DE3046393A1 - NEW GLUCOPYRANOSE-NITROSOURIDE COMPOUNDS WITH ANTITUM ORACTIVITY, METHOD FOR PRODUCING THE COMPOUNDS AND THE PHARMACEUTICAL AGENT CONTAINING THEM - Google Patents

Description

New glucopyranose-nitrosourea compounds with antitumor activity, Process for the preparation of the compounds and pharmaceutical agent containing them

The invention relates to new agents having anti-tumor activity. More particularly, the invention relates to novel glucopyranose nitrosourea compounds having a wide range of anti-tumor activity, a method of manufacture the same and a pharmaceutical agent containing these compounds.

Various kinds of glucopyranose-nitrosourea compounds having antitumor activity have heretofore been described, which compounds having a 2-chloroethyl-nitrosourea group bonded to a carbon atom of the D-glucopyranose skeleton are believed to show excellent activity. This type of glucopyranose-nitrosourea compounds includes, for example, 3- (n-alkyl (with 1-4 carbon atoms) -D-glycopyranos-6- or -2-yl) -1- (2-chloroethyl) -1-nitrosourea, 3- (D-Glucopyranos-6- or -2-yl) -1- (2-chloroethyl) -1-nitrosourea and 3- (L-glucopyranosyl) -1- (2-chloroethyl) -1-nitrosourea (see Japanese patent specification 902,656, Japanese Patent Publication 78/95 917 ⁺ , U.S. ^{Patents 4,057,684, 4,086,415 and 4,156,777 +} , Canadian Patent 1,044,228, British Patent

1 499 760, French patent 75/21144, German Auslegeschrift 2 530 416, German Offenlegungsschrift

2 805 185 ⁺ , Dutch patent publication 75 07 973 and 78 00 92O ⁺ , Swiss patent specification 610 334, USSR patent specification 670 225, Hungarian patent specification 172 906, Spanish patent specification 465 846 ⁺ , Journal of Med. Chem. 163, 104, 1975, Cancer Treatment Report, 60, 801, 1976 and Cancer Research, 22, 783, 1977 ·) ·

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There were now the chemical structures of the above Glupopyranose compounds of the 2-chloroethyl-nitrosourea type, in particular, the kinds of the hydrocarbon group as a substituent for the hydrogen atom in the The hydroxyl group bonded to the carbon atom in the 1-position of the glucopyranose skeleton is examined in detail, according to which the existence of many new 2-chloroethyl-nitrosourea-glucopyranose compounds with a wide range of anti-tumor activity, low toxicity, lower Water solubility and high oil solubility was found. The new compounds show excellent Activity against Lewis lung carcinoma and the so-called acites hiptatoma, although it is difficult to detect them Situation due to the characteristics of the conventional 2-Ohloräthyl-nitrοsourea-glucopyranoseverbindungen to suspect.

The novel compounds of the invention have the following general formula:

OH ₃ HH-C-IT I * ö

desolate

CH ₂ OH

1 'nh-o-n ^ ^ NO -c V cc Ib ^l \
HO 1 C. CH 7 0 ^Of 300GG / IF -8th - TGlNAL INSPECTED

wherein E is a member of the group consisting of branched chain alkyl with 4 to 9 carbon atoms, cyclohexyl, mono- (or tri-) methyleye1ohexyl, benzyl, Methylphenyl, phenylethyl and morma] em-alkyl with 5 bis Consists of 10 carbon atoms. Each of the above compounds occurs as two stereoisomers, i.e., oC anomers and / 3 anomers.

These anomers or mixtures thereof all show excellent biological activity.

The glucopyranose nitrosourea compounds of the formula Ia or Ib according to the invention can be used with regard to the Types of the substituent R and the positions of the 2-chloroethyl-nitrosourea group be divided into the following eight groups on the scaffolding:

Group A:

3- (branched-chain-alkyl-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea compounds, e.g.

3- (Isobutyl-θύ- or - / SD-glucopyranos-ö-yl) -1- (2-chloroethyl-1-nitrosourea / designation "AI" for the oc anomer; see later example \ /,

3- (sec.Butyl-06- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea Designation "A-II" and "A-III" for dasoC- or the β- anomer; see Examples 2 and

3- (tert. Butyl-oC / - or - / 3-.D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / designation ¹¹ A-IV "or" AV "; cf. . Example 4b7,

3- (Isoamyl-c </ - or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / I ¹ A-VI ¹¹ for the <*>anomer; example

13006G / 0B70

3- (sek.Amyl-oc / - or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitroso] i2 iarnstoff ⁷ A-VH "for the /"3-anomer; Example 157,

3- (3-Pentyl-o £ / - or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / "" A-VIII "for the oC-anomer; Example 167,

. 3- (tert.amyl - <? £ - or - / 3-D-glucopyranos-6-yl) -1- (2-ch.loräth.yl) -1-nitrosotiarnstoff / "A-IX" for the oC - Anomer; Example ^ 7,

3- (2-methyl-1-pentyl-co or - / S-D-glucopyranos-e-yl) -1- (2-chloroethyl) -1-nitroso urea / "'A-X" for the X - anomer; Example 177,

3- (3-Methyl-3 ~ pencyl-oC- or / 3 -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea Ζ ⁵ »A-XI" for the -Xr anomer ; Example 87,

3- (4-Liethyl-2-pentyl-od / - or -β- D-glucopyranos-6yl) -1- (2-cliloroethyl) -1-iitrosoliar / T ¹ A-XII "for the .X-anomer; Example 77i

3- (2-Ethylbutyl-c6- or - / 3-D-glucopyranos-yl) -1- (2-cliloroethyl) -1-nitrosourea Z ^ A-XIII "for the> v anomer; Example 18 /,

3- (2-Heptyl-o ( _r . Or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea Z ^ A-XIV "for the -ß anomer; Example

3- (3-heptyl- (xy- or -yO-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea Z ^ A-XV "for the ~,. \> -Anomer; Example 27,

3_ (4_Heptyl-c ^ - or - / 3-D-glucopyranos-6yl) -1- (2-chloroethyl) -1-nitrosoic oxygen / EA-XVI "for the cV anomer; Example 10 /,

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44

3- (2,4-Dimethyl-3-pentyl-iX'- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / I ¹ A-XVII ¹¹ for the <06 anomer; Example 147,

3- (2-Ethylnexyl) -oG- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosoliar ZfA-XVIII "or" A-IX "; Examples 11 and 127,

3- (2,6-Dimethyl-4-heptyl-pC-cder - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / 5A-XX "for the oO-anomer; Example 13J7,

Group B:

3- (branched-chain-alkyl-D-glucopyranos-2-yl) -1- (2-clilorätliyl) -1-nitrosoliarnstoffverbindungen, e.g.

3- (Isobutyl-c? C / - or -y3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosohamstoff / T ¹¹ BI "or" B-II "; Example 3Q7,

3- (sec. Butyl-iX / - or -y3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea / T ¹¹ B-III "or" B-IV "; example 317,

3- (tert-butyl- <X '- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea / T "BV" for the c6 anomer; Example 3Z7,

3- (Isoamyl-cx> - or - ^ 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea / T ¹¹ B-VI "for the 06-anomer; Example 327 ,

3- (sec.amyl-o £ - or -β- D-glucopyranos-2-yl) -1- (2-chloroethyD-1-nitrosourea / T "B-VII" or "B-VIII"; Example 3 ^,

3 ~ (3-Pentyl- c ^ - or -e-D-glucopyranos-2-yl) -1- (2-chloroethyl ) -1-nitrosohamstoff f,

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3- (tert-Amyl-O6- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea Z? B-IX "or ¹ JB-XV Example 357,

3- (2-methyl-1-pentyl-0C- or - / 3-D-glucopyranos 2-yl) -1- (2-chloroethyl) -1-nitrosourea,

3- (3-methyl-3-pentyl-oO- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea Z ^ B-XI "for the> 6-anomer; Example 35 /,

3- (4-methyl-2-penty2-c6- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrous urine ^ "B-XII" or "B-XIII"; Example 3 ^ 7 »

3- (2-lth.ylbutyl- oO- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea /? "B-XIV" for the / 3 anomer; Example 387,

3- (2-heptyl-06- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea,

3- (3-heptyl-oC- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea,

3- (4-heptyl-o6 - or - _J / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea /. "B-XY" for the oC anomer; Example 397,

3- (2,4 ~ dimethyl-3-pentyl-o6- or - / 3-D-glucopyranos-2-yi) _1_ (2-chloroethyl-1-nitrosourea,

3- (2-Ethylhexyl- o (y or - / 3 -D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosohamstoff ^ 'B-XVI "or" B-XVII "; Example 4Q7,

3- (2,6-Dimethyl-4-heptyl-o </ - or - / 3_D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea /: ^r B-XVIII "for the qO -Anomer; Example 4i7,

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Group G:;

3- / ΓCyclohexyl- or nono- (or tri-) methylcyclohexyl -D-glucopyranos-ö-yl / -1- (2-chloroethyl) -1-nitrosourea compounds, e.g.

3- (Cyclohexyl-c6- or - / 3-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / ⁷¹ CI "or" G-II "; Example 2Q7,

3- (cis-2-methylcyclohexyl-CX> - or -, / 3-D-glucopyranos-6-yl7-1- (2-chloroethyl) -1-nitrosourea Z ^ G-III "or" C-IY "; Example 2l7,

3- (trans-2-Methylcyclohexyl-06- or - / ^ - D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea /? CV " or" C-VI "; Example 22 /,

J-Ccis-A-methylcyclohexyl-cO- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea,

"3 ^ - (trans-4-methylcyclohexyl- σί- or -ίο -D-glucopyranos-6yl) -1- (2-chloroethyl) -1-nitrosourea /." C-YII "or" C-VTII "; Example 2 ^ 7,

3- (cis-, trans-mixed-3,3,5-trimethylcyclohexyl -.- N> or - / 3 -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / "" G-IX "for the O-anomer; Example 247.

Group D:

3- / Cyclohexyl- or.-Mono- (or tri-) methylcyclohexyl-D-glucopyranos-2-yl7- ^/ 1- (2-chloroethyl) -1-nitrosourea compounds, e.g.

3- (Cyclohexyl- φ- or - / 5-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea /. ^π σ-Ι "or" D-II "; Example 4-2 /,

3- (cis-2-methylcyclohexyl-cvy- or - / 3-D-glucopyranos -2-yl) -1- (2-chloroethyl) -1-nitrosourea,

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-λ / - 3046333

3- (trans-2-methylcyclohexyl- <X / - or - / 3-D-glucopyranos-2-yl) -1 - (2-clilorätliyl) -1 -nitrosourea /! ¹ D-III "or ¹¹ D-IY"; Example 4-J7,

3- (cis-4-methyl cyclohexyl) - ^ - or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea Zl ¹ DV ¹ 'or "D-VI"; Example 447,

3- (rans-4-methylcyclohexyl-co- or - / 3-D-rglucopyranos-2yl) -1- (2-chloroethyl) -1-nitrosourea / "D-VII" and "D-VIII", respectively; Example 4 ^ 7,

3- (cis-, trans-mixed-3,3,5-trimeth.ylcyclohexyl -. ^ C / - or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea / ¹¹ D-IX "for the (τΟ-anomer; Example 4-67 ·

Group E:

3- / Senzyl- or methylphenyl- (or phenylethyl) -D-glucopyranos-6-yl7-1- (2-chloroethyl) -1-nitrosourea compounds, e.g. "

3- (Benzyl-X- or - / <3-D-glucopyrahos-6-yl) -1- (2-chloroethyl) -1 -nitrosourea / ⁵¹ EI "or" E-II "; Examples 25 and 26 / ,

3- (2-Methylphenyl- oC- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / ¹⁷ E-III "or" E-IV "; Example 277 ,

3- (Phenyl-ex / - or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / ^ EV "for the CO anomer; Example 287,

3- (Phenyl- / 5-ethyl-OL · - or - / SD-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / ¹¹ E-VI for the / 5-anomer; Example 297.

1300G6 / 0570

Group F:

3-Z.Benzyl- or Methylphenyl- () der Ph.enylath.yl-)

^? , -D-glucopyranos - ^ - yl / fi - (2. Chloroethyl) -1 -nitrosoharnst of f -

. ' connections, e.g.

j 3- (Benzyl -oO- or - y3-D-glucopyranos-2-yl) -1-

((2-chloroethyl) -1-nitrosourea / ⁷⁷ FI "or" F-II ";

! Example 4- ¹ Z /,

3- (2-methylphenyl-o6'- or - / 3-D-glucopyranos -2-yl) -1- (2-chloroethyl) -1-nitrosourea ^ F-III "or" F-IV "; Example 4-8 /,

3- (Phenyl-oC / -äthyl-oc / - or - / 3-D-glucopyranos -2-yl) -1-nitro sourea,

3- (Phenyl- / 3> -äthyl-o <C'- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea / ^ FV "for the <X / -Anomer, example 4-9 /,

Group G: ^ __

3- (n-Alkyl-D-glucopyranos-6-yi) -1 - (2-chloroethyl -) - 1 nitrosoureal compounds, e.g. ■ - = -

3- (n-Amyl-o <> - or - /6-D-glusop.'ranos-6-yl)-1-(2-chlorathyl)-1-nitrosourea / ^ G-I "or" G-II "; Example 50 /,

3- (n-Hexyl-oO- or - / 3-D-glucopyranos-6yl) -1- (2-chloroethyl) -1-nitrosourea Z ^ G-III "or" G-IV "; Example 51 /,

3- (n-heptyl-c </ - or - / e-D-glucopyranos-6-yl) - "1- (2ch.lorethyl) -1-nitrosourea,

3_ ( _n _Octyl-C </ - or - _j eD-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea / "" GV "or" G-VI "; Example 52 /,

3- (n-Nonyl-cv- or - / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea,

3_ ( _n _Decyl-cO- or - | 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea ^ "G-VII" or "G-VIII"; Example 55 /,

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ORIGINAL INSPECTED

44 »

ί Group H:

3- (n-Alkyl-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea compounds, e.g.

3- (n-Amyl- (X- or - / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea ^] ¹ HI "or" H-II "; Examples 54 and 557,

3-Cn-HeXyI-CXU. or - / 3-D-glucopyranos-2-yl) ~ 1- (2-chloroethyl) -1-nitrosourea Z) ^ H-IH "or" H-IV "; Example 567,

.3- (n-Heptyl-oC / - or -yö-D-glucopyranos-2-yl) -1- (2-cb.loroethyl) -1-nitrosourea £ "Έ-Υ" or "H-VI"; Example 5 ¹ Z /,

3- (n-Octyl-cC> - or -yS-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea,

3- (n-Nonyl-OC- or - / <3-D-glucopyranos-2-yl) -2- (2-chloroethyl) -1-nitrosourea,

3- (n-Decyl-c6- or - ^? - D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosoliar / 5H-VII "or-" H-VIII "; example

The glycopyranose-nitrosourea compounds of the ohen given formulas Ia and Ib are all new and have improved biological activity. These connections can generally according to the known method of preparation of glucopyranose-nitrosourea compounds are made ago and can be particularly advantageous after Process are formed which corresponds to that in the above-mentioned references, which are marked with the "+" are provided is described (hereinafter referred to as "pre-invention process" or the like.). Accordingly, the method of the present invention an amino-gluccpyranose compound having the following general formula

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130066/0570

-I.lAL iHSPSCTED

Ha

or

Man

1 p

(where R di'6 "has the meaning given above and R is an amino group or an acid addition-amino group) \ with an ortho- or para-substituted-phenyl-N- (2-chloroethyl) -N-nitrosocarbamate compound with the following general formula

-0-CN-CH ₂ -CH ₂ CI III

0 NO

(in which R ^ represents a nitro or cyano group) reacted, so that the desired compounds of the formula Ia or Ib are obtained as a condensation substitution product will.

Compounds of the general formula Ha or Hb for ver Use in the above process can be easily prepared by known methods. For example, when 6-amino-6-deoxy-N-carbobenzoxy-D-glucopyranoside in the presence of a

130066/0570 ORIGINAL INSPECTED

Reduction catalyst is hydrogenated in the usual way, the corresponding cyclohexyl-6-amino-6-deoxy-D-glucopyranoside can be produced in extremely high yield. These compounds of formula Ha or Hb are like the starting materials (of the formula IV) in the pre-invention process, Resistant over a relatively wide range of temperatures, pH and moisture levels. However, the water solubility of the former compounds of the formula Ha or Hb is only 1/10 to 1/2 that Water solubility of the latter materials (of Formula IV). Compounds of Formula Ha or Hb include the following four connection groups:

Group (a): Compounds in which R is branched-chain alkyl with A to 9 carbon atoms; d-h-, branched-chain-alkyl-ö-amino-ö-deoxy-D-glucopyranoside, branched chain alkyl-2-amino-2-deoxy-D-glucopyranoside and the acid addition salts thereof;

Group (b): Compounds in which R is cyclohexyl or mono-C or tri-) methylcyclohexyl; i.e., cyclohexyl-6-amino-6-deoxy-D-glucopyranoside, Cyclohexyl-2-amino-2-deoxy-D-glucopyranoside, Mono- (or tri-) methylcyclohexyl-6-amino-6deoxy-D-glucopyranoside, Mono- (or tri-) methylcyclohexyl-2-amino-2-deoxy-D-glucopyranoside and the acid addition salts thereof;

Group (c): Compounds in which R is benzyl or methylphenyl (or phenylethyl); i.e., benzyl-öamino-ö-deoxy-D-glucopyranoside, Benzyl-2-amino-2-deoxy-D-glucopyranoside, methylphenyl- (or phenylethyl) -6-amino-6-deoxy-D-glucopyranoside, Methylphenyl (or phenylethyl) 2-amino-2-deoxy-D-glucopyranoside and the acid addition salts thereof;

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Group (d): Compounds in which r ' ^{1 is} n-alkyl of 5 to 10 carbon atoms, ie; n-Alkyl-6amino-6deoxy-D-glucopyranoside, n-alkyl-2-amino-2-deoxy-D-glucopyranoside and the acid addition salts thereof.

Above-mentioned compounds of the formula Ha ader Hb of the corresponding groups (a), (b), (c) and (d) correspond to the materials (of the formula IV) of the group (a) or (c) in the pre-invention process. Each compound of the formula Ha or Hb also occurs as a vV anomer, β anomer, or a mixture thereof, all of which can be used in the present process. Further, of the compounds in the individual groups (a), (b), (c) and (d), the acid addition salts of basic compounds (ie, aminoglucopyranose compounds) are most preferred as starting materials in this process.

Compounds of the general formula III correspond with regard to the use in this process to those compounds (of the formula V) which are mentioned in the pre-invention process. Compounds of formula III, however, o- or p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate and o- or £ - cy-anophenyl-N- (2-chloroethyl) -N-nitrosocarbamate belong, while the corresponding materials (of the formula V) in the pre-invention process only relate to o-nitro- or o-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate. That is to say, as for the substituent R * in the phenyl nucleus of the compounds of the formula III, a detailed preliminary test was carried out, similar to that in the pre-invention process, whereby it was found that the compounds with p-nitro or p-cyano as well as. Nitro and o-cyano as R ^ can also be used in the condensation-substitution reaction with the compounds of the formula Ha or Hb in the present process.

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The reaction temperatures and the kinds of available organic solvents in the above condensation-substitution reaction of the compounds of the formula Ha or Hb with the compounds of the formula III are the same as those in the corresponding reaction (of compounds of formula IV with compounds of formula V) in the pre-invention process. With regard to another aspect, however, were at the pre-invention process does not include anhydrous solvents and solvents with a moisture content over 1% used to prevent decomposition of the desired compounds (of the formula I) that are formed during the reaction, to prevent. In contrast, the compounds of formula Ia and Ib of the present invention have as mentioned above is, in general, poor in water solubility so that the solvents for use in the reaction are considerable May contain proportions of moisture, e.g., 2 to 10% moisture, without decomposition of the desired compounds of formula Ia or Ib is effected in the reaction. This situation makes a major difference between the present process and the process of the previous invention. · (In this description and the claims all! percentages relate to weight).

Likewise, in the present process, those desired for use in the purification step of the formed can be used Compounds provided solvents also contain significant amounts of moisture, in particular Mixtures of lower alcohols such as methanol, ethanol, isopropanol, etc., with water can be used for the Recrystallization of the desired compounds can be used.

A mixture of o6-anomer and / ^ - anomer of a compound of

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- 2Ö -

Formula Li or Ib, which when using a of 06 anomer and / 3 anomer of the corresponding

Mixture
is formed in starting compound of the formula Ha or Hb, can
into the relevant oC-anomer and / 3-anomer compounds of formula Ia or Ib using known procedures such as column chromatography with silica gel.

Tests were carried out to compare the physicochemical and pharmacological properties of the compounds of the Formula Ia or Ib of the invention with those of the conventional 2-chloroethyl-nitrosourea-glucopyranose compounds carried out. As conventional 2-chloroethyl-nitrosourea-glucopyranose compounds The following have been used, which have heretofore been generally believed to have excellent antitumor activity:

3- (Methyl -; & - D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea (referred to as 2MCoi / G),

3- (Methyl-cv-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea (referred to as 6MO3 / G),

3- (D-Glucopyranos-2-yl) -1 - (2-chloroethyl) -1 -nitrosourea (referred to as DCNU),

3 - (/ 3 -D-glucopyranosyl) -1- (2-chloroethyl) -1-nitrosourea (referred to as GANU).

In addition to the above-mentioned conventional 2-chloroethyl-nitrosourea-glucopyranose compounds the following non-glucopyranose compounds that have a 2-chloroethyl-nitrosourea group and according to the previous assessment an excellent activity against * - should possess about tumor systems, as a comparative connection

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fertilize in the antitumor activity tests given later used:

-3- (2-chloro-

ethyl) -3-nitrosourea hydrochloride (referred to as ACNTJ),

1,3-bis (2-chloroethyl) -1-nitrosourea (referred to as BCNU ),

1- (2-chloroethyl) -3-cyclohexyl-1-nitrosourea (as CONU),

N- (2-chloroethyl) -N '- (trans-A-methylcyclohexyl) -N-nitrosourea (referred to as MeCCNU),

(A) Solubility in water and chloroform

Table I shows the solubility (mg / ml) of the test compounds in water and chloroform in each case at 23 ^° C.
The table shows that the compounds of the
Formula Ia or Ib have a considerably lower solubility in water but an increased solubility in chloroform compared to the solubilities of the conventional compounds 6MCoO G and 2MCoCG.

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Table I.

Te s t connection

Solubility (ui ^ / iuQ Q 4 6 3 9

tfasser

chloroform

AI
A-II
A-IV
A-XVIII

14.4

22.0

551-

737

440 Ö8C

BI
B-III

B-VI "

7 «30

C-I

C-II

C-VII

34

345

I) -I
I) -III

35 30

EGG

E-III

E-V

685 720 78U

F-I

F-III

F-V

50 45

U-VII
G-VIlI

1705

800

(Verg1e i chsve rb inaung)

2MCoUS 40.0

6MC0U1 1210.0

42

130066 / 0B70 _{BAD 0R1G} , _NA L

(B) Antitumor Activity

(1) Activity in Leucemia L-1210

The determination of the antitumor activity was carried out according to the Method of the National Cancer Center, Tokyo (A.Hoshi et al .: Farumashia, ^, 464 · »1973) carried out. That is, the Test compounds were BDF ^ mice, 6 per group, 24 hours after implantation of 10 L-1210 cells in each animal entered by a single intraperitoneal (ip) or by a single oral (po) administration, whereupon the number of Test animals were determined which survived 60 days, and the degree of increase in life span (referred to as ILS%) of the same was calculated from the mean life compared to the control. The test compounds were in a 0.5% aqueous solution of sodium carboxymethyl cellulose (referred to as CMC) dissolved or suspended just prior to administration. Results of the test are in the Table II, from which it can be seen that the activity of the compounds of formula Ia or Ib against L-1210 is quite similar to the activity of the conventional compounds 2MCo6G, 6MCo6G, CCNU and MeCCNU.

- 24 -

13 0 0 6 6/0570 ^0RlGlNAL inspected

treatment Table'I! "" ILS; έ 3046393 Te s t connection po dosage
(mg / kg) > 574
> 7ÜÜ Survivors A-I po 56.4
79.0 6/6
6/6 A-II po 5b, 4
79.0 > 700
> 700 6/6
o / o A-IIl po 5b, 4
79.0 > 700
> 700 0/6
6/6 A-IV po 56.4
79.0 .V 700
> 700 6/6
b / b A-VI po 58.6
82.0 > 700 6/6
6/6 A-XI po 70.0
100.0 >57'i
i> 7üÖ 6/6
6/6 A-XVIII po 70.0
100.0 > 700 6/6
6/6 A-XX po 70.0
100.0 > 7 OK 0/6
6/6 BI po 5b, 4
79.0 > 700
> 7G0 6/6
0/6 B-IV ip
po 5υ, 4
79.0 > ?! £ 6/6
6/6 B-VI po 5 ^, 6
82.0 6/6
6/6 B-Xl po Ιϋυ, Ο > 654 6/6
0/6 B-XV po 70.0
100.0 > 700 6/0
ü / 6 B-XVII 70.0
100.0 6/6
6/6

13 0066/0570

BATH ORIGINAL

Te s t connection

Table II (-Font-iung}

treatment

Dosage (mg / kg)

ILS Jo

Survivors

C-I po 85.0
100.0 > 70Ü
^ 700 6/6
6 / b C-II po 85.0
ICO, 0 > 70C 6 / b
6/6 C-III po IUU, 0 > 7üü b / 6
6/6 C-VI po «5.0
ILU, Ü > 57'i if
b / b C-VII po 85.0
IUU, 0 > 7uu 6/6
b / b D-I po 85.0
1LÜ, Ü > 7C0 b / o
b / 6 D-II i'O 85.0
100.0 > 57 · '* if
υ / ο D-III ■ P
i'O 35.0
100.0 > bbü ü / 6
b / 6 D-VII po 85.0
100.0 > bbö b / 6
6/6 BI po 61.6 -r ^
Sb, "2 _; - >J7't
>'fUU (// U
If U-III po 61.6 " ^
86.2 > 7tL o / O E-V po 70, U
100, U > 7Uu b / b
b / u IJ-VI po 70, U
1UÜ, O > 7UU 6 / b
6 / b

- 26 -

130066/0570

BAD ORIGINAL, _{t (} ; _opY

Table II (continued)

Test connection. treatment dosage
(mg / kg) F-I po IbU, 0 F-II po δ6.2
100.0 F-IV po 85.0
100.0

1L6

Lberlebeude

>
> 70G

> bbU

> 574

b / b

b / b

O / b b / o

b / b ü / 6

GI
G-III

G-V

po
po
po

70.0 100.0

'.0.0 100.0> 700
> 700

> 7U0

> 57-Ί

b / 6 6/6

6 / b 6 / b

6/6 6/6

Ii-i

H-III

TGt-VIl
H-VIII

po
po
po

70.0 100.0

70.0 100.0

> 57

6/6

b / b

6/6 b / 6

6/6 6/6

5/6 5/6

(Comparison connection)
2MC <G

6MCcACr

CCNU
MeCCNU

12.5
25.0 > 70u
> 700 6/6
6/6 25.0
35.0 > 7CU 6/6
b / 6 5C, 0 > 650 b / b 50.0 > 65C b / b

130066/0570 copy - 27 -

ORIGINAL

(2) Activity in Lewis lung carcinoma

It has heretofore been known that 2-chloroethylnitrosourea type glucopyranose compounds generally show activity in Lewis lung carcinoma when used by the so-called early treatment method in which the drugs are administered to animals 1 day or 2 days after the tumor is implanted, but these compounds (with the exception of GMCt-C G) generally do not show activity when using the so-called established treatment method in which the drugs are given to the animals, for example 7 or 13 days after the tumor has been implanted. However, the compounds of the formulas Ia and Ib of the invention surprisingly showed a pronounced activity even with the said introduced treatment method. That is, 10 Lewis lung carcinoma cells were implanted in female BD2F mice (5 to 8 per group) and the test compounds were administered intraperitoneally -TCß.r to each animal after 7 days or after 7 and 13 days, after which the number of animals who had survived 60 days with or without a tumor, and the degree of increase in life span was determined. Tumors found in test animals prior to said administration of the compounds weighed 400-500 mg and about 1200 mg after 7 days and after 13 days, respectively. The activity level of the test compounds was classified according to the values for the ILS % as follows: "-" if ILS % is 0-24%, "+" if this is 25-49%, "++" if this is 50- Is 99 % , and "+++" if it is 100% or more. The results of the test are given in Table III and indicate that the compounds of formula Ia and Ib show marked activity in Lewis lung carcinoma, this activity being fairly equal to or slightly less than that of the conventional compounds and MeCCMJ.

CC: 7-28-130006 _{/0570 CBiQ1NAL}

Table III

Te a tv he bond

Behaudluiigstajr (e)

ILS MjL Tumor I pear lumor , * LberleuiMKiu / IVs i-

Li ere

A-I

A-II

"· A-VI

'A-VII

A-XI

A-XII

A-XIII

A-XV

A-XVI

A-XVlII

95.9 112.8

79.0 112.8

79.0 112.8

82.0 99.5

82.0

99.5

70.0

100.0

70.0 100.0

■ 70.0 100.0

85.0 100.0

85.0 100.0

70.0 100.0

7, 13 7, 13 7

7, 13 7

7, 13

7.13
7, 13

7, 13 7, 13 7, 13 7, 13

7.13
7, 13

7, 13 7, 13

7, 13 7, 13

7, 13 7, 13

7, 13 7, 13

υΐ 1/6 υ / ο ; ι 0/7 0/7 71 If 0 / b ^: 54 0/5 0/5 t, 4 1/7 0/7 65 0/6 0/6 65 0/6 0 / b 70 0/6 0/6 61 6/7 0/7 65 0/6 b / b 60 υ / 6 Ο / υ 71 0/6 0/6 "8th θ / ό 0/6 68 0/6 0/6 98 0/6 0 / b 64 0/6 ü / 6 ^ o 0/6 0/6 14th 0/6 0 / b 2 0/6 0 / b ο 0/6 0/6 *, 7 0/6 0/6 35 0/6 0/6 36 0/6 U / 6

BATH ORIGINAL

- 29 -

130066/0570

COPY

Table HX (i \) rt3etzunjg) ~ ~ - ': ~:

Fixed compound dosage Treatment day (s) ILS Mj t tumor / liiüTei ^ mur activity (mg / kg) ß> L survivors / test

animals

BI

B-IV

B-VI

B-Al

B-XIII

B-XlV

79, over 112.8

79.0 112.8

82.0 99.5

70, υ ιου, ο

70.0 100.0

70.0 100.0

54 u / 6 60 0/6 52 0/6 61 0/6 55 u / 6 62 0/6 54 o / b 64 (j / 'b 54 ü / 6 60 0/6 55 0/6 61 0/6

0/6 U / 6

ü / 6 ü / b

υ / 6 0 / b

over / over over / over

ü / ü ü / 6

0/6

U / 6

C-I

C-IV

C-VII

85.0 7, 13 63 0/6 0/6 100.0 7, 13 53 0/6 U / 6 85.0 7, 13 61 ü / 6 o / b 100.0 7, 13 70 G / b ü / 6 85.0 7, 13 60 ü / 6 0 / b 100.0 7, 13 88 0 / b o / b

D-I

D-III

D-IV

85.0 7, 13 55 ü / 6 0/6 100.0 7, 13 52 0/6 0/6 85.0 7, 13 . 52 0/6 0/6 100.0 7, 13 58 0/6 0/6 85.0 7, 13 54 0/6 0/6 100.0 7, 13 56 0/6 0/6

130066/0570

- 30 -BA

Test connection

Table III (continued) ^

Dosage B _e viable options (e} (mg / kg)

ILS With Tuinür | OJine tumor [activiti $ Survivors / remnants

Lie re

EGG 86.2 35.0 7, 13 5a 0570 l / b U / b ++ 104.7 20.0 7, 13 82 0/7 0/7 ++ JB-III 70.0 7, 13 60 If U / b ++ 100.0 7, 13 68 u / b U / b ++ E-VI 70.0 7, 13 57 if 0 / b ++ 100.0 7, 13 60 0/6 0/6 ++ F-I 86.2 7, 13 52 0/6 u / b -H- 104.7 7, 13 64 U / 6 U / 6 ++ F-III 86.2 7, 13 51 0/6 U / b ++ 104, 7 7, 13 60 0/6 U / b ++ F-V 86.2 7, 13 35 0/6 L / 6 + G-I 82.0 7, 13 60 0/6 U / b ++ 99.5 7, 13 72 0 / b u / 6 ++ G-V 70.0 7, 13 47 · If o / b ++ 100.0 7, 13 62 o / b U / b ++ G-VII 70.0 7, 13 32 If u / b + 100.0 7, 13 38 0/6 U / 6 + HI 82.0 7, 13 54 0/6 0/6 ++ 99.5 7, 13 62 0/6 0/6 ++ H-IV 50.0 7, 13 32 0/6 0 / b + 70.0 7, 13 40 0/6 / 6 + (Comparison connection) 6MCc (G. 7, 13 80 2 / Ö 2/6 ++ MeCCiNU 7, 13 81 0 / b l / ö ++ 130066 / - 31 - BATH ORIGINAL

(3) activity against acites heptatoma

The test to determine anti-tumor activity was carried out performed using 11 strains of acites heptatoma, i.e. strains AH13, 130, 272, 44, 66F, 66, 7974, 41C, 6OC, 1O9A and 414, all from the Sasaki Institure, Sasaki Foundation, Tokyo. Ten cells from each heptatoma strain were intraperitoneally in female Donryu rats weighing about 150 g, 6 each Group, implanted, and the test compounds dissolved or suspended in 0.5% aqueous CMC solution were given to each animal on the 3rd and 7th day or on the 3rd, 7th and 11th day or continuously for 10 days from the 3rd day after the Tumor implantation administered intraperitoneally. The degree of activity of the test compounds was determined using the ILS% values the test animals are classified as follows:

"-", if ILS % is below 50 % , "-", if this is 50-200 % , and "+", if this is above 200 % , also by the designation "0" for '! - "," 1 "for" ± "and" 2 "for V, the total of these values being calculated for each test compound for all of the heptatoma strains mentioned. The results of the test are given in Table IY and indicate that the compounds of formula Ia or Ib show an actuator superior to that of the conventional compounds SMCi & G, GAMJ, CCNU, BCMJ and ACMT.

- 32 130066/0570

Table IV

Te s tve r b ι nd uiiff dosage
(mg Ag
χ Application
frequency) A-I 50 χ 2 A-II 50 χ 2 A-VI 50 χ 2 B-III 50 χ 2 C-I 50 χ 2 L-I 50 χ 2 D-VIII 50 χ 2 EGG 50 χ 2 F-III 50 χ 2 G-III 50 χ 2 H-III 50 χ 2

AH 13 AH I3O 'All 272 All 44 AH 66F All 66 AH7974 Ail 41C AU 6OC .4JJ lü $ A Ail 414 Gesaintbei counting

11 10

12 10

CD Jt--

(Comparison connection) χ 3

4 χ 10

1 χ lü

7.5 x 10

3 χ 10

4 χ 10

GANU
CC.VÜ
BCNTJ
ACKU

3045393

(C) Acute toxicity

Dissolved or suspended in 0.5% aqueous CMC solution Test compounds were injected intrsperitoneally into ICR mice in a volume of 0.2 ml per 10 g of body weight Test animals administered. The LD ™ (mg / kg) of each compound was taking out the mortality of the test animals for 30 days Application of the Behrens-Kärber method, according to which then also the value for the LDcq / molecular weight (Denoted MG) (mg / kg.mol) was calculated. The results are given in Table V, from which it can be seen that the acute toxicity of the compounds of formula Ia or Ib only 1/2 to 1/3 times the acute toxicity of the conventional compounds 6MCOSG, 2MCoCG, DCNTJ and GANU is what matters.

From the above toxicity and anti-tumor activity in the respective ones detailed in (B) above Tumor systems were called the smallest effective dose (MED) and the largest tolerated dose (MTD called) calculated from each connection. The types of hydrocarbons and the number of carbon atoms they contain form the group R in the compounds of formula Ia or Ib according to the invention, were determined by examining the MED, MTD and other factors (such as ease of manufacture) are assessed.

- 34- 130066/0570

ORiGiNAL INSPECTED

35
Table V MG ft 1 1 - - ■ *, -,
* * · · * - *
3046393 Te s tverbin & ung ^LD 50
(mg / kg) 369.0 LJj JhG
(mß / kjL>; · mol) A-I U6.7 369.8 L, 3 ^l > 7 A-II 150.0 369.8 0.4Gb A-IJI 148.0 369.8 b, 'iU A-IV 155.0 333.8 U, 'il'J A-VI 148.2 383.8 C, 30b A-IX 150.2 397.9 0.391 A-Xl 14b, 2 411.9 υ, 372 A-XVI 150.5 425.9 ■ o, 3b5 A-XVIII 145.3 439.9 0.336 A-XX 148.8 369.0 0.338 BI 154.2 369.8 0.417 B-IV 156.8 383.0 0.424 B-VI 145.4 397.9 0.379 B-Xl 153.7 397.9 ϋ, 3 »υ B-XlI 146.2 425.9 0.367 B-XVI 151.2 425.9 o, 355 B-XVII 142.2 395.8 0.334 C-I 173.3 395.8 0.438 C-II 165.4 409.9 U, 418 C-V 169.2 409.9 0.413 C-VII 178.2 0.435

130066/0570

BATH ORIGINAL

Teaether bond

- is: -

Table V (F _o tinue)

MG

Li) / MG (mg / kg η; θΐ)

D-II
D-IV
D-IX

180.2 174.0

182.8 160.2

395.8 395.8 409.9 437.9

0.455 0.440 0.446 0.366

EGG

E-II

E-V

170.2 168.2 155.0

403.8 403.8 417.9

0.421 0.417 0.371

F-I

F-III

F-V

174.2 170.2 172.5

403.8 403.8 417.9

0.431 0.421 0.413

G-I

G-III

G-V

138.2 136.7 103.3

383.8 397.9 425.9

0.360 0.344 0.243

H-I-H-III

H-IV
H-VII

146.2

143.5

138.2

9 ^, 2

397.9

397.9 454.0

ü, 3bl

0.347 0.216

(Comparison connection)

6MCcCG 40

2MC <G 48

DCNU 44

GANU 24

327.7 327.7 313.7 313.7

13ÖÖ66 / 057U

0.122 0.146 0.140 0.077

- 36 "OPEN INNÄTTRSPECrED"

As indicated above, the novel compounds of formula Ia or Ib of the invention are excellent physicochemical and pharmacological properties so that they are similar to the conventional useful Compounds with antitumor activity by mixing with physiologically suitable solid or liquid Carriers can be formulated into pharmaceutical agents. The means can, for example, be in the form of tablets, coated tablets or coated tablets, capsules, powders, granules, injection liquids, Have emulsions, suspensions or suppositories.

Carriers for use in such compositions include, for example, commonly used fillers (or binders), disintegrants such as starch, dextrin, glucose, lactose, sucrose, methyl cellulose, calcium carboxymethyl cellulose, Sodium carboxymethyl cellulose, crystalline cellulose, magnesium stearate, sodium alginate, Witepsol E85, Witepsol W35 and polyvinyl alcohol, Gleitbzw. Lubricants such as talc, stearic acid, waxes, hydroxypropyl cellulose and boric acid, coating materials, such as shellac, cellulose acetate phthalate and polyvinylacetaldiethylaminoacetate, Solubilizers, such as glycerine, propylene glycol and mannitol, emulsifying or suspending agents, such as polyoxyethylene stearate, polyoxyethylene acetyl alcohol ether, Gum arabic and soda soap, stabilizers such as sorbitol, Twenn 80, Span 60 and fats and oils, and solvents of many kinds.

For example, the pharmaceutical compositions of the invention can be applied to an animal (including a human) of body weight of 60kg are used in such a way that the compounds of the formula Ia

- 37-130066/0570

or Ib conform to the following guidelines: A single dose of 20-2000 mg / 1-6 weeks; a 2 to 3 fold dose of 1-1000 mg / once in 2-3 weeks; a dose of 1-1000 mg / once for consecutive days of 1-3 weeks and the like. However, the indicated dosages may of course be varied as appropriate depending on the treatment regimen, the conditions of the patients or the forms of the agents.

The composition of the pharmaceutical agents with the compounds Ia or Ib as active ingredients are explained below by way of example:

- 38 -

130066/0570

ORIGINAL INSPECTED

Tablets

i) A-I 50 mg

Lactose 108 mg

Magnesium stearate 2 mg

all in all ii) C-I all in all Capsules all in all ii) B-I 160 mg crystalline cellulose i) A-III crystalline cellulose ISO mg Strength . crystalline cellulose strength 45 mg glucose strength glucose 25 mg Calcium carboxymethyl cellulose Lactose C _a lciuw carboxymethyl cellulose 48 mg Magnesium stearate Calcium carboxymethyl cellulose Magnesium stearate 25 mg Hydroxypropyl cellulose Magnesium stearate Hydroxypropyl cellulose 2 mg Hydroxypropylene cellulose 5 mg 300 mg 100 mg 20 mg 18 mg 40 mg 15 mg 2 mg 5 mg 200 mg 100 mg 20 mg 18 mg 40 mg 15 mg 2 mg 5 mg

total 200: mg - 59 -

A-V Suppositories Suspensions 150 mg crystalline cellulose D-I EGG 20th mg strength Vitepsol W35 Sodium carboxymethyl cellulose 20th mg Lactose Witepsol E85 deionized if _a sser 40 mg Calciuracarboxymethyl cellulose Polyoxyethylene ester 15th mg Hydroxypropyl cellulose all in all 5 mg all in all 25O mg 340 mg 83O mg 82 mg 48 mg I3OO mg 30th mg 2 mg 68 mg

a total of 100 mg

Emulsions all in all In.iection liquids 10 mg F-I A-I 3 mg Gum arabic physiological saline solution 87 mg deionized WSseer 100 mg 20th mg lü ml

- MO -

130066/0570

ORIGINAL INSPECTED

Drip injection liquids

A-II 100 mg Mannitol 150 mg physiological Saline solution 300 ml

The following examples are intended to illustrate the production of the new compounds of formula Ia or Ib according to the invention explain. In all examples, the organic solvents used refer to those with a Moisture content of 2-4%.

example 1

7.96 g (29.1 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in 40 ml of tetrahydrofuran, and the solution is cooled to a temperature of 0-5 ° C. To this solution is added dropwise a solution obtained by dissolving 6.49 g (27.6 mmol) of isobutyl-6-amino-6-deoxy-D-glucopyranoside in 50 ml of ethanol while at Q-5 ° C is stirred for 10 minutes. The resulting solution is stirred at the same temperature for a further 2 hours. Termination of the condensation reaction is confirmed by thin layer chromatography / adsorbent: silica gel 60 (trademark; manufactured by Merck GmbH); Flux: chloroform-ethanol (10: 1); TLC genannt7 subsequently checked, and the thus reacted solution is concentrated at 30 ⁰ C and below, under reduced pressure. The concentrate obtained is subjected to column chromatography / solid support: silica gel 60 (trademark; manufactured by Merck GmbH; the same solid support is used below;) mobile phase: benzene,

- 41 -

130066/0570

Chloroform-ethanol (10: 1 ^ 7 to separate it into oO and / 3 anomeric fractions. The cC anomeric fraction, which was mainly eluted in the first stage, is at 25 ° C and below with reduced Pressure concentrated, and the crystalline residue obtained is recrystallized from a mixture of ethyl acetate and water to give 3- (isobutyl-iX, -D-glucopyranos-6yl) -1- (2-chloroethyl) -1-nitrosourea.

Yield: 3 59 g (35.2 % of Theory). F. 72-74 ⁰ C Cl, (J ' tip + 76.0 ° (C 1. 0, Methanol). Cl, Analysis for ί 1 * 24. ; -0r, Cl V ¹¹⁰ 369.80): Calculated 0 έ) C, 42.22 H, 6.54 N, 11.36 9 , 59 Found 0 έ) C, 42.13 H, 6.58 N, 11.38 9 , 51

IR spectrum (KBr, cm " ¹ ): 3350 (r0-H), 1700 (rC = 0), 1520 ( -r NH), 1490 (-yNO),

NMH spectrum (DMSO-dg, ^: 0.77 (d, J- 7Hz, 6H), 4.61

d, J «4Hz), 8.42 (t, NH)

Example 2

19.20 g (81.6 mmol) of sec-butyl-δ-amino-δ-deoxy-D-glucopyranoside are dissolved in 200 ml of methanol, and 5 S dry ice are gradually added to this solution so as to convert the glucopyranoside into its carboxylic acid addition salt. This acid addition salt solution is then added dropwise to a solution which is obtained by dissolving 23.23 g (84.9 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been obtained in 200 ml of tetrahydrofuran, within 'on 10 minutes with stirring at 0-5 ° C The obtained solution is at the same temperature for

- 42 -

130066/0 57 0 originally inspected

30Α6393

stirred for a further 2 hours. The completion of the reaction is checked by means of TLC, and the solution converted in this way is ^{concentrated at 30 °} C. and under reduced pressure. The concentrate obtained is subjected to column chromatography

subject / Ii ¹ eluent: chloroform chloroform

Methanol (39: 1) J <> to separate it into ^r c6 and β anomeric fractions.

The fractions in question are ^{concentrated at 30 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of acetone, isopropyl ether and water and give 3- (sec-butyl - <? </ -D-glucopyranos-6 -yl) -1- (2-chloroethyl) -1-nitrosourea (i.e. theoC-anomer) and 3- (sec-butyl- ß -D-glucopyranos | 6-yl) -1 - (^ - chloroethyl) -1- nitrosourea (i.e. the / 3-fanomer).

For daso ^ anomer: 11.31 S j yield (37.5%) »F. 59-61 ⁰ C; foCj ² ^ + 59.9 ° (6 1.0, methanol; analysis for O ₇ Cl (MW 369.80):
(%)

Calculated (%)

C, 42.22 H, 6.54 N, 11.36 01.9.59

Found (%) c, 42.28 H, 6.43 N, 11.44 Cl, 9.66

(KBr, cm " ¹ ): 3400 (r * 0-H), 1540 (VN-H), 1500 (YN = O),

IR spectrum (KBr, cm " ¹ ): 3400 (r * 0-H), I710

CH ₅ NMR spectrum (DMSO-d ^, ^): 0.83 (t, 3H, CH ^),

1.00 (d, 3H CH ^), 3.57 C * »

^ CHCH

CH ₂ CH ₂ Cl, 4.05 (t, CH ₂ CH ₂ Cl),

and for the / 3 anomer: yield 8.51 g (28.2%); F. 110-112 ⁰ C (decomposition); C °° J ² \ -7.8 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₄ N ₅ O ₇ Cl (MW 369.80):

- 43 -

130066/0570

Calculated (%): C, 42.22 H, 6.34 N, 11.36 Gl, 9.59 Found (%): G, 42.34 H, 6.51 N, 11.42 Cl, 9.62

Example 3

18.49 g (78.6 mmol) of selcButyl-e-amino-ö-dexy - ^ - D-glucopyranoside are dissolved in a mixture of 100 ml of methanol and 100 ml of dioxane, and 5 g of dry ice are added to this solution convert the glucopyranoside into its carboxylic acid addition salt. This acid addition salt solution is then added dropwise with stirring at 0-5 ⁰ G within 10 minutes to a solution which, by dissolving 22.60 g (82.6 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbomate has been prepared in a mixture of 150 ml of tetrahydrofuran and 30 ml of toluene, and stirring is then continued at the same temperature for 2 more hours. The completion of the reaction is checked by means of TLC, and the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The crystalline residue obtained is washed with chloroform and then recrystallized from a mixture of ethanol and water and gives 3- (sec-butyl- / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea . Yield 22.81g (78.5%). M.p. 110-112 ⁰ G (decomposition). FAJ 25 _7 _i8 ° (c 1.0, methanol).

Analysis for C ₁₅ H ₂₄ N ₃ O ₇ Cl (MW 369.80):

Calculated (%) C, 42.22 'H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.29 I H, 6.47 N, 11.42 Cl, 9.64

Example 4 ι

19.20 g (81.6 mmol) of tert. Butyl-ö-amino-e-deoxy-D-glucopyranoside are in a mixture of 100 ml of methanol and

- 44 130066/0570

ORIGINAL INSPECTED

and 100 ml of dimethyl sulfoxide are dissolved, and lactic acid is added to this solution with stirring so that the pH of the solution is adjusted to 9.2. The solution is then added dropwise with stirring at 0-5 ⁰ C within 10 minutes to a solution prepared by dissolving 22.93 g (83 »8 mmol) of p-nitrophenyl-2- (2-chloroethyl) -N- nitrosocarbamate in 200 ml of tetrahydrofuran, and stirring is then continued at the same temperature for 2 more hours. The completion of the reaction is checked by TLC, and the reacted solution is ^{concentrated at K) 0} C and below under reduced pressure. The concentrate obtained is subjected to column chromatography / mobile phase: chloroform - * - ♦ chloroform-methanol (39 '* 1) _7 to separate it into ^ 6 and / 3 anomeric fractions. The fractions in question are ^{concentrated at 30 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of ethanol, isopropanol and water and give the oO-anomer, ie 3- (tert-butyl-oO ~ D- glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer compound. For dasoG - anomer: yield 4.71 g (15.6%), mp 55-57 ⁰ C; 3ψ + 60.2 ° (C 1.0, methanol); Analysis for C ₁₃ H ₂₄ N ₅ O ₇ CI (MW 369.80):

Calculated (%) C, 42.22, H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.17 .H, 6.60 N, 11.42 "Cl, 9.53

and for the / 3 anomer: yield 3.41 g (11.3%); F. 104-106 ⁰ C (decomposition); / ZcJψ -8.8 ° (C 1.0 methanol); Analysis for G ₁₅ H ₂₄ N ₃ O ₇ Cl (MW 369.80):

Calculated (%) C, 42.22 H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.32 IH, 6.48 N, 11.42 Cl, 9.63

- 45 130066/0570

Example 5

6.71 g (26.9 mmol)
pyranoside are dissolved in 100 ml of methanol, and this solution is added dropwise with stirring at 0-5 ° C within 10 minutes to a solution which is obtained by dissolving 7 »66 g (28.0 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been prepared in 100 ml of tetrahydrofuran, after which stirring is continued at the same temperature for a further 2 hours. The completion of the reaction is checked by means of TLC, and the reacted solution is ^{concentrated at 30 °} C. and below under reduced pressure. The crystalline residue obtained is washed with benzene and then recrystallized from a mixture of methanol and water and gives 3- (isoamyl-o (/ - D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea.

Yield 7.92 g (7 *, 7%). M.p. 66-68 ° C £ c7 ψ + 73.2 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.89 H, 6.77 N, 10.99 Cl, 9.18

IR spectrum (KBr, cm " ¹ ): 1700 (-TC = O), 1520 (rN-H

1490 (VN »0), 840

Nuclear Magnetic Resonance Spectrum (DMS0-dg, p: 0.80 (d, 6H, CH ₂ CH ₂ CH.), 1.37 Cm ₁ 2H, -OCHpCHp CH ^ ³ ),

WXiTf

3.56 (t, 2H, CH ₂ CH ₂ Cl), 4.06 (t, 2H, CH ₂ CH ₂ Cl), 4.57 (d, 1H, C ₁ -H), 8.32 (t, 1H, NH)

Example 6
25.30 g (101.5 mmol) tert-amyl-e-amino-ö-deoxy-D-gluco-

- 46 - 130066/0570

ORIGINAL INSPECTED

pyranoside are dissolved in a mixture of 150 ml of methanol and 50 ml of isopropanol, and formic acid is added to this solution with stirring in order to adjust the pH to 9 »7. The resulting solution is then added dropwise with stirring at 0.5 ° O within 10 minutes to a solution which is obtained by dissolving 27.29 g (107.6 mmol) of p-cyanophenyl-N- (2-chloroethyl) -N -nitrosocarbamate has been prepared in a mixture of 150 ml of tetrahydrofuran and 50 ml of acetone, after which stirring is continued at 10-15 ° C for a further 2 hours. The completion of the reaction is checked by means of TLC, and the reacted solution is ^{concentrated at 30 °} C. and below under reduced pressure. The concentrate obtained is subjected to column chromatography

subject / "eluent: benzene _> chloroform-ethanol

(10: 1) J7 to separate the ino6 and / 3 anomeric fractions. The oC / anomer fraction which was eluted first is concentrated at 25 ° C and below under reduced pressure, and the resulting crystalline residue is recrystallized from a mixture of ethanol and water to give 3- (tert-amyl-c </ -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 6.74g (17.3%). F. 68-70 ⁰ C. £ bcj ψ + 74.2 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 01, 9.23 Found (%) C, 43.77 H, 6.90 N, 10.92 Cl, 9.18

Example 7

26.41 g (100.3 mmol) sec. Hexyl-e-amino-ö-deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol and 150 ml of tetrahydrofuran, and this solution is added drop by drop under stirring at 0-5 ⁰ C within 10 minutes

- 47 13 0066/0570

wise added to a solution which has been prepared by dissolving 27.11 g (106.9 mmol) ρ cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 80 ml of acetone and 70 ml of dioxyn, after which stirring is continued at the same temperature for another 2 hours. After the completion of the reaction has been checked by means of TLC, the solution is ^{concentrated at 30 °} C. and below under reduced pressure. The concentrate obtained is subjected to column chromatography / "mobile phase: chloroform → chloroform-methanol

(59; 1), 7 »to separate it into ^ c and / 3 anomeric fractions. The u ^ anomer fraction is concentrated at 25 ° C and below under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of ethanol and petroleum ether to give 3- (sec.hexyl -. \ '- D-glucopyranos-6- yl) -1- (2-chloroethal) -1-nitrosourea. Yield 6.19g (15.5%). M.p. 64-66 ° C. C ^ J ψ + 64.4 ° (C 1.0 methanol). Analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86)

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.33 H, 7.14 N, 10.64 Cl, 8.86

Example 8

8.58 g (32.6 mmol) of 3-methyl-3-pentyl-6-deoxy-D-glucopyranoside are dissolved in a mixture of 40 ml of methanol, 40 ml of dioxane and 30 ml of lylene, and the solution is then added dropwise Stirring at 0 ^ -5 ⁰ C within 10 minutes to a solution, which by dissolving 9.28 g (33.9 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 40 ml of tetrahydrofuran and 40 ml of acetone has been established, after which continued stirring at 5-25 ⁰ C for 1.5 hours. After the exam

- 48 130066/0570

ORiGiNAL INSPECTED

means TLG unseeded solution at 25 ⁰ C and under reduced pressure will honzentriert. The concentrate is subjected to column chromatography / mobile phase: chloroform ^ chloroforu-methanol (39'-O. /,

to separate it into x, - and / 3 anomeric fractions. The ί-6-anomer fraction is ^{concentrated at 25 0} C and below under reduced pressure, and the crystalline residue formed is recrystallized from a mixture of methanol and water and gives 3- (3-methyl-3-pentyl ci- D-glucopyranos- 6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 1.92g (14.8%). 68-70 ° C. / 'x.' / Jp + 60.2 ⁰ (C 1.0, methanol). Analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.34 H, 7.14 N, 10.48 Cl, 8.97

Example 9

27.80 g (100.2 mmol) of 3-heptyl-6-amino-6-deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of ethanol and 100 ml of dioxane, and this solution is added dropwise with stirring at 0 _→ 5 ° G added within 10 minutes to a solution that was obtained by dissolving 29.00 g (106.0 mmol) of p-nitrobhenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 100 ml of tetrahydrofuran and 50 ml Methyl ethyl ketone has been prepared, after which the stirring is continued at 20-25 ⁰ C for 1.5 hours. After testing by TLC, the reacted solution is concentrated at 25 ° C. and below reduced pressure.

The concentrate is subjected to column chromatography £ eluent: chloroform ^ chloroform-methanol

(39: 1) .7 to put it in oO -and /? -Separate anomeric fractions. DievXz-Anomerfraktion is concentrated at 25 ⁰ C and below, under reduced pressure, and the crystalline formed

- 49 13 0066/0570

The residue is recrystallized from a mixture of methanol and water and gives 3- (3-heptyl-oO -D-glucopyranos

-6-yl) -1- (2-chloroethyl) -1-nitrosourea.

Yield 6.03 g (14-, 6 #). 64-66 ⁰ C. foC J ψ + 62.2 °

(C 1.0, methanol). Analysis for C ₁₆ H ₃₀ N ₃ O ₇ Cl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.71 H, 7.28 N, 10.16 Cl, 8.72

Example 10

4.83 S (17.4 mmol) of 4-Hep _r tyl-6-amino-6-deoxy-co-D-glucopyranoside are dissolved in a mixture of 20 ml of tetrahydrofuran and 20 ml of toluene, and to this solution 2 g Added dry ice to convert the glucopyranoside to its carboxylic acid addition salt. This acid addition salt solution is added dropwise under stirring at 0-5 ⁰ C within 20 minutes to a solution, prepared by dissolving, 4.95 g (18.1 mmol) of o-nitrophenyl N- (2- chloroethyl) -N-nitrosocarbamate dissolved in a mixture of 20 ml acetone and 20 ml of methyl ethyl ketone was prepared, after which stirring is continued at 5-25 ⁰ C for 1.5 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is recrystallized from a mixture of methanol and water and gives 3- (4-heptyl -.- </ - D-glucopyranos-6-yl) -1 - (2-chloroethyl) -1 -nitrosourea. Yield 5.51g (76.8%). P. 64-65 ⁰ C jToOj ψ + 62.4 ° (C 1.0, methanol). Analysis for C ₁₆ H ₃₀ N ₃ O ₇ Cl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.72 H, 7.28 N, 10.12 Cl, 8.69

- 50 130066/0570

ORIGINAL INSPECTED

Example 11

5.49 g (12.9 mmol) of 2- & thylhexyl-6-amino-6-deoxy-N-carbobenzoxy-D-glucopyranoside are dissolved in a mixture of 60 ml of methanol and 5 ml of triethylamine, and 1 g Raney nickel catalyst given. The mixture is at 25-30 ⁰ C under a water

material pressure of 3-4 kg / cm stirred. The resulting liquid mixture is filtered to remove the catalyst and the filtrate is concentrated at 30 ° C and below under reduced pressure to give an oily residue of 2-ethylhexyl-6-amino-6-deoxy-D-glucopyranoside (3 , 71 g; 12.7 mmol). This oily residue is dissolved in a mixture of 20 ml of 10 ml of tetrahydrofuran, and 1 g of dry ice is added to this solution to convert the glucopyranoside into its carboxylic acid addition salt. The acid addition salt solution is added dropwise with stirring at 0-3 ° C within 20 minutes to a solution which is obtained by dissolving 4.61 g (16.8 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been prepared in 30 ml of tetrahydrofuran, after which stirring is continued at the same temperature for 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The concentrate is subjected to column chromatography, eluent: chloroform _r chloroform-methanol (39: 11 /, in order to separate it into the ^ O and ^ anomer fractions. The O ^ anomer fraction is reduced at 25 ° C and below Pressure concentrated, and the crystalline residue obtained is recrystallized from a mixture of methanol and water to give 3- (2-ethylhexyl-cX / -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 1.74 g (32.1%). M.p. 63-64 ° C / "^ 7 Jp + 64.5 ° (C 1.0 methanol). H-0.44 by thin layer chromatography

- 51 -

13 0066/0570

BATH ORIGINAL

C Adsorbent: Silicagel 60F254 (trademark; manufactured by Merck GmbH; hereinafter the same adsorbent is used

.used); Superplasticizer: \ Analysis! For O

Chloroform-ethanol (8: 1) J. 31 (MG 425.91):

Calculated (.%) C, 47.94 H, 7.57 N, 9.87 Cl, 8.32 Found (%) C, 48.03 H, 7.49 N, 9.81 Cl, 8.28

IR spectrum (KBr, cm ' ¹ ): 3500, 3360 (γ-NH, yO-H), 2950, 2860 (y * CH, Ύ ^Ί 0Η _ο , Y "CH _x ), 1700 (tfC ^ O), 1520 (γ "Ν-Η), 1480 (-ΓΝ-0), 840 (TC ₁ -H).

Example 12

5.89 g (20.2 mmol) of 2-ethylhexyl-6-amino-6-deoxy-D-glucopyranoside are dissolved in a mixture of 40 ml of methanol and 10 ml of isopropanol, and phthalic anhydride powder is added to this solution while stirring adjust the pH of the solution to 8.8. The solution is added dropwise with stirring at 0-10 ° within 20 minutes to a solution which is obtained by dissolving 5.96 g (21.8 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 20 ml of tetrahydrofuran and 10 ml of acetone, after which stirring is further continued at the same temperature for 2 hours. After filtering, the reacted solution is ^{concentrated at 30 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography / 'eluent: chloroform, chloroform-methanol (39 * 1) ./, um

separate it inoO and / 3 anomeric fractions. The fractions concerned are concentrated at 25 ° 0 and below under reduced pressure, and the crystalline residues obtained are made from a mixture of methanol and water

- 52 130066/0570

ORIGINAL INSPECTED

■ recrystallized, so that the 06-anomer, ie, 3- (2-ethylhexyl-Q0-D-glucopyranos-6-yl) -1 ~ 2-chloroethyl) -1-nitrosourea and the corresponding / i-anomer compound are obtained. For the 06 anomer: yield 2.31 g (26.8%); M.p. 63-64 ° C; C ^ J ψ + 64.5 ° (C 1.0, methanol); R _f 0.44- / mobile phase: chloroform-methanol (8: 1), /; Analysis for C ₁₇ H ₅₂ N ₅ O ₇ Cl (MW 425.91):

Calculated (%) C, 47.94 H, 7.57 N, 9.87 Cl, 8.32 Found (%) C, 47.91 H, 7.62 N, 9.92 Cl, 8.32

For the fb anomer: yield 2.02 g (23.5%); F. 118-120 ⁰ C (decomposition); fco / Jp -10.5 ° (C. 1.0, methanol); H _f 0.40 / eluent: chloroform-methanol (8: 1) 7; Analysis for C ₁₇ H ₃₂ N ₃ O ₇ Cl (MW 425.91):

Calculated (%) C, 47.9A H ₁ 7.57 N, 9.87 Cl, 8.32 Found (%) C, 48.01 H, 7.64 N, 9.79 Cl, 8.35

Example 13

3.Ο5 g (10.0 mmol) of 2,6-dimethyl-4-heptyl-6-amino-6-deoxy -D-glucopyranoside are dissolved in a mixture of 10 ml of methanol and 5 ml of dioxane, and this solution becomes Add succinic acid powder with stirring to adjust the pH * Vert to 9.4. The solution is then added dropwise with stirring at 0t5 ° C within 10 minutes to one Solution given by dissolving 2.95 S (10.8 mmol) p-Nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 10 ml of tetrahydrofuran and 5 ml of methyl ethyl ketone has been prepared, after which stirring is further continued at the same temperature for 3 hours. The reacted solution, after being filtered at 25 O and below, is concentrated under reduced pressure.

- 53 130066/0 57 0

3Q46393

The concentrate obtained is subjected to column chromatography / solvent: chloroform chloroform-methanol (39: 1) _7 _{t in} order to separate it into oO - and / 3-anomer fractions. The -Anomerfraktion is concentrated at 25 ⁰ C and below, under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of methanol and water to give 3- (2,6-dimethyl-A - heptyl-cC -D-Glucopyranos -6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 0.65 S (14.8 %). M.p. 65-66 ⁰ C. / 'cC / ψ + 62.4 ° (C 1.0, methanol). Analysis for C ₁₈ H ₃ ^ N ₃ O ₇ Cl (MW 439.94):

Calculated (%) <, 49.1 'H, 7.79 N, 9.55 Cl, 8.06 Found (%) C, 49.06 H, 7.84 N, 9.52 Cl, 8.1?

Example 14

8.57 g (30.9 mmol) of 2,4-dim-3thyl-3-pentyl-6-amino-6-deoxy -D-glucopyranoside are dissolved in a mixture of "40 ml of methanol and 40 ml of tetrahydrofuran, and to of this solution are added 4 g Trocheneis to the glucopyranoside in its carboxylic acid Additio'nssalz convert. this acid addition salt solution is added dropwise with stirring at -10- -15 ⁰ C within 10 minutes to a solution prepared by Dissolving 8.92 g (32.6 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 30 ml of acetone and 30 ml of methyl ethyl ketone has been obtained, after which stirring at the same temperature for The reacted solution is concentrated at 25 ° C. and below under reduced pressure, and the concentrate obtained is subjected to column chromatography C , mobile phase: chloroform, chloroform-methanol (39: 1), J.

130066/0570

- 54 -

copy

thrown to separate it into the 06 and / 3 anomeric fractions. The oC anomer fraction is concentrated at 25 ° C. and below under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of methanol and water to give 3- (2,4-dimethyl-3-pentyl-i> O-D -glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 3.65g (28.7%). P. 60-62 ° C / c-ij ψ + 60.4 ° (C 1.0, methanol). Analysis for C ₁₆ H ₃₀ N ₅ O ₇ Cl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.74 H, 7.28 N, 10.17 Cl ₁ 8.52

Example 15

5.88 g (23.2 mmol) of o-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in a mixture of 50 ml of tetrahydrofuran and 50 ml of acetone, and the solution is brought to a temperature of 0 _→ 5 ° C cooled. Then add drop by drop to this solution:? Stirring at 0-5 ⁰ C given a solution within 10 minutes, which by dissolving 5 »64 g (22.6 mmol) sec. Amyl-6-amino-6-deoxy - / ^ -D-glucopyranoside has been prepared in 80 ml of methanol, after which stirring is continued at the same temperature for a further 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is washed with benzene and then recrystallized from a mixture of methanol and water and gives 3- (sec. Amyl- / 3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea .
Yield 6.11g (70.4%). M.p. 112-114 ⁰ C (decomposition). ψ -10.5 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl

130066 / 0B70

COPV

(MW 385.83):

Calculated (%) O, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.77 Ξ, 6.92 N, 10.88 Cl, 9.12

Example 16

7.22 g (26, A- mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in a mixture of 50 ml of acetone and 30 ml of tetrahydrofuran, and the solution is brought to a temperature of 0 - -5 ° C cooled. A solution is added dropwise to this solution with stirring at a temperature of 0-5 ° C. over the course of 10 minutes, which is obtained by dissolving 6, c5 g (25.0 mmol) of 3-pentyl-6-amino-6-deoxy -oC -D-glucopyianoside has been prepared in a mixture of 50 ml of methanol and 30 ml of isopropanol, after which stirring is continued at 5-15 ° 0 for 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The obtained concentrate is subjected to column chromatography / "Eluent: benzene ". ^ Chloroform-ethanol (10: 1) _7, and the cKz-anomer fraction thereof is concentrated at 25 ° C and below under reduced pressure. The obtained crystalline residue is made from a Mixture of methanol and water recrystallizes and gives 3- (3-pentyl-o6-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 2.25 g (23.4%). F. 64-66 ⁰ C. £ ~ <jj ψ + 70.5 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (#) C, 43.92 H, 6.71 N, 10.92 Cl, 9.16

130036/0570 - 56 -

ORlGlNAL IMSPECTED

Example 17

8.84 g (32.3 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in 80 ml of tetrahydrofuran, and the solution is cooled to a temperature of 0-5 ° C. To this solution, a solution is added dropwise with stirring at 0-5 ° C within 10 minutes, which by dissolving 8.41 g (31.9 mmol) of 2-methyl-1-pentyl -ö-amino-ö- deoxy-D-glucopyranoside in 80 ml of methanol, after which stirring is continued at the same temperature for 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography

/ 'Eluent: chloroform _ψ chloroform-ethanol (10: 117,

to separate it inoC and / 3 anomeric fractions. The cC-anomer fraction is concentrated at 25 ° C and below under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of methanol and water to give 3- (2-methyl-1-pentyl-oC -D-glucopyranos- 6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 2.01g (15.8%). F. 64-65 ⁰ C />, / ψ + 67.2 ° (1.0, methanol). Analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.21 H, 7.18 N, 10.66 Cl, 8.84

Example 18

2.71 g (9.9 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in 30 ml of tetrahydrofuran, and the solution is cooled to a temperature of 0-5C.

- 57 130066 / 0S70

To this solution, a solution is added dropwise with stirring at ^{0-5 0} C within 10 minutes, which by dissolving 2.48 g (9.4 mmol) of 2-ethylbutyl-6-amino-6-deoxy-D- glucopyranoside in 30 ml of methanol, after which stirring is continued at the same temperature for 2 hours. The same process steps are then carried out as in Example 17, and 3- (2-ethylbutyl-O6- -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea is obtained. Yield 0.56g (14.9%). F. 60-62 ⁰ C / J ^ / ψ + 64.5 ° (C 1.0, methanol). Analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.33 H, 7.04 N, 10.68 Cl, 8.87

Example 19

3.50 g (12.8 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in 40 ml of acetone, and the solution is cooled to a temperature of 0-5 ° C. To this solution, a solution is added dropwise under stirring at 0-5 ⁰ C within 5 minutes, prepared by dissolving 3.45 g (12.4 mmol) of 2-heptyl-6-amino-6-deoxy - / 3-D glucopyranoside has been prepared in a mixture of 20 ml of methanol and 10 ml of tetrahydrofuran, after which stirring is continued at the same temperature for 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The concentrate is subjected to column chromatography £ eluent: _benzene>

Chloroform-methanol (39: 1) J, and the / 3-anomer fraction thereof, at 25 ° C and below under reduced pressure

- 58 13003 6/0670

ORIGINAL INSPECTED

concentrated. The crystalline residue obtained is recrystallized from a mixture of ^ ethanol and water and gives 3- (2-heptyl-y3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 1.09g (21.2%). M.p. 112-114 ⁰ C (decomposition). £ * ϊίψ -11.8 ° (C 1.0, methanol). Analysis for C ₁₆ H ₅₀ N ₃ O ₇ Cl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.75 H, 7.30 N, 10.18 Cl, 8.57

Example 20

19.77 g (50.0 mmol) of cyclohexyl-e-amino-ö-deoxy-N-carbobenzoxy-D-glucopyranoside are dissolved in a mixture of 60 ml of methanol and 5 ml of triethylamine, and 2 g of Raney Given nickel catalyst. The mixture is at 25-30 ⁰ C ^ for 18 hours under a water

hydrogen pressure of 3-4 kg / cm stirred. The liquid mixture obtained is filtered to remove the catalyst therefrom, and the filtrate is at 30 ⁰ C 'and including under reduced pressure to an oily residue of cyclohexyl-ö-amino-ö-deoxy-D-glucopyranoside (13.02 g) concentrated. 12.85 g (49.2 mmol) of this glucopyranoside compound are dissolved in 60 ml of ethanol, and 4 g of dry ice are added to this solution in order to convert the glucopyranoside into its carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at -10- -15 ° C within 20 minutes to a solution which is obtained by dissolving 14.00 g (51.2 mmol) of o-nitrophenyl-N- (2- chloroethyl) -N-nitrosocarbamate has been prepared in 80 ml of tetrahydrofuran, and stirring is continued at the same temperature for 2 hours, -fold examination by TLC, the reacted solution is ^{concentrated at 30 0} C and below under reduced pressure.

1-3 0066/0670 ~ ⁵⁹ ~

The concentrate obtained is subjected to column chromatography Z "mobile phase: chloroform → chloroform-methanol (39: 1) _7i in order to separate ea into 06 - and / O-anomer fractions. The fractions in question are concentrated at 25 ° C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the C-anomer, ie 3- (cyclohexyl- _l XD-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea and the relevant / door 3-Anomerverbindung the oC-anomer. yield 6.66 g (34- 2%); F. 63-64- ⁰ C; jj ß * ψ + 78.8 ° (C 1.0, methanol) ; R _f 0.4-3 C mobile phase: chloroform-ethanol (8: 1) _7; analysis for C ₁₅ H ₂₆ N ₅ O ₇ Cl (MW- 395.84-):

Calculated (%) C, 4-5.51 H, 6.62 N, 10.62 Cl, 8.96 Found (%) C, 4-5.4-8 H, 6.70 N, 10.59 Cl, 8.91

IR spectrum (KBr, cm "" ¹ ): 34-50, 3350 (f KH, Yt) -H), 2930,

2850 (^ CH ₂ ), 17OO (TO-O), I54-O (^ r NH), 14-90

Nuclear Magnetic Resonance Spectrum (ODOl ₃ , ^): 7.20 (IH, NH), 4-, 85 (d, IH, anomeric H, J-JHz), 4-, 12 (t, 2H, CH ₂ CH ₂ Cl , J = 6Hz), 3.4-6 (t, CH ₂ CH _-2 Cl, J >> 6Hz), 2.30-0.89 (TOH ₁ C ₆ H _-10 ) For the / 3 anomer: yield 5.29 g (26.6%); Mp 130-130.5 ° C (decomposition); ß ^ J ψ -13.0 ° (Cl, 0, methanol); R _f 0.34- C eluent: chloroform-ethanol (8: 1) ^; Analysis for C ₁₅ H ₂₆ N ₃ O ₇ Cl * 1/2 H ₂ O (MW 4-04-, 85):

Calculated (%) C, 44.50. H, 6.72 N, 10.38 Cl, 8.76 Found (%) C, 44.64-H, 6.74 N, 10.44 Cl, 8.69

IR spectrum (KBr, cm " ¹ ): 3610 (crist. Water), 3400, 3330 (fN-H, TO-H), 29ΟΟ, 2830 (VCH ₂ ), 1710 (fC = 0), 1610 (crist. Water), 1540 (fN-H), 1480 (TN = O), NMR spectrum (CDCl ₃ , ^): 7.28 (1H, NH), 4.31 (d, anomeric H, J * 7Hz), 4.08 (t, CH _-2 CH ₂ Cl, J «6 Hz), 3.45 2.33-0.83 (1 OH, C ₆ H _-10 ).

130066/0570 " ⁶⁰ "

ORIGINAL INSPECTED

Example 21

6.84 g (24.8 mmol) of cis-2-methylcyclohexyl-6-amino-6-deoxy-G-glucopyranoside are dissolved in 50 ml of methanol, and citric acid powder is added to this solution with stirring to bring it to pH 8.8 to set. The solution is added dropwise with stirring at 0-5 C within 5 minutes to a solution which is obtained by dissolving 6.92 g (25.3 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 70 ml of tetrahydrofuran has been obtained, after which the solution is stirred at the same temperature for a further 2 hours. After testing by TLC. the converted solution is ^{concentrated at 25 0} C and below under reduced pressure. The concentrate obtained is subjected to column chromatography / "mobile phase: benzene → chloroform-methanol (39: 1

to separate it into cO and / 3 anomeric fractions. The relevant fractions are concentrated at 25 ⁰ C 'and below under reduced pressure, and the obtained Cristal linen residues are recrystallized from a mixture of methanol and water to give that o6-anomer, that is to say 3- (cis-2-methyl-cyclohexyl oO-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3 -anomer compound, For theoO-anomer: yield 1.66 g (16.3%); F. 58-60 ⁰ C; £ <* J ψ + 74.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (MW 409.87);

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.84 H, 6.95 N, 10.22 Cl, 8.70

For da & anomer: yield 1.30 g (12.8%); 125-127 ° C (decomposition); foCj Jp -12.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 47.05 H, 6.86 N, 10.32 Cl, 8.58

130066/0570 - 61 -

Example 22

7.4-7 g (27.1 ml.iol) trans ^ -Methylcylohexyl-e-amino-edeoxy-G-glucopyranoside are dissolved in 80 ml of methanol, and succinic acid powder is added to this solution with stirring to adjust the pH set to 9.2. The solution is then added dropwise with stirring at -5- -10 ⁰ G over the course of 5 minutes to a solution which, by dissolving 7.69 g (28.1 mmol) of o-nitrophenyl-N- (2-chloroethyl) - N-nitrosocarbar: iat has been prepared in a mixture of 50 ml of tetrahydrofuran and 30 ml of acetone, after which stirring is continued at the same temperature for a further 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate obtained is subjected to column chromatography f eluent:

Chloroform chloroform-ethanol (10: 1) _ / to put it in <.-

and to separate / 3-anomeric fractions. The fractions in question are concentrated at 25 C- 'and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the o (/ - anomer, ie, 3- (trans-2-methylcyclohexyl- ^ -D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitroso urine storr, and the corresponding / ^ - anomer compound. For the o (/ - anomer: yield 4.09 g (36.8%) ; M.p. 54-56 / OC / jp + 73.5 ⁰ (G 1.0, methanol); analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.78 H, 6.92 N, 10.29 Cl, 8.72

For the .3 anomer: yield 3.39 g (30.5%); F. 120-121 ⁰ G (dec); / 30 / ψ -14.2 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (IG 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.78 "H, 6.92 N, 10.28 Cl, 8.80

130066/0570 -62-

COPY

Example 25

8.86 g (32.2 mmol) of trans-4-methylcyclohexyl-6-amino-6-deoxy-D-glucopyranoside are dissolved in a mixture of 50 ml of methanol and 50 ml of isopropanol, and 4 g of dry ice are added to this solution to form the carboxylic acid addition salt of glucopyranoside. This acid addition salt solution is added dropwise with stirring at -5-10 ⁰ C within 10 minutes to a solution which is obtained by dissolving 9.37 S (34.2 mmol) o-nitrophenyl-N- (2- chloroethyl) -N-nitrosocarbamate has been prepared in a mixture of 50 ml of tetrahydrofuran and 20 ml of nitroethane, and stirring is then continued at the same temperature for a further 3 hours. After testing by TLC, the solution is concentrated at 25 ° C. and below under reduced pressure. The concentrate is subjected to column chromatography

Z "eluent: chloroform ^ chloroform-methanol (39: 1) _7,

to separate it into 06 and / 3 anomeric fractions. The fractions concerned are concentrated under reduced pressure at 25 ° C. and below, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the 06 anomer, ie, 3- (trans-4-methylcyclohexyl-c6-di -glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the ^ - anomer compound. For the oC anomer: yield 4.29 g (32.5%); F. 68-70 ⁰ C; £> oj ψ + 72.5 ° (1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₃ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.75 H, 6.94 N, 10.34 Cl, 8.80

For the / 3-anomer: yield 3.73 g (28.3%), mp 131-135 ⁰ C (decomposition); / jUiJ jp -10.4 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₃ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N 10.25 Cl _1, 8.65 Found (%) C, 46.93 H, 6.81 N, 10.23 Cl, 8.73

13 0066/0570 ~ ⁶³ ~

ORIGINAL! N

COPY

Example 24

3.64 g (12.0 mmol) of ice, trans-mixed -3,3,5-trimethylcyclohexyl-δ-amino-e-deoxy-D-glucopyranoside are dissolved in a mixture of 20 ml of methanol, 10 ml of dioxane and 10 ml of isopropyl ether , and to this solution 1 g of dry ice is added to form the acid addition salt of glucopyranoside. This acid addition salt solution is added dropwise over 10 minutes with stirring at 0-5 ° 0 to a solution obtained by dissolving p-cyanophenyl -N- (2-chloroethyl) -N-nitrosocarbamate in 30 ml of tetrahydrofuran is, after which the solution is then stirred at the same temperature for a further 2 hours. After Pxüfung by TLC, the reacted solution at 25 ⁰ C-- and below under reduced pressure is concentrated. The concentrate obtained is subjected to column chromatography ^ f eluent: chloroform - * ■ chloroform-methanol (30: 5) J ⁷ ί in order to separate it into the t? C - and 3-anomer fractions. The ^ anomer fraction is concentrated at 25 ° C and below under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of methanol and water to give 3- (cis, transmixed-3,3 ^ -trimethylcyclohexyl-oG-D- glucopyranos-öyl) -1- (2-chloroethyl) -1-nitrosourea. Yield 0.62g (11.8%). M.p. 72-74 ° C fcOj ψ + 62.2 ° (C 1.0, methanol). Analysis for C ₁₈ H ₅₂ N ₅ O ₇ Cl (MW 437.92):

Calculated (%; Found (%)

ο, 49.37 H. , 7 , 37 ^Ν , 9 , 59 Cl, 8th , 10 σ, 49.4-5H , 7 A3 ⁹ , 51 Cl, 8th , 21 example 25th

26.93 S (100.0 mmol) of benzyl-ö-amino-ö-deoxy-oO-D- glucopyranoside are dissolved in 150 ml of ethanol and added to the solution

- 64 -

130086/0570

: ORIGINAL INSPECTED

7 S dry ice is added to form the carboxylic acid addition salt of the compound. This acid addition salt solution is added dropwise with stirring at 0-5 C within 20 minutes to a solution which, by dissolving 27.91 g (102.0 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 14-0 ml of tetrahydrofuran. The solution obtained is at 0-5 ⁰ C for 18 hours and allowed to stand concentrated after checking means TLO at 25 ° C and below, under reduced pressure. The concentrate obtained is dissolved in 100 ml of chloroform, and the solution is then washed twice with 80 ml of water. After drying, the chloroform solution is concentrated to obtain the ·. Remove solvent from it. The oily residue obtained is subjected to column chromatography / eluent: chloroform-acetone (4: 1) ^ 7, and the obtained O6-anomer fraction is concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is recrystallized from a mixture of ethanol, ethyl ether and η-hexane and gives 3- (benzyl-e <^ - D-glucopyranos-6-yl) -1- (2-chloroethyl) -1 -nitrosourea. Yield 26.81 g (66.4%). P. 4-9-51 ⁰ C. / oc / ψ + 63.5 ° (C 1.0, methanol). ß £ _f 0.58 eluant: chloroform-lthanol (4: 1), /. Analysis for C ₁₆ H ₂₂ N ₅ O ₇ Cl (HG 403.82): Calculated (%) C, 47.59 H, 5.4-9 N, 10.41 Cl, 8.78 Found (%) C, 47.63 H, 5.52 H, 10.34 Cl, 8.85

Nuclear Magnetic Resonance Spectrum (CDj) ₂ CO, ^): 3.60 (t, 2H, CH ₂ CH ₂ Cl), 4.20 (t, 2H, CH ₂ CH ₂ Cl), 7.35 (5H, benzene ring) , 7.95 (IH, JaH)

Example 26

8.46 g (31.4 mmol)

nosid are in a mixture of 50 ml of methanol and 20 ml

- 65 130066/0570

Tetrahydrofuran is dissolved, and succinic acid powder is added to this solution with stirring to adjust the pH to 8.8. The solution is then added dropwise with stirring at ^{0-5 0} CD within 10 minutes to a solution which is obtained by dissolving 8.78 g (32.1 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N -nitrosocarbamate has been prepared in 50 ml of acetone, after which stirring is continued at the same temperature for a further 2 hours. After testing by means of ¹ LC, the converted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography / "mobile phase: benzene _y

Chloroform-acetone (4: 1) _7, and the / 3-Anomerfraktion thereof is concentrated at 25 ⁰ C and below, under reduced pressure. The crystalline residue obtained is recrystallized from a mixture of methanol and water and gives 3- (benzyl - / <3-D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, yield 2.02 g (15.9%). Mp 83-85 ° C (decomposition). £ poj ψ -14.5 ° (C 1.0, methanol). Analysis for C ₁₆ H ₂₂ N ₅ O ₇ Cl (MW 403.82):

Calculated (%) C, 47.59 H, 5.4-9 N, 1Qf1 Cl, 8.78 Found (#) C, 47.48 H, 5.54 N, 10 β2 Cl, 8.72

Example 27

14.58 g (54.1 mol) of 2-methylphenyl-6-amino-6-deoxy-D-glucopyranoside are dissolved in a mixture of 150 ml of methanol and 50 ml of dioxane, and 5 g of dry ice are added to this solution, in order to form the carboxylic acid addition salt of the compound, ^ this acid addition salt solution is added dropwise with stirring at -10- -15 ⁰ C to a solution which is obtained by dissolving 14.10 g (55.6 mmol)

- 66 130066/0570

QBlX '> Al JNSPECTED

o-Cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been prepared in a mixture of 100 ml of tetrahydrofuran and 50 ml of acetone, after which the solution is stirred at the same temperature for a further 4 hours. To. Testing by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography

/ Eluent: chloroform ^ chloroform-methanol (39: 1) .7,

to separate it ino6 and β anomeric fractions. The fractions concerned are concentrated under reduced pressure and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the 06 anomer, ie 3- (2-methylphenyl -. </ - D-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer compound. For the x. Anomer: yield 7.26 g (33.2 #); F. 60-62 ⁰ C; / oo / jp + 55.7 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₂ N ₃ O ₇ Cl (MW 403.82):

Calculated (%) C, 47.59 H, 5.59 N, 10.41 Cl, 8.78 Found (%) C, 47.63 H, 5.40 N, 10.38 Cl, 8.83

For the / 3 anomer: yield 6.27 g (28.7%); M.p. 91-93 ° C (decomposition); £ U, J -12.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₂ N ₅ O ₇ Cl (MW 403.62):

Calculated (.% ) c, 47.59 H. , 5 , 56 I. , 41 Cl, 8th , 78 Found (% Α-7.55 H. , 5 , 49 Cl, 8th , 72 example 28 ί, 10 ϊ, 10

5.28 g (20.8 mmol) of o-cyanophenyl -N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in a mixture of 50 ml of acetone and 30 ml of acetonitrile, and this solution is on cooled to a temperature of 0-5 ° C. This solution becomes drop with stirring at 0-5 ° C within 10 minutes-

130066/0570 ^'67 "

wise given a solution made by dissolving 5.68 g (20.0 mmol) of phenyl-06-ethyl-6-amino-6-deoxy- - <• -D-glucopyranoside in a mixture of 30 ml of methanol, 30 ml of dioxane and 10 ml of benzene has been prepared, and the solution is then stirred at the same temperature for an additional 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C. and below under reduced pressure. The concentrate is subjected to column chromatography / eluent: chloroform chloroform-methanol (39: 1) 7, and its oC anomer fraction is concentrated at 25 ° (X and below under reduced pressure. The crystalline residue obtained is made from a mixture of methanol and water recrystallized and gives 3- (phenyl-o <r - ethyl-c> vD-glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 4.76 g (56.8%). M.p. 54-56 ° C £ oQ7 ψ + 58.2 ° (C 1.0, methanol). Analysis for C (MW 417.85):

Calculated (%) C, 48.87 H, 5.79 N, 10.06 Cl, 8.48 Found (%) C, 48.78 H, 5.84 N, 10.01 Cl, 8.55

Example 29

According to Example 28, using 3.26 g (11.5 mmol) of phenyl / 3-ethyl-6-amino-6-deoxy- ·? D-glucopyranoside and 3.26 g (11.9 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate instead of 5.68 g of phenyl-CC-ethyl-ö-amino-6-deoxy-cC -D-glucopyranoside and 5.28 g of o-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate 3- (phenyl- / 3 -ethyl) - / 3-D-glucopyranos-6-yl) -1- ( 2-chloroethyl) -1-nitrosourea obtained. Yield 3.02 g (62.8%). F. 86-88 ⁰ C (decomposition), faj ψ -10.4 ° (C, 1.0, methanol). Analysis for C ₁₇ H ₂₄ N ₅ O ₇ Cl (MW 417.85): Calculated (%) C, 48.87 H, 5.79 N, 10.06 Cl, 8.48 Found (%) C, 48, 92 H, 5.68 N, 10.14 Cl, 8.44

130066/0570. ₆₈ _

_... ORIGiNALlNSPECTED

Example 30

5.76 g of C2A-, 5 mmol) isobutyl ^ -amino ^ -deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol, 50 ml of dioxane and 30 ml of hexane, and 7 S dry ice are added to this solution to form the carboxylic acid addition salt of the compound. This acid addition salt solution is added dropwise with stirring at -5-10 ⁰ O within 10 minutes to a solution which is obtained by dissolving 6.84 g (25.0 mmol) of o-nitrophenyl-N- (2- chlorathyl) -N-nitrosocarbamate dissolved in a mixture of ml of tetrahydrofuran and 30 ml "carbon disulfide is obtained, after which stirring was continued at 0-5 ° C for an additional 2 hours. After checking by TLC the reacted solution at 25 ⁰ CJ is and concentrated below it under reduced pressure. The concentrate is subjected to column chromatography / "EluentJ: · Chloroform ^

Chloroform-methanol (10: 1) J ⁷ to separate it inc? 6 and / ^ anomer fractions. The fractions in question are ^{concentrated at 25 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of ^ ethanol and water and give theoiz anomer, ie, 3- (IsobuthyL- oO -Dj-glucopyranos-2 -yl) -1- (2-chloroethyl) -1-nitroso urine; off, and the corresponding / 3-anomer compound. For the. ^ 6 anomer: yield 3.28 g (36.2%); F. 100-102 ⁰ C (with decomposition); / ^ / ψ + 84.2 °; (C 1.0, methanol); Analysis for C ₁₅ H ₂ ^ N ₅ O ₇ Cl (MW 369.80)

Calculated (%) C, 42.22 H, 6.5 ^ N, 11.36 Cl, 9.59 Found (%) C, 42.3 ^ H, 6.51, N, 11.33 Cl ₁ 9, 62

IR spectrum (KBr, cm "" ¹ ): 1? 05 (γ * Ο0), 1515 (^ NH), 1490

For that anomer: yield 2.93.6 (32.4%); F. 110-112 ⁰ C (decomposition); £ φ / ψ -13.8 ° (C 1.0, methanol); analysis

- 69 130066/0570

for C ₁₅ H ₂₄ N ₅ O ₇ Cl (MW 369.80):

Calculated (%) C, 42.22 H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.18 H, 6.61 N, 11.31 Cl, 9.64

Example 31

15.27 g (64.9 mmol) sec. Butyl - ^ - amino ^ -deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol, 50 ml of toluene and 50 ml of dioxane, and this solution tartaric acid powder is added to the Adjust the pH of the solution to 9.5. The solution is then added dropwise with stirring at 0-5 ° C within Added 10 minutes to a solution that is made by dissolving

18:28 g (66.8 mmoles. "P-nitrophenyl N- (2-chloroethyl) -N-nitrosocarbamate obtained in 100 ml of acetone, after which stirring then for a further 1.5 hours at 20-25 ⁰ C is forge sets the reacted solution is concentrated by filtration at 25 ⁰ C and below, under reduced pressure the concentrate obtained is subjected to column chromatography JT eluent: chloroform chloroform-methanol (39.1) .7 to it in '^ - and..

Separate β- anomeric fractions. The fractions concerned are concentrated at 25 ° C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the oO-anomer, ie 3- (sec. Butyl-iX-D-glucopyranos-2 -yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer compound. For the O ^ / anomer: yield 3.24 g (13.5%); M.p. 85-87 ° C (decomposition); fo (J ψ + 66.2 ° (C 1.0, methanol); analysis for C ₁₅ H ₂₄ N ₅ O ₇ Cl (MW 369 »80):

- 70 -

130066 / OB70

Calculated (%) C ₁ 42.22 'H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.18 H, 6.61 N, 11.31 Cl, 9.64

Example 31

15.27 g (64.9 mmol) sec. Butyl ^ -amino-S-deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol, 50 ml of toluene and 50 ml of dioxane, and to this Solution, tartaric acid powder is added to the Adjust the pH of the solution to 9.5. The solution will be / then drop by drop with stirring at 0-5 ° C within / 10 minutes added to a solution which can be obtained by dissolving>,

18.28 g (66.8 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been obtained in 100 ml of acetone, where, after stirring, then for another 1.5 hours at 20-25 ⁰ C. After filtering, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate obtained is subjected to column chromatography / "Eluent: chloroform → chloroform-methanol (39: 1) .7, in order to separate it into and anomeric fractions. The fractions concerned are stored at 25 ° C. and below under reduced pressure concentrated, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the o ^ anomer, ie 3- (sec.Butyl-Xy-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding .Ö-Anomerverbindung For ;: \ anomer: yield 3.24 g (13.5 ° / °) \ J ¹ 85-87 ° C (decomposed); / _. ■. . '/ ψ + 66.2 ° (C 1.0, methanol); analysis for C ₁₃ H ₂₄ N ₃ O ₇ Cl (MW 369.80):

Calculated (%) C, 42.22 H, 6.54 N, 11.36 Cl, 9.59 Found (%) C, 42.35 H, 6.47 N, 11.45 Cl, 9.47

IR spectrum (KBr, cm ~ ¹ ): 3420 (γ-ΝΗ, ^ ΟΗ), 1705 (ΓC = O),

1535 (rur-H), 1490 (VN = O),

- 71 13 0066 / 0S70

3Q46393

Nuclear Magnetic Resonance Spectrum (DMSO-dg, ^): 0.82 (t, 3H, _{OEj ^ GR} ),

1.02 (d, 3H, CH ^ _n ; ), 3.53 (t. (2L ₅ CH ^ Cl), 4.02 (t, CH ₂ CH ₂ Cl)

For the / si anomer: yield 2.83 g (11.8 %); F. 114-116 ⁰ C.

(Decomposition); / j> Cj jp - ^/ ' ² »5 ^O (C 1.0, methanol); Analysis for C ₁₃ H ₂₄ N ₃ Q ₇ Cl (MW 369.80):

Calculated (%) C, 42.22 H, 6.54-N, 11.56 Cl, 9.59

Found (%) C, 42.30 H ₁ 6.48 N, 11.32 Cl, 9, όο

Example 52

25.87 g (1Ο2ςθ mmol) of o-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate are dissolved in 100 ml of tetrahydrofuran, and the solution is cooled to a temperature of 0-5 ° C. A solution is added dropwise to this solution with stirring at 0-5 ° C. over a period of 10 minutes, which is obtained by dissolving 25.55 g (100.0 mmol) of tert-butyl-2-amino-2-deoxy-0o'- D-glucopyranoside has been prepared in a mixture of 100 ml of methanol, 5C ml of dioxane and 50 ml of benzene, after which the solution is then stirred at the same temperature for a further 5 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The crystalline residue obtained is washed with chloroform and then recrystallized from a mixture of ethanol and water to give 5- (tert-butyl- _l ? VD-glucopyranos-2-yl) -1- (2-chloroethyl) -1 -nitrosourea. Yield 25.59g (69.2%). F. 80-82 ⁰ C (decomposition). / X / ψ + 64.7 ° (C 1.0, methanol). Analysis for C ₁₃ H ₂₄ N ₃ O ₇ Cl (MW 369.80): Calculated (%) C, 42.22 H, 6.54-N, 11.56 Cl, 9.59 Found (%) 0.22 , 31 H, 6.48 N, 11.42 Cl, 9.63

130066/0570

ORIGINAL INSPECTED ⁷²

Example 33

24.93 g (100.0 DiMoI) isoamyl-1-amino - ie oxy-oC "-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol, 50 ml of isopropanol and 50 ml of tetrahydrofuran, and 6 g dry ice is added to form the carboxylic acid addition salt. This acid-r addition salt solution is added dropwise with stirring at -5-10 ⁰ C within 10 minutes to a solution which is obtained by dissolving 27.91 g (102 , 0 mmol) of o-nitrophenyl -N- (2-chloroethyl) -N-nitrosocarbamate has been obtained in a mixture of 50 ml of methyl ethyl ketone and 100 ml of tetrahydrofuran, and the solution is then stirred at the same temperature for a further 3 hours Examination by TLC, the reacted solution is concentrated under reduced pressure at 25 ° C. and below, the crystalline residue obtained is washed with benzene and then recrystallized from a mixture of methanol and water to give 3- (isoamyl- <Χ / -D-glucopyranos -2-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 29, 36 g (76.5%) · P. 91-93 ⁰ C (decomposition). Iboj ψ + 75.2 ° (1.0 C, methanol). Analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.88 H, 6.77 N, 11.02 Cl, 9.17

IR spectrum (KBr, cm " ¹ ): 1700 (tTC-O), 1520 (γ ^ Ν-Η), 1490

Nuclear Magnetic Resonance Spectrum (DMSO-d ^ J): 0.78 (d, 6H, CHpGHgCif _CH ⁵ ),

ν · / ΧΧ -τ

1.36 (m, 2H, CHpCHpQg), 3.54 (t, 2H,

CH ₂ CH ₂ CL), 4-, 04 (t, 2H, CH ₂ CH ₂ Cl)

- 73 -

130066/0570

Example 54

8.48 g (34.0 mmol) of sec is set. The solution is then added dropwise with stirring at ^{0-5 0} C within 5 minutes to a solution which is obtained by dissolving 9.77 g (35 »7 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N nitrosocarbamate has been prepared in a mixture of 70 ml of tetrahydrofuran and 20 ml of methylene chloride, after which the solution is then stirred at the same temperature for a further 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C. and below under reduced pressure. ^! The concentrate obtained is subjected to column chromatography / "eluent:. ^ Benzene chloroform-methanol (39; 1) y, it -un o in </ - and / B to separate -Anomerfraktionen The relevant fractions are at 25 ° C and below, concentrated under reduced pressure and the crystalline residues formed are recrystallized from a mixture of methanol and water to give the c? C anomer, ie 3- (sec-amyl-o (/ - D-glucopyranos-2-yl) -1 - (2-chloroethyl) -1-nitrosourea, and the corresponding

/ 3 anomeric compound. For the o <> anomer: yield 1.99 g (15.2%). F. 86-88 ⁰ C (decomposition); foO / ψ + 64.8 ° (C 1.0, methanol); Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.88 H, 6.72 N, 10.86 Cl, 9.18

For that _; 3 anomer: yield 1.67 g (12.8%); F. 98-100 ⁰ C (decomposition); / ocj ψ -14.8 ° (O ₁ I ₁ O, methanol); Analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 O1, 9.23 Found (%) C, 43.92 H, 6.75 N, 10.90 Cl, 9.35

130066/0570 -74-

ORlGlNAL INSPECTED

Example 35

2.49 S (10.0 mmol) tert-amyl ^ -amino ^ -deoxy - ^ - D-glucopyranoside are dissolved in a mixture of 20 ml of methanol and 20 ml of dimethylformamide, and 1 g of dry ice is added to this solution, to form the carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at a temperature of -5-15 ° C
added within 10 minutes to a solution that
by dissolving 2.82 g (10.3 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 20 ml of acetone and 30 ml of tetradydrofuran, whereupon $> egg of the same Temperature for another 2.5
Is stirred for hours. After testing with TLC, the
reacted solution concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is washed with benzene and then recrystallized from a mixture of methanol and water and gives 3- (tert. Amyl- oo -D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea: yield 2.97 g (77Λ%) · F. 94-96 ⁰ C (decomposition). / MjJ ψ + 68.3 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl (MW 383.83):

Calculated (yes 43 , 81 H, 6th , 83 ^N , 10 , 95 Cl, 9 , 23 Found (% 43 , 92 H, 6th , 76 H, 10 , 84 Cl, 9 , 35 O c, ■) σ,

According to the above procedure, when using 2.49 g (10.0 mmol) tert. Amyl-2-amino-2-deoxy- _/ ^ D-glucopyranoside instead of 2.49 g (10.0 mmol) tert-amyl-2-amino-2-deoxy-OC / -D-glucopyranoside 3- (tert. Amyl - />'-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea obtained. Yield 2.82 g (73.5%). I "116-118 ⁰ C. (Decomposition). / JoC '/ ψ -10.4 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl

(MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.94 H, 6.76 N, 10.99 Cl, 9.18

;. 130066/0570 - 75 -

Example 36

2 "63 S (O 1O ₁ mmol) of 3-methyl-2-pentyl-2-amino-2-deoxy -X'-D-glucopyranoside are dissolved in a mixture of 20 ml ethanol and 10 ml of dioxane, and to this solution 1 g of dry ice is added to form the carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at 0-5 ° C within 10 minutes to a solution which is obtained by dissolving 2.79 g (10.2 mmol) of o-nitrophenyl-N- (2-chloroethyl ) -N-nitrosocarbamate has been obtained in 20 ml of tetrahydrofuran, which is then ^{stirred at the g 1} calibrated temperature for a further 2 hours. N; After testing by TLC, the reacted solution b-5i 2 ^ ⁰ C and below is concentrated under reduced pressure. The resulting crystalline residue is washed with chloroform and then from a mixture of methanol and Wa; water recrystallizes and gives 3- (3-methyl-3-pentyl-? CD-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 3.10 g (77.9%). E ¹ . 93-95 ° C

ψ + 646 °

(Decomposition). £ ~ ° W ψ + 64.6 ° (C 1.0, methanol). Analysis for C ₁₅ H ₂₈ N ₃ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.34 H, 7.08 N, 10.67 Cl, 8.85

Example 37

5.29 g (20.1 mmol) of 4-methyl-2-pentyl-2-amino-2-deoxy-D-r glucopyranoside in a mixture of 30 ml of dioxane dissolved by 10 ml of methyl ethyl ketone, and this solution is added dropwise with stirring at 0-5 ° C within 10 minutes to a solution, which by dissolving 5.61 g (20.5 mmol) o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 300 ml of tetrahydrofuran, and stirring is then continued at the same temperature for

- 76 130066 / 0S70

continued for 3 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 0} O and below under reduced pressure. The concentrate is subjected to column chromatography. C eluent: chloroform

Chloroform-methanol (39: 1) J _% to separate it into o6> - and / i -anomer fractions. The fractions in question are concentrated at 25 ° C and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the 06-anomer, ie 3- (4-methyl-2-pentyl-oC- D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer compound. For the -χ, -anomer: yield 2.73 g (34.2%); M.p. 88-90 ⁰ C (decomposition); £ c <J ψ + 68.3 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86):

Calculated (%) C, 4-5.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.35 H, 7.18 N, 10.47 Cl, 8.83

For the β anomer: yield 2.29 g (28.7%) \ F. 118-120 ⁰ C (decomposition); / / ψ -10.2 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₈ N ₃ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C, 45.21 H, 7.02 N, 10.68 Cl, 8.94

Example 38

4.60 g (16.8 mmol) of o-nitrophenyl N- (2-chloroethyl) -N-nitrosocarbamate dissolved in a mixture of 30 ml of tetrahydrofuran and 20 ml of nitromethane and the solution is cooled to -5 ⁰ C 0- cooled down. To this solution, a solution is added dropwise with stirring at -5 ⁰ C 0- added within 5 minutes, prepared by dissolving 4.23 6 (16.1 mmol

- 77-130086/0570

T-8

^ Ethylbutyl ^ -amino ^ -deoxy-zS-D-glucopyranoside has been obtained in a mixture of 30 ml of methanol and 20 ml of dioxane, which is then stirred at the same temperature for a further 2 hours. After checking by TLC, the solution is concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is washed with benzene and then uncrystallized from a mixture of ethanol and water and gives 3- (2-ethylbutyl- / 3-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea . Yield 4.81g (75.2%). M.p. 114-116 ⁰ C (decomposition), / bo / Jp -12.5 ° (C 1.0, methanol), analysis for C ₁₅ H ₂₈ N ₃ O ₇ Cl) MW 397.86):

Calculated (%) C. 45.28 H, 7.10 N, 10.56 Cl, 8.91 Found (%) C ₅ 45.31 H, 7.02 N, 10.42 Cl, 8.99

Example 39

2.77 g (10.0 milliliters) of 4-heptyl-2-amino-2-deoxy-v \, -D-glucopyranoside are dissolved in a mixture of 20 ml of ethanol and 15 ml of acetone, and fumaric acid powder is added to this solution Stir added to adjust pH to 9.4. The solution is then added dropwise with stirring at 0-5 ° C within 10 minutes to a solution which is obtained by dissolving 2.87 6 (10.5 mmol) p-nitrophenyl-N- (2-chloroethyl) -N- nitrosocarbamate has been prepared in 20 ml of tetrahydrofuran, which is then stirred at the same temperature for 2 more hours. The reacted solution is concentrated after filtration under reduced pressure, and the concentrate obtained is subjected to column chromatography £ eluent: benzene _ψ

Chloroform-ethanol (10: 1) .7, and then the cO-anomer fraction thereof at 25 ⁰ C and below under reduced

- 78 130066/0570

ORIGINAL INSPECTED

Focused pressure. The crystalline residue obtained is recrystallized from a mixture of methanol and water and gives 3- (4-heptyl-ol-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 0.63g (15.3%). F. 89-91 ⁰ C (decomposition). / vüj ψ + 66.2 ° (C 1.0, methanol). Analysis for C ₁₅ H ₃₀ N ₅ O ₇ Gl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.78 H, 7.32 N, 10.31 Cl, 8.57

Example 40

10.86 g (37.3 mmol) of 2-ethylhexyl-2-amino-2-deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol and 50 ml of acetone, and maleic acid powder is added to this solution while stirring adjust the pH to 9.5. The solution is added dropwise with stirring at -5-10 ⁰ C within 10 minutes to a solution which is obtained by dissolving 9.78 g (38.6 mmol) of p-cyanophenyl-N- (2-chloroethyl) -N -nitrosocarbamat obtained in 100 ml of tetrahydrofuran, after which stirring was continued at 15-20 ⁰ C for an additional 1.5 hours. The reacted solution is concentrated under reduced pressure after filtering. The concentrate is subjected to column chromatography / T eluent: benzene ^

Chloroform-methanol (30: 1) J ⁷ to separate inoO and / 3 anomeric fractions. The fractions in question are ^{concentrated at 25 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the / 3-anomer, ie 3- (2-ethylhexyl-oo-D -glucopyranos

- 79-130066/0570

-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / "3 - anomer compound. For the -χ, -anomer: yield 2.48 g (15.6%); F. 88-89 ° C (decomposition); Cy-J ψ + 68.3 ° (G 1.0, methanol); analysis for C K ₅ O ₇ Cl (MW 425.91):

Calculated (%) C, 47.94 H, 7.57 N, 9.87 Cl, 8.32 Found (%) C, 48.08 H, 7.51 N, 9.93 Cl, 8.26

For the / 3 anomer: yield 2.03 g (12.8 %) ; M.p. 116-118 ⁰ C (decomposition) C ^ J ψ -8.9 ° (C 1.0, methanol).

Example 41

3.15 6 (10.3 mmol) 2,6-dimethyl-4-heptyl-2-amino-2-deoxy - : <j -D-glucopyranoside are in a mixture of 20 ml of methanol, 20 ml of isopropanol and 10 ml Dissolved dioxane, and acetic acid is added to this solution with stirring in order to adjust the pH to 9.6. The solution is then added dropwise with stirring at 0-5 ° C within 10 minutes to a solution which is obtained by dissolving 2.90 g (10.6 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N- nitrosocarbamate has been obtained in a mixture of 20 ml of tetrahydrofuran and 20 ml of acetone, which is then stirred at the same temperature for a further 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The crystalline residue obtained is washed with ethyl ether and then recrystallized from a mixture of isopropanol and water and gives 3- (2,6-dimethyl-4-heptyl- oC-D-glucopyranos-2-yl) -1- (2-chloroethyl) - 1-nitrosourea. Yield 3.39 g (74.7 %). F. 90-92 ⁰ C (decomposition). ß & J ψ + 66.4 ° (C 1.0, methanol). Analysis for C ₁₈ H ₅₄ N ₅ O ₇ Cl (MW 439.94):

- 80 -

130066/0570

C- '■:; -: "■ *.:. Inspected

Calculated (%) C, 49.14-H, 7.79 N, $ 55 Gl, 8.06 Found (%) C, 49.28 H, 7.71 N, 9.64 Gl, 8.12

Example 42

26.13 g (100.0 mmol) of cyclohexyl-2-amino-2-deoxy-x.-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol, 50 ml of tetrahydrofuran and 50 ml of dioxane and added to this solution 8g of dry ice are added to form the carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at -5-10 ⁰ C within 10 minutes to a solution, which by dissolving 28.05 g (102.5 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate has been prepared in a mixture of 100 ml of acetone and 50 ml of tetrahydrofuran, which is then stirred at the same temperature for a further 3 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The crystalline residue obtained is washed with benzene and then recrystallized from a mixture of methanol and water and gives 3- (cyclohexyl- ^ -D-glucopyranos-2-yl) -1 - (2-chloroethyl) -1 -nitrosourea .. Yield 31.03 g (78.4 #). P. 89-91 ⁰ C (decomposition). (& J ψ + 79.4 ° (C 1.0, methanol). Analysis for C ₁₅ H ₂₆ N ₅ O ₇ Cl (MW 395.84): Calculated (%) C, 45.51 H, 6.62 N , 10.62 Cl, 8.96 Found (%) C, 45.64 H, 6.60 N, 10.58 Cl, 8.88

According to the above procedure, when using 26.13 g (100.0 mmol) of cyclohexy-2-amino-2-deoxy - /> - D-glucopyranoside instead of 26.13 g (100.0 mmol) of cyclohexyl-2- amino-2-deoxy-od / -D-glucopyranoside 3- (cyclohexyl- ./> D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea obtained .. Yield: 29.37 S ( 7 *, 2%). F. 135-136 ⁰ C.

- 81 1300B6 / 0570

(Decomposition). £ oüj ψ -14.3 ° (C 1.0, methanol). Analysis for C ₁₅ H ₂₆ N ₅ O ₇ Cl (MW 395.84):

Calculated (%) C, 45.51 H, 6.62 N, 10.62 Cl, 8.96 Found (%) C, 45.58 H, 6.57 N, 10.71 Cl, 8.98

Example 45

13.75 & (49.9 mmol) trans - ^ - methylcyclohexyl ^ -amino ^ - deoxy-D-glucopyranoside are dissolved in a mixture of 100 ml of methanol and 100 ml of acetone, and this solution Oxalic acid powder is added with stirring to adjust the pH to 9.5. The solution is then added dropwise added with stirring at -10-0 ° within 10 minutes to a solution that was obtained by dissolving 13.39 g (52.8 mmol) o-Cycynophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in one Mixture of 100 ml of tetrahydrofuran and 50 ml of dioxane has been obtained, followed by stirring at the same temperature continued for another 3 hours. The implemented Solution will be after the. Filter at 25 ° C and below concentrated under reduced pressure. The concentrate obtained is subjected to column chromatography / "eluent: chloroform chloroform-methanol (39: 1), 7 to it

to be separated into oL and <3 anomeric fractions. The fractions concerned are concentrated at 25 ° C and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the od / anomer, ie, 3- (trans-2-methylcyclohexyl-06 - D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding .Ä anomer. For the. ^ - Anorner: Yield 5.92 g (28.9%); M.p. 67-69 ° C /> / ψ + 74.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (MW 409.87):

- 82 130066/0570

ORIGINAL INSPECTED

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl ₁ 8.65 Found (%) C, 46.82 H, 6.95 N, 10.17 Cl, 8.58

For the β anomer: yield $ 4.6 g (22.6%); F. 112-114 ⁰ C (decomposition); £ öüj ψ -10.4 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₃ N ₃ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.93 H, 6.82 N, 10.34 Cl, 8.52

Example 44

13.27 g (48.2 mmoles) of cis ^ -Methylcyclohexyl ^ -amino - ^ - deoxy-D-glucopyranoside are in a mixture of 100 ml

Dissolved methanol and 50 ml of dioxane, and this solution is added dropwise with stirring at 0-5 ° C within 5 minutes to a solution which is obtained by dissolving 13.63 g (49.8 mmol) of o-nitrophenyl -N- (2-chloroethyl) nitrosocarbamate has been prepared in 100 ml of tetrahydrofuran, after which the solution is then stirred at the same temperature for a further 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The concentrate obtained is subjected to column chromatography / * mobile phase: chloroform → chloroform-methanol (39: 1) ./ in order to separate it into x / - and ^r / - anomeric fractions. The fractions in question are ^{concentrated at 25 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the ob anomer, ie, 3- (cis-4-methylcyclohexyl-06 -D -glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosohamstoff, and the corresponding β- anomer. For the

j> C / anomer: yield 7.05 g (35.7%); · 81-83 ⁰ C (decomposition);

- 83 130066/0570

/} J, J ψ + 74.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₃ O ₇ Cl ( MW 409.87):

Calculated (%) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.93 H, 6.87 N, 10.34 Cl, 8.62

For the / j anomer: yield 6.08 g (30.8%); F. 126-128 ⁰ C (decomposition); / / jp -11.0 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₃ O ₇ Gl (MW 409.87):

Calculated 0έ) C, 46.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) G, 46.78 H, 6.85 N, 10.33 Cl, 8.58

Example 45

12.18 g (44.2 mmol) of trans - ^ - methylcyclohexyl - ^ - amino - ^ - deoxy-D-glucopyranoside are dissolved in a mixture of 50 ml of methanol and 60 ml of tetrahydrofuran, and 4 g of dry ice are added to this solution to form the carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at 0-10 ⁰ C within 5 minutes to a solution which is obtained by dissolving 12.48 g (45.6 mmol) of p-nitrophenyl-N- (2-chloroethyl ) -N-nitrosocarbamate has been prepared in a mixture of 100 ml of acetone and 50 ml of dioxane, after which the solution is then stirred at the same temperature for a further 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography

/ "Superplasticizer: Benzene ^ Cnloroform-Ethariol (10: 1) _7, um

to separate it into (Xy and ,, ν anoner fractions. The fractions concerned are at 25 ⁰ C and below under different

- 84 130066/0570

ORIGINAL INSPECTED

concentrated under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the X anomer, ie, 3- (trans-4-methylcyclohexyl-.xD-glucopyranos-2-yl) -1- (2- chloroethyl) -1-nitrosourea, and the corresponding / C? -anomer compound. For the (S- anomer: yield 2.57 g (14.2%); m.p. 78-80 ⁰ CJ (decomposition); / x ^ J ψ + 7 ^, 2 ° (G 1.0, methanol) ; Analysis for C ₁₆ H ₂₈ N ₅ O ₇ Cl (MW 409.87):

Calculated (%) C, 4-6.89 H, 6.89 N, 10.25 Cl, 8.65 Found (%) C, 46.78'H, 6.93 N, 10.29 Cl, 8.67

For the / 5 anomer: yield 1.96 g (10.8%); F. 123-125 ⁰ C; /> / ψ -12.8 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₈ N ₃ O ₇ Cl (MW 409.87):

Calculated (%) C, 46.89 ^ H, 6.89 N, 10.25 Cl, 8.65 Found (%) C ₁ 46.94 H, 6.81 N, 10.32 Cl, 8.58

Example 46

6.82 g (22.5 mmol) of ice, trans-mixed -3, 3,5-trimethylcyclohexyl-2-amino-2-deoxy-D-glucopyranoside are dissolved in a mixture of 50 ml of methanol and 50 ml of dioxane, and this solution is added dropwise with stirring at -5-0 ⁰ C within 10 minutes to a solution, which by dissolving 6.51 g (23.8 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N- nitrosocarbamate has been prepared in a mixture of 30 ml of ethyl acetate and 50 ml of tetrahydrofuran, which is then stirred at the same temperature for a further 2 hours. After testing with TLC,

- 85 130066/0570

the converted solution at 25 ⁰ CJ and below concentrated under reduced pressure. The concentrate obtained is subjected to column chromatography / "eluent:

Chloroform chloroform-methanol (39: 1) _ / »to put it in

Separate oC and β anomeric fractions. The ° C anomer fraction is ^{concentrated at 25 0} C and below under reduced pressure, and the crystalline residue obtained is recrystallized from a mixture of methanol and water and gives 3- (cis, trans-mixed 3,3,5-trimethylcyclohexyl - t> 6-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea. Yield 1.55 g O 5.8%). M.p. 94-96 ⁰ C (decomposition). / <- / ψ + 66.5 ° (C 1.0, methanol), analysis for C ₁₈ H ₃₂ N ₅ O ₇ Cl (MW 437.92):

Calculated (%) C, 4-9.37 H, 7.37 N, 9.59 Cl, 8.10 Found (%) C, 49.42 H, 7.34 N, 9.64 Cl, 8.03

Example 47

2.78 g (10.3 mmol) of benzyl-2-amino-2-deoxy-D-glucopyranoside are dissolved in a mixture of 20 ml of methanol and 20 ml of tetrahydrofuran, and 1 g of dry ice is added to this solution to remove the carboxylic acid -Addition salt to form. This acid addition salt solution is added dropwise with stirring at -5 -10 ⁰ C. within 10 minutes to a solution prepared by dissolving 2.96 g (10.8 mmol) of o-nitrophenyl N- (2 -chloräthyl) -N-nitrosocarbamate dissolved in a mixture of 20 ml acetone and 10 ml dimethylacetone has been established, after which the stirring continued at 0-5 ⁰ C for 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate is subjected to column chromatography / "mobile phase: chloroform"

Chloroform-methanol (39 * 117, to it inc6- and /? -Anomerfrak-

- 86 -

130066/0570

nachoereichtI -

separate functions. The relevant fractions are ^{concentrated at 25 0} G and below under reduced pressure and give the 06-anomer, ie., 3- (Benzyl-o- · -D-glucopyranos-2-yl) -1- (2-chloroethyl) - 1-nitrosourea, and the corresponding / 3-anomer. For the cO anomer: yield 1.38 g (33.1%) '; M.p. 71-72 ° C; C ^ J ψ + 68.5 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₂ N ₃ O ₇ Cl (MW 403.82):

Calculated (%) C, 4-7.59 H, 5.49 N, 10.4-1 Cl, 8.78 Found (%) C, 47.63 H, 5.38 N, 10.53 Cl, 8.72

For the /? Anomer: yield 1.06 g (25.4%); F. 100-102 ⁰ C (decomposition); / / jp -8.6 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₂ N ₅ O ₇ Cl (MW 403.82):

Calculated (%) C ₁ 47.59 H, 5.49 N, 10.41 Cl, 8.78 Found (%) C ₁ 47.49 H, 5.53 N, 10.39 Gl, 8.82

Example 48

4.56 g (16.9 mmol) of 2-methylphenyl-2-amino-2-doxy-D-glucopyranoside are dissolved in a mixture of 20 ml of methanol and 20 ml of dioxane, and succinic acid powder is added to this solution with stirring to adjust the pH to 9.2. The solution is then added dropwise with stirring at 0-5 ° within 5 minutes to a solution which is passed through. Dissolving 4.36 g (7.2 mmol) of o-cyanophenyl -N- (2-chloroethyl) -N-nitrosocarbamate in 30 ml of tetrahydrofuran, after which stirring is continued at the same temperature for a further 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° G and below under reduced pressure. The concentrate obtained is subjected to column chromatography

- 87 130066/0570

/ "Eluent: benzene ^ chloroform-methanol (39 * 1) /,

to put it in (X -. to separate and / 3-Anomerfraktionen The relevant fractions are concentrated at 25 ⁰ C and below, under reduced pressure, and the resulting crystalline residue is recrystallized from a mixture of methanol and water to give the jv-anomer, ie, 3- (2-methylphenyl-o ( _/ -D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding 5-anomer. For the oC-anomer: Yield 2, 20 g (32.2%); F. 74-76 ⁰ C;

ψ + 708 °

ψ + 70 * 8 ° ( ^{c 1} »P» methanol); Analysis for C ₁₆ H ₂₂ N ₅ O ₇ Cl (MW 403.82):

Calculated (%) C, 47.59 H, 5.49 N, 10.41 Cl, 8, -78 Found (%) C, 47.67 H, 5.41 N, 10.55 Cl, 8.72

For the / 3 anomer: yield 1.63 g (23.8%); M.p. 105-107 ° C (decomposition); £ c <sj ψ -10.4 ° (C 1.0, methanol); Analysis for C ₁₆ H ₂₂ N ₃ O ₇ Cl (MW 403.82):

Calculated (%) C, 47.59 H, 5.49 N, 10.41 Cl, 8.78 Found (%) C, 47.62 H, 5.52 N, 10.38 Cl, 8.77

ti 3 ι ■ ij ι; : <j IJ Example 49 -

"• IS I ■"

3.84 g (13.6 mmol) of phenyl-y3-ethyl-2-amino-2-deoxy-i. -D-glucopyrano ^ id are inj a mixture of 50 ml of methanol and 10 ml-Ade ton dissolved,) and this solution is 2 g Dry ice added to the carboxylic acid addition salt form ^. This acid addition salt solution is added drop by drop

• - ^l 'to

se with stirring at -5-OrC within 10 minutes to one iiösun ^ given the 'by dissolving 3.80 g (13.9 mmol) o-Niro-pheüyl-li (2-chloroethyl) -li-nitrosocarbamate in 50 ml

as

Tetrahydrofuran has been prepared, after which the solution is then stirred at 0-5 ° C for an additional 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The resulting crystalline residue is washed with toluene and then recrystallized from a mixture of ^ ethanol and water and gives 3- (phenyl - / ^ · -äthyl- <-D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea: yield 4.33 g (76.5%). F. 80-82 ⁰ G (decomposition). CJ ψ + 65.3 ° (C 1.0, methanol). Analysis for G ₁₇ H ₂₄ N ₅ O ₇ Cl (MW 417.85):

Calculated (%) C, 48.87 H, 5.79 N, 10.06 Cl, 8.48 Found (%) G, 48.81 H, 5.74 N, 10.12 Cl, 8.42

Example 50

18.13 g (72.7 mmol) of n-amyl-6-amino-6-deoxy-D-glucopyranoside are dissolved in 150 ml of methanol and added to this solution 6 g of dry ice are added to form the carboxylic acid addition salt. This acid addition salt solution

is added dropwise with stirring at -5 10 ⁰ G within

10 minutes added to a solution which has been prepared by dissolving 20.47 g (7 ^, 8 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 150 ml of tetrahydrofuran, after which the same Temperature is stirred for a further 3 hours. The reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure. The concentrate obtained is subjected to column chromatography / "Eluent: chloroform → chloroform-methanol (1OzI) I ⁷ " in order to separate it into c </ - and β -anomer fractions.

- 89 -

j 13006J5 / 0S70

'I' ■ ORIGINAL INSPECTED

so

The fractions in question are concentrated at 25 C and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of ethanol and petroleum ether and give the cL -anomer, ie, 3- (n-amyl-MD-glucopyranos-6- yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer. For the oL, anomer: yield 9.27 g (33.2%); F. 62-64 ⁰ C; / boj Jp "+ 72.5 ° (C 1.0, methanol); analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.77 H, 6.79 N, 10.99 Cl, 9.21

For the 3-anomer: yield 7.87 g (28.2%); F. 114-116 ⁰ C (decomposition); / / Jp -10.2 ° (C 1.0, methanol); Analysis for C ₁₄ H ₂₆ N ₅ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.92 H, 6.88 N, 10.88 Cl, 9.19

Example 51

3.53 g (13.4 mmol) of n-hexyl-e-amino-δ-deoxy-D-glucopyranoside are dissolved in 50 ml of methanol, and 1 g of dry ice is added to this solution to form the carboxylic acid addition salt. This acid addition salt solution is added dropwise with stirring at 0-5 ° C within 10 minutes to a solution! <ü ^e 'has been prepared by dissolving 3.99 g (14.6 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 20 ml of tetrahydrofuran,

after which the solution is then partially stirred. The implemented under under prevented pressure

006

-15 ° C for a further 2 hours, the solution is concentrated at 25 C and dark, and the

- 90 -

5/0570

ORlGlNAt INSPECTED

9 *

The concentrate is subjected to column chromatography / "mobile phase: chloroform → chloroform-ethanol

(8: 1) .7 to separate it into oC and Q anome ^ fractions. The fractions concerned are concentrated at 25 ° C and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of ethanol and petroleum ether to give the; v-anomer, ie, 3- (n-hexyl-oC-D-glucopyranos -6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer. For the cO anomer: yield 1.94 g (36.4%); F. from 67.5 to 69 ⁰ C; / "c? O / ψ + 69.2 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₈ N ₃ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.65 Cl, 8.91 Found (%) C, 45.33 H, 7.04 N, 10.68 Cl, 8.90

IR spectrum (KBr, cm " ¹ ): I705 (/ O = O), 1525 (r" NH), 1490

Nuclear Magnetic Resonance Spectrum (CDCl ₃₁ J): 0.85 (3H, CH ₃ ), 1.23 (8H, CH ₂ (CH ₂ ) ₄ CH ₅ ), 4.10 (t, 2H, CH ₂ CH ₂ Cl) , 4.73 (d, IH, C ₁ -H), 7.23 (t, IH, NH)

For the / 3-anonier: yield 1.68 g 31.5 %) \ * '. 119-1 ^ 1 ⁰ C (decomposition), £ o0j ψ -14.3 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₈ N ₃ O ₇ Cl (MW 397.86):

Calculated (%) C, 45.28 H, 7.10 N, 10.65 Cl, 8.91 Found (%) C, 45.21 H, 7.19 N, 10.64 Cl, 8.84

IR spectrum (KBr, cm " ¹ ): 1715 (r0- = 0), 1530 (v ^ NH), 1480

(TN = O)

Nuclear Magnetic Resonance Spectrum (CDCl ₃ , £): 0.85 (3H, CH ₃ ), 8H, CH ₂ (CH_ ₂ ) ₄

CH ₃ ), 4.07 (t, 2H, CH ₂ CH ₂ Cl), 7.27 (t, IH, NH)

- 91 -

130066/0570

ORIGINAL INSPECTED

Example 52

13.26 g (45.5 mmol) of n-octyl-e-amino-δ-deoxy-D-glucopyranoside are dissolved in 100 ml of methanol, and this solution is added dropwise with stirring at 0-5 ° C. within 10 minutes added to a solution prepared by dissolving 13.05 g (47.7 mmol) of o-nitrophenyl N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 90 ml of tetrahydrofuran and 10 ml of benzene, followed by stirring continued for another 3 hours at the same temperature. After checking by TLC, the reacted solution is concentrated at 25 ° C. and below under reduced pressure. The concentrate is subjected to column chromatography / "eluent: chloroform-ethanol (8: 1) y in order to separate it into cv - and / (J-anomer fractions. The fractions concerned are concentrated at 25 ° C and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the a. anomer, ie, 3- (n-octyl-cX / -D-glucopyranos-6-yl) -1- (2-chloroethyl) - 1-nitrosourea and the corresponding h - anomer For the 06-anomer.:. yield 6.69 g (34.5%); F. 64-66 ⁰ C / V / ψ + 67.6 ° (C 1 , O ₁ methanol); R _f 0.50 / "mobile phase: chloroform-ethanol (10: 1) J _% analysis for C ₁₇ H ₅₂ N ₃ O ₇ Cl (MW 425.91):

Calculated (%) C, 47.94 H, 7.57 N, 9.87 01.8.32 Found (%) C, 47.88 H, 7.64 N, 9.82 Cl, 8.30

For the / 3 anomer: yield 5.56 g (28.7%); 104-106 ° C (decomposition); / / ^Λ ψ -7.1 (C 1.0, methanol) R _f 0.42 / mobile phase .: chloroform-ethanol (10: 1) J ⁷ ; Analysis for C ₁₇ H ₃₂ N ₃ O ₇ Cl (MW 425.91):

Calculated (%) C, 47.94 H, 7.57 N, 9.87 Cl, 8.32 Found (%) C, 47.83 H, 7.58 N, 9.93 Cl, 8.25

- 92 -

130066/0570

ORIGINAL INSPECTED

Example 53

31.94 g (100.0 mmol) of n-decyl-e-amino-e-deoxy-D-glucopyranoside are dissolved in a mixture of 150 ml of methanol and 50 ml of tetrahydrofuran, and to this solution Citric acid powder is added to adjust the pH to 9.5. The solution is then taken dropwise Stirring at 0-5 ° C added within 10 minutes to a solution that was obtained by dissolving 28.05 g (102.5 mmol) of o-nitrophenyl-N- (2-chloroethyl) -IT-nitrosocarbamate in a mixture of 150 ml of acetone and 50 ml of dioxane after which the solution is then stirred at the same temperature for an additional 2 hours. The implemented After filtering at 25 ° C and below, the solution is concentrated under reduced pressure, and the obtained The concentrate is subjected to column chromatography.

C solvent: chloroform ^ chloroform-ethanol (19: 1) 7,

to separate it inoC and / 3 anomeric fractions. The fractions in question are concentrated at 2 ^° C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of ethanol and water and give the ^ -anomer, ie, 3- (n-decyl-oO -D -glucopyranos-6-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / 3-anomer. For the rO anomer: yield 15.21 g (33.5%); F. 70-72 ⁰ C; / oC / ψ + 67.8 ° (C 1.0, methanol); Analysis for C ₁₉ H ₅₆ N ₅ O ₇ Cl (MW 453.96):

Calculated (%) C, 50.2? H, 7.99 N, 9.26 Cl, 7.81 Found (%) C, 50.43 H, 7.87 N, 9.23 Cl, 7.94

For the / 9_anomer: yield 12.12 g (26.7%); F. 106-108 ⁰ C (decomposition); / 5 ^ 7 ψ -8.2 ° (C 1.0, methanol); Analysis for C ₁₉ H ₅₆ N ₅ O ₇ Cl (Mo1.Gew. 453.96):

Calculated (%) C, 50.27 H, 7.99 N, 9.26 Cl, 8.81 Found (%) C, 50.37 H, 7.94 N, 9.34 Cl, 7.75

- 93 130066/0570

Example 54

8.53 g (34.2 mmol) of n-amyl-2-amino-2-deoxy- ₍ <-D-glucopyranoside are dissolved in 50 ml of methanol, and 3 g of dry ice are added to this solution to obtain the carboxylic acid addition salt This acid addition salt solution is added dropwise with stirring at -10 ° -15 ° C. within 10 minutes to a solution which is obtained by dissolving 9.77 g (35.7 mmol) of o-nitrophenyl-N- (2 -chloroethyl) -N-nitrosocarbamate has been prepared in a mixture of 50 ml of tetrahydrofuran and 20 ml of acetone, and stirring is then continued at the same temperature for a further 3 hours The crystalline residue obtained is washed with toluene and then recrystallized from a mixture of ethanol and water to give 3- (n-amyl-> x, -D-glucQpyranos-2-yl) -1- (2 -chloroethyl) 1-1nitrosourea. Yield 9.95 g (75.8 %). M.p. 87-89 ° (decomposition). / I * // ψ + 76.5 ° (C 1.0, methanol). Analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C, 43.81 H, 6.83 N, 10.95 Cl ₁ 9.23 Found (%) 3, 43.67 H, 6.92 N, 10.84 Cl, 9.38

l ice cream 55

12.45 g (49.9 mmol) of n-amyl-2-amino-2-deoxy- / "· <-D-glucopyranoside are dissolved in a mixture of 80 ml of methanol and 40 ml of acetone, and to this solution v / 4 g ground dry ice added to form the carboxylic acid-addition salt. This acid-Addtionssalz solution is added dropwise under stirring at -5-0 ⁰ C within 10 minutes

- 94 130066/0570

a solution given by. Dissolve 13.01 g (51.3 mmol) of o-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 40 ml of tetrahydrofuran and 20 ml of hexamethylphosphoramide, after which the solution was then prepared at 0- 5 ° C is stirred for a further 2 hours. After testing with a TLG, the reacted solution is concentrated at 25 ° C. and below under reduced pressure. The crystalline residue obtained is washed with benzene and recrystallized from a mixture of ^ ethanol and water and gives 3- (n-amyl- / 3 -D-glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourarnstolff . Yield 13.13g (58.5%). F. 126-128 ⁰ C (decomposition); / c <, / ψ> -4.8 ° (C 1.0. methanol). Analysis for C ₁₄ H ₂₆ N ₃ O ₇ Cl (MW 383.83):

Calculated (%) C \ 43.81 H, 6.83 N, 10.95 Cl, 9.23 Found (%) C, 43.75 H, 6.78 N, 10.98 Cl, 9.15

Example 56

26.33 g (100.0 mmol) of n ~ hexyl-2-amino-2-deoxy-D-glucopyranoside are dissolved in a mixture of 150 ml of methanol and 50 ml of tetrahydrofuran, and this solution is added dropwise with stirring at -5- 0 ⁰ C added within 10 minutes to a solution which by dissolving 28.32 g (103.5 mmol) of o-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 50 ml of carbon tetrachloride and 150 ml of tetrahydrofuran has been prepared, which is then stirred at the same temperature for a further 2 hours. After checking by TLC, the reacted solution is concentrated at 25 ° C and below under reduced pressure. The concentrate obtained is subjected to column chromatography £ eluent:

- 95 130066/0570

30A6393

Chloroform ^, chloroform-methanol (10: iy to it

to be separated into oC and β anomeric fractions. The fractions concerned are concentrated at 25 ° C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the χ.-anomer, ie, 3- (n-hexyl-o ^ -D -glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / "b -anomer. For the oO -anomer: Yield 13.45 g (33.8%); F. 92 -93 ° C (decomposition); £ boj jp + 74.6 ° (C 1.0, methanol); analysis for C ₁₅ H ₂₈ N ₅ O ₇ Cl (MW 397.86):

Calculated (%) C, 4-5.28 H, 7.10 N, 10.56 Found (%) C, 45.39 H, 7.04 N, 10.4-7

For the β anomer: yield 10.82 g (27.2%); F.

Cl, 8.91 Cl, 8.99

133-135 ^O C

(Decomposition); / jXjJ ψ -15.2 ° (C 1.0, methanol); Analysis for C ₁₅ H ₂₈ N ₃ O ₇ Ql (MW 397.86);

Calculated (%)
Found (%)

C, 4-5.28 C, 4-5.22

H, 7.10 H, 7.21

N, 10.56
N, 10.48

Cl, 8.91 Cl, 8.85

Example 57

11.04 g (39.8 mmol) of n-heptyl ^ -amino ^ -deoxy-D-glucopyranoside are dissolved in a mixture of 150 ml of methanol and 20 ml of η-hexane, and this solution is added dropwise with stirring at -5- 0 ⁰ C added within 10 minutes to a solution which has been prepared by dissolving 10.53 g (41.5 mmol) of p-cyanophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in 150 ml of tetrahydrofuran, after which then stirred at the same temperature for a further 2 hours. After checking by means of TLC, the reacted solution is ^{concentrated at 25 °} C. and below under reduced pressure.

1300r> 6/0570

- 96 -

ORIGINAL INSPECTED

-96- 30A6393

The concentrate is subjected to column chromatography / "mobile phase: chloroform chloroform-ethanol

(30: 2) ./ to separate the Inoi and / 3 anomeric fractions. The fractions in question are ^{concentrated at 25 °} C. and below under reduced pressure, and the crystalline residues obtained are recrystallized from a mixture of methanol and water and give the ^ -anomer, ie, 3- (n-heptyl-o6'-D- glucopyranos-2-yl) -1- (2-chloroethyl) -1-nitrosourea, and the corresponding / i-anomer. For the o6 anomer: yield 2.10 g (12.8%); M.p. 101-103 ° C (decomposition); £ <* J ψ + 66.4 ° (C 1.0, methanol); Analysis for C ₁₆ H ₅₀ N ₅ O ₇ Cl (MW 411.88):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 Cl, 8.61 Found (%) C, 46.71 H, 7.27 N, 10.18 Cl, 8.59

For the θ anomer: yield 1.77 S (10.8%); 123-125 ° C (decomposition); / / ψ -14.6 ° (C 1.0, methanol); Analysis for C ₁₆ H ₅₀ N ₃ O ₇ Cl (MW 411.83):

Calculated (%) C, 46.66 H, 7.34 N, 10.20 UI, 8.61 Found (%) C, 46.68 H, 7.51 N, 10.18 (Jx, ö, '/ y

Example 58

5.24 g (16.4 mmol) of n-decyl - ^ - amino ^ -deoxy-D-glucopyranoside are dissolved in a mixture of 50 ml of methanol and 10 ml of toluene, and this solution is added dropwise with stirring at -5 -1O ⁰ C added within 10 minutes to a solution, which by dissolving 4.62 g (16.9 mmol) of p-nitrophenyl-N- (2-chloroethyl) -N-nitrosocarbamate in a mixture of 30 ml of tetrahydrofuran and 10 ml Acetone has been prepared, and stirring is then continued at the same temperature for 2 hours. After exam

1 ^ 30066/0570 "

BATH ORIGINAL

the reacted solution is concentrated by means of TLC at 25 ^° C. and below under reduced pressure. The concentrate is subjected to column chromatography

/ "Eluent: benzene ^ chloroform-ethanol (10: 1) 7,

to separate it into oG and / S anomeric fractions. The fractions concerned are concentrated under reduced pressure at 25 ° C. and below, and the crystalline residues obtained are recrystallized from a mixture of methanol and water to give the anomer, ie, 3- (n-decyl-.XD-glucopyranos- 2-yl) -1- (2-chloroethyl) -1-ni - *; pink urea, and the corresponding 6-anomer. For the - ^ - anomer: yield 1.19 g (16.0%); F. 100-102 ⁰ C (decomposition); {R, -J ψ + 75.8 ° (C 1.0, methanol); Analysis for C ₁₉ H ₃₆ N ₅ O ₇ Cl (MW 453.96):

Calculated (%) C, 50.27 H, 7.99 N, 9.26 Cl, 7.81 Found (%) C, 50.33 H, 7.94 N, 9.33 Cl, 7.94

For the / 3 anomer: yield 1.01 g (13.6%); F. 118-120 ⁰ C (decomposition); fvOj ψ -6.8 ° (C 1.0, methanol); Analysis for C ₁₉ H ₅₆ N ₃ O ₇ Cl (MW 453.96):

Calculated (%) C, 50.27 H, 7.99 N, 9.26 Cl, 7.81 Found (%) C, 50.21 H, 7.94 N, 9.35 Cl, 7.88

130066/0570 - 98 -

ORIGINAL INSPECTED

Claims (17)

- PAT E N TAN WALTS OFFICE BERLIN - MÖNCHEN 3Ü46393 PATENT LAWYERS DIPL.-ING. W. MEISSNER DIPL.-ING. P. E. MEISSNER DIPL-ING. H.-J. PRESTING Authorized representatives before the European Patent Office - Professional Representatives before the European Patent Office Your sign Your letter of Our signs ΈΑΒΕ-261 HERBERTSTR. 22, 1000 BERLIN 33 0SJ2J9Z0 Tokyo Tanabe Co, Ltd. Novel glucopyranose nitrosohamea compounds with antitumor activity, Process for the preparation of the compounds and pharmaceutical agent containing them Claims t i.yGlucopyranose-nitrosourea compounds with the following general formula or HO • Branch (§ 28 PaO) Munich: St. ANNASTR. 11 8000 MÖNCHEN TEL: 089/22 35 44 TELEX: 1-856 INVEN d Yes CH ₂ OH OH Ib NH-C-N = 0 CH ₂ CH ₂ CL TELEGRAM: INVENTION BERLIN PHONE: BERLIN 030/891 60 37 030/89223 82 BANK ACCOUNT: BLRLINtR BANK AQ. BERLIN 31 3695716000 POSTSCHfCK ACCOUNT W. MEISSNER, BLN-W 122 82 -109 1 3 0 0 θ Θ / .. 0 B 7 0 ORIGINAL INSPECTED " wherein R is a member of the group consisting of branched-chain alkyl having 4 to 9 carbon atoms, Cyclohexyl, mono- (or tri-) methylcyclohexyl, benzyl, Methylphenyl, phenylethyl and normal-alkyl with 5 to Consists of 10 carbon atoms. 2. glucopyranose nitrosourea compounds according to claim 1, characterized in that R represents a member of the group consisting of isobutyl, sec-butyl, tert-butyl, isoamyl, sec-amyl, 3-pentyl, tert-amyl, 2-methyl-1-pentyl, 3-methyl-3-pentyl, 4-methyl-2-pentyl, 2-1thylbutyl, 2-heptyl, 3-heptyl, 4- Heptyl, 2,4-dimethyl-3-pentyl, 2-ethylhexyl and 2,6-dimethyl-4-heptyl consists. 3. glucopyranose nitrosourea compounds according to claim 1, characterized in that R represents a member of the group consisting of cis-2-methylcyclohexyl, trans-2-methylcyclohexyl, cis-4-methylcyclohexyl, trans -4-methylcyclohexyl and cis, trans-mixed -3 »3,5-trimethylcyclohexyl consists. 4-, glucopyranose-nitrosourea compounds according to claim 1, characterized in that R represents a member of the group consisting of 2-methylphenyl, Phenyl-i ^ -ethyl and phenyl- / 3-ethyl consists. 5. glucopyranose-nitrosourea compounds according to claim 1, characterized in that R represents a member of the group consisting of n-amyl, n-heptyl, n-octyl, n-nonyl and n-decyl. 6. Process for the preparation of glucopyranose nitrosourea compounds with the general formula Ia or Ib 130066/0570 CW - '* !, INSPECTrD (where R is a member of the group consisting of branched-chain alkyl having 4 to 9 carbon atoms, Cyclohexyl, mono- (or tri ~) methylcyclohexyl, benzyl, Methylphenylethyl and normal alkyl with 5 to 10 carbon atoms consists), characterized in that there is an aminoglucopyranose compound with the following general formula Ha Man (where R has the meaning given above and R is an amino group or an acid addition amino group) with an otho- or para-substituted phenyl-N- (2-chloroethyl) -N-nitrosocarbamate compound with the following general formula ; · - O-CN-CH ₂ -CH ₂ Cl ΙΙΪ 0 NO
(where R ^ represents a nitro or cyano group). 130066/0570 - ⁴ - 7. The method according to claim 6, characterized in that - indicates that R is a member of the group consisting of isobutyl, sec.Butyl, tert. Butyl, isoamyl, sec-amyl, 3-pentyl, tert-amyl, 2-methyl-1-pentyl, 3-methyl-3-pentyl, 4-methyl-2-pentyl, 2-ethylbutyl, 2-heptyl, 3-heptyl, 4-heptyl, 2,4 ~ dimethyl-2-pentyl, 2-ethylhexyl and 2,6-dimethyl-4-heptyl. 8. The method according to claim 6, characterized in that that R is a member of the group consisting of cis-2-methylcyclohexyl, trans-2-methylcyclohexyl, cis-A-methylcyclohexyl, trans -4-methylcyclohexyl and ice, trans mixed 3 »3» 5-trimethylcyclohexyl consists. 9. The method according to claim 6, characterized in that that R is a member of the group consisting of 2-methylphenyl, phenyl-tfC -ethyl and Phenyl-ζβ-ethyl consists. 10. The method according to claim 6, characterized indicates that R is a member of the group consisting of n-amyl, n-hexyl, n-heptyl, n-octyl, consists of n-nonyl and n-decyl. 11. The method according to claim 6, characterized in that that the reaction is carried out using an organic solvent with a Peutigkeitshalt of 2 to 10%. 12. Pharmaceutical agent against tumor systems, thereby characterized in that it contains as the active ingredient the glucopyranose-nitrosourea compounds of the general formula Ia or Ib contains (where R is a 130086/0570 " ⁵ " ORIGINAL INSPECTED Represents a member of the group consisting of branched • chain alkyl with 4 to 9 carbon atoms, cyclohexyl, Mono- (or tri-) methylcyclohexyl, benzyl, methylphenyl, Phenylethyl and normal-alkyl with 5 to 10 carbon atoms). 13 · Pharmaceutical agent against tumor systems according to claim 12, characterized in that R is a member of the group consisting of isobutyl ', sec-butyl, tert-butyl, isoamyl, sec-amyl, 3-pentyl, tert-amyl, 2-methyl-1-pentyl, 3-methyl-3-pentyl, 4-methyl-2-pentyl, 2-ethylbutyl, 2-heptyl, 3-heptyl, 4-heptyl, 2,4-dimethyl-2-pentyl, 2-ethylhexyl and 2,6-dimethyl-4-heptyl consists. 14. A pharmaceutical agent against tumor systems according to claim 12, characterized in that R represents a member of the group consisting of cis-2-methylcyclohexyl, trans-2-methylcyclohexyl, cis-4-methylcyclohexyl, trans -4-methylcyclohexyl and cis, trans-mixed -3,3,5-trimethylcyclohexyl consists, 15. A pharmaceutical agent against tumor systems according to claim 12, characterized in that B ^ represents a member of the group consisting of 2- methylphenyl, phenyl-oC '-ethyl and phenyl- / 3 -ethyl. 16. A pharmaceutical agent against tumor system according to claim 12, characterized in that R represents a member of the group consisting of n-amyl, n-hexyl, n-heptyl, n-octyl, n-nonyl and n-decyl. 130065/0570 17. Pharmaceutical agent against tumor systems according to one of claims 12 to 16, characterized in that it is in the form of tablets,
coated tablets or coated tablets, capsules, powders, granules, injection liquids, emulsions, suspensions or suppositories. 130066/0570 ORIGINAL INSPECTED