DK175507B1 - N-substituted staurosporine derivatives and salts thereof, process for their preparation, pharmaceutical compositions containing them and use of the N-substituted staurosporine derivatives for the preparation of pharmaceutical preparations - Google Patents

Abstract

N-Substituted derivatives of staurosporin of the formula [Stau]-N(CH3)-R (I> in which [Stau] represents the radical of the sub-formula <IMAGE> in which R represents a hydrocarbyl R<0> or an acyl Ac, which preferably have at most 30 C atoms, and salts of compounds of the formula I having salt-forming properties, are distinguished as selective inhibitors of protein kinase C. They are prepared by conventional alkylation or acylation of staurosporin.

Description

I DK 175507 B1 I

I I

In the present invention, N-substituted staurospo-I

In purification derivatives of the general formula I

In [traffic jam] -N (CH3) -R (I) I

I 5 i

In which [Stau] means the group of partial formula I

I H I

I S A I

I / \ / \ / ~ \ I

I V- / \ = y I

I \ a ^ I

I j J-CH3 I

I 15 V V0CH3 I

I and R are as defined in claim 1, as well as salts of form I

In binders of formula I with salt-forming properties. IN

I 20 I

The invention also relates to a process for the preparation of I

In the compounds defined above, pharmaceutical compositions, I

Containing these compounds, as well as their use

In compounds for the preparation of pharmaceutical compositions. IN

I 25 I

In Staurosporin of the formula [Stau J-NH-CH3 (II) (meaning I

I of the [Stau] group is explained above) as the basic substance for I

In the compounds of the invention were isolated already in I

In 1977, from cultures of Streptomyces staurosporeus AWAYA, 'I

In 30 TAKAHASHI and OMURA, sp. November AM 2282, cf. S. Omura, Y. I

In Iwai, A. Hirano, A. Nakagawa, J. Awaya, H. Tsuchiya, Y- I

In Takahashi and R. Masuma: J. Antibiot. 30, 275-281 (1977), I

I and were tested for antimicrobial action. It turned out you

In that the compound is effective against yeast-like microorganisms

In 35 niches and fungi (MIC of 3-25 mcg / ml), and the hydrochloride I

2 DK 175507 B1 has an LDsg value of 6.6 mg / kg (mouse, intraperitoneal). Recently, extensive screening has shown that the compound has a potent inhibitory effect on protein kinase C (from rat brain), cf. T. Tamaoki, H. Nomoto, I. Takahashi, Y. Kato, M. Morimoto and F. Tomi ta: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986).

The phospholipid and calcium-dependent protein kinase C 10 occurs within the cell in several forms and participates in various fundamental processes, such as signal transmission, proliferation and differentiation, as well as secretion of hormones and neurotransmitters. As is known, the activation of these enzymes occurs either by a receptor-mediated hydrolysis of phospholipids in the cell membrane or by a direct interaction with certain tumor-promoting active substances. The sensitivity of the cell to the receptor mediated signal transfer can be significantly affected by modifying the activity of protein kinase C (as 20 signal transducer). Compounds that can selectively modify the activity of protein kinase C can be used as tumor-inhibiting, anticancer, immunomodulatory and antibacterial active substances, and may even be of interest as an agent for arthrosclerosis and diseases of the cardiovascular and central nervous system.

Although staurosporin exerts a strong inhibitory effect on protein kinase C (see above), it has an equally potent inhibitory effect on other protein kinases and therefore does not have the selectivity necessary for therapeutic use. Surprisingly, it has been found that upon removal of the hydrogen atom in the methylamino group in staurosporin upon substitution, such N-substituted derivatives selectively retain the inhibitory effect of staurosporin against protein kinase C, but have a substantially less effect on other protein kinases. As a result of this significantly increased selectivity,

I DK 175507 B1 I

I I

thus, the elements of the invention also include the important I

In condition of the therapeutic use in the above I

In specified indication areas, primarily for impact I

of the cell proliferation. IN

Is I

To determine the inhibitory effect of protein kinase I

In C, protein kinase C is first recovered from swine I

In the brain and purification is done using it

I by T. Uchida and C.R. Filburn in J. Biol Chem. 259, I

In method described in 12311-12314 (1984). For certain- I

In view of the inhibitory effect on protein kinase of compound I

In the formulas of formula I, the method of D. Fabro et I is used

In all .. Arch. Biochem. Biophys. 239, 102-111 (1985). There- I

You state a significant inhibition of protein kinase C from an I

At a concentration of approx. 0.01 µΜ / 1, I

Accordingly, the compounds of formula I may

In and their pharmaceutically useful salts, e.g. IN

I as drugs, especially for anti-tumor, anti-inflammatory

In 20, immunomodulatory, antibacterial applications, as well as I

In the remedy for artherosclerosis, diseases of the cardiovascular I

In the system and in the central nervous system. The invention relates to

In addition, the use of the compounds of the invention I

I for the manufacture of drugs, e.g. to the one above

In the 25 listed use, for therapeutic and prophylactic I

In the treatment of humans and animals. In addition, the invention comprises:

In late industrial production of the active substances. IN

In formula I, R is an acyclic, carbocyclic or car I

In 30 bocyclic-acyclic hydrocarbon group R ° containing a total of I

There are at most 18 carbon atoms and are saturated or unsaturated and I

In unsubstituted or optionally mono-, di- or tris-substituted I

In the case of C (1-7) alkyl, C (1-4) alkoxy, hydroxy, halogen, I

In nitro, trifluoromethyl, carboxy, C (1-7) -alkoxy-carbonyl, I

In benzyloxycarbonyl, methylenedioxy and / or cyano, and as in I

Instead of one, two or more carbon atoms may contain I

B1 is the same or different heteroatoms selected from oxygen, sulfur and nitrogen in such a way that R ° means 2-aziridinyl, pyrryl, pyridyl, thienyl, furyl, indolyl, quinolyl, isoguinolyl, benzofuranyl, chrotnenyl, benzothienyl, imidazolyl / pyrimidinyl, oxazolyl, isoxazolyl, thiazolyl, benzimidazolyl, benzoxazolyl, quinazolyl, 2-tetrahydrofuryl, 2-pyrrolidyl, 3-pyrrolidyl, 2-piperidyl, 3-piperidyl, 4-piperidyl 3-morpholinyl, 2-thiomorpholinyl, 3-thiomorpholinyl, 2-piperazinyl or N, N'-bis-C (1-7) -alkyl-2-piperazinyl, or R means an acyl group Ac, a) wherein R del is C (1-7) alkyl which is unsubstituted or optionally substituted by halogen, carboxy, C (1-4) alkoxycarbonyl or an amino group of formula -NR1R2 wherein and R 2 are each hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkenyl, or is phenyl which is unsubstituted or optionally substituted with C 1 -C 4 alkyl, C (1) -4) -alkoxy, halogen, nitro, trifl non-methyl, carboxy or C (1-4) -alkoxycarbonyl, b) having the partial formula R ° -O-CO- wherein R ° is C (1-20) -alkyl which is unsubstituted or optionally substituted by a carboxyl group (also as salt, cyano or C (1-4) alkyl ester) or an unbranched C (4-20) alkyl group wherein 1 to 6 C atoms from C-3 are replaced by oxygen atoms separated from each other with at least 2 C atoms, or optionally with C (1-7) alkyl, C (1-7) alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxycarbonyl, methylenedioxy and / or cyano-substituted phenyl, or benzyl, or c) of the partial formula R ° -O-CO- wherein R ° represents C (1-7) -alkyl, pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by C (1-4) alkyl, C (1-4) alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxy-carboxylic acid;

I DK 175507 B1 I

I 5 I

In bonyl, methylenedioxy and / or cyano. IN

In Unsaturated groups are those containing one or I

In several, especially conjugated and / or isolated multiple-bin I

In 5 things (double and / or triple bonds). The term I

In cyclic groups also include aromatic groups, e.g. IN

In those wherein at least one 6-membered carbocyclic or one 5- I

The I to 8 membered heterocyclic ring contains the maximum I

In number of non-cumulated double bonds. Carbocyclic I

In 10 groups in which at least one ring is present as a 6-member I

In aromatic ring, i.e. benzene ring, are referred to as aryl groups. IN

In particular, an acyclic unsubstituted hydrocarbon group is an I

In an alkyl group such as methyl, ethyl, n-propyl, isopropyl, η-I

In butyl, isobutyl, sec-butyl or tert-butyl, also I

In n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl, furthermore I

In an alkenyl group such as allyl, propenyl, isopropenyl, 2- I

I or 3-methallyl and 2- or 3-butenyl, in addition an alkadiene I

In a nyl group such as 1-penta-2,4-dienyl and an alkynyl group I

In such as propargyl or 2-butynyl. In correspondingly unsaturated

In groups, the double bond is located mainly in a higher I

In stance than the a position of the free valence. IN

I As carbocyclic hydrocarbon groups, groups I are preferred

In 25 with a maximum of 14, especially 12, ring carbon atoms and 3- to 8-, form I

In stepwise 5- to 7-, especially β-membered rings, since they can also

You carry one or more, e.g. two, acyclic groups, e.g. H

In the above, and especially the alkyl groups, or other I

In carbocyclic groups. Carbocyclic-acyclic groups are I

In 30 such, wherein an acyclic group, especially one having a maximum of 7, I

Preferably not more than 4, carbon atoms, primarily methyl,

In ethyl and vinyl, one or more carbocyclics, optionally I, carry

In aromatic groups of the above definition. Especially you

You should mention cycloalkyl-loweralkyl and aryl-loweralkyl groups I

In 35 as well as their in the ring and / or chain unsaturated analogs, such as H

bears the ring at the terminal carbon atom of the chain. H

6 DK 175507 B1

Cycloalkyl contains primarily 3 to 10 carbon atoms and is e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, and bicyclo [2.2.2] octyl, 2-bicyclo [2.2.1] heptyl and adamantyl, which may also be substituted by one, two or more, e.g. lower, alkyl groups, primarily methyl groups. Cycloalkenyl is, for example, one of the above-mentioned monocyclic cycloalkyl groups which carry a double bond at the 1, 2 or 3 position. Cycloalkyl-lower alkyl or -lavalkenyl is e.g. a substituted -methyl, -1- or -2-ethyl, -1- or -2-vinyl, -1-, -2- or -3-propyl or -allyl where one of the above cycloalkyl groups is preferred, groups which are substituted at the end of the linear chain.

15

An aryl group is primarily a phenyl group, furthermore a naphthyl group such as 1- or 2-naphthyl, a biphenyl yl group, such as in particular 4-biphenylyl, in addition also an anthryl group, fluorenyl group or azulenyl group, and their aromatic analogs with one or more saturated rings. Preferred aryl avalcyl and lavalkenyl groups are e.g. phenyllavalkyl or phenyllavalkenyl with terminal phenyl group, e.g. benzyl, phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, and also 1- or 2-naphthylmethyl. Examples of aryl groups bearing acyclic groups, such as lower alkyl, include in particular o-, m- and p-tolyl and xylyl groups having differently substituted methyl groups. 1 2 3 4 5 6

As indicated above, a hydrocarbyl group (including a 2 heterocyclyl group) may be substituted by one, two or 3 more uniform or different substituents (functional 4 groups). In particular, the substituents may be free, 5 etherated and esterified hydroxyl groups, mercapto and 6 lower alkylthio and optionally substituted phenylthio groups, halogen atoms such as chlorine and fluoro, but also bromine and iodine, oxo groups present in the form of formyl (i.e. aldehydo) and keto groups, and similarly

I DK 175507 B1 I

I 7 I

In acetals or ketals, azido and nitro groups, primary, I

In secondary and preferably tertiary amino groups, with I

In conventional protecting groups, primary I protected

I or secondary amino groups, acylamino groups and diacyl-I

In 5 amino groups as well as optionally functionally converted sulfo-I

In groups such as sulfamoyl groups or in salt form I

In emerging sulfo groups. All of these functional groups

You do not necessarily need to be bound to the carbon I

In the atom from which the free valence originates, and they are preferably I

I 10 separated from this carbon atom by two or more I

In carbon atoms. The hydrocarbyl group can also carry free and I

In functionally converted carboxyl groups, e.g. in salt form I

In present or esterified carboxyl groups, optionally I

In one or two hydrocarbon groups bearing carbamoyl, I

In 15 ureido and guanidino groups, and cyano groups. IN

I As a substituent in the hydrocarbyl group present I

In the etherified hydroxyl group, for example, is a lower alkoxy-I

In a group such as a methoxy, ethoxy, propoxy, isopropoxy, I

In the butoxy and tert-butoxy group, which may also be substituted

In the square. Thus, such a lower alkoxy group may be substituted

In halogen atoms, e.g. mono-, di- or trisub- I

In the stituate, especially in the 2-position, such as in 2,2,2-trichloroeth-I

In the oxy, 2-chloroethoxy or 2-iodoethoxy group, or with I

In 25 hydroxy or lower alkoxy groups, each preferably I

You are monosubstituted, especially in the 2-position, as in 2-methoxy-I

In the ethoxy group. A particularly preferred form of etherified I

In hydroxyl groups, oxalalkyl groups, wherein in one, are preferably I

In some linear, alkyl group, one or more carbon atoms are I

In exchange with oxygen atoms which are preferably interconnected

Separated by several, primarily 2, carbon atoms, I

In such a way that they form one, possibly several times

In group - (- 0-CH 2 CH 2 -) n, wherein n = 1-14. Furthermore, you are

In such etherified hydroxyl groups also optionally sub-I

In 35 substituted phenoxy groups and phenyllavalalkoxy groups such as I

Primarily benzyloxy, benzhydryloxy and triphenyl-I

In methoxy (trityloxy), as well as heterocyclyloxy groups such as I

In particular 2-tetrahydropyranyloxy. A particularly etherified hydroxyl I

8 DK 175507 B1 group is methylenedioxy and ethylenedioxy, the former usually bridging two neighboring carbon atoms, especially in aryl groups, and the latter must be considered as bound to one and the same carbon atom and considered as 5 protecting group for oxo.

In this context, etherified hydroxyl groups also include silylated hydroxyl groups, e.g. such as these occur in trilavalkylsilyloxy, such as trimethylsilyloxy and dimethyl-tert-butylsilyloxy, or phenyldilavalkylsilyl-oxy or low-alkyl-diphenylsilyloxy.

An esterified hydroxyl group present as a substituent in the hydrocarbyl group carries a hereafter defined acyl group Ac, especially an acyl group having a maximum of 12 carbon atoms, or is lactonized with a carboxyl group also present in the hydrocarbyl group.

An esterified carboxyl group as substituent in the hydrocarbyl group is one in which the hydrogen atom is exchanged with one of the hydrocarbon groups characterized above, preferably a lower alkyl or phenyllavalkyl group. As an example of an esterified carboxyl group may be mentioned lower alkoxycarbonyl or optionally substituted phenylalloalkoxycarbonyl, especially the methoxy, ethoxy, tert-butoxy and benzyloxycarbonyl group, as well as a lactonized carboxyl group.

A primary amino group -NH 2 as a substituent in the hydrocarbyl group may also be present in protected form as an acylamino group of the formula -NH-Ac ° corresponding to this group, wherein Ac ° has the meaning given below. A secondary amino group, instead of one of the two hydrogen atoms, carries a hydrocarbyl group, preferably an unsubstituted one, such as one of the above, especially a lower alkali. yl group, and may also be present in a protected form as a derived acylamino group having a monovalent acyl group Ac ° as characterized below.

In DK 175507 B1

I I

In the acyl group Ac °, which acts as an amino protecting group, I

Preferably, you are derived from a carbonic acid derivative and are preferred

Optionally, especially with lower alkyl, lower alkoxy, nitro I

I and / or halogen, substituted lower alkoxycarbonyl or I

5 aryllavalkoxycarbonyl, such as methoxycarbonyl, I

In ethoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxy-I

carbonyl, 2-iodoethoxycarbonyl, benzyloxycarbonyl, 2-phenyl

In yl-2-propoxycarbonyl, 2-p-tolyl-2-propoxycarbonyl, 2- (p-I)

In biphenylyl) -2-propoxycarbonyl or 9-fluorenylmethoxy-I

In 10 carbonyl. IN

I A substituent present in the hydrocarbyl group I

In the tertiary amino group carry two different or preferably I

In similar hydrocarbyl groups (including the heterocyclic groups)

In 15 per cent, such as the unsubstituted I characterized above

In hydrocarbyl groups, especially lower alkyl. IN

In a preferred amino group is one of the formula

In R 1 -N-r 2 wherein R 1 and R 1 are each hydrogen, I

In unsubstituted acyclic C (1-7) -hydrocarby1 (such as in particular I

In C (1-4) -alkyl or C (1-4) -alkenyl) or monocyclic, I

Optionally with C (1-4) alkyl, C (1-4) alkoxy, halogen I

I and / or nitro substituted aryl, aralkyl or aralkenyl I

In 25 with a maximum of 10 carbon atoms, where the carbonaceous groups I

You may be interconnected through a carbon-carbon bond.

In a thing or an oxygen atom, a sulfur atom or an optional I

In nitrogen substituted with hydrocarby 1. In this I

In case, they form together with the nitrogen atom of the amino group I

In a pen a nitrogen-containing heterocyclic ring. As examples of I

Particularly preferred free amino groups include dilavalk-I

In ylamino such as dimethylamino, diethylamino, pyrrolidino, I

In piperidino, morpholino, thiomorpholino and piperazino or I

In 4-methylpiperazino, optionally, especially in the phenyl moiety, e.g. IN

In low alkyl, lower alkoxy, halogen and / or nitro substituents

In the case of diphenylamino and dibenzylamino, among the protected I

In particular, lower alkoxycarbonylamino, such as tert-butoxycarbonyl-H

In amino, phenyllavalkoxycarbonylamino such as 4-methoxybenzene

B1 zyloxycarbonylamino, as well as 9-fluorenylmethoxycarbonylamino.

Unless otherwise stated, the aromatic carbocyclic and heterocyclic hydrocarbyl groups listed above and below may be mono- or polysubstituted, such as di- or trisubstituted, especially with C (1-4) -alkyl, C (1-4) - alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxycarbonyl, methylenedioxy and / or cyano. The above-mentioned reduced indications as to the substituents set forth below can be considered as preferred examples.

Preferred compounds of formula I are also those wherein R is a hydrocarbyl group R ° having the following preferred meanings for a carbocyclic or heterocyclic and also carbocyclic-acyclic or heterocyclic-acyclic hydrocarbyl group: a bicyclic or preferably monocyclic and aryl group, further naphthyl which can carry one or more of the following substituents: halogen atoms, especially fluorine, chlorine and bromine, C (1-4) alkyl groups, especially methyl, C (1-4) alkoxy groups, especially methoxy, methylenedioxy, nitro groups and and / or carboxyl groups which may be in free form, in salt form or as C (1-4) alkyl ester, especially methoxycarbonyl or ethoxycarbonyl. The aryl groups preferably carry at most 2 substituents, especially two of the same species, or only a single substituent. They are preferably unsubstituted. As an example of a preferred heterocyclic hydrocarbyl group (heterocyclyl) may be mentioned a group analogous to the above preferred aryl groups and instead of one or two carbon atoms containing one or two heteroatoms, especially nitrogen such as a pyridyl or quinolyl group or quinazolyl group, where the free valence is located at a carbon atom and which can also Η Η

I DK 175507 B1 I

I 11 I

You are similarly substituted. Preferred Carbocyclic I

acyclic and heterocyclic-acyclic hydrocarbyl groups I

You are those in which two or three, however, preferably only one of you

In the cyclic groups defined above, preferably the I

In 5 unsubstituted, are carried by a C (1-3) alkyl group, the I

Preferably all are located on a carbon atom,

preferably the end position. Unsubstituted benzyl is I

Especially preferred. IN

Particularly preferred compounds of formula I are those, I

In which R ° means C (1-7) alkyl, especially C (1-4) alkyl, hydroxy

In C (2-18) alkyl, especially hydroxy-C (2-14) alkyl, cyano-C (1-7) - I

In alkyl, especially cyano-C (1-4) alkyl, carboxy-C (1-7) alkyl, especially I

carboxy-C (1-4) -alkyl, C (1-7) -alkoxy-carbonyl-C (1-7) -alkyl, I

Especially C (1-4) -alkoxy-carbonyl-C (1-4) -alkyl, benzyloxy-carboxyl

bonyl-C (1-7) -alkyl, especially benzyloxy-carbonyl-C (1-4) -alkyl, I

In C (3-7) -alkenyl, phenyl, naphthyl, pyridyl, quinolyl or I

In quinazolyl, or phenyl-C (1-7) alkyl, especially phenyl-C (1-3) - I

In alkyl, the aromatic groups concerned furthermore I

I may also be substituted with C (1-7) alkyl, especially C (1-4) - I

In alkyl, C (1-7) alkoxy, especially C (1-4) alkoxy, halogen, nitro, I

In trifluoromethyl, in addition, carboxy, C (1-4) -alkoxy-carbonyl, I

In methylenedioxy and / or cyano, where the hydroxy group of the I

In the corresponding substituted alkyl group, in particular, I is located

25 in the 2-position and wherein cyano, carboxy, alkoxy-carbo-I

the nyl, behzyloxy-carbonyl or phenyl group of the to-I

In the corresponding substituted acyl group is especially located in I

In the 1- or ω position. IN

I 30 I

Particularly preferred compounds of formula I are those, I

In which R ° means C (-C4 alkyl such as methyl or ethyl I

In hydroxy-C (2-14) alkyl, such as 2-hydroxy-propyl, -hexyl, I

I -decyl or -tetradecyl, cyano-C (1-4) alkyl, such as I

In 2-cyanoethyl, carboxy-C (1-4) alkyl such as carboxymethyl, I

C (1-4) -alkoxycarbonyl-C (1-4) -alkyl, such as methoxycarbonyl-C

B1 methyl or ethyl, C (3-7) -alkenyl such as allyl, or phenyl, wherein the hydroxy group of the corresponding substituted alkyl group is preferably located in the 2-position, and the cyano, carboxy or alkoxycarbonyl group in particular 5 is located in the 1- or ω-position.

The acyl group Ac is derived from an optionally functionally converted carboxylic acid, from an organic sulfonic acid or from an optionally esterified phosphoric acid such as pyro or orthophosphoric acid, and preferably contains at most 30 carbon atoms.

In particular, one acyl group derived from an optionally converted carboxylic acid, referred to as Ac1, is a group of the partial formula ZC (= W) - wherein W may mean oxygen, sulfur or imino and Z may be hydrogen, hydrocarbyl R hydrocarbyloxy R ° O, an amino group, especially an amino group of the formula 20 R 1 -N-R 2, or, when W is oxygen or sulfur, as well as chlorine.

The meanings of R 1, R 1 and R 2 correspond to the general and preferred meanings stated above, the latter being here also generally the preferred range.

Acyl derived from an organic sulfonic acid, designated 30 Ac2, is especially acyl of the sub-formula R ° -SO2 ', wherein R ° represents a hydrocarbyl group having the general and preferred meanings set forth above, the latter also usually constituting the preferred range here.

35

I DK 175507 B1 I

I 13 I

Acyl derived from a possibly esterified phosphoric acid, and as I

denoted as Ac 1, is in particular a group of partial formula I

In r1 ° I

I 5> P (= 0) - / I

I r2o I

In which R 1 and R 2 each have the general ones listed above

In and preferred meanings. Preferably R 1 and R 2 have the same I

In 10 meaning. IN

Preferred acyl groups Ac 2 · are acyl groups of a carboxyl I

In acid characterized by the partial formula Rofc-C0- wherein I

R ° b either means hydrogen (and thus forms the formyl group I)

In pen) or have one of the general and aforesaid

drawn meanings for the hydrocarbyl group R ° and thus I

Derived from an optionally substituted acyclic, I

In carbocyclic, carbocyclic-acyclic, heterocyclic or I

In heterocyclic-acyclic monocarboxylic acid. A preferred I

20 hydrocarbyl group in such an acyl group is, for example, an I

In the C (1- 19) alkyl group, primarily a C (1-7) - or I

In the C (1-4) alkyl group, especially a group which, in the case of more I

than 5 carbon atoms have a linear chain, and so can you

You carry the following substituents: A carboxyl group which even-

It may also be present in salt form or as a cyano-I

In group or a C (1-4) alkyl ester (C (1-4)) alkoxycarbonyl-I

In group), and preferably in the "position," I

In the amino group of formula I defined above

30, -N-r2, preferably one wherein r! and R 1 separately

You mean hydrogen and then preferably are in 1-style I

In the ring, or one or more halogen atoms, especially fluorine I

I or chlorine, preferably in neighboring positions I

I to the carbonyl group. Another preferred acyl group is an I

In bicyclic or especially monocyclic aroyl group, first and I

Benzoyl which may also carry one or more of the following substituents: halogen atoms, especially chlorine or fluorine, nitro groups, C (1-4) alkyl groups, especially methyl, 5 hydroxyl groups and etherated hydroxyl groups, especially C (1- 4) -alkoxy, such as methoxy, phenoxy and methylenedioxy, as well as carboxyl groups which may also be present in salt form or as a cyano group or a C (1-4) alkyl ester (C (1-4) -alkoxycarbonyl). The aroyl groups preferably carry at most 2, at most, only 1 such substituent. Analogous heteroaroyl groups are also preferred, especially those derived from pyridine, furan, thiophene and imidazole, and from their analogs with condensed benzoring such as guinoline, isoguinoline, benzofuran and benzimidazole and optionally also substituted as indicated above. Preferred acyl groups of this kind are also derived from monocyclic aryl-alkenyl, e.g. corresponding aryl-C (2-5) -alkenyl such as benzyl and styryl, i.e. phenacetyl and cinnamoyl. They may also be substituted in the manner indicated above. Such acyl groups, with the basic structure of the staurosporin, form similar acyl amides, with those having the above meanings for Ae * being particularly preferred. Examples include staurosporine amides derived from the following carboxylic acids: aliphatic monocarboxylic acids having a maximum of 20 carbon atoms, such as lower alkane carboxylic acids, e.g. propionic acid, butyric acid, isobutyric acid, valeric acid, isovalerianic acid, capric acid, trimethylacetic acid, oenanthic acid and diethylacetic acid, in particular of acetic acid, and of lauric acid, myristic acid, palmitic acid and stearic acid, as well as of oleic acid, elaidic acid, such as chloroacetic acid, trifluoroacetic acid or trichloroacetic acid, bromoacetic acid or α-bromo isovaleric acid, carbocyclic or carbocyclic-acyclic monocarboxylic acids, e.g. cyclopropane, cyclopentane and cyclohexane carboxylic acid or cyclopentane or cyclohexane acetic acid or propionic acid, aromatic carbocyclic carboxylic acids,

I DK 175507 B1 I

I 15 I

In e.g. benzoic acid which may be mono- or polysubstituted-I

right, e.g. as stated above, aryl- or aryloxy-low-I

In alkanecarboxylic acid and their 1 chain unsaturated analogs, I

In 5 e.g. optionally, as indicated above for benzoic acid, I

In substituted phenylacetic or phenoxyacetic acids, I

In phenylpropionic and cinnamic acids, as well as heterocyclic I

In acids, e.g. furan-2-carboxylic acid, 5-tert-butyl-furan-2- I

In carboxylic acid, thiophene-2-carboxylic acid, nicotine or I

In 10 isonicotinic acid, 4-pyridine propionic acid and optionally with I

lower alkyl groups substituted pyrrole-2 or -3-carb-I

In oxylic acids, also corresponding α-amino acids, especially I

In the naturally occurring α-amino acids of the L series, e.g. IN

I glycine, phenylglycine, alanine, phenylalanine, proline, I

In leucine, serine, valine, tyrosine, arginine, histidine and I

In asparagine, preferably in an N-protected form, i.e. in an I

In such form where the amino group is substituted by an I

In conventional, e.g. one of the amino acids listed above

In protecting groups, also dicarboxylic acids such as I

In oxalic, malonic, mono- or dilavalkylmalonic acids, I

In succinic, glutaric, adipic, erucic, maleic, and I

I with halogen such as fluorine, chlorine or bromine, and / or I

In lower alkyl, hydroxy, lower alkoxy and nitro optionally I

In substituted phthal, quinoline, isoquinoline or I

In phenyl succinic acid, as well as glutamic acid and aspartic acid, I

In which the latter two acids are preferably present with I

In protected amino groups. As stated, the other I

In carboxyl group not only occur in free form but also in I

In functionally transformed form, e.g. as a 0 (1-4) - I

In alkyl ester or as a salt, preferably as a

In reasonably acceptable salt, with a salt-forming basic I

In component. As the salt-forming basic component used in I

Primarily metal or ammonium salts such as alkali I

number and alkaline earth metal salts, e.g. sodium, potassium, I

35 magnesium or calcium salts, or ammonium salts with I

ammonia or suitable organic amines. IN

Another preferred acyl group Ac1 is derived from carbonic acid

monoesters and is characterized by the partial formula R ° -O-CO-. IN

16 I

DK 175507 B1 I

Along with the staurosporase base structure, this acyl I forms

group corresponding to N-disubstituted urethanes. Among I

particularly preferred hydrocarbyl groups R ° in these derivatives

For example, the following may be mentioned: acyclic hydrocarbyl, I

In particular, a C (1-20) alkyl group, preferably a linear group, I

I which may be substituted by a carboxyl group, preferably I

In a sense, in a functionally transformed form, such as salt, cyano I

I or C (1-4) alkyl ester preferably in I

In the 10 ω position, or an analog linear (mono- to hexa -) - I

In oxalkyl group having 4-20 chain links, especially one which is I

I characterized above as particularly preferred. With this I

In the case of R °, optionally substituted I is also preferred

In phenyl and benzyl groups, e.g. those above as preferred I

In 15 mentioned. IN

A further preferred acyl group Ac 1 is derived from I

In amides of carbonic acid (or thiocolic acid) and are characterized I

You know the formula I

I R1 I

I 20 ^> N-C (= W) - I

In R2

wherein R 1 and R 1 have the above meanings, and W

You mean sulfur or especially oxygen. Along with the basic staurosporin, this acyl group forms similar urine or thioureas. Among preferred compounds of the invention which carry this acyl group, I particularly mention those in which W means oxygen, one I of the groups R 1 and R 2 represents hydrogen, and the other I represents a C (1-7) - alkyl group which may be substituted with hydroxyl, mercapto, methylthio, phenyl, p-hydroxy-1-phenyl, p-methoxyphenyl, 2-indolyl, 2-imidazolyl and, first and foremost, with carboxyl (free or on a functional I converted form, such as C (1-4) -alkoxycarbonyl, carbamoyl I or amidino), one of which is preferably in the 2 I-1 position, and preferably corresponds to a radical whose

I DK 175507 B1 I

I 17 I

In free valence, the amino group is substituted for any I

In amino acids such as ε-alanine, γ-amino butyric acid or norvaline, I

I and especially one found in nature as a peptide building block I

In 5 α-amino acid of the L series, or an antipode thereof. IN

In addition, compounds with acyl must be highlighted by the I

In the latter species, in which W means sulfur, one of the groups R1 I

I and means hydrogen and the other means a 0 (1-7) - I

In an alkyl group or, in particular, a C (1-7) alkenyl group, wherein the I

In 10 free valence starts from a carbon atom other than double I

In the bond, such as allyl. IN

In addition, the relevant relations with I

In formula I wherein R is chloroformyl or I

In thiochloroformyl, which are particularly excellent as advantageous I

In 15 intermediates for the production of modified carbonic acid I

In acyl esters. IN

The acyl group Ac 1 is derived from an acyclic, carbocyclic I

I or heterocyclic, moreover, also of a carbocyclic I

In acyclic or heterocyclic-acyclic sulfonic acid and I answer

In 20 to the above-mentioned partial formula R ° -SO 2 - wherein R ° means- I

In there hydrocarbyl with the generic listed above and in particular I

In preferred meanings. Among the compounds of I

In particular, the invention which carries the group Ac

In those wherein R ° means a C (1-7) alkyl group, especially one

In a linear, a bicyclic or especially monocyclic aryl group, I

I, such as phenyl in particular, which may be substituted analogously to I

In the above preferred aroyl groups. Furthermore, I

You emphasize analogously constructed bicyclic and monocyclic I

In aromatic heterocyclyl groups wherein one or two of H

In the 30 carbon atoms, they are exchanged with heteroatoms such as I

In pyrimidyl, e.g. 2- or 4-pyrimidyl, quinolyl or I

In isoguinolyl. The heterocyclyl groups may also carry subst

In tuents, especially those for aroyl, whereby e.g. et i

In hydroxyl derivative by tautomeric displacement of double bond I

35 equals a dihydro-oxo derivative. H

18 DK 175507 B1

For example, the acyl group derived from a phosphoric acid Ac3 is an acyl group derived from pyrophosphoric acid or, first of all, from orthophosphoric acid, which may also be present in a functionally converted form, e.g. as a salt, hydrocarbyl ester or amide. In particular, among the compounds of the invention of formula I wherein R is Ac 3 are those in which Ac 3 corresponds to the partial formula

RiO

10 ^> P - (= 0) - r2o wherein r! and R 2 has the above general and particularly preferred meanings and both are preferably the same and represent hydrogen or an unsubstituted C (1-7) alkyl group, especially a linear such as primarily methyl or ethyl, or also optionally especially with C (1-4) alkyl, C (1-4) alkoxy, halogen and / or nitro substituted phenyl group.

Particularly preferred are compounds of formula I wherein R is an acyl group of the sub-formula ZC (= W) - wherein W is oxygen or sulfur and Z is C (1-7) alkyl which may be substituted by halogen, carboxy and C (l-4) alkoxycarbonyl.

Particularly preferred are such compounds of formula 1 wherein R is an acyl group of the sub-formula ZC (= W) -, wherein W is oxygen or sulfur and Z is phenyl, moreover pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted by C (1-4) alkyl, C (1-4) alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxycarbonyl, methylenedioxy and / or cyano.

Particularly preferred are compounds of formula I wherein R is an acyl group of the sub-formula RO RO -CO- wherein R ° is

I DK 175507 B1 I

I 19 I

I means C (1-7) alkyl, especially C (1-4) alkyl such as methyl II or tert-butyl which may also be substituted with II halogen such as fluoro or chloro, carboxy or C (1-4) ) - II alkoxy-carbonyl, such as methoxycarbonyl, such as trifluoro-II or trichloromethyl, 2-carboxy- or 2-methoxycarbonyl-II-ethyl. IN

I Particularly preferred are compounds of formula I wherein RII represents an acyl group of the sub-formula R ° ^-CO0 wherein R ° b is II phenyl which may be unsubstituted or substituted by I I (1-4) alkyl, C (1) -4) alkoxy, halogen such as fluoro or II chloro, nitro, trifluoromethyl, carboxy or C (1-4) alkoxy-II carbonyl. IN

Particularly preferred are compounds of formula I, I I 15 wherein R is an acyl group of the sub-formula R ° -SO 2 -, I I wherein R ° is C (1-7) alkyl, especially C (1-4) alkyl. IN

Particularly preferred are compounds of formula I, II wherein R is an acyl group of the sub-formula R--SO₂2, II wherein R ° is phenyl, further pyridyl, furyl, II thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl II or benzimidazolyl. each of which may be unsubstituted or substituted by C (1-4) alkyl, C (1-4) alkoxy, II halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxy-II carbonyl, methylenedioxy and / or cyano. IN

Particularly preferred are such compounds of formula I, II wherein R is an acyl group of the sub-formula R °-SO₂2, II wherein R ° is phenyl or with C (1-4) alkyl or II halogen substituted phenyl or isoquinolyl such as In 5-isoquinolyl. I 1

Particularly preferred are such compounds of formula I wherein I R represents an acyl group of the sub-formula R ° -O-CO- wherein R ° I I is C (1-7) alkyl, especially C (1-4) alkyl. IN

20 DK 175507 B1

Particularly preferred are those compounds of formula I wherein R is an acyl group of the sub-formula R ° -O-CO- wherein R ° is phenyl, further pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of itself may be unsubstituted or substituted with C (1-4) alkyl, C (1-4) alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxy-1 carbonyl, methylenedioxy and / or cyano.

Particularly preferred is the compound of formula I wherein R

Y is an acyl group of the partial formula R ° -O-CO- wherein R ° is In unsubstituted phenyl.

Particularly preferred are such compounds of formula I, wherein R is an acyl group of the subform I I R 1 = N (= W) - I R 2 3 wherein W is sulfur or especially oxygen, R 2 is hydrogen, and R 3 represents C (1-7) alkyl, especially C (1-4) alkyl, I C (3-7) alkenyl or phenyl, further pyridyl, furyl, I thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl I or benzimidazolyl, which are each unsubstituted I or substituted by C (1-4) alkyl, C (1-4) alkoxy, I halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxy-I Carbonyl, methylenedioxy and / or cyano.

Particularly preferred are such compounds of formula I, I wherein R is derived from an α-amino acid, especially one of the naturally occurring o-amino acids of the L series.

2

Particularly preferred are such compounds of formula I, I wherein R is derived from an α-amino acid selected from glycine, I phenylglycine, alanine, phenylalanine, proline, leucine, serine, 3 I valine, tyrosine, arginine, histidine and asparagine.

I DK 175507 B1 I

I 21 I

In particular, compounds of formula I in which R is I are preferred

I derived from an α-amino acid selected from glycine, alanine, I

In phenylalanine, serine, arginine and histidine. IN

According to their nature, the compounds of the invention can be I

In the late, if they contain salt-forming groups, also I

You are in the form of salts, especially of pharmaceutical use

In straight, ie. physiologically acceptable, salts. For insulation I

In or purification, pharmaceutically unsuitable I can also be used

In 10 salts. For therapeutic purposes only pharmaceutical I is used

In usable salts which are preferred. IN

Thus, for example, compounds with free acid groups, I

I such as, for example, a free sulfo, phosphoryl or carboxyl I

In the yl group, especially one located in the acyl group Ac, I

I is present as a salt, preferably as a physiological I

In acceptable salt, with a salt-forming basic component. 1 I

In the first instance mention may be made of metal or ammonium salts such as I

In alkali metal and alkaline earth metal salts, e.g. sodium, I

In potassium, magnesium or calcium salts, or ammonium salts

In 20 teas with ammonia or suitable organic amines, especially I

In tertiary monoamines and heterocyclic bases, e.g. tri- I

In ethylamine, tri- (2-hydroxyethyl) -amine, N-ethylpiperidine I

I or N, N'-dimethylpiperazine. If such an acid group I

If present in a hydrocarbyl group R °, it may also form

In an inner salt with the amine nitrogen atom in staurosporase-I

In the structure or with another, possibly present I

In amino group * I 1

Compounds of the invention having a basic character can be

You also exist as addition salts, especially as acid addition I

In 30 salts with inorganic and organic acids, but also as I

In quaternary salts. Thus, for example, compounds I

I of formula I, which in the group Ac as a substituent carries an I

In basic group, such as an amino group, form acid addition I

In salts with commonly found acids. In particular, I

In 35, addition salts of formula I are raised

Wherein [Stau] and R ° have the above meanings, R§ means hydrogen or an unsubstituted, preferably linear C (1-4) alkyl group, especially ethyl or first and methyl, or benzyl is promoted, and X "represents the anion of an inorganic or organic acid or of a carboxyl group present in the group R, with physiologically acceptable salts being preferred. Quaternary salts of formula la are preferred, wherein the first carbon atom in the hydrocarby group R ° is present as methylene.

For example, to form the anion X, the following commonly occurring acids may be used: Hydrogen halide acids, e.g. hydrochloric acid and hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid or perchloric acid or aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, lactic acid, lactic acid, lactic acid, lactic acid hydroxymalic acid, oxalic acid, pyruvic acid, phenylacetic acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid, p-amino-salicylic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, , in addition, methionine, tryptophan, lysine or arginine, as well as ascorbic acid. In quaternary salts, as "X" anions are preferred by strong inorganic acids such as hydrogen halide acids, especially bromides and iodides, or by organic sulfonic acids such as methanesulfonates (mesylates), p-toluenesulfonates (tosylates), p-bromobenzene sulfonates (brosylates) and p -nitrobenzensulfonater.

I DK 175507 B1 I

I 23 I

Particularly preferred compounds of formula I or Ia are I

those described in the Examples. IN

In the compounds of the invention of formula 1 and their I

Five salts are prepared using prior art I

In general organic-chemical processes, and method I

according to the invention is peculiar in that you react

staurosporin of the formula [Stau] -NH-CH3 wherein [Stau] has I

In the meaning of claim 1, or an acid addition salt I

In 10 thereof with either I

In a) a reagent of formula R-Y (III) wherein R has it in I

the meaning of claim 1, and Y is a reactive I

In activated hydroxyl group or a further single bond, I

At its other end, a hydrogen atom in the group R, or I, substitutes

I b) for the preparation of compounds of formula I wherein I

In R, the group of the partial formula H-R ° - wherein R ° means an I

In di valent, to the general structure of the one defined in claim 1

In 20 prepared acyclic hydrocarbon group R ° corresponding to aliphatic I

In group, with a carbonyl reagent of the formula R ° = O (IV) wherein I

I q θ I

In R ° the meaning given above and at the same time or therein

I to I

You then react with a reducing agent and, if desired, convert

You form a compound of formula I for another form

In association with formula I and / or converting one into free form I

In the compound of formula I formed into a salt thereof and / or I

You convert a salt formed compound of formula I to I

In the free form or to another salt. IN

The present reaction of staurosporin with a reagent of I

In type a), ie. a reagent of formula III, I is carried out

Under known process conditions, generally I

I is used in organic chemistry for the substitution of I

In amines, usually at temperatures between freezing point I

At 35 and the boiling point of the reaction mixture, e.g. in an I

In the temperature range from approx. -10 to approx. 160 ° C, especially from approx. IN

I 20 to 50 ° C, at atmospheric or higher pressure, in I

Heterogeneous phase, such as suspension, with stirring or shaking, or preferably in homogeneous liquid phase, such as in excess of liquid reagent or especially in the presence of solvents, especially organic solvents, and optionally in the presence of acid-binding inorganic or organic agents. Suitable solvents are, for example, aprotic low polar solvents such as aliphatic and aromatic hydrocarbons of the pentane type, hexane, heptane and cyclohexane or benzene, toluene and xylenes, as well as halogenated, especially chlorinated, aliphatic hydrocarbons such as chloroform and dichloromethane, and especially polar aprotic solvents. such as aliphatic and cyclic ethers, e.g. diethyl ether, 1,2-dimethoxyethane and diisopropyl ether or dioxane and tetrahydrofuran, low aliphatic esters and amides such as ethyl acetate or formamide, acetamide, N, N-dimethylacetamide and dimethylformamide, as well as acetonitrile, dimethylsulfoxide and hexamethylphosphorotriamide. Under certain conditions, it is advantageous as a solvent to also use water or a protic organic solvent such as a low alkanol, e.g. methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, as well as glycol or diglycol monoethers, e.g. 2-methoxyethanol. In this case, it is often advantageous to promote the reaction rate at increased pressure, e.g. by carrying out the reaction in sealed containers to increase the boiling and reaction temperature. The solvents can also be used in convenient combinations, e.g. to achieve greater solubility of the components. 1 2 3 4 5 6

As an acid-binding agent, two arbitrary basic compounds, such as partly organic 3 nitrogen-containing bases, e.g. tertiary amines of the type 4 triethylamine, ethyl diisopropylamine, N, N-dimethylaniline, 5 N-ethylpiperidine or N, N * -dirnethylpiperazine, or 6 aromatic heterocyclic bases of the pyridine type, collidine, quinoline or 4-dimethylaminopyridine, partly basic reactants, especially alkali-

I DK 175507 B1 I

I 25 I

In character, i.e. that the free valence starts from a carbon atom,

I which is a component of an aromatic carbocyclic or I

In heterocyclic ring, esters of hydrogen halo are preferred

In 5 acids, especially bromides and iodides. IN

A reagent of formula III wherein Y means an additional I

In single bond to a hydrocarbyl group R ° (under exchange I

I of a hydrogen atom therein, for example, is an alkene, especially an I

In such, if double bond is further activated as I

In consequence of a structural characteristic, such as in 2-methylpropylene, I

I or substitution such as especially in acrylonitrile. Defini- I

The ion of Y also includes such a single bond if I

At the other end is not immediately connected to a carbon atom I

I in the hydrocarbyl group R °, but with one as substituent I

In heteroatom occurring, such as oxygen (i.e., an oxygen atom I)

I in a hydroxy group) or nitrogen (in an amino group), I

In which it replaces a hydrogen atom in this group. Especially you

Preferred are reagents of the formula R ° Y which contain I

In the α-epoxide group (oxiranes) or the α-imine group I

I (aziridines) and which serve as an advantageous source of I

In groups R ° with a 2-hydroxy or 2-amino-alkyl group. IN

The reaction with these reagents is preferably carried out in I

In the presence of lower temperature canals, e.g. IN

In from approx. 100 to approx. 150 ° C, and optionally under increased pressure I

I to increase the boiling temperature of the reaction mixture or in I

In basic environment and especially with an excess of reagent. IN

In accordance with the above definition, the group R I

represent an acyl group Ac and consequently form the basis for I

acylating agent of formula AcY wherein both Ac and Y have I

30, such as for Ae *, Ac ^ and Ac ^ general and I

preferred meanings. Preferably, Y means halogen, I

especially chlorine, bromine and iodine. IN

In acylating agents derived from the above I

defined acyl group Ae * of a carboxylic acid, Y I

For example, a reactively activated hydroxyl-I

26 DK 175507 B1 group. One already exists in the free carboxyl group of a carboxylic acid of the formula R ° -COOH when, due to structural features, such as in trifluoroacetic acid and, first of all, formic acid, has a sufficient reactivity, but especially when activated by action. of activation reagents, e.g. carbodiimides such as especially dicyclohexylcarbodiimide or di- (2-imidazol-yl) carbodiimide and other analogous compounds, and optionally in the presence of excipients which form active esters such as substituted phenols and especially N-hydroxy amino compounds of type 1 -hydroxybenzotriazole, N-hydroxyphthalimide and N-hydroxymaleinimide or N-hydroxysuccinimide.

One for acyl groups of all species, e.g. at Ae *, Ac2 and Ac2, advantageously activated hydroxyl group is a reactive, strong acid esterified hydroxyl group, such as that defined above in connection with the hydrocarbyl group R °, which forms a mixed acid anhydride with the acyl group. Among these, in particular, mixed anhydrides should be highlighted with hydrogen halide acids, especially with hydrobromic acid and first of all with hydrochloric acid, ie. acid bromides and acid chlorides, e.g. such with the formula

R 10 is Z-C (= W) -Hal, R ° -SO 2 -Hal and R 2> P (= O) -Hal R 20 wherein Hal represents bromine and preferably chlorine, and Z, W, R

R 1 and R 2 have the above meanings. As a particular embodiment of these compounds may be mentioned phosgene 30 and thiophosgene.

For acyl groups Ae * of carboxylic acids (including acyl groups of a functionally converted carbonic acid), the reactive esterified hydroxyl group may also be esterified either with another carboxylic acid residue, especially by a strong carboxylic acid residue.

I DK 175507 B1 I

I 27 I

In acid, such as formic acid, chloroacetic acid and preferably I

In trifluoroacetic acid, forming the basis of a mixed anhydride I

You or esterified with the same acyl group to form an I

In symmetric carboxylic anhydride of the formula Ac1-0-Ac1, I

In particular, a symmetrical carboxylic anhydride of formula I

R ° -CO-CO-R ° or R ° -O-CO-O-CO-O-R ° (or a sulfur-I

You log off). IN

In acylations with the above acylating agents I

Preferably in 10, in the presence of an acid-binding I

In agent, such as one of the above, preferred

In some use in equivalent amount or a small excess, I

In which usually two equivalents do not exceed. IN

In acylating agents of the formula AcY, wherein Y is an outer I

In 15 more binding to the group Ac, is especially derived from acyl group I

I per Ac 2 of carboxylic acids, especially of those at 1

In the neighboring atom of the carbonyl group, i.e. at the neighboring I

In the carbon atom or nitrogen atom, carries a hydrogen atom. The I

You belong to the category of ketene or isocyanates and you answer

I 20 for the formula R§ = C = 0 or R1-N = C = 0, wherein R§ has the I

In the sense given above for a divalent, to the group R ° I

In the corresponding hydrocarbyl group of aliphatic character, and R1

You have the general and particularly preferred I mentioned above

In meanings with the exception of hydrogen. Furthermore, you must

25 mentions an analogous sulfur-containing acylating agent isothio-I

In cyanate of formula r 1 -n = C = S, wherein R 1 has the above I

I have the general and preferred meanings, except I

In hydrogen. The acylation with such agents may depend on

By their nature also carried out without acid binding agents, and

In 30 it is recommended to carry out the turnover under pure exclusion

In humidity and / or protic solvents. IN

Process b) is well known and commonly used under I

In the term "reductive alkylation". For carbonyl reagents with I

In the above formula R§ = 0 (IV) belongs in the first row I

In 35 aldehydes, but also ketones, hex rounds of cyclic ketones, I

Wherein the carbonyl group is a member of an alicyclic ring. Preferably, these reagents are derived from unsubstituted hydrocarbyl groups, or they carry at least 5 substituents which are resistant to reduction. As reducing agents, complex metal hydrides such as alkali metal aluminum hydrides and especially alkali metal borohydrides, e.g. lithium aluminum hydride, potassium borohydride, lithium borohydride, and most importantly sodium borohydride, and derivatives thereof wherein one or more hydrogen atoms are exchanged with alkoxy groups or cyano, e.g. methoxy sodium borohydride, tri- (tert-butoxy) -lithium borohydride or di- (2-methoxyethoxy) disodium-lithium hydride or sodium cyanoborohydride, and also diborane. These reducing agents are preferably added first in the second phase of the alkylation, ie. after the primary addition of the carbonyl reagent. Another frequently used reducing agent is elemental hydrogen, which is used under the usual conditions for the catalytic hydrogenation, at temperatures of about 20 to 1 100 ° C, and if necessary at overpressures of up to approx. 150 I atm. simultaneously with the carbonyl component. As catalyst I, Raney nickel, but also palladium I or platinum, is usually used, preferably on an inert carrier, such as calcium carbonate, barium sulfate or alumina.

In another embodiment of the reductive alkylation I, the reducing agent is formic acid, which is particularly suitable for methylation with formaldehyde. 1

In the process of the invention, if desired, one can convert a formed compound of formula I to another

In connection with formula I. In particular, one in the group R is converted

In the present functional group to another group.

For example, a functionally converted, in particular a protected hydroxyl, carboxyl or amino group, is converted to the free form, or a reactive chlorine atom, such as in the chloroformyl group, is exchanged with the group R (-R 2) -. For example, the release of a functionally converted group I is the conversion of an esterified carboxyl group

I DK 175507 B1 I

I 29 I

I to the free carboxyl group, which usually can

is carried out by conventional hydrolysis, primarily I

Under the influence of bases, preferably alkali metal hydride

In 5 oxides, carbonates or hydrogen carbonates, or in I

In suitable esters, e.g. esters of tertiary alcohols, e.g. IN

In tert-butyl alcohol, by acidolysis, e.g. with hydrogen I

In fluoride or trifluoroacetic acid. Esters with benzyl alcohol- I

Clay can also be cleaved by conventional hydrogenolysis. Then I

10 esterification is one of the most common methods for I

In protecting carboxyl groups, the above described I

conversion as well as an effective method of removing I

In carboxyl protecting groups. IN

In The temporary protection of hydroxyl groups I used

In 15 groups and cleavage methods are also well known, I

In e.g. from the peptide synthesis. In particular, hydroxyl-I is protected

In groups in the form of esters with carboxylic acids, e.g. with I

lower alkanoic acids or with monoesters of carboxylic acids, I

In e.g. partly formates or acetates or partly tert-but-I

In oxy or benzyloxycarbonates, or in the form of ethers, I

In e.g. especially ethers of tertiary alkols, e.g. tert-butyl-I

In alcohol, or also in the form of acetals, e.g. especially as you

In 2-tetrahydropyranyl ether. The former protection groups

per split usually in the same way as ester I

In 25 carbonyl groups, whereas the latter two preferably I

You are removed by acidolysis. I 1

Those for the temporary protection of primary and secondary

amino groups useful protecting groups correspond to those I

In groups that have been extensively studied by I

In the 30 peptide synthesis and has found the widest use. IN

Preferably, the above-mentioned amino protectors are used

In reference groups whose cleavage generally depends on I

In their specific nature, are carried out under generally known I

conditions of hydrolysis, especially the basic hydrolysis, I

Acidolysis or hydrogenolysis. IN

30 DK 175507 B1

Preferably, the general conditions for the conventional cleavage of the functionally transformed groups are chosen so that neither the bond 5 between the group R and the methylamino group in the staurosporin is damaged nor its basic structure. Since these structural features are generally characterized by good stability, common reaction conditions can be used without special security measures.

In particular, any subsequent conversion of a reactive chlorine atom is the conversion of the chloroformyl group (C1-C0) to the hydrocarbyloxycarbonyl group (R0-O-C0-) or the aminocarbonyl (carbamoyl -) group [R -].

This conversion is carried out under known conditions, reacting N-chloroformylstaurosporine with an alcohol of the formula R ° -OH or an amine (including ammonia) of the formula R ^-NH-R₂, preferably in the presence of an acid-binding agent such as an organic base, e.g. one of the above tertiary amines. The general reaction conditions are analogous to the conditions detailed above in connection with the reactions with reagents having reactively esterified ester hydroxyl groups, especially for acid chlorides.

The optional salt formation and release of the basic forms 25 of the compounds of formula I from their salts is carried out in a conventional conventional manner. Thus, carboxyl-containing acyl derivatives of formula I are converted to the corresponding salts with bases, primarily alkali metal salts, by treatment with a corresponding base, especially a basic reacting compound such as a hydroxide, carbonate or hydrogen carbonate. The salts can be converted to free carboxyl compounds by acidification, e.g. with inorganic acids such as hydrogen halide acids. End products that react basic, e.g. tertiary and quaternary amines of formula I or Ia can be converted into salts with acids, e.g. by treatment with an acid suitable for salt formation,

I DK 175507 B1 I

I 31 I

I such as one of the above. Conversely, such an I

basic basic form of a tertiary amine of formula I is released

I by treatment with basic agents, e.g. with inorganic I

In 5 hydroxides, carbonates and hydrogen carbonates or I

In organic bases and ion exchangers. IN

Suitable compounds of the invention may also form I

In internal salts, e.g. by usual acid-base titration to I

At the neutral point or isoelectric point or form I

10 quaternary ammonium salts of formula I, e.g. by treatment I

In lation with a quaternizing agent corresponding to group I

In pen R§, such as a reactive ester of a corresponding I

In hydroxy compound with a strong acid such as a hydrogen I

In haloic acid, sulfuric acid or a strong organic sulfonic acid

In 15 acid. IN

In these or other salts of the compounds of the invention,

In e.g. The picrates can also be used to purify the I

In formed compounds, converting the free compounds

In salts, isolate the salts and release the free I

In 20 compounds from the salts. As a result of the narrow I

In relationship between the compounds in free form and in the form of I

In their salts, above and below, the free I

Compounds optionally also include the corresponding salts, I

In including Quaternary salts. IN

In 25 Certain carbonyl functions can be converted to the corresponding; IN

In thioform e.g. by means of suitable reagents which provide

You can substitute 0 with S. Thus, for example, by I

In reaction with Lawesson reagent [2,4-bis- (4-methoxyphenyl) - I

2,4-dithioxo-1,3,2,4-dithiadiphosphetane] in compounds I

30 of formula I and their salts, which as carbonyl function H

eg. contains a carboxamide, ketone and lactone group, I

replace the O atom with the S atom. IN

The invention also relates to such embodiments of I

the method by which one assumes one on any condition- H

35 is an intermediate step of the process as intermediate formed for H

32 DK 175507 B1 and performs the missing steps or uses a starting material in the form of a derivative, e.g. a salt, or form it under the reaction conditions.

In the process of the invention, known starting materials or starting materials which can be prepared by known methods are used, preferably those which lead to the particularly valuable compounds described above.

10

Due to the above-described pharmacological properties, the compounds of the invention can be used alone or optionally with excipients, or in combination with other active substances, e.g. antibiotics or chemotherapeutics are used as agents for the treatment of diseases in which, as described above, cell growth is important, both prophylactic and curative. When used as a medicament, the present active substances are administered in prophylactically or curatively effective amounts preferably in the form of pharmaceutical compositions together with conventional pharmaceutical carriers or excipients. For humans or warm blooded animals with a body weight of approx. 70 kg of daily doses are administered from 1 to 1000 mg, which can be exceeded in acute cases, depending on the species, body weight, age and individual condition, and the mode of application and, in particular, of the disease picture. The invention also includes the corresponding method of the medical treatment.

The pharmaceutical compositions of the invention are, for example, preparations for enteral, such as oral or rectal, as well as for parenteral administration to humans and warm blooded animals. Corresponding dosage unit forms, especially for oral administration, e.g. dragees, tablets or capsules, preferably contain from ca. 5 to 500 mg, especially from ca.

35 io to 100 mg of active substance together with pharmaceutical use

I DK 175507 B1 I

I 33 I

In partial carriers or excipients. IN

In suitable carriers, in particular fillers such as sugars, I

In e.g. lactose, sucrose, mannitol or sorbitol, I

In cellulose preparations and / or calcium phosphates, e.g. IN

In tricalcium phosphate or calcium hydrogen phosphate, I

In addition, binders such as starch adhesives (under I

Using e.g. maize, wheat, rice or potato I

In starch), gelatin, tragacanth, methyl cellulose and / or, if I

If necessary, disintegrants such as those above I

In stated starch types, in addition, carboxymethyl starch, I

In cross-linked polyvinylpyrrolidone, agar, alginic acid or an I

In salt thereof, such as sodium alginate. Aids are in the first I

In a variety of flow regulators and lubricants, e.g. IN

In silica, talc, stearic acid or salts thereof, such as I

In magnesium or calcium stearate, and / or polyethylene I

In glycol. Dragon cores can be provided with suitable, optionally I

In abdominal resistant coatings, do you apply

In concentrated sugar solutions, optionally containing I

In Arabic rubber, talc, polyvinylpyrrolidone, polyethylene-I

In glycol and / or titanium dioxide, or lacquer solutions in suitable I

In organic solvents or solvent mixtures

In yeast or, for the preparation of gastric juice resistant super- I

In a row, solutions of suitable cellulose preparations such as I

Acetylcellulose phthalate or hydroxypropylmethylcellulose

phthalate. The tablets or kite coatings may be added

dyes or pigments are added, e.g. to identi- I

active or characterizing different doses of active I

fabric. IN

30 I

Other oral pharmaceutical preparations are I

gelatine capsules and soft closed gelatine capsules I

and a plasticizer such as glycerol or sorbitol. IN

The capsules may contain the active substance in the form of an I

Granules, e.g. in admixture with fillers such as I

B1 lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, and stabilizers may also be added.

For example, pharmaceutical compositions for rectal use may be suppositories which consist of a combination of the active substance with a suppository matrix. As a suppository matrix, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols may be used. Furthermore, gelatin rectal capsules may be used which contain a combination of the active substance with a matrix. Liquid triglycerides, polyethylene glycols or paraffin hydrocarbons may be used as matrix materials. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

For parenteral administration, aqueous 2 solutions of a water-soluble forums of the active substance, 3 e.g. a water-soluble salt, or aqueous injection 4 suspensions containing viscosity enhancers, e.g. sodium carboxymethyl cellulose, sorbitol and / or 6 dextran and optionally stabilizers. The active substance 7 may optionally, together with excipients, also be in the form 8 of a lyophilizate which is dissolved before the parenteral administration 9 by the addition of suitable solvents 10.

11 12

The pharmaceutical compositions of the invention may be prepared in a manner known per se, e.g. using conventional mixing, granulation, coating, dissolution or lyophilization methods. Pharmaceutical preparations for oral administration can be prepared, for example, by combining the active substance with solid

I DK 175507 B1 I

I 35 I

In carriers, optionally a formed mixture granulates and I

You process the mixture or granulate, if desired or I

If necessary after the addition of suitable excipients, to

In tablets or drill cores. IN

Is I

The invention is further illustrated by means of the invention

In the following examples. IN

The compounds' nomenclature is derived from the complete I

In structure of staurosporin ([Stau] -NH-CH3) I

I a

IN

I A / A A I

II I \ / I II I

, - »· · = · · · ν · vVaVv

I J "" CH3 I

H

I Nj / N0CH3 (II) I

I fairy I

Cfl3

I 2 where the substituent denoted by N- is * at I

In nitrogen atoms in the methylamino group. IN

In Example 1 I

I N-Methoxycarbonylmethyl-staurosporin I

To a mixture of 233 mg (0.5 mmol) of staurosporin, 0.1 ml of I

I (0.59 mmol) N, N-diisopropyl-ethylamine and 2 ml of dimethyl-I

In formamide, add 0.056 ml (0.6 mmol) I at room temperature

In bromoacetic acid methyl ester. The reaction mixture is stirred for 1 hour

In the closed flask for 48 hours at room temperature. The product | You precipitate by adding 1 ml of water, after which it |

You recrystallize from methanol. Mp. ~ 210 ° C (decomposition, I

I from 170 ° C tan). |

I 35 I

36 DK 175507 B1

H

\ / \

/ ___ v / • "N ___ A

II I \ / I «• - · IS · ·. * n / VaVv Y N * i »CH3 • ·

0 Y VOCHj HjCO-C-HjC-H

CH3

Example 2 N-Carboxymethyl-staurosporine 5 269 mg (0.5 mmol) of N-methoxycarbonylmethyl-staurosporine (Example 1) is refluxed in 15 ml of methanol and 0.3 ml of 2 N sodium hydroxide solution for 18 hours. After cooling to room temperature, neutralize with 0.1 ml of acetic acid and the product is precipitated by the addition of 15 ml of 10 water. Snip. > 230 ° C (decomposition, from approx. 220 ° C tan).

Example 3 N- (1-Methoxycarbonylethyl) -staurosporine

To a mixture of 233 mg (0.5 mmol) of staurosporin, 0.12 ml of 15 (0.71 mmol) of N, N-diisopropylethylamine and 2 ml of dimethylformamide is added at room temperature 0.085 ml (0.75 mmol) o -bromopropionic acid methyl ester. The reaction mixture is stirred for 20 hours at room temperature in the closed flask. After adding an additional 0.044 ml (0.038 mmol) of α-bromo-20-propionic acid methyl ester, the mixture is heated to 80 ° C for another 20 hours. After cooling to room temperature, the product is precipitated by the addition of 2 ml of water. The crude product is purified by chromatography on silica gel (eluent: methylene chloride / ethanol 9: 1). Mp.

25 ~ 150 <> C (decomposition).

I DK 175507 B1 I

I 37 I

In Example 4 I

In N-Benzyl-staurosporin I

To a mixture of 116.5 mg (0.25 mmol) of staurosporin, 0.06 I

In 5 ml (0.35 mmol) of N, N-diisopropyl-ethylamine and 1 ml of dimethyl-I

In formamide, 0.048 ml (0.38 mmol) I is added at room temperature

In benzyl bromide and the reaction mixture is stirred at room temperature

Stir for 6 hours in the closed flask. The product is precipitated

I by adding 1 ml of water, then filtering it off and I

In 10, recrystallized from methanol. Mp. ~ 170 ° C (decomposition). IN

In Example 5 I

In N-Allyl-staurosporin I

To a mixture of 116.5 mg (0.25 mmol) of staurosporin, 0.06 I

In ml (0.35 mmol) of N, N-diisopropyl-ethylamine and 1 ml of dimethyl-I

In room formamide, 0.032 ml (0.38 mmol) I is added at room temperature

In allyl bromide and the reaction mixture is stirred in the closed I

In flask for 6 hours at room temperature. The product is precipitated by I

Add 1 ml of water and filter it off. IN

The product is purified by chromatography on silica gel with I

20: 1 as eluent. Mp. IN

160 ° C (dec.). IN

Example 6 I

N, N-Dimethyl-staurosporinium iodide (N-methyl-staurosporin-I

iodine methylate) I 1 2 3 4 5 6

To a mixture of 233 mg (0.5 mmol) of staurosporin, 0.12 ml of I

2

(0.71 mol) N, N-diisopropyl-ethylamine and 2 ml of dimethyl-I

3

formamide is added at room temperature 0.046 ml (0.75 mmol) I

4

methyl iodide and the reaction mixture is stirred in the closed I

5

flask at room temperature. After approx. one hour course is formed

6

a precipitate. After adding an additional 0.023 ml of I

B1 (0.038 mmol) of methyl iodide and 0.06 ml (0.038 mmol) of N, N-di-isopropyl-ethylamine are stirred for an additional 4 hours at room temperature, then 2 ml of water is added, and the mixture is filtered. The solid crude product is slurried in hot methanol and, after cooling, again filtration and drying of the product. Mp. 260 DEG C. (decomposition).

In Example 7 In N-Ethyl-staurosporine I To a mixture of 116.5 mg (0.25 mmol) of staurosporine, 0.06 I ml (0.35 mmol) of N, N-diisopropylethylamine and 2 ml of dimethyl In formamide, 0.029 ml (0.38 mmol) of ethyl iodide is added at room temperature and the mixture is stirred in the closed flask for 24 hours at room temperature. The product is precipitated by the addition of 2 ml of water and then filtered off. Mp.

At 170 ° C (dec.).

In Example 8 IN, N-Ethyl-methyl-staurosporinium iodide (N-Ethylstaurosporin-iodine methylate) I To a mixture of 115 mg (0.2 mmol) of N-ethyl-staurosporine I (Example 7) and 2 ml of dimethyl formamide is added at room temperature 0.018 ml (0.3 mmol) of methyl iodide. After 16 hours I at room temperature and 16 hours at 50 ° C, further 0.018 ml (0.3 mmol) of methyl iodide is added and the mixture I 25 is stirred for 6 hours at 80 ° C. The crude product is precipitated by the addition of 2 ml of water and then recrystallized from 1 dimethylformamide / chloroform. Mp. 265 ° C (dec.).

I DK 175507 B1 I

I 39 I

In Example 9 I

In N- (2-Hydroxyhexyl) -staurosporin I

A suspension of 116.5 mg (0.25 mmol) of staurosporin and I

In 0.054 ml (0.45 mmol) of 1-hexene oxide 1 3.5 ml of absolute ethanol I

You heat for 36 hours in a pressure tube to 110 ° C. The cooled I

In reaction mixture, dilute with water and extract with I

In methylene chloride. The organic phase is dried with magnesium I

In sulfate, it is evaporated and chromatographed on silica

In 10 gel (eluent: methylene chloride / ethanol 9: 1). After I

In recrystallization from ether / petroleum ether, product I is obtained

I with m.p. 110 ° C (dec.). IN

In Example 10 I

In N- (2-Hydroxytetradecyl) -staurosporine I

I A suspension of 116.5 mg (0.25 mmol) of staurosporin and I

In 0.075 ml (0.30 mmol) of 1-tetradecene oxide in 3.5 ml of absolute I

In ethanol, heat in a pressure tube to 110 ° C for 68 hours. The I

In cooled reaction mixture is diluted with water and then I

You extract with methylene chloride. The organic phase is dried

20 with magnesium sulfate and evaporate and chromatograph

I on silica gel (eluent: methylene chloride / ethanol I

I 9: 1). After recrystallization from ether / petroleum ether I

You get the product with m.p. 120 ° C (dec.). IN

In Example 11B

N- (2-Hydroxydecyl) -staurosporin B

A suspension of 116.5 mg (0.25 mmol) of staurosporin and B

0.055 ml (0.30 mmol) of 1-decene oxide in 3.5 ml of absolute ethanol fl

heated for 43 hours in a pressure tube to 110 ° C. The cooled B

dilute reaction mixture with water and extract B

30 with methylene chloride. The organic phase is dried with magnetic B

40 S 175 sulphate and evaporated, then chromatographed on silica gel (eluent: methylene chloride / ethanol 9: 1).

After recrystallization from ether / petroleum ether, the product is obtained with m.p. 140 ° C.

Example 12 N- (2-Cyanoethyl) -staurosporine

A suspension of 116.5 mg (0.25 mmol) of staurosporin in 2.5 ml (38 mmol) of acrylonitrile is heated for 70 hours to 140 ° C in a pressure tube. After cooling, the reaction mixture is evaporated, I and chromatographed on silica gel (eluent: in methylene chloride / ethanol 9: 1). After recrystallization from chloroform / methanol, the product is obtained with m.p. ~ 210 ° C.

In Example 13 In N-Acetyl-staurosporin I To a solution of 116.5 mg (0.25 mmol) of staurosporine and In 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform is added at room temperature 0.03 ml (0.3 mmol) in acetic anhydride and the mixture is stirred for 2 hours in the closed flask. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried with magnesium sulfate and evaporated. The product is recrystallized from chloroform / methanol, m.p. 240eC.

In Example 14 In 25 N- (3-Carboxypropionyl) -staurosporin I To a solution of 116.5 mg (0.25 mmol) of staurosporine and I 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml chloroform is added at room temperature 40 mg (0.4 mmol) succinic anhydride and the mixture is stirred for 28 hours at room temperature.

I DK 175507 B1 I

I 41 I

closed flask. The reaction mixture is diluted with chloro-I

In form, wash with 0.1 N hydrochloric acid, dry with magnesium sulfate

Grab and evaporate. The crude product is chromatographed on silica gel I

5 (eluent: methylene chloride / ethanol 9: 1), m.p. IN

At 140 ° C. IN

In Example 15 I

In N- (5-Isoquinoline sulfonyl) -staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

0.118 ml (0.69 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of I

In chloroform, at room temperature 105 mg (0.4 mmol) I are added

In 5-isoquinoline sulfonyl chloride and the mixture is stirred for 29 L

For hours in the closed flask. The reaction mixture is diluted

I with chloroform, washed with sodium hydrogen carbonate solution-I

For 15 minutes, dry with magnesium sulfate and evaporate. Product I

I recrystallized from chloroform worm / methanol. Mp. 240 ° C

I (decomposition). IN

In Example 16 I

I N-Methylsulfonyl-staurosporine I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and

In 0.065 ml (0.38 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of I

In chloroform, at room temperature 0.023 ml (0.38 mmol) I is added

In methanesulfochloride, and the mixture is stirred for 24 hours in it

In closed flask. The reaction mixture is diluted with chloroform.

In form, wash with sodium hydrogen carbonate solution, IN I

In hydrochloric acid and saturated sodium chloride solution, dry with I

In magnesium sulfate and evaporated. The crude product is chromatographed

on silica gel (eluent: methylene chloride / ethanol 9: 1) I

and recrystallized from chloroform / methanol, m.p. 230eC. IN

42 DK 175507 B1

Example 17 N- (p-Tosyl) staurosporin

To a solution of 116.5 mg (0.25 ramol) of staurosporin and 5 0.065 ml (0.38 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of chloroform is added at room temperature 57 mg (0.3 mmol) of p-toluenesulfochloride. and the mixture is stirred for 68 hours in the closed flask. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride / ethanol 9: 1) and recrystallized from chloroform / methanol, m.p. 245 ° C.

Example 18 N-Benzoyl-staurosporine

To a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of Ν, di-diisopropyl-ethylamine in 2 ml of chloroform is added at room temperature 0.035 ml (0.3 mmol) of benzoyl chloride and the mixture stir for 10 minutes. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride / ethanol 30: 1), m.p.

235-247 ° C during tanning.

Example 19 N-Trifluoroacetyl-staurosporine

To a solution of 233 mg (0.5 mmol) of staurosporin and 0.13 ral (0.6 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of chloroform is added 0.5 ml (3.57 romol) of trifluoroacetic anhydride at room temperature. and the reaction mixture is stirred for 15 minutes in B1

. 43 I

I ter. The reaction mixture is diluted with chloroform, washed I

I with sodium hydrogen carbonate solution, dried with magnetic I

In sium sulfate and evaporated. The crude product is chromatographed on I

Silica gel (eluent: methylene chloride / ethanol 20: 1), I

In m.p. > 220 ° C. IN

In Example 20 I

In N-Phenoxycarbony1-steurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

In 0.065 ml (0.38 mmol) of Ν, Ν-diisopropylethylamine in 2 ml of I

In chloroform is added 0.035 ml (0.28 mmol) of chloroformic acid I

In phenyl ester at room temperature, and the reaction mixture I

Stir in the closed flask for 30 minutes. Reaction bias I

In the dilution, chloroform is diluted, washed with sodium carbohydrate

In 15 night solution, dried with magnesium sulfate and evaporated. IN

The residue is evaporated with hot methanol, after which I

You cool and the product is filtered and dried. Mp. > 210 ° C I

I (decomposition). IN

In Example 21 I

I N-Methoxycarbonyl-staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

0.065 ml (0.38 mmol) of N, N-diisopropylethyl amine in 2 ml of I

chloroform is added 0.025 ml (0.32 mmol) of chloroformic acid I

methyl ester at room temperature, and the reaction mixture I

25 is stirred for 1 hour in the closed flask. The reaction mixture I

diluted with chloroform, washed with sodium hydrogencarbonate.

bonate solution, dried with magnesium sulfate and evaporated. IN

The crude product is recrystallized from methanol, m.p. > 220 ° C

(Decomposition). IN

44 DK 175507 B1

Example 22 N-Allyl aminothiocarbonyl-stososporin (N-allylthiocarbamoyl-staurosporine) To a solution of 116.5 mg (0.25 mmol) of staurosporin in 2.5 ml of chloroform is added 0.029 ml (0.3 mmol) of allylisothio - cyanate and the reaction mixture is stirred in the closed flask at room temperature for 12 hours. The reaction mixture is evaporated and the crude product is recrystallized from chloroform / methanol, snip. 220®C.

Example 23 N-Methylaminothiocarbonyl-staurosporine (N-methylthio-carbamoyl-staurosporine)

To a solution of 116.5 mg (0.25 mmol) of staurosporin in 2.5 ml of chloroform is added 0.022 mg (0.3 mmol) of methyl isothiocyanate and the mixture is stirred for 12 hours in the closed flask at room temperature. The reaction mixture is evaporated and the crude product is recrystallized from chloroform / methanol, m.p. 235-238'C.

Example 24 N-Phenylcarbamoyl-staurosporine

To a solution of 116.5 mg (0.25 mmol) of staurosporine in 2.5 ml of chloroform is added 0.033 ml (0.3 mmol) of phenyl isocyanate and the reaction mixture is stirred for 15 minutes at room temperature. The reaction mixture is evaporated and the crude product is recrystallized from chloroform / methanol, m.p. 225-229 ° C (tan).

I DK 175507 B1 I 45

In Example 25 I

In N-Trichloroacetyl-staurosporine I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

0.1 ml (0.58 mmol) of Ν, Ν-diisopropyl-ethylamine in 1 ml of I

In chloroform, 0.04 ml (0.35 mmol) of trichloroacetyl-I is added

In chloride at room temperature and the reaction mixture is stirred

For an hour. The reaction mixture is diluted with methylene I

In chloride, wash with sodium hydrogen carbonate solution, dry

In 10 res with magnesium sulfate and evaporate. The crude product chromato- I

graphene on silica gel (eluent: ethyl acetate), IR: I

In 1682 (strong). FAB-MS: 611. I

Example 26 I

In N- (3-Chlorobenzoyl) -staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

In 0.065 ml (0.38 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of I

In chloroform is added 0.038 ml (0.38 mmol) of 3-chlorobenzoyl-I

In chloride at room temperature and the reaction mixture is stirred

For an hour. The reaction mixture is diluted with chloroform, I

I 20 is washed with sodium hydrogen carbonate solution, 1 N hydrochloric acid I

I and saturated sodium chloride solution, and then dried with I

In magnesium sulfate and evaporated. The crude product is chromatographed

I on silica gel (eluent: methylene chloride-ethanol I

I 95: 5), m.p. 240 DEG C. (decomposition). IN

Example 25 I

In N- (2-Chlorobenzoyl) -staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

In 0.065 ml (0.38 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of I

In chloroform is added 0.038 ml (0.38 mmol) of 2-chlorobenzoyl-I

In chloride at room temperature, and the reaction mixture is stirred

46 DK 175507 B1 for 1 hour. The reaction mixture is diluted with chloroform, washed with sodium hydrogencarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5), m.p. 255 ° C (decomposition).

Example 28 N- (3-Nitrobenzoyl) -staurosporine 10 To a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform is added 55, 5 mg (0.30 mmol) of 3-nitrobenzoyl chloride at room temperature and the reaction mixture is stirred for 1 hour. The reaction mixture is diluted with chloroform, washed with sodium hydrogencarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5), m.p. 230 ° C.

Example 29 N- (4-Methoxybenzoyl) -staurosporine

To a solution of 116.5 mg (0.25 mmol) of staurosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform is added 0.083 ml (0.38 mmol) of a 58% solution. 4-methoxybenzoyl chloride solution in toluene at room temperature and the reaction mixture is stirred for 1 hour. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5), m.p. 220'C.

I DK 175507 B1 I

47 I

In Example 30 I

In N- (4-Fluorobenzoyl) -staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin and I

0.065 ml (0.38 mmol) of Ν, Ν-diisopropyl-ethylamine in 2 ml of I

In chloroform is added 0.036 ml (0.30 mmol) of 4-fluorobenzoyl-I

In chloride at room temperature, after which the reaction mixture I

You stir for 1 hour. The reaction mixture is diluted with 1

chloroform, washed with sodium bicarbonate solution, 1 L

In 10 N hydrochloric acid and saturated sodium chloride solution, on which I

Dry with magnesium sulfate and evaporate. The raw product I

Chromatograph on silica gel (eluent: I

In methylene chloride ethanol 95: 5), m.p. 225 ° C (dec.). IN

In Example 31 I

In N- (4-Chlorobenzoyl) -staurosporin I

To a solution of 233 mg (0.5 mmol) of staurosporin and 0.13 L

In ml (0.76 mmol) of Ν, Ν-diisopropylethylamine in 4 ml of chloroform I

Add 0.077 ml (0.6 mmol) of 4-chlorobenzoyl chloride to 1

At room temperature, and the reaction mixture is stirred for 1 hour. IN

The reaction mixture is diluted with chloroform, washed with I

In sodium bicarbonate solution, 1 N hydrochloric acid and saturated I

In sodium chloride solution and then dried with I

In magnesium sulfate and evaporated. The crude product is chromatographed

on silica gel (eluent: methylene chloride-ethanol I

I 95: 5), m.p. 220 ° C (dec.). IN

In Example 32 I

In N- (3-Fluorobenzoyl) -staurosporin I

To a solution of 233 mg (0.5 mmol) of staurosporin and 0.13 L

In ml (0.76 mmol) of Ν, Ν-diisopropylethylamine in 4 ml of chloroform I

To 0.072 ml (0.6 mmol) of 3-fluorobenzoyl chloride is added at room I

The reaction mixture is stirred for 1 hour. The reaction mixture is diluted with chloroform, liquid with sodium bicarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5),

Mp. 240 ° C (dec.).

Example 33 N- (4-Nitrobenzoyl) -staurosporine

To a solution of 233 mg (0.5 mmol) of staurosporine and 0.13 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform is added 0.11 ml (0.6 mmol) of 4-nitrobenzoyl chloride at room temperature, and the reaction mixture is stirred for 1 hour.

The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5), m.p. 255 ° C.

Example 34 N- (4-Methoxycarbonylbenzoyl) -staurosporine

To a solution of 466 mg (1 mmol) of staurosporine and 0.26 ml (1.52 mmol) of N, N-diisopropyl-ethylamine in 8 ml of chloroform is added 237 mg (1.2 mmol) of 4-methoxycarbonylbenzoyl chloride. at room temperature, and the reaction mixture is stirred for 1 hour at room temperature. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, dried with magnesium sulfate and evaporated. The crude product is chromatographed. on silica gel (eluent: methylene chloride-ethanol 95: 5), m.p. 240 ° C (dec.).

I DK 175507 B1 I

I 49 I

In Example 35 I

I N-Thiobenzoyl-staurosporin I

I A mixture of 180 mg (0.31 mmol) of N-benzoyl-staurosporin I

I (Example 18) and 132 mg (0.326 mmol) of Lawesson Reagent I

I (Fluka AG) 1 2 ml of toluene is stirred for 48 hours at room temperature

In perature. For reprocessing, dilute the mixture with I

In methylene chloride, wash with saturated sodium bicarbonate

In night solution and saturated sodium chloride solution, dry with I

In 10 magnesium sulfate and evaporate. The crude product is chromatographed

I on silica gel (eluent: ethyl acetate), FD-MS: 586, I

H-NMR (300 MHz in CDCl 3): 2.99 s (3H), 2.62 s (3H), 2.56 s I

I (3H). IN

In Example 36 I

In N-tert-Butoxycarbonyl-staurosporin I

To a solution of 116.5 mg (0.25 mmol) of staurosporin 12 I

In ml of tetrahydrofuran a solution is added at room temperature

Recovery of 65 mg (0.297 mmol) of di-tert-butyl dicarbonate in 1 ml of I

In tetrahydrofuran, the reaction mixture is stirred for 9 hours. IN

The reaction mixture is evaporated and chromatographed on silica

In gel (eluent: methylene chloride / ethanol 95: 5), m.p.

At ~ 160 ° C. IN

In Example 37 I

In N- (4-Carboxybenzoyl) -staurosporine sodium salt I

A mixture of 314 mg (0.5 mmol) of N- (4-methoxycarbonyl-I)

In benzoyl) -staurosporine (Example 34), 10 ml of methanol and 0.3 L

In ml of 2N sodium hydroxide solution is heated for 24 hours under H

reflux. After cooling, the mixture is filtered, I

then diluted with 10 ml of water and neutralized with I

30 ml of acetic acid. The desired compound precipitates as 50 DK 175507 B1 acid (snip. 275 ° C). To prepare the sodium salt, the acid is suspended in 10 ml of methanol and 1 equiv (5 ml) of 0.1 N sodium hydroxide solution is added. The resulting solution is evaporated and the residue is recrystallized from methanol / ether. FAB-MS: 637 (M + M) +, 659 (M + Na) +.

Example 38 N- (3,5-Dinitrobenzoyl) -staurosporine

To a solution of 233 mg (0.5 mmol) of staurosporin and 0.13 10 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform was added 138 mg (0.6 mmol) of 3,5-dinitrobenzoyl chloride. at room temperature and the reaction mixture is stirred for 1 hour. The reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution, 1N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent: methylene chloride-ethanol 95: 5),

Mp. ~ 250 ° C (dec.).

Example 39 N-f (tert-Butoxycarbonylamino) -acetyl 1-staurosporine

To 699 mg (1.5 mmol) of staurosporin in 40 ml of dry chloroform are added 264 mg (1.5 mmol) of BOC-glycine (Fluka AG) and 340 mg (1.65 mmol) of dicyclohexylcarbodiimide and the reaction is stirred for 1.5 hours. at room temperature. Then, the reaction mixture is diluted with chloroform, washed with sodium bicarbonate solution and saturated sodium chloride solution, then dried with magnesium sulfate and evaporated. The residue is slurried in a little methylene chloride and filtered (dicyclohexylurea removal).

The filtrate is evaporated and dried to give the product with m.p. 190eC.

In DK 175507 B1

51 I

In Example 40 I

In N- (2-Aminoacetyl) -staurosporine I

To a solution of 187 mg (0.3 mmol) of N- [(tert-butoxycar-I)

In 5 bonylamino) -acetyl] -staurosporin (Example 39) in 1 ml of I

In ethyl acetate, at room temperature, 1 ml of a saturated I is added

In solution of hydrochloric acid in ethyl acetate. Immediately an I is formed

precipitate. The suspension is stirred for a further 10 hours

The product is filtered off and washed with ethyl acetate. Mp. IN

At 10 280 ° C (dec.). IN

In Example 41 I

In N- (2-Hydroxy-propyl) -staurosporin I

I A mixture of 23.3 mg (50 μπιοί) of staurosporin in 1 ml of I

In dioxane, 0.5 ml (0.05 M) borate buffer (pH 10.0) and 100 μΐ I

In 15 (1.5 mmol) propylene oxide is stirred for 13 days. The mixture I

You are extracted twice with dichloromethane. The organic phase I

Dry with Na 2 SO 4 and remove the solvent in vacuo. IN

The reaction product is purified by semi-preparative HPLC I

I (Lichrosorb Si 60.5 / m, 8 x 250 mm) using I

In 20 dichloromethane / 2-propanol (98: 2, r / r) saturated with water at 1

At a flow rate of 5 ml / min. and a detector with 295 l

In nm. 20 injections are made. The retention time of the pro- I

The duration of the screen is 15.4 minutes. The structure is confirmed by means of I

1 of E1-MS and 1-H-NMR (360 Hz).

Example 25 I

In N-Phenyl-staurosporin I

I A solution of 2.4 mg (51 μΐηοΐ) of staurosporin in 0.5 ml I

In dioxane and 50 μΐ 1 N phenyldiazonium chloride solution I

I (Organikum, 13th ed. Deutscher Verlag der Wissenschaften, I

In Berlin, 1974, page 583) is stirred for 1 hour, after which it is set

B1 is added to a mixture of 1 ml of 1 N NaHCO 3, 50 ml of dichloromethane and 5 ml of methanol. The organic phase is dried over Na 2 SO 4, the solvent is removed and the product is purified by semi-preparative HPLC under the conditions of Example 41. The retention time of the product is 5.1 minutes and the structure is confirmed by E1-MS and 1 H-NMR (360 Hz).

Example 43 Analogous to the methods described in the above examples, the following compounds are prepared: N-alanyl-staurosporine, N-arginyl-staurosporine, N-phenylalanyl-staurosporine, N-histidyl-staurosporine, N-seryl-staurosporine.

Example 44

Tablets containing 20 mg of active substance, e.g. N-methoxy-carbonylmethyl-staurosporine is prepared in the usual manner with the composition set forth below:

composition

Active substance 20 mg

Wheat starch 60 mg Milk sugar 50 mg 25 Colloidal silicic acid 5 mg

Talc 9 mg

Magnesium stearate 1 mg 145 mg

I DK 175507 B1 I

I 53 I

In Preparation I

In the active substance, mix with part of the wheat starch, flour I

In cottage sugar and colloidal silicic acid, the mixture is screened

In 5 through a sieve. Another portion of wheat starch explains

You are stressed with the 5 times the amount of water in a water bath, and I

In the powder mixture, knead with this paste until you have

You formed a weak plastic mass. IN

I The plastic mass is pressed through a sieve with a mask

At a width of 3 mm, dried and the formed dry granulate I

Again in term. Then add the rest of the wheat starch, I

In talc and magnesium stearate, the mixture is compressed to 1

In slices with a split peel weighing 145 mg. IN

In Example 45 I

In 15 tablets containing 1 mg of active substance, e.g. N-methoxy-I

In carbonylmethyl-staurosporine, I is prepared in the usual manner

Having the following composition:

I S Employment I

I Active substance 1 mg I

I 20 Wheat starch 60 mg I

Milk Sugar 50 mg I

In Colloidal Silica 5 mg I

In talc 9 mg I

I Magnesium stearate 1 mg I

I 126 mg I

In Preparation I

In the active substance, mix with part of the wheat starch, flour- H

In cottage sugar and colloidal silicic acid, the mixture is screened H

You through a sieve. Another subset of the wheat starch for- H

In 30, paste with the 5-fold amount on a water bath, and pulse

DK 175507 B1 I

54 I

the verb mixture is kneaded with this paste until you are

formed a weak plastic mass. IN

The plastic mass is pressed through a sieve with a mask

5 mm wide, dried, and the resulting dry granulate I

sifted again. Then the remaining amount of I is mixed

wheat starch, talc and magnesium stearate, and the mixture I

is pressed into tablets with a split joint weighing 126 mg. IN

Example 46 I

10 Capsules containing 10 mg of active substance, e.g. N-methoxy-I

carbonylmethyl-staurosporine, is prepared in the usual manner I

as follows: I

Employment I

Active substance 2500 mg I

Talc 200 mg I

Colloidal silica 50 mg I

Preparation I

The active substance is thoroughly mixed with talc and colloid I

silicic acid, the mixture is sieved through a sieve with a mesh width of 0.5 mm, and the mixture is filled into 11 mg aliquots in appropriate sized hard gelatin capsules.

Example 47 In place of the compound described in Examples 44-46, pharmaceutical compositions may also be prepared containing as active ingredient another of the compounds described in Examples 1-43.

Claims (11)

Compound according to claim 1, characterized in that R ° means C (1-7) alkyl, hydroxy-C (2-18) alkyl, cyano-C (1-7) alkyl, carboxy-C (1-7) alkyl, C (1-7) alkoxy-carbonyl-C (1-35 7) alkyl, benzyloxycarbonyl-C (1-7) alkyl, C (3-7) alkenyl, phenyl, naphthyl, pyridyl, quinolyl, quinazolyl or phenyl- (DK-7175) B1 II 57 IIC (1-7) alkyl, wherein the aromatic groups concerned are optionally II substituted by C (1-7) alkyl, C (1-7) alkoxy, halogen, II nitro, trifluoromethyl, carboxy , C (1-4) alkoxy-carbonyl, methyl IIylenedioxy and / or cyano, or salts thereof. I I I A compound according to claim 1, characterized in that R ° is C (1-4) alkyl, hydroxy-C (2-14) alkyl, cyano-C (1-4) alkyl, carboxy-C (1- 4) alkyl, C (1-4) alkoxycarbonyl-C (1- II 4) alkyl, C (3-7) alkenyl or phenyl, or salts thereof. I I 10 I A compound according to claim 1, characterized in that R is acyl of the formula R R-CO- wherein R, is IIC (1-7) alkyl which is unsubstituted or optionally substituted by halogen, carboxy or C (1-4) alkoxycarbonyl, II or means phenyl which is unsubstituted or optionally II is substituted with C (1-4) alkyl, C (1-4) alkoxy, halogen, II nitro, trifluoromethyl, carboxy or C ( 1-4) alkoxycarbonyl, II or salts thereof. A compound according to claim 1, characterized in that R is an acyl group of the partial formula R ° -O-CO-, II wherein R ° is C (1-20) alkyl which is unsubstituted or even H substituted by a carboxyl group (also as salt, II cyano or C (1-4) alkyl ester), or an unbranched C (4-20) - II alkyl group wherein 1 to 6 C atoms from C-3 are replaced by II oxygen atoms separated from each other by at least two C-II atoms, or optionally with C (1-7) alkyl, C (1-7) alkoxy, II halogen, nitro, trifluoromethyl, carboxy, C (1- 4) -alkoxy-carbonyl, methylenedioxy and / or cyano-substituted phenyl, I or benzyl. H A compound according to claim 1, characterized in that R is an acyl group of the sub-formula R ° -O-CO-, II wherein R ° is C (1-7) alkyl, phenyl, pyridyl, furyl, thienyl, II imdiazolyl , quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, each of which is unsubstituted or substituted with C (1-4) alkyl, C (1-4) alkoxy, halogen, nitro, trifluoromethyl, carboxy, C (1-4) alkoxy-carbonyl, methylenedioxy and / or cyano, or salts thereof. A compound of formula I according to claim 1, characterized in that it is selected from N- (3-carboxypropionyl) -staurosporine, N-trifluoroacetyl-staurosporine, N-methylaminothiocarbonyl-staurosporine, and N-phenylcarbamoyl-staurosporine. . A compound of formula I according to claim 1, characterized in that it is selected from N- (3-nitrobenzoyl) staurosporin, N- (3-fluorobenzoyl) -staurosporine, N-tert-butoxycarbonyl-staurosporine, N- (4-carboxybenzoyl) -staurosporine sodium salt N- (3,5-dinitrobenzoyl) -staurosporine, N - [(tert-butoxycarbonylamino) acetyl] -staurosporine and N- (2-aminoacetyl) -staurosporine. A compound of formula I according to claim 1, characterized in that it is N-benzoyl staurosporin. 1 2 3 4 5 6 7 8 9 10 11 A process for preparing a compound 2 of formula I according to claim 1 or a salt thereof, characterized by reacting staurosporin of formula 4 with the formula [Stau] -NH-CH3 wherein tStau] has it in claim 5, or an acid addition salt thereof having either 6 a) a reagent of the formula RY (III) wherein R is as defined in claim 8 and Y means a reactive 9 activated hydroxyl group or a further single bond; the other end of which replaces a hydrogen atom in the group R, or 11 b) for the preparation of compounds of formula I wherein the group of the sub-formula HR ° - wherein R ° represents a II divalent, for the general structure of the aliphatic II group of the acyclic hydrocarbon group R ° defined in claim 1, having a carbonyl reagent of the formula R ° = 0 (IV), wherein II η 'I 5 R ° has the meaning given above and simultaneously or thereafter IIHI after translator m with a reducing agent and, if desired, converting a formed compound of formula I into another compound of formula I and / or converting a free compound II of formula I to a salt thereof and / or II 10, a compound of formula I to II formed as a salt converts the free form or to another salt. IN Pharmaceutical composition, characterized in that it contains as active substance at least one of the compounds listed in Claims 1-9 and one or more pharmaceutically acceptable excipients. IN Use of one defined in any one of claims 1-9 in connection with the preparation of pharmaceutical compositions I I 20 for therapeutic or prophylactic tumor inhibiting use. I 1