IE57950B1

IE57950B1 - Salts of oxazaphosphorine derivatives

Info

Publication number: IE57950B1
Application number: IE510/85A
Authority: IE
Original assignee: Asta Medica Ag
Priority date: 1984-03-01
Filing date: 1985-02-28
Publication date: 1993-05-19
Also published as: ES540777A0; IE850510L; FI78705B; KR850007067A; HUT36829A; EP0158057B1; FI78705C; KR890003789B1; DE3569737D1; ES8607332A1; FI850800L; CA1254903A; IL74473A0; FI850800A0; EP0158057A1

Abstract

1. Salts of oxazaphosphorine derivatives of the general formula see diagramm : EP0158057,P15,F1 wherein R1 , R2 and R3 , which can be identical or different from one another, represent hydrogen, methyl, ethyl, 2-chloroethyl or 2-methanesulphonyloxyethyl and in this case at least two of these radicals are 2-chloroethyl and/or 2-methanesulphonyloxyethyl and A is the group -S-alk-SO3 H or -N(OH)-CONH-alk-CO2 H and alk represents a C2 -C6 -alkylene radical optionally containing a mercapto group, where alk can also be -CH2 - if the carboxyl group is on the group alk, with homocysteine thiolactone or alpha-amino-epsilon-caprolactam or a basic compound of the formula see diagramm : EP0158057,P15,F2 wherein R4 is a hydroxyl group, an amino group or a C1 -C6 -alkoxy group, R5 is hydrogen or a difluoromethyl group, R6 denotes hydrogen, a 3-indolylmethyl radical, a 4-imidazolylmethyl radical, a C1 -C10 -alkyl group or a C1 -C10 -alkyl group which is substituted by a hydroxyl group, a C1 -C6 -alkoxy group, a mercapto group, a C1 -C6 -alkylthio group, a phenyl group, a hydroxyphenyl group, an amino-C1 -C6 -alkylthio group, an amino-C1 -C6 -alkyloxy group, an amino group, an aminocarbonyl group, a ureido group (H2 NCONH-), a guanidino group or a C1 -C6 -alkoxy-carbonyl group, or wherein R6 together with the structural moiety =CR5 (NR7 R6 ) forms the proline radical, the 4-hydroxy-proline radical or the 2-oxo-3-amino-3-difluoromethylpiperidine and the radicals R7 and R8 represent hydrogen or C1 -C6 -alkyl radicals.

Description

The present invention relates to new salts of oxazaphosphorine derivatives having anti-tumour activity.

Belgian patent 892589 describes oxazaphosphorine-*»thio-alkanesulfonic acids and salts thereof of the general formula: Θ in which R j , R^, and R^, which may be the same or different, each represent hydrogen, methyl, ethyl, 2-chloroethyl or 2methanesulfonyloxyethyl, at least two of the groups Rp ft? and R^ being 2-chloroethyl and/or 2-methanesulfonyloxyethyl, R^ is hydrogen or methyl, X is a straight or branched chain C2-Cg alkylene group which can have a mercapto group on the 1-, 2-, 3-, 4-, or 5- carbon atom of the alkylene chain, and © Y is the hydrogen cation, an alkali metal or alkaline earth metal cation, the guanidinium, morpholinium or cyclohexylammonium cation or the cation derived from an I amine of the formula NRCR,R„ wherein Rn, R, and R„, which oof do 7 may be the same or different, are each hydrogen, C^-C^-alkyl groups or hydroxyethyl groups, or Y is the ethyleneo o diammonium cation H^N-CH^-Cf^-NH^ or the piperazinonium -> cation and z is 1 where Υφ is a monobasic cation, or z is where Y is a dibasic cation or the cation of a compound having two monobasic cations.

Furthermore, German Offenlegungsschrift 3133309 concerns A-carbamoyloxyoxaphosphorine derivatives of the general formula wherein X is oxygen or sulphur, R^ and R^, which may be the same or different, each represent hydrogen, methyl, \ethyl, 2-chloroethyl or 2-methanesulfonyloxyethyl, the 15 residues R^, which may be the same or different, each ~ represent hydrogen, methyl or ethyl, R^ is hydrogen, alkyl, hydroxy-C1_^-alkyl or phenyl and Z amongst other things, may represent a C^C^-alkylamino group which can contain different substituents including a carboxy group, and pharmaceutically acceptable salts thereof. One example in this German OS is a compound wherein Z is the group -NH-CI^-COOH and the corresponding cyclohexylamine salt.

The compounds of Belgain patent 892589 and German published application 3133309 possess antitumor activity as well as an immunosuppresive activity.

The present invention provides salts of oxazaphosphorine derivatives of formula (I) in which R?, and R2> which may be the same or different, each represent hydrogen, methyl, ethyl, 2-chloroethyl, or 2-methanesulfonyloxyethyl at least two of the groups R^ R^ and R^ being 2-chloroethyl and/or 2-methanesulfonyl-oxyethyl and A is the group -S-Alk-SO3H or -N( OH)-CONH-Alk-CO^H where Aik represents a C^-C^-alkylene group optionally containing a mercapto group, in addition to which Aik can also represent -CH^- in the case where there is a carboxy group attached thereto, with homocysteinethiolactone or α-amino-t-caprolactam or a basic compound of formula (II) R, - CRc - COR. (II) o | 5 A NR7R8 in which R^ is a hydroxy group, an amino group or a C^-Cg5 alkoxy group, R^ is hydrogen or a dif1uoromethy1 group, R^ is hydrogen, a 3-indolylmethyl residue, 4-imidazolvlmethyl residue, a alkyl group or a C^C^-alkyl group which is substituted by a hydroxy group, a C^C^alkoxy group, a mercapto group, a C-C^-alkylthio group, a phenyl group, a hydroxyphenyl group, an amino-C^C^alkylthio group, an amino-C-C^-alkvloxy group, an amino group, an aminocarbonvl group, a ureido group (H^NCONH-), a guanidino group or a C1-C^-alkoxycarbony1 group, or wherein R^ together with the structural portion >CR^(NR^Rg) forms a proline residue, a A-hydroxy-proline residue or a 2-oxo-3-amino-3-difluoromethyl-piperidine residue and R? and Rg each represent hydrogen or C^-C^-alkyl radicals.

The present invention also provides a process for the production of oxazaphosphorine derivatives of formula (I) as defined above which comprises: (a) reacting a compound of the formula (III) (III) wherein X is a hydroxy group or a C^C^-alkoxy group with a salt of a compound of formula (IV) AH (IV) in which A is as defined above and the basic component of the salt is homocysteinethiolactone, a-amino-grcaprolactam or the basic compound of formula II as defined above or is first reacted with the compound AH and subsequently reacted with the basic compound defined above; or a compound of formula (III) in which X is benzylthio, C^-C^- alkanoylthio or C1-C1θ-alkylthio, optionally substituted by a carboxy group, a hydroxy group or a C1-C^-carbalkoxy group or in which X is the group -N ( OH )-CO-NHR , where R is hydrogen, C^C^-alkyl or benzyl or phenyl optionally substituted'by C^-C^-alkyl or halogen, or in which X is the group A and X can also exist in salt form, is reacted with an excess of a compound of formula (V) A’H (V) or a salt thereof or with homocysteinethiolactone, a-aminoς,-caprolactam or a basic compound of formula II as defined above, wherein A' is a group as defined for A but is different from A; or (b) reacting a compound of formula I or the salt thereof with homocysteinethiolactone, a-amino-fc.-caprolactam or a basic compound of formula II as defined above to form the corresponding salt and optionally exchanging the basic component in the compound produced, or the acid hydrogen of the group A in the case where A is not in salt form, for another basic component within the scope of the definition given above.

The compounds of the invention show strong antitumor activity and can be used especially to combat cancer. Compared to the known compounds of Belgian patent 892589 and German Offenlegungsschrift 3133309 they have, for example, reduced toxicity (for example reduced acute toxicity and leucotoxic action) and therefore they have an improved therapeutic index and better local and systemic as well as venous compatibility. Furthermore, the compounds of the invention show reduced immunosuppressive action, reduced local tissue irritation and frequently lower haemolytic action. Furthermore, the compounds of the invention do not have or have only slight circulatory side effects (for example, sympathetic actions). influenced less disturbingly.

The compounds of the formula I Also blood pressure is have the following structure: N in which R1# R2, R3 and A have the above mentioned meanings. Included within the invention are the salts of such compounds of the formula I with homocys.teinethiolactone or a-amino-c-caprolactam or a compound of the formula II.

The alkylene group (Aik) in formula X can be straight or branched. Examples are methylene, dimethylene, trimethyl ene, tetramethylene, pentamethylene or hexamethylene residues and also, for example, the residues -CH-CH^, ch3 -CH-CH ( CH_ ) _-, -C(CH-)_-CH_- and -CH--CH-CH--; I 2 2 3 2 2 2,2 ch3 ch3 the chain especially consisting of 2 or 3 carbon atoms when it is unbranched. In the event of Aik being branched, the portion which is attached to the acid group, and the sulfur or nitrogen atom especially, consists of 2 or 3 carbon atoms. If the group Aik has a carboxy substituent, then Aik is preferably -CH^-· If the group Aik has a mercapto substituent (especially when A is the group -S-AlkSC>3H), the mercapto group can be on the 1-, 2-, 3-, A-, or 5- carbon atom. Numbering begins with the carbon atom bearing the acid group, for example, the -S03H group. In this case the group -CHp-CH(SH)-CH^- is preferred.

Preferred compounds are those in which R3 is hydrogen, Rj and R2 are both 2-chloroethyl· and A is the group -S-CH2CH2-SO3H or -N(OH)-CO-NH-CH2-CO2H.

Alkyl groups, alkoxy groups, and alkylthio groups which are present, in formula II can be straight or branched. The C.j-Cjg-a 1 ky 1 group preferably contains 1-6 carbon atoms. The alkoxy and alkylthio groups preferably contain 1 to A especially 1 or 2, carbon atoms; the same applies in the case when the groups Fi? and Rg are alkyl groups. When Rg in formula II is an alkyl group which contains an amino-C^Cg-alkylthio C^-Cg-alkyl group then the groups H_N-CH_-CHo-S-CIL·- and H_N-CHo-CH_-0-CH_- are preferred.

CCC (. CCC c.

Preferred compounds of formula IT are those in which R^ is a hydroxy group, the groups Rg, R?, and Rg are hydrogen and Rg especially takes the meanings stated below.

Preferred basic compounds of formula II are for example those in which R^ is a hydroxy group, Rg is hydrogen or di fluoromethyl , Rg is a C^-C^q- alkyl group, especially a C.j-Cg-alkyl group, which contains an amino group, preferably in the 2-, 3-, 4-, 5-, or 6- position where numbering always begins at. the point where the alkyl group is linked with the rest of the molecule, more preferably in the 3- or A- position, or Rg is an amino-C2-CZ)-a Iky 1 th io group, an amino-02-C^-alkoxy group, a guanidino residue, an imidazolyl-(4)-methyl residue or an indolyl-(3)- methyl residue and R? and Rg are hydrogen or a C^C^-alkyl radical; or aminoacid derivatives of formula II where R. is an amino 4 group or a C^C^- alkoxy group, Rg is hydrogen, Rg is 5 hydrogen, a phenylmethyl group, a 4-hydroxyphenylmethyl group or a C^-Cg-alkyl group which contains a hydroxy group, a mercapto group, a C -C^-alkylmercapto group, an aminocarbonyl group, a C-C^-alkoxycarbony1 group or a ureido group (preferably in the 2-, 3-, 4-, 5-, or 6- position) and R? and Rg are hydrogen or a C^-C^-alkyl group.

In the aminoacids or aminoacid derivatives mentioned above the salts for example are formed from, in each case one.mole of oxazaphosphorine of formula I and one mole of the compound of formula II.

Further examples of basic compounds of formula II are compounds in which R^ is an amino group or a C-C^-alkoxy group, Rg is hydrogen or difluoromethyl, Rg is a C^C^alkyl group, especially a C^-Cg-alkyl group which contains an amino group, an amino-C^-C^-alkylthio group, an amino20 C^-C^-alkoxy group, a guanidino residue, an imidazolyl-(4) methyl residue or an indolyl-( 3)-methyl residue (preferably in the 2-, 3-, 4-, or co-position) and R? and Rg are hydrogen or a C.j-C^-alkyl group.

In these aminoacid derivatives, the salts are formed for example from, in each case, 2 moles of oxazaphosphorine and 1 mole of the amino acid derivatives of the formula II. i 1 Specific examples of compounds of formula II are: aspartic acid diamide (DL-form), diethyl ester of aspartic acid (L-form), citrullinamide (H^N-CO-NH-(CH^)^CH(NH^)-CONHp, L-form), arginine, arginiamide (L-form), 4thialysine (H2N-CH2-CH2-S-CH2-CH(NH^)-COOH), 2,6-diamino enanthic acid (e.-methyl lysine), A-oxalysine (F^N-CF^CF^-OCF^-CH(NH^)-COOH), glycinamide, Ν,Ν-dimethyl glycinamide as well as the corresponding methyl and ethyl esters, prolinamide, hydroxyprolinamide, phenylalaninamide, the methyl and ethyl esters of alanine or phenylanine, homocysteinethiolactone (DL-form), a-amino-ε,-caprolactam (D(+)-form, lysine (especially L-lysine), difluoromethylornithine (DL- or L-form), methyl ester of valine (L-form), ethyl ester of threonine, methyl ester of histidine, histidinamide, alaninamide and ornithine.

Where R^ in the compound of formula II in the salts of the invention is an amino group or an alkoxy group and no other basic group is present or where R^ is a hydroxy group and no other basic group is present, compound I (acidcomponent) and Compound II (basic component) are present essentially in the ratio 1:1. (This is also true in the event that the basic component is homocysteinethiolactone or α-amino-^-caprolactam.) On the other hand if R^ in the compound of formula II is an amino group or an alkoxy group which contains besides the a-amino group an additional basic group, then generally the ratio of compound I to compound II is 2:1. The salts of the invention are neutral salts.

In the case of the sulfonic acid salts the pH for example is between 3.5 and 6. In the case of carboxylic acids the pH for example is from 6 to 9, especially 6 to 8.

Process (a ): The process is carried out in a solvent at temperatures between -60°C and +90°C, preferably -30°C to +60°C, especially -20 to +30°C, that is in a particular case with cooling, at room temperature or with heating. The reaction can be carried out in the presence of an acid catalyst, such as an inorganic or organic acid for example trichloroacetic acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid or even a Lewis acid such as AlCl^, ZnCl^, TiCl^, boron trifluoride etherate. The pH for the reaction is adjusted to between 1 and 8, preferably between 2 and 6. This is 3 especially the case if the starting compounds are employed in form of the salts, and optionally also if the free acid AH is employed and A contains a carboxy group.

Examples of suitable solvents include: water, alcohols, especially alkanols having 1-6 carbon atoms such as methanol, ethanol, propanol, isobutanol or hexanol, alkyl ketones containing 1-4 carbon atoms in the alkyl groups such as acetone or methyl ethyl ketone, aprotic solvents (for example dimethyl sulfoxide, acetonitrile, N-methyl pyrrolidine, dimethyl formamide, hexapiethylphosphoric acid triamide), halogenated hydrocarbons having 1-3 carbon atoms such as chloroform, ethylene dichloride, saturated cyclic ethers such as tetrahydrofuran, dioxane, saturated lower aliphatic ethers such as diethyl ether, similar solvents, and mixtures of two or more of such solvents.

In case where the symbol X in the starting compound III X is a hydroxy or alkoxy group, the reaction can, for example, also be carried out in 2 steps by first reacting 4 compound III with compound AH (without acidification) and subsequently adding to the reaction mixture, optionally after concentration and addition of another of the solvents referred to above, the basic component II or homocysteinethiolactone or α-amino-t-caprolactam in a solvent.

The use of a compound III wherein X is the hydroxy group or an alkoxy group, is especially suited to produce the end product in crystalline form.

In the event that X is not hydroxy or alkoxy or X is in salt form, the compound A’H, or compound A’H in salt form, is employed in excess, for example, 1.5-10 molar, preferably 2-5 moles of the compound A’H or the salt of A’H per mole of compound III. The pH of the reaction solution is adjusted for example to 5-5-9, preferably 6.5-8 by means of alkali solution, e.g. aqueous sodium hydroxide, or with the amine which is already present as the basic component in the salt employed. Under certain circumstances a pH up to 12 can also be favorable especially if the starting compounds are employed in salt form or in form of the free acids (for example if A contains a carboxy group). The reaction temperature is for example 10-90°C, preferably 25-60°C. The reaction time?is for example several seconds to several hours. Subsequently for example the reaction solution is cooled to below 10°C and brought to a pH between 4 to 5.5 or optionally to pH 7 with a mineral acid (H^SO^, HCl, phosphoric acid, a sulfonic acid (for example mercapto-C^-C^-alkanesulfonic acids, e.g. mercaptomethanesulfonic acid or mercaptohexanesulfonic acid, or an ion exchanger (H+) form).

The isolation of the product of the process for example can be carried out: by crystallization or by a chromatographic process, especially by preparative high pressure liquid chromatography, optionally once again with subsequent reaction in the desired salt form on a correspondingly loaded cation exchanger.

In the case where the group A of formula III is present in salt form for example, salts such as those described in German Offenlegungsschrift 3133309 or Belgian patent 892589 (the entire disclosure of which are hereby incorporated by reference) can be used. For example the ammonium salt, the cyclohexylammonium salt or the guanidinium salt can be used. It goes without saying that other conventional salts can also be employed, for example, conventional optical bases used for resolution of a recemate, which salts can be produced in a manner analogous to the methods described therein.

Starting compounds of formula III for example are also described in the following references or may be produced in a manner analogous to the methods described therein: Tetrahedron Letters Nr. 10 (1979), pages 883-886, Cancer Treatment Reports 60, Nr. 4 (1976) pages 429-435. If X is an optionally substituted C-Cjθ-alky1th io group compounds of formula III are used wherein X especially has the following meanings: Cj-Cg-alkylthio, the group -S-(CH^)n-CO2H (n = 1-6, especially 1-3), the group -S-(CH2)n~OH (n = 2-6, especially 2-4) or the group —S—(CH^)n-C00C2H^ (n = 1-6), especially 1-3). If X is a Cj-Cg-alkanoylthiogroup preferably acetylthio is used.

If X is the group -N(OH)-CO-NHR and R is Cj-Cg-alkyl preferably R consists of 1-4 especially 1-2 carbon atoms.

The production of the starting salts AH of formula IV, and the starting salts A’H of formula V can be carried out for example by reaction of a compound AH or A’H with a basic compound or homocysteinethiolactone or a-amino-tcaprolactam or a compound of formula II with or without a solvent at temperatures between 0 and 40°C. As solvents there can be used for example water, C-Cg-alkanols (methanol, ethanol), lower aliphatic ketones (acetone), cyclic ethers (dioxane), chlorinated hydrocarbons (methylene chloride, ethylene dichloride, chloroform, carbon tetrachloride), saturated lower aliphatic ethers (diethyl ether), aprotic solvents (for example dimethylformamide, dimethylsulfoxide, acetonitrile) or mixtures of two or more of these solvents. 7 The production of this type of salt can also be carried out for example by dissolving an alkali salt (sodium salt) of the acid AH or A'H in water (for example 1 to 20% solution; % = weight percent), allowing this solution to run through a column containing a strongly acid ion exchanger (H+ form, 3 fold excess) and neutralising the free acid in the eluate with the basic component, concentrating the mixture in a vacuum, and optionally recrystallising the residue from a lower alcohol (methanol, ethanol), a lower ketone (acetone) or an ether (diethyl ether ) .

Process (b): This process is carried out at temperatures between 0-25°C, preferably 0-5°C. The following are examples of solvents which can be used for this process: water, lower aliphatic alochols, lower aliphatic ketones or mixtures of these solvents. One mole of component I as reacted with 1 mole of component II. It is suitable to operate at a pH range between 3 and 8. When compounds I are used in which A is the S-Alk-SO^H group (or a salt thereof), a pH between 3-6, preferably 3.8-5, especially pH 4 is preferably used. When compounds I are used in which A is -N(OH)-CO-NH-AlkCO^H (or a salt thereof) a pH between 6-8, preferably pH 7, is preferably used.

Frequently the addition of a buffer is favorable.

Examples of buffer systems with a pH range between 3.8 to 5.0 include the following: citric acid/sodium citrate; acetic acid/sodium acetate; phosphoric acid/sodium hydrogen phosphate; tartaric acid/sodium tartrate; aminoacid/sodium formate; sodium hydrogen phosphate/citric acid; succinic acid/sodium succinate; propionic acid/sodium propionate; aconitic acid/sodium aconitate; (i, β-dimethylglutaric acid and its sodium salt; maleic acid/sodium maleate; compound II/citric acid. Examples of buffers for a pH range of 6 to 8 include the following: sodium citrate/NaOH, trishydroxymethyl )-aminomethane-maleate/NaOH, KH^PO^/NaOH, KH2P0a/Na2HP0A.

Instead of using sodium hydroxide solution to produce the buffer, homocysteinethiolactone or a-amino-ζ.caprolactam or a basic compound of formula II can also be used so that the buffer already contains the basic component, which is also to be present in the end product of formula I.

The exchange of the basic component of a salt of compound I with a basic component of the invention can be carried out for example using acid ion exchangers which are loaded with homocysteinethiolactone, a-'e-caprolactam or a basic compound of formula II. In this case the basic compound II (which now is bound.to the acid groups of the ion exchanger) is employed in excess (for example 2 to 10 9 moles, preferably 5 moles of component II to 1 mole of component I). Examples of acid ion exchangers which can be used are those whose polymeric matrix carries sulfonic acid groups or carboxylic acid groups. The matrix of the ion exchanger can, for example, consist of a polystyrene resin optionally containing 2 to 16%, preferably 4 to 8% of divinyl benzene or a phenol resin. The polystyrene ion exchanger is preferably in gel form. The loading of the ion exchanger with the basic components can be carried out for example in the following manner: The producer of the ion exchanger states the capacity of the ion exchanger, that is the amount of functional groups such as -SO^H, -CO^H , in mval/ml or mval/g. 15Ό ml of ion exchanger resin, 1.2 mval/ml, in a column (diameter about 4 cm) with a cooling jacket is regenerated with hydrochloric acid, washed with distilled water until neutral and free of chloride ions.

The ion exchanger is then treated with a 10% aqueous solution of the basic compound (220 moles) and washed with distilled water. Additionally, the ion exchanger can be treated with a buffer (citric acid/citrate or acetic acid/ acetate) of about pH 4 and subsequently the buffer again washed out. Furthermore, the ion exchanger can also be loaded with neutral aminoacid salts of formula II or neutral salts of homocysteinethiolactone or a-amino-f caprolactam (for example the hydrochloride or hydrobromide).

In the case where an ion exchanger is used it is favorable to add the buffer in the receiver for the eluate.

In a few cases the elution of the salt together with the buffer and/or the salt of a mercapto-C^-Cg-alkanesulfonic acid through the ion exchanger is also advantageous. For example, the starting compound, that is the compound I (A = S-Alk-SOgH) or a known salt of compound I is dissolved in a buffer at pH 3.8 to 5.0, preferably 4.1 and this solution is passed over the ion exchange column and the eluate is collected in a corresponding buffer solution.

The eluate or the lyophilizate produced therefrom then consists of the salt according to the invention and the buffer and/or the salt of the mercaptoalkanesulfonic acid. Preferably the eluate, in a given case after dilution with water, may be immediately frozen or lyophilized. In the case where the symbol A in the starting compound I is the group -N(OH)-CO-NH-Alk-CO^H, an analogous procedure is used but then the pH is between 6-8 (for example pH 7).

However, in this case, an alternative procedure can be used in which a known salt of compound I (for example an alkali metal salt) in aqueous solution is allowed to run through an acid ion exchanger as mentioned above in the H+ form and the compound I then neutralized in the eluate with the basic component of formula II or with homo25 cysteinethiolactone or α-amino-t-caprolactam. This way • of proceeding is especially suitable if the end product is to be produced in crystalline form.

Starting salts of the compound of formula I are for example those described in German Offenlegungschrift 3133309 or Belgian patent 892589. For example, the ammonium salt, the cyclohexylammonium salt or the guanidinium salt. However, other customary salts (for example salts with optically active bases which are known for resolution of a racemate) can also be used, which can be produced in a manner analogous to the methods described therein.

Included in the oxazaphosphorine derivatives of formula I are all possible stereoisomers and mixtures thereof. In particular, For example, the cis-trans isomers on the oxazaphosphorine ring, that is the cis-or-transposition of the group A to the oxo-group on the 2-position (phosphoryl oxygen). Thus for example, the compounds exist as a mixture of cis isomers and trans isomers (and at times the racemate and the corresponding enantiomers), the separated cis isomers and the separated trans isomers. Diastereomer salts (for example if a chiral amine is used for salt formation), can be separated in known manner, preferably through fractional crystallization. The pure enantiomers can be obtained according to the conventional methods of resolving racemates, for example through fractional crystallization of the diastereomer salts from racemic acids of formula I and optically active bases or in a given case, through use of optically active starting materials according to formula III in the synthesis.

Generally in the synthesis cis/trans mixtures are formed. Generally, mixtures are formed which consist preponderantly of the cis isomers and up to about 5-10% of the trans isomers. For example, the compounds according to Examples 1-5 consist of the cis isomers with less than 5-10% of the trans form.

In the case of compounds which crystallize readily, the crystallized cis or the trans form, especially the cisform, can be obtained from such mixtures. However, if the reaction is carried out in solvents which are free of water or in solvents with only a small proportion of water, one form, especially the cis-form, is obtained exclusively or preponderantly. Thus, for example, the pure cis-form of a noncrystallizing or poorly crystallizing compound of formula I can be produced by adding a solution of the compound of formula III in acetone to an aqueous solution of the compound of formula IV or its salt at temperatures between -30 and +20°C and after completion of the reaction precipitating several times.

The starting compounds of formula III can be employed as racemic cis and trans isomers (production of which are as described above), as optically active cis and trans forms and as mixtures thereof (in this connection see Belgian patent 892589 and German Offenlegungschrift 3133309, page 12).

Examples of optically active bases which can be used for resolution of the racemate include: 1-phenylethylamine, brucine, guanidine, strychnine and cinchonine as well as the further bases and methods which are described in Optical Resolution Procedures for Chemical Compounds, volume 2, Paul Newman, 1981, published by Optical Resolution Information Center, Riverdale, USA. For this purpose, for example, a racemic salt of the invention can be converted into a salt with one of the previously mentioned optically active bases in the manner already stated, the enantiomers separated in known manner and then the optically active base of the enantiomers obtained in this way replaced again by a basic compound according to the invention. However, the optically active bases mentioned above can also be employed in the synthesis in process (a) in the reaction of a compound of formula III with a compound of formula IV or V or in process (b) as basic salt component. In this case this optically active base is subsequently exchanged in conventional manner with the basic salt component of the invention corresponding to the definition already given.

The basic salt components of the invention, homocysteinethiolactone, α-amino-t-caprolactam as well as the compounds of formula II can be employed as the racemate or in the form of the pure enantiomers.

Generally the L-forms are preferred.

The salts of the invention include all forms which result from the presence of the various asymmetric carbon atoms, for example, racemates, optically active forms, and diastereomeric forms.

It is recommended in the production of the salts of the invention to hold them in solution for as short a time as possible in order to prevent hydrolysis to 4hydroxyoxazaphosphorines and/or oxazaphosphorine ring (conversion of the cis-form into the trans-form) or at least to hold such hydrolysis to as low a level as possible.

In the event that the salts of the invention are strongly contaminated (for example contain large amounts of starting compounds), they can be purified by means of conventional chromatographic methods or preparative high pressure liquid chromatography .

The salts of the invention are stable, have storage stability (especially at 4°C), and can be readily processed galenically. For galenic preparations (for example hydrolysis stable injection solutions, lyophilizates), especially to provide storage stability, it is also recommended to establish a pH range of about 3.5-7 with the sulfonic acid derivatives by means of conventional buffers (for example citrate buffer). The optimum pH is 4.0-4.3.

In the case where the residue A is derived from the group N(OH)-C0-NH-Alk-C02H, a suitable pH is 6.5-7.5. These pH adjustments can be carried out both for solutions and suspension and also for solid galenic preparation.

Furthermore, and independently of the addition of a buffer, the addition of 0.5 to 5 equivalents of a salt (for example alkali metal salt, especially the sodium salt) of a mercapto C2-Cg-alkylsulfonic acid (for example a salt of 2-mercapto-ethane-sulfonic acid) or its disulfide or further thiols (for example cysteine) is also advantageous. Types of thiols and disulfides and the methods of their use are described in European patent application Publication No. 83439- Examples of this kind of salt are the alkali metal salts (Na,K) or the salts with a basic component according to the invention (compound of formula II, homocysteinethiolactone, a-amino-t-caprolactam).

The addition of the salt of mercapto-C^-Cgalkanesulfonic acid for example can be carried out by addition of an aqueous solution of the salt of the sulfonic acid (alkali salt, for example 20 weight percent) to an aqueous solution of the salt of the invention (preferably buffered to a pH between 4 and 4.3). The mixture thus obtained is for example then lyophilized.

The advantages of adding amercaptoalkanesulfonic acid salt in this way are as follows: improvement of the storage stability as well as of the stability in aqueous solution with the salts of the invention. (For example this is of significance in the production of the salts but also for example is useful in solution of lyophilizates before use); improvement in chemotherapy of cancer illnesses by means of the salts of the invention, especially in regard to toxic side effects (cf. European patent application publication No. 83439 and European Patent 2495).

The salts of the invention are suitable for the production of pharmaceutical compositions or preparations. The pharmaceutical compositions or drugs contain one or more of the salts of the invention as active material, optionally in admixture with other pharmacologically or pharmaceutically active materials. The production of the drugs can be carried out using known and conventional pharmaceutical carriers and adjuvants.

The drugs for example can be administered enterally, parenterally, orally, perlingually or in the form of sprays. Dispensing can be carried out for example in the form of tablets, capsules pills, dragees, plugs, liquids, or aerosols. Examples of liquids are: oily or aqueous solutions or suspensions, emulsions injectable aqueous or oily solutions or suspensions.

The compounds of the invention show a good cytostatic and curative effect in intravenous, intraperitoneal, or oral application with various experimental tumors of the rat and the mouse. For example a curative effect, depending on the dosage, was produced with the compounds of the invention on the rat 5 days after intra5 peritoneal implantation of 10 cells of leukemia 15222 with different doses applied intravenously, intraperitoneally, or orally. Healing is defined recedive and metastasis free survival of tumor carrying animals after 90 days. The average curative dose (DC 50), i.e. the dose which healed 50% of the tumor carrying animals, was calculated from the frequency of healing obtained with different doses by means of the test analysis according to R. Fisher.

For example, the compounds of the invention were also dispensed at various doses intravenously, intraperitoneally, or orally one day after the implantation of 10^ cells of Yoshida-Ascites-Sarcoma AH 13 and a curative effect was produced depending on the dosage. In this case also, the curative effect was defined as recedive and metastasis free survival of the tumor carrying animals for 90 days. The average curative dose (DC 50) i.e. the dose at which 50% of the tumor carrying animals were healed, was calculated in a corresponding manner by means of the test analysis according to R. Fisher.

Furthermore, for example, the compounds of the invention were dispensed with various doses intravenously, intraperitoneally, or orally once or a number of times (4x) on successive days after intraperitoneal implantation of 103 cells of the mouse leukemia L1210 and a cytostatic effect was produced. The cytostatic effect is shown as an increase of the median survival time of the tumor bearing animals and is expressed as a dosage dependent percent increase of the survival time compared to an untreated control group. The average curative dose with the rat tumours is independent of the form of dispensation in the range of 0.1-10 mg/kg. With the same doses an increase of the median survival time of 100% is produced with the mouse leukemia L1210.

Furthermore, the compounds of the invention stimulate the production of antibodies in a specific lower dosage range. This dosage range for example for the compound according to Example 5 is between 20-50mg/kg rat (intravenously, intraperitoneally). By comparison in the same dosage range the antibody production of the known antitumor agent cyclophosphamide is already suppressed.

Literatrue: N. Brock: Pharmakologisch Grundlagen der Krebs Chenotherapie in A. Georgu (Hrsg), Verhandlungender Deutschen Krebgesellschaft Volume 1, pages 15-42, Gustav Fischer Verlag, Stuttgart (1978).

This curative and cytostatic effect is comparable with the effect of the known medicines cyclophosphamide and ifosfamide.

The lowest curative or cytostatically effective dosage in the animal experiments referred to above are for example: 0.01 mg.kg orally 0.01 mg/kg intraperitoneally 0.01 mg.kg intravenously A general dosage range for the curative and cytostatic action (animal experiments as above) is: 0.01-100 mg/kg orally, especially 0,1 - 10.0 mg/kg 0.01-100 mg/kg intraperitoneally, especially 0.1-10.0 mg/kg 0.01-100 mg/kg intravenously, especially 0.1-10.0 mg/kg The compounds of the invention are indicated for 15 use in malignant diseases of man and animals.

The pharmaceutical preparations generally contain between 1 mg and 1 g, preferably 100 to 1000 mg of the active component (or components) of the invention.

Dispensing can be carried out for' example in the 20 form of tablets, capsules, pills, dragees, plugs, salves, gels, creams, powders, dusts, aerosols, or in liquid form. Examples of liquid forms include oily or alcoholic or aqueous solutions as well as suspensions and emulsions.

Preferred forms of use are tablets which contain between and 200 mg or solutions which contain between 0.1 to 5% of active material.

The individual dosage of the active components according to the invention for example can be (a) with oral forms of the medicine between 1-100 mg/kg, preferably 10-60 mg/kg (b) with parenteral forms of the medicine (for example intravenously, intramuscularly between 1-100 mg/kg, preferably 10-60 mg/kg (c) with forms of the medicine for application rectally or vaginally between 1-100 mg/kg, preferably 10-60 mg/kg, (d) with forms of the medicine for local application to the skin and mucous membranes (for example in the form of solutions, lotions, emulsions, salves, etc.) between 1-100 mg/kg, preferably 10-60 mg/kg The doses in each case are based on the free base.

For example, times daily 1 to 10 tablets having an active meterial content of 10 to 300 mg can be recommended 1-3 times daily or for example with intravenous injection one or more ampoules containing 1 to 10 ml containing 10 to 250 mg of material can be recommended 1 or 2 times daily. The minimum daily dosage with oral administration for example is 200 mg; the maximum daily dosage with oral administration should not exceed 5000 mg.

In individual cases, doses over 12 and more hours corresponding to continuous infusion, can also be recommended.

The individual dose in treating dogs and cats orally is generally between 10 and 60 mg/kg bodyweight; the parenteral dose is between about 10 and 60 mg/kg bodyweight.

The individual dose in treating horses and cattle orally is generally between about 10 and 60 mg/kg bodyweight; the parenteral individual dose is between about 10 and 60 mg/kg bodyweight.

The acute toxicity of the compounds of the invention on the mouse/expressed by the LD 50 mg/kg; method according to Miller and Tainter: Proc. Soc.. Exper. Biol. a. Med. 57 (1944) 261), for example with oral application is between 100 and 1000 mg/kg (or about 1000 mg/kg).

The drug can be used in human medicine, veterinary medicine as well as in agriculture alone or in admixture with other pharmacologically active materials.

The invention is illustrated by the following examples: Example 1 A-(2-Sulfo-ethylthio)-CyclophosphamideGlycinamide Salt (Cyclophosphamide is 2-[2-( bis-(2-chloroethyl) amino)]-2-oxo-tetrahydro-2H-1,3,2oxazaphosphorine) A.O grams (18 mmoles) of A-hydroxy-cyclophosphamide in 10 ml of distilled water were treated with 5 grams (18 mmoles) of 2-mercaptoethanesulfonic acid-glycinamide salt in AO ml of acetone.’ The reaction solution was acidified with trichloroacetic acid to a pH of A, kept for 2 hours at 5°C and for 20 hours at -25°C. The salt separated out in crystalline form and was filtered off with suction, washed, dried, and recrystallized from water/ acetone.

M.P. 90-98°C; Yield 7.2 grams (76% of theory).

The salt contains about 1 equivalent of acetone.

Example 2 A-[1-Hydroxy-3-carboxymethyl-ureido-(1)]cyclophosphamide-Lysine salt (L-Lysine) 7.5 grams (2A.6 mmoles) of A-ethoxycyclophosphamide and 3 grams (22.A mmoles) of 1-hydroxy-3-carboxymethyl-urea were kept in 50 ml of dry alcohol for 20 hours at 0°C.

Subsequently the reaction solution was concentrated at 20°C in a vacuum, the residue taken up in 200 ml of acetone, treated with 3.3 grams (22.6 mmoles) of L-lysine in 25 ml of methanol and the gelatinous precipitate centrifuged after standing for a short time. The residue was dissolved in water, filtered, precipitated with acetone, filtered off with suction and washed with acetone/ether.

M.P. 125-128°C; Yield: 6.5 grams (54% of theory).

Example 3 4-(2-Sulfo-ethylthio)-cyclophosphamideGlycinamide Salt A solution of 3.1 grams (6.5 mmoles) of 4(3-sulfopropylthio)-cyclophosphamideguanidine salt and 4.2 grams (19-6 mmoles) of 2-mercaptoethanesulfonic acidglycinamide salt in 15 ml of water was adjusted to pH 7.5 with aqueous sodium hydroxide and heated for 5 minutes at about 40°C. Subsequently the reaction solution was cooled to 0°C, adjusted to pH 4.5 with sulfuric acid, treated with 70 ml of acetone and kept for 3 days at 40°C. The precipitate filtered off with suction and recrystallized from water/acetone.

M.P. from 85°C (decomposition); Yield: 430 mg (14% of theory).

Example 4 4- (2-Sulfo-ethylthio)-Cyclophosphamide-Arginine Salt (L-Arginine) 37.2 grams (74.5 mmoles) of 4-(2-sulfoethylthio) cyclophosphamide-cyclohexylamine salt were dissolved in 320 ml of distilled water at 5°C (pH 4.3) and passed over a column cooled to 4°C and containing 150 ml of cation exchanger. A gel form polystyrene resin was used containing 8% divinyl benzene and also containing sulfonic acid groups, which cation exchanger was loaded with arginine. Velocity of flow through the column: 6 ml/minute. The column was rinsed with 250 ml of water. The eluate, cooled to 4°C, was diluted with cold water to form a 5% solution and subsequently lyophilized.

M.P. 85-90°C (decomposition); Yield: 42.9 grams (100% of theory).

The addition of a buffer and/or a mercaptoalkylsulfonic acid can be carried out as follows: (a) Addition of Sodium Citrate Buffer The procedure is as stated above but the eluate is collected in sodium citrate buffer (pH 4.1) and diluted for example subsequently to a solution which is 0.5 molar in sodium citrate and 5% inactive material. Subsequently the solution was lyophilized.

Yield: 42.9 grams (100% of theory), compound of Example 4 with sodium citrate buffer. (b) Addition of Sodium Citrate Buffer and Sodium2-mercapto-ethanesulfonate (Mesna) The procedure is as stated above except that the eluate is collected in a cooled sodium.citrate buffer solution (pH 4.1) which contains 8.2 grams (50 mmoles) Mesna and the solution is subsequently lyophilized.

Yield: 42.9 grams (100% of theory) of compound of Example 4 with Mesna and sodium citrate buffer.

Example 5 4-(2-Sulfo-ethylthio)-CyclophosphamideLysine Salt (L-Lysine) (a) 37.3 grams (74.5 mmoles) of 4-(2-sulfoethylthio)-cyclophosphamide-cyclohexylamine salt were eluated in a manner analogous to Example 4 on an ion exchanger (protonated lysine form) and subsequently lyophilized .

M.P. from 85°C (decomposition); Yield: 40.8 grams (100% of theory). (b) A alternative procedure for the example is the following: 82.4 grams (16.5 mmoles) of 4-(2-sulfoethylthio)-cyclophosphamide cyclohexylamine salt were dissolved in 850 ml of distilled water at 5°C. The solution was adjusted to pH 4.1 with several particles of strongly acid ion exchanger (having sulfonic acid groups) and at a 6 dropping speed of 50 ml/minute passed over a column cooled to 4°C and containing 800 ml of ion exchanger (the same ion exchanger as in Example 4) containing 820 mmoles of sulfonic acid-L-lysine groups. The first 180 ml of the eluate were discarded and the following eluate continuously adjusted under stirring and ice water cooling to pH 4.1 with in all about 1.5 ml of strongly acid ion exchanger (having sulfonic acid groups). The ion exchanger was rinsed with 900 ml of distilled water cooled to 0°C. Subsequently the eluate was diluted with cold water to a 5% solution and immediately lyophilized.

M.P. from 85°C; Yield: 90 grams (100% of theory). (c) Compound According to Example 5(a) with Lysine-Citrate Buffer (Lysine + Citric Acid) 7.2 grams (14.4 mmoles) of 4-(2-sulfoethylthio)cyclophosphamide-cyclohexylamine salt were dissolved in 80 ml of 0.05 molar sodium citrate buffer (pH 4.1) at 4°C and passed over a column containing 40 ml of cation exchange resin (protonated lysine form) cooled to 4°C. It was rinsed with 80 ml of buffer solution, the eluate was made up to 150 grams of solution and lyophilized.

Yield: 7.9 grams (100% of theory) of the compound of Example 5(a) with lysine-citrate buffer. (d) Compound According To Example 5(a) With 2Mercaptoethanesulfonic Acid-Lysine Salt and Lysine-Citrate Buffer 7.2 grams (14.4 mmoles) of 4-(2-sulfoethy1th io ) cyclophosphamide-cyclohexylamine salt and 1.5 grams (9.2 mmoles) of Mesna were dissolved in 80 ml of 0.05 molar sodium citrate buffer pH 4.1 and 4°C and passed over a column containing 40 ml of cation exchange resin (protonated lysine form) and cooled to 4°C. It was rinsed with 50 and 30 ml of buffer solution, the cooled eluate made up to 150 grams of solution and lyophilized.

Yield: 7.9 grams (100% of theory) of the compound of Example 5(a) with 2.6 grams (100% of theory) of 2mercaptoethanesulfonic acid-lysine salt and lysine citrate buffer (pH 4.1) Example 6 4-(2-sulfo-ethy1th io)-eyelophosphamide-glycinamide salt 2.9 grams (8.6 mmoles) of 4-(hydroxy-ethylthio) cyclophosphamide and 5.6 grams (26 mmoles) of 2-mercaptethanesulfonic acid-glycinamide salt were dissolved in 35 ml of distilled water. The pH was adjusted to 8 with glycinamide. The reaction solution was heated for about 4 minutes at about 40°C. Subsequently the reaction solution was cooled to 0°C, adjusted to pH 4.5 with 2mercapto-ethanesulfonic acid and 500 ml of acetone were added. The reaction mixture was then kept for several days at 4°C, the precipitate was filtered off with suction and recrystaiiized from water/acetone.

M.P. from 85°C; Yield 410 mg (9 % of theory).

The salt contains about- 1 equivalent of acetone.

Examples of Pharmaceutical Preparations (a) Production of a Lyophilizate of 4-Sulfoethylthio-cyclophosphamide-Lysine Salt grams of 4-sulfo-ethylthiocyclophosphamideL-lysine salt were dissolved with stirring in 1500 ml of water suitable for injection purposes and cooled to 4°C. Subsequently the solution was made up to 1800 ml with water at 4°C. The pH was adjusted to about 4.2 with several particles of regenerated cation exchanger (H+ form). The above solution was subjected to a sterile filtration in known manner to produce the lyophilizate. The receiving vessel was cooled. All of the processes subsequent to the sterile filtration were carried out under aseptic conditions.

The sterile solution was filled to 2 ml in a 10 ml injection flask. The active material content was 100 mg.

The flasks were provided with sterile freeze drying stoppers and lyophilized in a freeze drying unit. Subsequently the unit was deaerated'with sterile, dried nitrogen and the ampoule flasks closed in the unit. For the production of an injection solution the contents of the flasks were dissolved in 5 ml of water suitable for injection purposes.

The lyophilizate is stored at 0-6°C (refrigerator). (b) Production of a Lyophilizate of 4-(2Sulfo-ethylthio)-cyclophosphamide-Lysine Salt (L-Lysine) with Citric Acid Lysine Buffer 1. An ion exchange column having a cooling jacket was loaded with 1300 ml of an acid ion exchanger,. regenerated with 2 liters of 10% hydrochloric acid and washed with water suitable for injection purposes until neutral and free of chloride. 2. Subsequently the column was loaded with the help of 3 liters of a 10% lysine solution, freed of excess lysine by washing with water suitable for injection purposes and washed until neutral. 3. 1.4 liters of the following composition were passed over the column: 4-(sulfo-ethylthio)-cyclophosphamide cyclohexylamine salt 137.12 g Citric Acid, water free 28.83 g 1 N NaOH 193.20 ml Water for injection purposes to 1.4 liters Active agents and adjuvant were dissolved in water at about 4°C. The pH of the solution was 4.1. The cation exchange column was then also cooled to about 4°C. The above solution was passed over the column. The speed of flow through the column was 10 ml/minutes.

The eluate was collected in a cooled receiver, whereby the first 300 ml was discarded as forerunner. Subsequently the column was washed with water suitable for injection purposes and cooled to 4°C and the entire volume of the eluate made up to 3 liters.

The eluate which should be further processed to a lyophilizate has the following composition: 4-(2-Sulfo-ethylthio) cyclophosphamide Lysine salt (L-lysine) 150.00 g Citric Acid water free 28.83 g L-Lysine water free 28.24 g Water for injection purposes 2870.93 g 3078.00 g = 3000 ml 4. For the production of the lyophilizate the above solution was subjected to a sterile filtration in known manner. The receiving vessel was cooled. All the procedures following the sterile filtration were carried out under aseptic conditions.

The sterile solution was filled into injection flasks as follows: ml of solution in a 10 ml injection flask.

Active material content 100 mg. 1 ml of solution in a 30 ml injection flask.

Active material content 500 mg.

The flasks were provided with sterile freeze drying stoppers and lyophilized in a freeze drying unit. Subsequently the unit was deaerated with sterile, dried nitrogen and the ampoule flasks closed in the unit.

For the production of an injection solution the contents of the flasks containing 100 mg of active material were dissolved in 5 ml of water suitable for injection purposes and the contents of the flasks containing 500 mg of active material were dissolved in 25 ml of such water. f (c) Production of a Lyophilizate of 4-Sulfoethy1thiocyclophosphamide-Arginine Salt grams of 4-sulfo-ethylthiocyclophosphamidearginine salt and 135 grams of sodium-2-mercapto-ethanesulfonate were dissolved with stirring in 1500 ml of water, cooled to 4°C and suitable for injection purposes. After complete solution it was made up to 1800 ml with water at 4°C. The pH was adjusted to about 4.2 with several particles of regenerated cation exchanger (H+ form). For the production of the lyophilizate the above solution was subjected to a sterile filtration in known manner. The receiving vessel was cooled. All of the procedures subsequent to the sterile filtration were carried out under aseptic conditions. The sterile solution was filled to 2 ml in a 10 ml injection flask. The content of active material is 100 mg. The flasks were provided with sterile freeze drying stoppers and lyophilized in a freeze drying unit. Subsequently the unit was deaerated with sterile, dried nitrogen and the ampoule flasks closed in the unit. For the production of an injection solution the contents of the flasks were dissolved in 5 ml of water suitable for injection purposes.

The lyophilizate is stored at 0-6°C (refrigerator)

Claims

1. Ά salt of an oxazaphosphorine derivative of formula (I) 5 in which Rp R^, and R^, which may be the same or different, each represent hydrogen, methyl, ethyl, 2-chloroethyl, or 2. -methanesulfonyloxyethyl, at least two of the groups Rp R^ and R^ being 2-chloroethyl and/or 2-methanesulfonyloxyethyl and A is the group -S-Alk-SO^H or -N(OH)-CONH-Alk10 CO^H where Aik represents a C2-C^-alkylene group optionally containing a mercapto group, in addition to which Aik can also represent -CH?- in the case where there is a carboxy group attached thereto, with homocysteinethiolactone or a-amino-tz-caprolactam or a basic compound of formula (II) R, — CRr — COR, 6 | □ 4 NR ? Rg (II) in which R^ is a hydroxy group, an amino group or a C.j-C^-alkoxy group, R^ is hydrogen or a difluoromethyl group, Rfc is hydrogen,a 3-indolylmethyl residue, a 4-imidazolylmethy1 residue, a Cj-C^g-alkyl group or a Cj-Cθ-aIky1 group which is substituted by a hydroxy group, a Cj-C^-alkoxy group, a mercapto group, a Cj-Cg-alkylthio . group, a phenyl group, a hydroxyphenyl group, an amino-C-C^-alkylthio group, an amino-C } -C^-alkyloxy group, an amino group, an aminocarbonyl group, a ureido group (H^NCONH-), a guanidino group or a Cj-C^-alkoxycarbonyl group, or wherein Rg together with the structural portion >CRg(NR 7 Rg) forms a proline residue, a 4-hydroxy-proline residue or a 2-oxo-3-amino-3-difluoromethyl-piperidine residue and R? and Rg each represent hydrogen or Cj-Cg-alkyl radicals.

2. A salt according to Claim 1, wherein the basic compound is a compound of the formula II, wherein R 4 is a hydroxyl group or an amino group, the radicals R 5 , R ? and R g are each hydrogen and R g denotes hydrogen or a C 1 -C 4 -alkyl group which, in particular in the ω-position, can be substituted by an amino group or a guanidino group.

3. A process for the production of a salt of an oxazaphosphorine derivative as defined in claim 1 which comprises reacting a compound of the formula (III) (III) 5 wherein X is a hydroxy group or a C-C^-alkoxy group with a salt of a compound of formula (IV) AH (IV) in which A is as component of the ε-caprolactam or defined in claim 1 and the basic salt is homocysteinethiolactone, oc-aminothe basic compound of formula II as defined in claim 1. 4. 6

4. A process for the preparation of a salt of an oxazaphosphorine derivative of the general formula I according to Claim 1, which comprises first reacting a compound of the general formula (HI) group, (IV) wherein X is a hydroxyl group or a C 1 ~C 4 -alkoxy with the compound AH and subsequently with homocysteine thiolactone, “-amino-e-caprolactam or the basic compound of the formula II.

5. A process for the preparation of a salt of an oxazaphosphorine derivative of the general formula 1 according to Claim 1, which comprises reacting a compound of the general formula III, wherein X is a C^-C^-alkylthio group which is optionally substituted by a carboxyl group, a hydroxyl group or a C^-C^carbalkoxy group, a benzylthio group or a C^C^-alkanoylthio group, or wherein X represents the group -N(OH)-CO-NHR and R denotes hydrogen, a C -C -alkyl X O group, a benzyl group or a phenyl group which is optionally substituted by -alkyl radicals or halogen, or wherein X is the group A and the radical X 4 7 can also be present in the salt form, with excess of a compound of the formula A'H (V) or a salt of this compound A’H or with homocysteine thiolactone, α-amino-e-caprolactam or the basic compound of the formula II having the meanings indicated for the radicals R 4 to R g , where A' is different from A and has one of the meanings indicated for A.

6. A process for the preparation of a salt of an oxazaphosphorine derivative of the general formula I according to Claim 1, which comprises reacting a compound of the formula I or the salt of a compound of the general formula I with homocysteine thiolactone, a-amino-ε-caprolactam or a basic compound of the formula II having the meanings indicated for R 4 to R g or with their salts with the formation of the corresponding salts.

7. A process for the preparation of a salt of an oxazaphosphorine derivative of the general formula I according to Claim 1, which comprises exchanging the basic component or the acidic hydrogen of the group A, if this is not present as a salt, for another basic compound in the context of the definition given therefor in compounds of the formula I.

8. A medicament containing a salt according to one or more of the foregoing claims in addition to customary excipients and/or diluents or auxiliaries.

9. A medicament according to Claim 8, which additionally contains a buffer and/or the alkali metal salt of a mercapto-C 2 -C 6 -alkanesulphonic acid.

10. A process for the preparation of a medicament, which comprises processing a compound according to Claim 1 or 2 to give a pharmaceutical preparation using customary pharmaceutical excipients or diluents or other auxiliaries, or bringing it into a therapeutically utilizable form.

11. A process according to Claim 10, wherein buffer and/or the alkali metal salt of a mercapto-C_-C-alkanesulphonic acid are additionally used.

12. Use of a compound according to Claim 1 or 2 for the preparation of a medicament.

13. A compound according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

14. A process for the preparation of a compound according to Claim 1, substantially as hereinbefore described with particular reference to the accompanying Examples.

15. A compound according to Claim 1, whenever prepared by a process claimed in any one of Claims 3 to 7 or 14.

16. A medicament according to Claim 8, substantially as hereinbefore described.