2H, -CH2CH2CH2-) (2) 5.3 g of 1 -(2-chloroethyl )-3-(3-ethoxy-n-propyl )-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D- glucopyranosyl]urea and 8 g of nitrogen tetroxide gas are treated in the same manner as described in Example 9-(2), whereby 3.0 g of 1 -(2-chloroethyl)-1 -nitroso-3-(3-ethoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl- (1- > 4)-D-glucopyranosyl]urea (i.e., 1-(2-chloroethyl)-1 -nitroso-3-(3-ethoxy-n-propyl)-3-D-maltosylurea) are obtained as pale yellow powder.
M.p. 63 C (decomp.) |R# Nujol (cm-1)=3350, 1695, 1070,1020 max.
NMR(D2O)ô: 1.17(t, 3H, OCH2CH3) 1.80 - 2.30(m, 2H, -CH2CH2CH2-) 32 [a] D +63.2 (C=1.1, in methanol) Example 13 (1) 7.2 g of D-maltose monohydrate, 3.0 g of 2-methoxy-n-propylamine and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-(1), whereby 8.1 g of 1 -(2-chloroethyl) 3-(2-methoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-3-(2- methoxy-n-propyi)-3-D-maltosylurea) are obtained as colorless powder.
|R#Nujol(cm-1):3380,1640,1550,1070,1030 max.
NMR(D2O)ô: 2.20(d, 3H, -CH(OCH3)CH3) 3.42(s, 3H, OCH3) (2) 5.2 g of 1 -(2-chloroethyl)-3-(2-methoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D- glucopyranosyl]urea and 8 g of nitrogen tetroxide gas are treated in the same manner as described in Example 9-(2), whereby 3.3 g of 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxy-n-propyl)-3-[O-a-Dglucopyranosyl-( 1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-1 -nitroso-3-(2-methoxy-n-propyl )-3-D- maltosylurea) are obtained as pale yellow powder.
M.p. 51 C(decomp.) lRv Nujol (cm-1): 3380,1700,1075,1030 max.
NMR(D2O)ô: 2.20(d, 3H, -CH(OCH3)CH3) 3.36(s, 3H, OCH3) 28 [a] D +55.3'(C=1.1, in methanol) Example 14 (1) 7.2 g of D-maltose monohydrate, 3 g of 2,3-dimethoxy-n-propylamine [Said amine is prepared by condensing 2,3-dihydroxy-n-propylazide with methyl iodide and hydrogenating the resultant 2,3-dimethoxy n-propylazide in the presence of palladium-carbon.Hydrochloride: M.p. 73'- 74"C, Mass (m/e) 120 (M+ + 1)] and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-( 1), whereby 5.8 g of 1 -(2-ch loroethyl )-3-(2,3-dimethoxy-n-propyl )-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e.,1-(2-chloroethyl)-3-(2,3-dimethoxy-n-propyl)-3-D-maltosylurea) are obtained as colorless powder.
lRv Nujol (cm-1): 3350, 1640, 1550, 1080, 1030 max.
NMR(D2O)ô: 3.35(s, 3H, OCH3) 3.42(s, 3H, OCH3) (2) 5.5 g of 1-(2-chloroethyl)-3-(2,3-dimethoxy-n-propyl)-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D- glucopyranosyl]urea and 8 g of nitrogen tetroxide gas are treated in the same manner as described in Example 9-(2), whereby 2.8 g of 1 -(2-chloroethyl)-1 -nitroso-3-(2,3-dimethoxy-n-propyl )-3-[O-&alpha;-D- glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-1 -nitroso-3-(2,3-dimethoxy-n-propyl)-3- D-maltosylurea) are obtained as pale yellow powder.
M.p. 54'C(decomp.) IRu Nujol (cm-1):3350,1700,1070,1020 max.
NMR(D2O)ô: 3.38(s, 3H, OCH3), 3.43(s, 3H, OCH3) 4.18(t, 2H, -N(NO)CH2CH2CI) 26 [a] D + 50.7 (C=1.1, in methanol) Example 15 (1) 7.2 g of D-maltose monohydrate, 3 g of 2-(methoxy-methoxy)ethylamine [Said amine is prepared by condensing 2-hydroxy-ethylazide with chloromethyl methyl ether and reducing the resultant 2-(methoxy methoxy)ethylazide with lithium aluminium hydride. B.p. (30 mmHg) 56 C] and 2.5 g of 2-chloroethyl isocyanate are treated in the same manner as described in Example 9-(1), whereby 6.8 g of 1-(2-chloroethyl) 3-[2-(methoxy-methoxy)-ethyl]-3-[O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl]urea (i.e., 1 -(2- chloroethyl)-3-[2-(methoxy-methoxy)ethyl]-3-D-maltosylurea) are obtained as colorless powder.
Nujol (cm-1): 3350, 1640, 1545, 1070, 1030 max.
NMR(D2O)ô: 3.32(s, OCH3) (2) 5.3 g of 1-(2-chloroethyl)-3-[2-(methoxy-methoxy)-ethyl]-3-[O-a-D-glucopyranosyl-(1 > 4)-D- glucopyranosyl]urea are dissolved in 200 ml of tetrahydrofuran, and 20 g of sodium carbonate anyhdrate are added thereto. 8 g of nitrogen tetroxide gas are introduced into the mixture for 20 minutes under ice-cooling and stirring. The mixture is further stirred at the same temperature for 30 minutes. 200 ml of n-hexane are added to the reaction mixture, and said mixture is filtered. 10 ml of methanol are added to the filtrate, and the resultant oil is collected therefrom. Said oil is washed with ether and then purified by silica gel chromatography (Solvent: ethyl acetate - chloroform - methanol (2:1:1)), whereby 2.6 g of 1 -(2-chloroethyl )-1 -nitroso-3-[2-( methoxy-methoxy)ethyl]-3-[O-a-D-gl ucopyranosyl-(1 < 4)-D- glucopyranosyl]urea (i.e., 1 -(2-chloroethyl)-1 -nitroso-3-[2-(methoxy-methoxy)ethyl]-3-D-maltosylurea) are obtained as pale yellow powder.
M.p. 60'C(decomp.) Nujol (cm-1): 3360, 1710, 1070, 1025 max.
NMR(d6-DMSO)ô: 3.24(s, 3H, OCH3) 4.56(s, 2H, -O-CH2-O-) [a]32 + 49.2 (C=1.2, in methanol) D

Claims (24)

1. Acompound ofthe formula:
wherein R1 is hydrogen, alkyl of one or two carbon atoms, alkoxy of one or two carbon atoms or alkoxymethyl of two or three carbon atoms, R2 is alkoxy of one or two carbon atoms of alkoxymethoxy of two or three carbon atoms, R3 is aldopentofuranosyl, aldo-pentopyranosyl, aldo-hexopyranosyl or O-aldo-hexopyranosyl-(1 < 4)-aldo-hexopyranosyl, and n is an integer of one or two.
2. A compound as claimed in claim 1 in which R' is hydrogen, R2 is alkoxy of one or two carbon atoms, and R3 is D-ribofuranosyl, L-arabinopyranosyl, D-xylopyranosyl, D-mannopyranosyl, D-galactopyranosyl, D-glucopyranosyl, or O-a-D-g I u co pyra nosyl-( 14)-D-glucopyranosyl.
3. A compound as claimed in claim 1 in which R' is hydrogen, R2 is methoxy or ethoxy, and R3 is L-arabinopyranosyl, D-xylopyranosyl, D-galactopyranosyl or O-a-D-glucopyranosyl-(1 4)-D- glucopyranosyl.
4. A compound as claimed in claim 1 in which R' is hydrogen, R2 is methoxy or ethoxy, R3 is L-arabinopyranosyl or O-&alpha;-D-glucopyranosyl-(1- > 4)-D-glucopyranosyl and n is one.
5. A compound as claimed in claim 1 in which R3 is D-aldo-pentofuranosyl, D- or L-aldo-pentopyranosyl, D- or L-aldo-hexopyranosyl or O-D-aldo-hexopyranosyl-(1 < 4)-D-aldo-hexopyranosyl.
6. A compound as claimed in claim 5 in which R' is hydrogen or alkoxy of one or two carbon atoms.
7. A compound as claimed in claim 5 in which R' is hydrogen or alkyl of one or two carbon atoms.
8. A compound as claimed in claim 5 in which R' is hydrogen or alkoxymethyl of two or three carbon atoms.
9. A compound as claimed in claim 5 in which R1 is hydrogen.
10. A compound as claimed in any of claims 6 to 9 in which R2 is alkoxy of one or two carbon atoms.
11. A compound as claimed in any of claims 6 to 10 in which R3 is D-ribofuranosyl, L-arabinopyranosyl, D-xylopyranosyl, D-mannopyranosyl, D-galactopyranosyl, D-g lucopyranosyl or O-a-D-glucopyranosyl- (1 < 4)-D-glucopyranosyl.
12. A compound as claimed in claim 10 in which R3 is L-arabinopyranosyl, D-xylopyranosyl, D-galactopyranosyl or O-a-D-glucopyranosyl-(1 > 4)-D-glucopyranosyl.
13. A compound as claimed in claim 10 in which R3 is L-arabinopyranosyl, D-xylopyranosyl or O-&alpha;-D-glucopyranosyl-( 1- > 4)-D-glucopyranosyl.
14. A compound as claimed in claim 13 in which n is one.
15. A compound of the general formula:
wherein R1 is hydrogen, alkyl of one or two carbon atoms, alkoxy of one or two carbon atoms or alkoxymethyl of two or three carbon atoms, R2 is alkoxy of one or two carbon atoms or alkoxymethoxy of two or three carbon atoms, R3 is aldo-pentofuranosyl, aldo-pentopyranosyl, aldo-hexopyranosyl or O-aldo-hexopyranosyl-(1 < 4)-aldo-hexopyranosyl, and n is an integer of one or two.
16. A process for preparing a compound of the general formula given in claim 1 which comprises nitrosating a compound of the general formula:
wherein R1, R2, R3 and n have the meanings given in claim 1.
17. A process as claimed in claim 16 wherein the nitrosation is effected by contacting the compound of general formula [II] with nitrous acid, nitrogen trioxide or nitrogen tetroxide at -20 C to 20"C in an inert solvent.
18. A process as claimed in claim 17 in which the temperature is from about O"C. to about 5'C.
19. A process as claimed in claim 17 or 18 in which the nitrosation is effected by nitrous acid immediately after preparation from an alkali metal salt of nitrous acid and a mineral or organic acid.
20. A process as claimed in claim 17 or 18 in which the nitrosation is effected by nitrogen trioxide or nitrogen tetroxide by dissolving the compound of general formula II in the inert solvent and introducing the nitrogen trioxide or nitrogen tetroxide in the presence or absence of an acid acceptor.
21. A therapeutic composition which comprises a therapeutically effective amount of a compound of the general formula given in claim 1 and a pharmaceutically acceptable carrier therefor.
22. A composition as claimed in claim 21 in which the carrier does not react with the compound of general formula I.
23. Nitrosourea compounds of the general formula given in claim 1 substantially as herein described with reference to and as illustrated in any of the Examples.
24. Process for the preparation of compounds of the general formula given in claim 1 substantially as herein described with reference to and as illustrated in any of the Examples.
GB7834564A 1978-08-25 1978-08-25 Novel nitrosourea compounds and process for preparing the same Withdrawn GB2028795A (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
GB7834564A GB2028795A (en) 1978-08-25 1978-08-25 Novel nitrosourea compounds and process for preparing the same
US06/066,421 US4241053A (en) 1978-08-25 1979-08-14 Novel nitrosourea compounds and process for preparing the same
NL7906191A NL7906191A (en) 1978-08-25 1979-08-14 NEW NITROSOURUM DERIVATIVES AND THEIR METHOD OF PREPARATION.
JP54105184A JPS6055077B2 (en) 1978-08-25 1979-08-17 Nitrosourea derivatives and their production method
DE2933663A DE2933663C2 (en) 1978-08-25 1979-08-20 1- (2-chloroethyl) -1-nitroso-3-substituted-3-glycosylureas, processes for their preparation and pharmaceuticals containing these compounds
IT25246/79A IT1193213B (en) 1978-08-25 1979-08-21 NITROSOUREA DERIVATIVES AND RELATED MANUFACTURING PROCEDURE
CA000334307A CA1121347A (en) 1978-08-25 1979-08-23 Nitrosourea compounds and process for preparing the same
FR7921268A FR2434174A1 (en) 1978-08-25 1979-08-23 NITROSURES, THEIR PREPARATION AND THEIR USES AS ANTI-TUMOR DRUGS
ES483636A ES483636A1 (en) 1978-08-25 1979-08-24 Novel nitrosourea compounds and process for preparing the same
AT0568979A AT368517B (en) 1978-08-25 1979-08-24 METHOD FOR PRODUCING NEW NITROSOURIDE COMPOUNDS
GB7929525A GB2031875B (en) 1978-08-25 1979-08-24 Nitrosourea compounds and process for preparing the same
CH773279A CH640867A5 (en) 1978-08-25 1979-08-24 NITROSOURIDE COMPOUNDS, METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THEM.
BE0/196867A BE878412A (en) 1978-08-25 1979-08-24 NOVEL NITROSO-UREA DERIVATIVES WITH ONCOSTATIC ACTIVITY AND PREPARATION METHOD

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0062329A1 (en) * 1981-04-02 1982-10-13 Tanabe Seiyaku Co., Ltd. Novel nitrosourea derivative, process for preparing same and therapeutic composition containing said derivate
US5001158A (en) * 1984-04-11 1991-03-19 Centre National De La Recherche Scientifique Nitrosoureas compounds preparation thereof and utilization thereof in anticancerous

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5220039A (en) * 1989-03-07 1993-06-15 Aerojet General Corporation Energetic azide plasticizer

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0062329A1 (en) * 1981-04-02 1982-10-13 Tanabe Seiyaku Co., Ltd. Novel nitrosourea derivative, process for preparing same and therapeutic composition containing said derivate
US5001158A (en) * 1984-04-11 1991-03-19 Centre National De La Recherche Scientifique Nitrosoureas compounds preparation thereof and utilization thereof in anticancerous

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BE878412A (en) 1980-02-25
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