DE2163601A1 - Medicaments containing (3,5,3,5-tetraoxo) -1,2-dipiperazinoalkane compounds and process for the preparation of the compounds - Google Patents

Description

OR. ING. F. "WUIiSTHOFF

DR.E. ir. PECHMANJi DR. IXG. ». BF-ItRKSS DIPL. IXG. R. GOETZ

PATEXTAN W-OLD

8 MUNICH

SCIIWEIOSRSTIUSSI 8 TKlIFOIt (OSIl) βη 20 TEI.YCX 3 24 OTO

TZLIOIIUtMI: PROTEOTPATEST -MiJNCIIEK

1A-40 706

Description of the patent application

NATIONAL RESEARCH DEVELOPMENT CORPORATION 66-74 Victoria Street, London, S.W.1, England

concerning

Medicaments with a content of (5,5,3 ', 5'-tetraoxo) -1,2-dipiperazinoalkanverhindun ^ en and process for the preparation

of connections.

Addition to main patent 1 910 283 (patent application P 13 10 283.1)

The main patent relates to medicaments which are characterized by a content of a (3,5,3 ', 5 ^I- tetraoxo) -1,2-dipiperazinoalkane compound of the general formula

N CHR ₁ CHR ₂ H

(D

CH,

CfL

-co -co

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in which R ₁ and R "each denote a hydrogen atom or a methyl group or together a saturated hydrocarbon bridging group with 2 carbon atoms, in which case R 1 and R _{2 are} both methyl groups, the steric meso form is present. The studies at that time led to the result that the anti-cancer activity was limited to this small group of compounds of the formula I. It was found that the ethyl analog dl-1,2-bis (3,5-dioxopiperazin-1-yl) butane of dl-1,2-bis (3 »5-dioxopiperazin-1-yl) propane (R ₁ = H, R ₂ = CH,) was essentially inactive in this respect. Surprisingly, however, it has now been found that certain other compounds, carefully selected for both structure and stereoisomerism, have valuable anti-cancer effects and that in some cases these compounds have advantages over those of the main application. In contrast to the above-mentioned ethyl analog, the diethyl analog 3 »4-bis (3» 5-dioxopiperazin-1-yl) hexane has a stronger anti-cancer effect than dl-1,2-bis (3,5-dioxopiperazin-1-yl ) propane itself, but only if the ethyl groups are in the meso position to one another, the activity of the dl compound being significantly lower.

The present invention therefore relates to medicaments which are characterized by a content of a (3f5 »3 ^l _J 5 ^l -Tetraoxo) -1,2-dipiperazinoalkane compound of the general formula

CO CH ₉ HH CH ₉ C

HN:? N 0 C N

CO CH ₂ R ₁ R ₂ ^ CH ₂ CO

(H)

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in R .. and R «each mean an unsubstituted alkyl, alkenyl and alkynyl group with 1 to 4 carbon atoms, a substituted alkyl, alkenyl and alkynyl group with 1 to 3 carbon atoms, provided that R ₁ and R ₂ have none Mean methyl group and that the substituted groups except im]? All of fluorine contain only one substituent and their physiologically acceptable acid addition salts.

The formula II relates not only to the structure of the compounds, but also to their steric configuration, ie the invention relates to compounds with such a configuration that the groups R ₁ and R ₂ are next to one another in the meso or erythro configuration and not opposite in the dl or threo configuration If R .. and R _{2 are} not identical, the compounds of formula II can exist in two enantiomorphic forms and the present invention relates to both the dl, d and 1 isomers such compounds, in which differences in the effectiveness and / or the physical properties, for example the solubility, can occur The groups R. and R ₂ can be straight or branched-chain.

The chain length of the groups R ₁ and R ₂ is preferably | wise 1 to 3 carbon atoms when the groups are unsubstituted and when the substituents are fluorine atoms and 1 or 2 carbon atoms when the groups have other substituents. Although the invention also relates to compounds in which the groups R ₁ and R _{2 are} branched chain, straight chain alkyl, alkenyl and alkynyl groups are preferred and, in the case of substituted groups, those groups which are substituted on the terminal carbon atom of the chain are preferred . So are highly branched groups, like

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t-butyl less interesting and from the alkyl groups with

4 carbon atoms, the n-butyl group is the most interesting and compounds containing n-propyl groups are more interesting as those with isopropyl groups.

Although unsubstituted groups are preferred, are also substituted groups interesting, especially substituted alkyl groups in contrast to alkenyl and alkynyl groups. The substituted alkyl, alkenyl and alkynyl groups can contain various substituents, e.g. phenyl and carbalkoxy groups, but especially halogen atoms, hydroxyl and alkoxy groups. However, it is preferred that the groups not be too large as this will lower the activity. Therefore the substituted groups should preferably exert a steric effect in the molecule that is not essential is greater than that of a butyl group, especially an n-butyl group, and conveniently more similar to that of a Propyl group such as n-propyl group. Therefore they are preferred Substituents ÜPluoratome, hydroxyl and methoxy groups, however also chlorine atoms and also ethoxy, carboxy and methoxycarbonyl groups. For similar reasons, it is preferred that the number of fluorine atoms in each substituted group be increased

5 and is conveniently limited to 3. Especially in the case of larger substituents such as phenyl, ethoxy, carboxy and methoxycarbonyl groups, also with other substituents, substituted ethyl and especially methyl groups are of particular interest.

The groups R ^ and Rp can, for example, be unsubstituted saturated groups such as methyl, ethyl, n-propyl and i-propyl groups, unsubstituted unsaturated groups such as Yinyl and especially allyl and propargyl groups, and substituted saturated groups such as chloromethyl, pentafluoroethyl and especially hydroxymethyl, 2-hydroxyethyl, methoxy

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methyl, trifluoromethyl and 2,2,2-Trifluor'äthylgruppen be.

Compounds in which the sum of the carbon atoms in the chains of the groups R ₁ and R _{2 is} not more than 5, especially not more than 4, are of particular interest. For example, compounds in which R .. is a methyl, ethyl or n-propyl group, especially one of the first two groups and especially a methyl group, are noteworthy.

Special compounds according to the invention, which depending on the meso or erythro form and in the dl-, d-. or 1-form are those in which the radicals R ^ and R _{2 have} the following meaning:

R ₁ = CH ₅ - and R ₂ = C ₂ H ₅ -, R ₁ = CH ₅ - and R ₂ = UC ₃ H ₇ -,

R ₁ = CH ₃ - and R ₂ =! -C ₅ H ₇ -, R ₁ = CH ₃ - and R ₂ = nC ^ -,

R ₁ = CH ₅ - and R ₂ = CH ₂ = CH-,.

R ₁ = CH ₅ - and R ₂ = CH ₂ = CH-CH ₂ -, R ₁ = CH ₃ - and

Λλ - CH = O-UIiQ "*,

R ₁ = CH ₃ - and R ₂ = HIGH ₂ -, R ₁ = CH ₃ - and R _? = HOOH ₂ CH ₂ -,

. R ₁ = CH ₃ - and R ₂ = CH ₃ OCH ₂ -, R ₁ = CH ₃ - and R ₂ = ClCH ₂ -,

R ₁ = CH ₃ and R ₂ = CP ₃ -,

R ₁ = CH ₃ - and R ₂ = CF ₃ CH ₂ -,. ₍

R ₁ = CH ₃ - and R ₂ = CF ₃ CF ₂ -,

R ₁ = CH ₃ - and R ₂ = CF ₃ CH ₂ CH ₂ -, R ₁ = C ₂ H ₅ - and R ₂ = C ₂ H ₅ -,

R ₁ = C ₂ H ₅ - and R ₂ = UC ₃ H ₇ -, R ₁ = C ₂ H ₅ - and R ₂ = 1-C ₃ H ₇ -,

R ₁ = C ₂ H ₅ - and R ₂ = HOCH ₂ -, R ₁ = C ₂ H ₅ - and R ₂ = CH ₂ = CH-,

R ₁ = C ₂ H ₅ - and R ₂ = CH ₂ = CH-CH ₂ -, R ₁ = C ₂ H ₅ and R ₂ = CH = C-CH ₂ -,

R ₁ = C ₂ H ₅ - and R ₂ = HOCH ₂ CH ₂ -, R ₁ = C ₂ H ₅ - and R ₂ = CH ₃ OCH ₂ -,

R ₁ = C ₂ H ₅ - and R ₂ = CF ₃ CH ₂ -, R ₁ = C ₂ H ₅ - and R ₂ = CF ₃

R ₁ = CH ₂ Cl- and R ₂ = GH ₂ Cl-, R ₁ = CF ₃ - and R ₂ = CF ₃ -,

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The present invention also relates to. a. Options for the preparation of compounds of the general formula II in which R ^ and R ₂ each have a separate unsubstituted alkyl, alkenyl or alkynyl group with a chain length of 1 to 4 carbon atoms or a substituted alkyl, alkenyl or alkynyl group a chain length of 1 to 3 carbon atoms, with the proviso that the two R .. and Rp are not a methyl group and that the .substituierten groups contain only one substituent, except in the case of fluorine, which is characterized in that one compound the general formula

YCH ₂ ,

Y ¹ CH ₂ '

'Ή CHR ₁ CHR ₂ -

in which R 1 and R _{2 have} the meaning given, or are groups which can be converted into groups of the meaning given, and Y and Y ¹

a) individually the same or different aliphatic marriage

mean groups or together an aliphatic group \ which by

Reaction with a suitable nitrogen-containing compound can be converted into a group -CO.HH.CO-; fe b) individually the same or different aliphatic Mean groups which can be cyclized either directly or indirectly to a group -CO.NH.CO- or

c) together represent a group -00.KX.CO-, where X is a group that can be replaced by a hydrogen atom j.! by reaction with a suitable nitrogen-containing one Connection by cyclization or by replacement of the group X

if necessary, through a hydrogen atom, converts the groups R-. and R ₂ converts in a suitable manner into the desired groups R ^ and Rg and / or the desired compound from that of

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separates, in. which the groups R ^ and Rp in opposite Position. The term "directly or indirectly" under b) means that the groups optionally before the cyclization can be modified. The group X can, for example, be a benzyl group be.

The process preferably consists in that a) an H, N, N ^I _f N ^l -tetracarboxymethyldiamine of the formula given above in which R .. and Rp are groups as defined above or groups which can be converted into such groups and X and T ^{1 are} carboxy groups or their bisanhydride, where Y and Y ¹ together are a -00.0.CO group, heated with one of the following reagents *.

I. '. inem acid amide of the general formula RCONHp, where R is a hydrogen atom, an aliphatic radical having 1 to 4 carbon atoms or a primary amino group or

II. Ammonia in an acid amide of the general formula

in which R ^{1 is} a hydrogen atom or an aliphatic radical having 1 to 4 carbon atoms and R ″ and R ^{111 are} the same or different aliphatic radicals having 1 to 4 carbon atoms or one of the radicals R ¹¹ and R ¹¹¹ together with R ¹ and the COH group mean a 5- or 6-membered lactam.

Advantageously, the method is used in which a suitable nitrogen-containing compound is used, especially one of the general formula J ^ ^{% t} ^ ⁿ

RCONHo or R ¹ CON

I I

² \

R, R ¹ , R ¹¹ and R ^{flt have} the meanings given above. Included

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the term "aliphatic radical" means groups such as Ethoxy and n-propoxy groups as well as groups such as alkyl groups, e.g. those with 1 to 4 carbon atoms, such as ethyl or especially methyl groups. A preferred reagent is formamide.

The use of a N, N, N ^1, N Tetracarboxymethyldiamin precursor is preferred, particularly when it is reacted with formamide or urea, conveniently at a temperature of at least 10O ⁰ C and with ammonia in dimethylformamide, conveniently at a temperature of at least 120 ⁰ C and with Äthylcarbamat or n-propyl carbamate, conveniently at a temperature of at least 140 ⁰ C, for example 140 to 180 ° 'C, and optionally in the presence of a halogenated aromatic hydrocarbon as a diluent or solvent, for example 1.2, 4-trichlorobenzene. If a Ν, Κ, Ν ¹ , N'-tetracarboxyamidomethyldiamine is used as a precursor, acidic reagents such as polyphosphoric acid and phenol are preferred, the reaction in the first case advantageously at a temperature of at least 80 ^° C., especially 80 to 150 ^{° C.} C, for example, is chgeführt-dur at about 135 ° C and above, and at least 130 ⁰ C, particularly 130 to 190 ⁰ C, for example at about 170 ⁰ C or above. When an N, N, N ¹ , N'-tetracyanomethyldiamine is used as a precursor, the preferred alkali amide is sodium amide and the reaction is most conveniently carried out in an amide solvent, especially an amide in which the nitrogen atom is unsubstituted or monosubstituted, and especially carried out in formamide. The mineral acids which can be used in the second stage of the reaction include acids such as methanesulfonic acid, but the hydrohalic acids, for example hydrochloric acid, can also be used very well. The second stage is advantageously carried out in the presence of an alcohol as solvent, such as methanol.

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As mentioned above, in some cases it is advantageous to use a reactant in which the groups R 1 and R p are groups which are desired in the final compound. Groups can be converted. This is the case, for example, with unsaturated groups, especially vinyl groups. Other examples are the formation of a HOCH ₂ group from a CH, OCH ₂ group and a HOCH ₂ 'CH ₂ group from a> ^ v. Group and a C1CH ₂ group from a

H ₂ C CH-

HOCH ₂ group. Except under very specific circumstances, however, it is simpler if R .. and R ₂ in the reactant already correspond to those in the desired product. Ί

It has been found to be particularly advantageous to use a reactant which is in the meso or erythro form, in which the groups R ₁ and R ₂ are located next to one another and which is essentially free of compounds of the dl and threo Form in which the groups R .. and R _{2 are} opposite. If the d- or 1-isomer of an erythro compound is to be produced, which essentially contains no 1 and dl or d and dl isomers, a reactant of the corresponding configuration can be used or the end product can optionally be used in the corresponding isomers are separated. As mentioned above, the use of> an N, N, N ¹ , IP-tetracarboxymethyldiamine precursor is preferred. ™ These compounds can be prepared in a number of ways, usually including preparing the corresponding unsubstituted diamine and reacting it with a monohaloacetic acid. In order to obtain the substituted diamine in the meso or erythro form, this isomer has to be separated off at some stage of the process. Thus, according to a process, the diamine is produced from the corresponding succinic acid and the separation is carried out in the stage of the succinic acid.

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acid carried out. In a generally more favorable process however, the corresponding dioxime is used as a Yorstufe for the diamine is used and in this case the diamine itself is used separated. This is generally achieved with the aid of an acid addition salt, the sulfate being used for this purpose. is particularly suitable.

The compounds of the invention can also be prepared by methods other than those specifically described Methods are and can of course be chemically equivalent by any known method for the preparation of analogous compounds or their equivalents Process are produced.

The individual compounds of the invention may have different forms and intensities of anti-cancer activity, and a particular compound or compounds may be of particular interest for the treatment of any particular type of disease. It has been shown that while meso-3,4-bis (3,5-dioxopiperazin-1-yl) -hexane and erythro-2,3-bis (3,5-dioxopiperazin-1-yl) -pentane both have a cytotoxic activity in that they lead to an in vitro inhibition of the 3H-thymidine uptake of the cells? \ all the first-mentioned compound only a slight inhibition of cell division * ~ " , even in doses as high as 25 / ug / ml, whereas the latter compound is a _very; is strong inhibitory agent for cell division, with a clearly detectable effect ug / ml occurs already at a dose as low as 0.03 _/.

The present invention also relates to pharmaceuticals Agent containing, as active ingredient, a compound of the formula II in which R ^ and R «have the meaning given above

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have and extends to means in which the active Compound in the form of Salssen is present with physiologically suitable inorganic or organic acids. The invention Compounds can optionally be combined with other compounds suitable for treating such diseases are, e.g. methotrexate, can be combined, in some Cases a synergistic effect is observed.

The compounds of formula II can be formulated for use as pharmaceuticals by various methods will. For example, they can be used as aqueous, oily (e.g. as a suspension

in isopropyl myristate) or in some cases emulsified agents

for parenteral administration and therefore preferably sterile and administered free of inflammatory agents.

In general, they are relatively low Solubility in aqueous media and are therefore normally in the form of aqueous suspensions containing suitable surface-active substances Means administered. Without strictly limiting the individual dose, it can be said that "a daily dose of active ingredient, if appropriate divided into individual portions, from about 10 mg to about 3 g, preferably from about 25 mg to about 3 g can be administered to mammals as a solution in approximately 500 to 1000 ml of liquid for intravenous administration * Administration by slow infusion or as a solution or suspension in 10 ml intramuscularly or in small volumes subcutaneously. The substances can also be formulated for oral administration and in similar doses or even as high Doses, such as 1 to 3 g daily, are administered in the presence of customary solid carriers such as starch, Lactose, dextrin and magnesium stearate or as aerosols or Capsules are prepared. For the treatment of local forms of

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Disease, suitable creams or drops can be made that contain the active substance. Suppositories and other preparations can also be used. The compounds can be in the form of unit doses, i.e. "in discrete proportions, each a unit dose or a

en

A multiple or a / part of a unit dose of the active Containing substance or substances.

When the compounds are formulated as salts, they are preferred. Preparations those with methanesulphonic acid, isätmonsäure, Tartaric acid and other solubilizing acids. Such salts are often difficult to isolate because of their basicity some connections is low. However, their aqueous solutions are physiologically suitable after setting pH-value stable for a long time with the help of a buffer. Solutions of similar strength, i.e. $ 0.5 can also be used with hydrochloric acid The invention is accomplished by the following Examples explained in more detail.

example 1

meso-3,4-bis (3,5-dioxopiperazin-1-yl) -hexane

in meso-diethylsuccinic acid (mp. 190 to 193 ° C), the ⁷ 44-pro-

centigef yield by reacting diethyl ethyl malonate with Ethyl 2-bromobutyrate and hydrolysis of the product with formic acid / methanesulf acid was obtained -, metha-

chlorine

treated nolic hydrogen to give the crude diester which was reacted directly with hydrazine in n-propanol to give the dihydrazide (m.p. 288 ° C, 92 % yield). In a customary Curtius reaction, comprising treatment with sodium nitrite / hydrochloric acid and subsequent thermal rearrangement and reaction with benzyl alcohol, meso-3,4-dibenzyloxycarbonylaminohexane (melting point 203 to

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205 ⁰ C, yield $ 38). The dibenzyl carbamate (7 * 0 g) was dissolved in a solution of hydrogen bromide in acetic acid (63 ml, 45 #) at room temperature. After 1 hour, 100 ml of diethyl ether were added and the mixture was cooled with ice and filtered. Recrystallization of the solid product from ethanol / diethyl ether gave 3.5 g of meso-3,4-diaminohexanedihydrobromide (yield $ 74, melting point 224 to 225 ° C.).

5.0 g of meso-3,4-diaminohexanedihydrobromide were treated with 12.4 g of bromoacetic acid at 45 ° C. essentially according to the method of Okaku, 'loyoda, Moriguchi and Ueno, Bull. Chem. Soc. (Japan), 1967, 40, 2326 implemented, the pH value being kept at 11.3 by adding 6N NaOH using an autotitrator. After the neutralized reaction mixture had been eluted through a column with a cation exchanger "Zeo-Karb 225", 2.12 g (34 $) of meso-3,4-diaminohexanetetraacetic acid, boiling point 183 ° C. (decomp. ) _{For a time of >} 9 were obtained -'g meso-3,4-diaminohexanetetraacetic acid and 10 ml of formamide were ^{heated together to 155 to 160 0} G for 5 h under a nitrogen atmosphere. The mixture was then cooled and filtered and the product recrystallized from dimethylformamide. 0.235 g ($ 21) of meso-3,4-bis (3 ", 5-dioxopiperazin-1-yl) -hexane, boiling point 280 ° C. (decomp.) Were obtained.

Example 2 -.

dl-erythro-2,3-bis- (3 , 5-dioxopiperazin-1-yl) pentane

dl-erythro-ethylmethylsuccinic acid (pp. 177 to 179 ° C) was obtained in 18 percent yield essentially by the method described in Example 1 for the diethy] y analog and reacted via the following intermediate stages, each of which was obtained in the indicated yields. dl-erythro-ethylmethylsuccinic acid - dihydrazide

Pp. 210 to 212 ^° C., 85 $ dl-erythro-2,3-dibenzyloxycarbonylaminopentane

Pp. 194 to 195 ° C, 22.5ε -14-

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dl-erythro-2,3-diaminopentane dihydrobromide

Pp. 218 Ms 221 ⁰ C, 83? £. . dl-erythro-2,3-diaminopentane-tetraacetic acid

Pp 193 Ms 196 ° C, $ 33

where dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane, Mp. 274 to 277 ° C. (decomp.) After recrystallization from dimethylformamide in 24 percent yield from the tetraacetic acid was obtained. - ■ -

Example 3'dl-erythro-2,3-bis- (3 »5-dioxopiperazin-1-yl) -hexane

dl-erythro-methylpropyric succinic acid, pp. 166 to 168 ° C, was in 18 percent yield essentially according to the method described in Example 1 for the diethyl analogue obtained and reacted via the following intermediates, each of which was obtained in the indicated yields.

dl-erythro-methylpropylsuccinic acid dihydrazide

Pp. 205 to 209 ^° C., 60 <$> dl-erythro-2,3-dibenzyloxycarbonylaminohexane

Mp 174-175 ° C, 48 # dl-erythro-2,3-diaminohexane dihydrobromide

■ pp. 181 ° c 71 $>

dl-erythro-2,3-diaminohexane-tetraacetic acid, glass $ 23, where dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) hexane, Pp. 278 to 279 ° C (decomp.) Obtained in 35 percent yield from the tetraacetic acid.

Example 4

dl-erythro-3> 4-Bi3- (3 _f 5-dioxopiperazine-1 -)

dl-erythro-ethylpropylsuccinic acid, pp. 180 to 181 ⁰ C, was obtained in 32 percent yield according to the example for the

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Obtain diethyl analogous methods described and on the the following intermediates, each obtained in the given yields, implemented,

dl-erythro-ethylpropylsuccinic acid dihydrazide

Pp. 284 to 285 ^C , 52 f> dl-erythro-3,4-dibenzyloxycarbonylheptane

Pp. 179 to 180 ⁰ C, 41 $ dl-erythr 0-3,4-diaininoheptane-dihydr obr omid

Mp. 177 to 178 ⁰ C, £ 86

dl-erythro-3,4-bis (3,5-dioxopiperazin-1-yl) -heptane, pp. 285 to 290 ^c G (decomp.) was obtained in 30 percent yield from g of tetraacetic acid.

The product of Example 4 and also those of Examples 1, 2 and 3 were also essentially prepared according to the in Example 1 prepared method described, however, the formamide by acetamide or urea in the last stage was replaced.

Example 5

dl-erythro-2,3-bis (3 »5-dloxopiperazln-1-yl) pentane

2,3-Diaminopentane was prepared by hydrogenating 2,3-dioximinopentane over a platinized nickel catalyst, according to the process described by Suzanne Samne (Annal chimie (Paris), 1957, ^ 2 ^ ² '656). The alcoholic solution of 2,3-diaminopentane obtained in the hydrogenation was concentrated, and the resulting oil, if necessary, was distilled and taken up in water. The aqueous solution was with 2nH _? S0. acidified to pH 5, evaporated and the residue triturated with methanol. The resulting solid was recrystallized from dioxane, giving dl-erythro-2,3-diaiainopentane sulfate, melting point 300 ° to 30 ° C. (decomp.).

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dl-erythro-2,3-diamonopentane sulfate was obtained according to the in Example 1 for the dihydrobromide of meso-3 »4-diaminohexane described method in dl-erythro-2,3-diaminopentanetetraacetic acid converted and this reacted again essentially according to the method described in Example 1, being dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane received.

The products of Examples 1, 3 and 4 were also used produced by a process analogous to the process described,

Example 6

dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) -4-methylpentane

2,3-Dioximino-4-methylpentane (Pp. 155 to 160 ⁰ C after recrystallization from aqueous ethanol), which was prepared essentially according to the analöge methylethyl-in Example 5 for the described process, was prepared essentially as in Example 5 described, over dl-erythro-2,3-diamino-4-methylpentane-sulphate, mp. 272 to 275 ° C (decomp.) and dl-erythro-2,3-diamino-4-methylpentane-tetraacetic acid, glass, reacted , where dl-erythro-2,3-bis- (3,5-dioxopiperazin-1-yl) -4-methyl-pentane, -Fp. 259 to 263 ° C (decomp.) Arose.

Example 7

dl-erythro-2,3-bis- (3,5-dioxopiperazin-1-yl) -1-methoxybutane

1-Methoxy-2,3-diaminobutane (melting point 145 ° to 146 ° C.) after recrystallization from water which had been prepared from 1-methoxybutan-3-one essentially by the process described in Example 5 for the methylethyl analogue which in turn was obtained essentially by the method of Elderfield, J. A, CS, 1950, 72, 1341, was in

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essentially according to the method described in Example 5 on dl-erythro-i-methoxy ^^ - diaminobutane sulfate, Ep. 295 to 298 ° C (decomp.), and dl-erythro-i-methoxy ^^ - diaminobutanetetraacetic acid monotiydrate, Pp. 96 converted to 98 ° C (dec _p) from HPO / acetone to give dl-erythro-2,3-bis- received (3,5-dioxopiperazin-1-yl) -1-methoxybutane.

Alternative procedure Example 8

dl-erythro-2,3-bis (3 »5-dioxopi-perazin-1-yl) pentane '"

dl-erythro-Ιί, ΙΤ, Ν- ^1, F ¹ -Tetracarboxamidomethyl ^, 3-diaminopentane to polyphosphoric acid (prepared by heating 2-stündige3 of 5 g of phosphorus pentoxide and 5 ml of orthophosphoric acid at 120 ⁰ C and then cooling to 25 ⁰ C ) was added and the mixture heated 10 min auf'105 ⁰ C and another 30 min at 120 ⁰ C. The viscous brown solution was cooled, treated with ice and neutralized by adding 0.88 aqueous ammonia (approx. 10 ml), whereby dl-erythro-2,3-bis- (3,5-dioxopiperazin-1-yl) - pentan precipitated Pp. 274-277 ⁰ C (dec.) after recrystallization from dimethylformamide.

The products of Examples 1, 3, 4, 6 and 7 were also prepared in an analogous manner.

Example 9

dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane

0.5 g of dl-erythro-ΙΙ, Ν, Ν ¹ , N ^f -Tetracarboj {am.idoaethyl-2,3-diaminopentane and 10 g of phenol were heated together to 165 ° C for 20 h under a nitrogen atmosphere. The phenol was evaporated and the residue burnt with methanol, cooled in ice;

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and filtered. This gave dl-erythro-2,3-bis (3i5-dioxopiperazin-1-yl) pentane, Bp 274 Ms 277 ° C (dec.) After recrystallization from dimethylformamide.

The products of Examples 1, 3 »4» 6 and 7 were also used produced in an analogous manner.

Example 10 dl-erythro-2,3-bis (3 »5-dioxopiperazin-1-yl) -pen.tane

1 g of sodium amide was added in individual portions to 10 ml of formamide at ^{0 0} O and 1.8 g. dl-erythro-ϊί, Η, Ιϊ ¹ , 5Γ ¹ -tetracyanomethyl-2,3-diaminopentane was added to the clear solution with stirring and cooling. The temperature rose to 65 ° C. and was held at this value for 1 hour. The thick dark suspension was cooled with ice and filtered and the solid was washed with formamide and acetone. The solid was suspended in 50 ml of methanol and the suspension was cooled in ice and slowly treated with 2 ml of concentrated hydrochloric acid, a precipitate of the crude hydrochloride being formed. The hydrochloride was suspended for 3 h at 0 ° in 50 ml of a saturated sodium bicarbonate solution, filtered off and washed with water and acetone. Dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane dihydrochloride was obtained.

The products of Examples 1, 3, 6 and 7 were also used produced in an analogous manner.

Example 11

A mixture of 10 g of erythro-2,3-DiamLnopenfcanfcetraessLg acid and 40 g of Athylcarbarna fc were echi under reflux for 6 h. fczb and stirred, the resulting ethanol through the Rückt'Luß

§AD ORIGINAL

2 0 9 B 2 6/1 1 4 6

• - 19 - 1A-4O 706

could escape cooler. The reaction mixture was cooled and 100 ml of water was added to the mixture to remove the ethyl carbamate to solve. The insoluble product was filtered off and stirred for 15 min with 200 ml of water, the 7 ml of aqueous Ammonia (specific gravity 0.88). The mixture was filtered and the solid product washed with water and recrystallized from dimethylformamide. This gave dlerythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane, Mp. 274 to 277 ° C (dec.).

In an alternative process, the ethyl carbamate was replaced by n-propyl carbamate.

The products of Examples 1, 3, 4 _; 6 and 7 were also prepared in an analogous manner using both of the carbamates.

Example 12

dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane

6 g of erythro-2,3-diaminopentane-tetraacetic acid were dissolved in 50 g of boiling dimethylformamide. After the process was completed, the Reaktionsgeraisch was heated to 150 ⁰ C and Amraoniakgas 8 1/2 initiated hours while the water formed as an azeotropic water / xylene mixture was distilled off. The reaction mixture was then cooled, whereupon dl-erythro-2,3-bis (3,5 »dioxopiperazin-1-yl) pentane, mp 274 to 277 ° C. (decomp.) Separated out.

The products of Examples 1, 3, 4, 6 and 7 were also used produced in an analogous manner.

- 20 -

209826 / 1W, 6

- 20 - 1A-4O 706

Example 15

Laboratory studies of physiological effectiveness

I. BLe overall effect of various compounds the rate of DNA synthesis in mammalian cell cultures was determined by the method of Birnie and Simons (Experimental Cell Research, 1967, 46, 355) determined by measuring the changes in the amount of ^ H-thymidine, which in 1 h 'in · "., secondary mouse firbroblast cultures were incorporated with a special compound had been incubated for 22 hours. Typical results that affect the degree of inhibition of the ^ H-thymidine incorporation of the treated fibroblasts compared with untreated fibroblasts, are shown in Table I. specified. The results obtained can be viewed as a measure of the cytotoxicity and agree well with the results obtained with tumors implanted in mice. Typical results for dl-1,2-bis (3,5-dioxopiperazin-1-yl) propane and dl-1,2-bis (3,5-dioxopiperazin-1-yl) butane are also given for comparison.

- 21 -

209826/1 1 46

! Table I.

U-40 706

Inhibition of the ^ H-ihymidine incorporation

link concentration
iig / nil. % Inhibition CO-CH ₂ / ^H 2 ~ ^C \
HN N-CH ₀ -CH (CH ₀ ) -N ^% NH dl
CO-CH ^ L CHr-CO
Ct ö - - 5
1
0.3 63
48
15th / J-CH ₀ -CH (C.H_) - N dl
/ 2 2 5 \ 67
13th 36;
8th / —S / ^ \
, HN N- ~ CH- CH N .- ■ NH dl-erythro
j cV- / CH ₃ C ₂ H ₅ ^N ^ 2
O _r o8 81;
72 i
J ^X jy CH-— CH Ν. dl-erythro
CH ₃ C ₃ H ₇ " 10
1
0.1 ί
71!
68
41 \ /
N CH CH N meso
/ ii N
^C 2 ^H 5 ^C 2 ^H 5 10
o _r i 75
38 N CH CH - N * dl-erythro
^ S S ^H 7 ⁿ 10
2
⁰ J ⁴ 58
26th
8th

209826/1 U6

- 22 - 1Ar-4O 706

II. A suspension of leukemia cells from DBA2 mice, who were severely infected with L121O leukemia was made, by rubbing one or more spleens in sterile saline (1 Ms 2 ml salt per spleen). The suspension was injected subcutaneously (0.1 ml per mouse) into a group of female BDPi mice.

A starting solution of dl-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane in dimethyl sulfoxide (DMSO) was prepared (3.2 mg / ml) and stored frozen. It was thawed every morning and a portion thereof to the 10-fold volume of diluted with brine (320 / ug / ml), and five 2-fold serial dilutions of this solution in 10 $> DMSO in saline. Daily intraperitoneal injections of 0.5 ml of the six solutions were started the day after the leukemia cells were inoculated. A comparison group of mice was injected with 10% DMSO in saline.

In general, the mice in a group died within a few days of one another. If one or more mice have a Group lived 5 days longer than any other of this group, the injections were stopped and if these mice lived an additional 5 days, the transplant was assumed not to be transplanted succeeded. That is only an objective criterion for a " Situation that can be determined visually. The mice that have not ingested the leukemia parts are typical smooth and healthy looking and have no tumor at the inoculation site and their bellies are not ascitic Fluid swollen.

203826/1 U6

Table II

Effect of dl-erythro-2,5-bis- (3,5-dio3copiperazin-1-yl) pentane against leukemia L1210 in mice

daily
dose
(mg / kg) not
recorded
men Medium body size
weight
Day 1 Day S Day 1'5 Survival time
(Days) middle
• % Increase 8th
4th
; 2
i ι
i
2
1
10% DMSO 0/10
1/10
ο / ίο
0/10
2/10
1/10
1/10 19.7 21.3 (22.6)
19.3 21.1 (22.6)
17.0 18.6 (18.0)
16.9 18.9
20.0 22.0
20.1 22.9
17.1 16.18.18.18.18.18.19i20.20 * 22.
15.15.16.16.17.18.19.10.21.
13.15 · 15.16.I7.17 »l8» l8.22.24
9.10.11.12.13.13.13,14.15.15.
9.10.11.12.12.12.12.12.
9. 9. 9.10.10.11.11.11.12
8. 8. 8. 8. 8. 9. 9. 9.10 18.7
17.4
17.5
12.0
11.2
10.2
8.6 11796
102%
104 #
40 #
3096
19 #

CD CO CO O

- 24 - 1A-4O 706

III. Small pieces of Sarcoma 180 were injected into the sides of mice and the animals became meso-3,4-bis- (3,5-dioxopiperazin-1-yl) -hexane or dl-erythro on the day after injection and 7 days after -2,3-bis- (3 _f 5-dioxopiperazin-1-yl) pentane. On the 8th day thereafter, the tumor was removed and weighed. Typical results for the mean tumor weight of the treated / control tumors were $ 12.6 at 10 mg / kg for the hexane compound and $ 4 »0 at 0.5 mg / kg for the pentane compound.

»■,

Patent claims

¹ ' η? «■; / 1 1 / ·.

Claims (1)

Godfather sayings 1, drug containing a (3> 5,3 '»5'-tetraoxo) -1 , 2-dipiperazinoalkane compound of the general formula HN CO CH CO CH I _c __jj / -CO, CO NH according to main patent 1 910 283 (patent application P 19 10 283.1), characterized in that the groups R .. and R _{2 are} next to each other in the meso or erythr ο configuration and each individually an unsubstituted alkyl, alkenyl or alkynyl group with 1 to 4 carbon atoms or a substituted alkyl, alkenyl and alkynyl group with 1 to 3 carbon atoms, with the proviso that R ₁ and R ₀ are not methyl groups and that the substituted »I / h
Groups, except when the sub ^ uent is a fluorine atom, contain only one substituent and their physiologically acceptable acid addition salts. Compounds of the formula given above, which are contained as active ingredient in the medicament according to Claim 1. - 26 - 209826/1 UG INSPECTED - 26 - 1A-4O 706 3. Compounds according to claim 2, characterized in that the unsubstituted groups 1 to Contain 3 carbon atoms and the substituted groups are straight-chain and contain 1 to 3 carbon atoms, when the substituting groups are fluorine atoms and 1 or 2 carbon atoms if other substituents are present. 4. Compounds according to claim 2 or 3t, characterized in that the substituted groups Are alkyl groups and contain a maximum of 5 fluorine atoms. 5. Compounds according to claim 4, characterized in that the substituted groups are substituted Are methyl and ethyl groups. 6. Compounds according to claim 2 to 5 »thereby g e characteristic h η e ■ £ that the substituents fluorine or Are chlorine atoms or hydroxyl or methoxy groups and the substituted groups contain a maximum of 3 fluorine atoms. 7. Compounds according to claim 6, characterized in that R ₁ and Rp methyl, ethyl, n-propyl, i-propyl, vinyl, allyl, propargyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl , Chloromethyl, trifluoromethyl, 2,2,2-trifluoroethyl and / or pentafluoroethyl groups are. 8. Compounds according to claim 7, characterized in that R ₁ and Rp methyl, ethyl, n-propyl, i-propyl, allyl, propargyl, hydroxymethyl, 2-hydroxyethyl-methoxymethyl, trifluoromethyl and / or 2,2,2-trifluoroethyl groups. - 27 - 209826/1 146 '- 27 - - 1A-4O 706 9. Compounds according to claim 7 »characterized in that RJ and R _{2 are} methyl, ethyl, n-propyl, i-propyl, hydroxymethyl, 2-hydroxyethyl, methoxymethyl, trifluoromethyl and / or 2.2 , 2-trifluoroethyl groups. 10. Compounds according to claim 2, 3 »7, 8 or 9> characterized in that R .. and Rp are unsubstituted Are alkyl groups. 11. Compounds according to claim 2 to 10, characterized in that the sum of the carbon atoms of the groups R ^ and R ₂ in both alkyl groups is not more than 4 is. 12. Compounds according to claim 2 to 11, characterized in that R.J is a methyl or ethyl group is. 13. dl-, d- and l-erythro-2,3-bis (3,5-dioxopiperazin-1-yl) pentane and its physiologically acceptable acid addition salts. 14. meso-3,4-bis- (3 »5-dioxopiperazin-1-yl) -hexane and its physiologically compatible acid addition salts. 15. dl-, d- and l-erythro-2,3-bis- (3,5-dioxopiperazin-1-yl) -hexane and its physiologically acceptable acid addition salts. 16. dl-, d- and l-erythro-3,4-bis (3,5-dioxopiperazin-1-yl) -heptane and its physiologically acceptable acid addition salts. - 28 - 1A-4O 706 ij-7. Process for the preparation of compounds according to Claim 2, characterized in that one is a compound of the general formula YCH ₂ N CHR ₁ CHR ₂ N In which R 1 and R _{2 have} the meaning given above or are groups which can be converted into such groups and Y and Y ¹ a) individually identical or different aliphatic groups or together an aliphatic group denote by Reaction with a suitable nitrogen-containing compound can be converted into a group -CO.NH.CO-, b) individually mean the same or different aliphatic groups, which together either directly or indirectly are cyclizable to form a group -CO.NH.CO- or c) together a group -CO.NX.CO-, in which X one through is a hydrogen atom replaceable group, converted by reaction with a suitable nitrogen-containing compound by cyclization or by replacement of the group X by a hydrogen atom and optionally the groups R. gg ppe ™ and Rp converts into the desired groups and / or the desired compound of compound
Groups R .. and R _{2 are} opposite d Ο * ΏOTT the desired compound separates from compounds, in 7 the 18. The method according to claim 17, characterized in that one a) a Ν, Ν, Ν ¹ , N'-tetracarboxymethyldiamine of the formula given in claim, in which Y is carboxyl groups or their bisanhydride, where Y and Y ¹ together are a group f * τ * lr \ i / t " 7 " t *
-CO.0.CO- mean together / with a reagent that is either - 29 - 209826/1 U6 - 29 - 1A-4O 706 is an acid amide of the general formula RCONHp, where R is a hydrogen atom, an aliphatic radical having 1 to 4 carbon atoms or a primary amino group, or ammonia in an acid amide of the general formula R " in which R ^{1 is} a hydrogen atom or an aliphatic radical having 1 to 4 carbon atoms and R ¹¹ and R ^{111 are} identical or different aliphatic radicals having 1 to 4 carbon atoms or one of these radicals together with R ¹ and the CON group is 5- or 6 -form parted lactan, b) an N, W, N ¹ , N'-tetraearboxamidomethyldiamine of the formula given in claim 17, in which Y and Y ^{1 are} carboxamido G groups, heated together with an acidic reagent such as polyphosphoric acid, a phenol or boron trifluoride, c) a. N, U, IT ¹ , N'-tetracyanomethyldiamine of the formula given in claim 17, in which Y and Y ^{1 are} cyano groups, are reacted with an alkali amide and the product is treated with a mineral acid d) an NjN'-dicarboxymethyl-NjN'-dicarboxamidomethyldiamine of the formula given in claim 17, in which Y is a carboxy group and Y ^{1 is} a carboxamido group, cyclizes or e) a Ν, Ν'-disubstituted 3,5 »3 ', 5 ^f -tetraoxodipiperazine of the formula given in claim 17, in which Y and Y ¹ together represent a group -CO.NX.CO-, where X is a group , which can be replaced by a hydrogen atom, so that the group X is replaced by a hydrogen atom and, if necessary, converts the groups R- and Rp into the groups desired for the end product and / or separates the desired compound from the compound, in dli ^ aie groups R ^ and R _{2 are} opposite. - 30 - 209826/1 U6 - · 3Ο - 1A-4O 706 19. The method according to claim 17 or 18, characterized. marked that one with a suitable nitrogen-containing compound converts. 20. The method according to claim 18, characterized in that there is an N, N, N ¹ , N'-tetracarboxymethyldiamine of the general formula HOOC - CH ₂ -CHR ₁ - - < HOOC CH ₂ "" ^. CH ₂ COOH -CHR ₂ ^ N-
^^ ^ CH ₂ COOH ^^ in which R .. and R _{2 have} the meaning given in claim 1 or are groups which can be converted into the groups given there, with formamide or urea at a temperature of at least 100 ^° C., ammonia in dimethylformamide at a temperature of at least 120 ° or ethyl carbamate or n-propyl carbamate at a temperature of at least 140 ⁰ C and, if necessary, converts the groups R ^ and R ₂ into those desired in the end product and / or separates the desired compound from that in which the aliphatic groups are opposite. 21. The method according to claim 20, characterized in that geke η η -. draws that one reacts Ν, Ν, Ν ¹ , N'-Tetracarboxymethyldiainin with Pormamid at a temperature of at least 100 ⁰ C * 22. The method according to claim 18, characterized in that there is an N, N, N ¹ , N'-tetracarboxamidomethyldiamine of the general formula H ₂ NCO CH ₂ ^ ^λ1 Ζ ^CONH 2 * ^ N CHR ₁ CHR ₂ NC ^ H ₂ NCO CH ₂ ^ ^ CH ₂ CONH ₂ - 31 - 209 8 2S / 1US - 31 - 1A-4O 706 in which R ₁ and Rp have the meaning given in claim 1 or can be converted into such groups, heated with polyphosphoric acid or phenol and, if necessary, the groups R ₁ and R ₂ converts and / or groups such as are desired for the end product separates the desired compound from that in which the aliphatic groups are opposite. 23. The method according to claim 22, characterized in that the reaction is carried out at a temperature of at least 8O ⁰ C in the case of polyphosphoric acid and 130 ⁰ C in the case of phenol. 24. The method according to claim 18, characterized in that one. N, N, N ¹ , N'-tetracyanomethyldiamine of the general formula NC-CH ₀ CH ₀ -— CN TT CHR ₁ CHR ₂ - NO - CHo CHo CN in which R ₁ and R _{2 have} the meaning given in claim 1 or are groups which can be converted into such groups, react with sodium amide and treat the product with a mineral acid and, if necessary, the groups R ₁ and R ₂ into such converts groups desired for the end product and / or separates the desired compound from that in which the aliphatic groups are located opposite. 25. The method according to claim 18 or 24, characterized in that the reaction with the alkali amide in formamide. - 32 - 209826/1146 -'32 - 1A-4O 706 26 »The method of claim 24 or 25, characterized ge - ■ ke η η ζ η e -t calibration that is used as the mineral acid for the treatment of the reaction product with the alkali metal amide hydrochloric acid" 27. The method according to claim 17 or 26, characterized in that the compound is in a transferred physiologically suitable acid addition salt. 28. The method according to claim 17 or 27, characterized in that one starts from a compound in which R ^ and R _{2 have} the meaning given in claim 1. 29. The method according to claim. 17 to 28, characterized in that the reaction partner used is a compound in the der'ineso or erythro porm in which the groups R ^ and R ₂ are located next to one another, which is essentially free of the dl or threo IOrm , in which the groups R .. and R _{2 are} opposite. 30. Process for the preparation of the raw material used F, N ", N ', N'-tetracarboxymethyl diamines of the formula HOOCCH ₉ HH CH ₀ GOOH ^ M ^ - C - 0 - IT
A 1 HOOCCH ₂ R ₁ R ₂ ^ CH ₂ COOH in which R ^ and R _{2 have} the meaning given above, thereby characterized in that the corresponding meso- or erythro-diamine of the formula HH ι t Ho E - ^ - C ^ --C --— NH, RR XX .. · ti / -, 209826/1146 - 33 - - 33 - 1A-4O 706 separates from a mixture with the dl or threo isomers als.Säureadditionssalz and converts the diamine into the Ν, Ν, ΕΓ ¹ , N'-iDetracar'boxymethyldiamine by reaction with a monohaloacetic acid. ·. ... 31. The method according to claim 30, characterized in that the acid addition salt is the sulfate used. 32. The method according to claim 30 or 31, characterized in that the monohaloacetic acid Bromoacetic acid used. · ' ORIGINAL INSPECTED 209826 / 1U6