SI8811154A - Process for the preparation of staurosporine derivatives substituted on methylamine nitrogen - Google Patents

Abstract

We propose a procedure for the preparation of methylamine nitrogen-substituted derivatives, in particular N-substituted stavrosporine derivatives with general the formula (Stau) -N (CH3) -R (I) wherein (Stau) is a residue of is a partial formula (Stau) and R is hydrocarbyl R ° or acyl Ac containing preferably up to 30 carbon atoms as well as salts of the compounds of formula I with the solubility properties of which excel as selective inhibitors of protein kinase C, which is carried out in such a way that stavrosporine of formula (Stau) -NH-CH3 (II) where (Stau) has the above meaning, or its acid addition salt is reacted with the reagent of the formula R-Y (lil), wherein R has the above given meanings and Y means reactions capable an activated hydroxyl group or additional single bond, the other end of which replaces hydrogen in residue R, and optionally obtained compound of formula and converted into one another compound of formula I and / or free form the compound of formula I is converted into a salt thereof, and / or the compound of formula I obtained as a salt is converted to its free form or other salt.

Description

Process for the preparation of stavrosporine derivatives substituted with methylamine nitrogen

Technical field of the invention

MPK: CO 7D / A 61 K

The present invention relates to the field of organic chemical synthesis and pharmacy, specifically to a process for the preparation of novel stavrosporine derivatives substituted with methylamine nitrogen for use in medicine.

A technical problem

There was a need to find out a technologically advanced process for the preparation of new methyl starchy-substituted derivatives of stavrosporine, useful as selective therapeutic agents, with good yields and satisfactory purity. The state of the art

Stavrosporin 3 formula / Stau / -NH-CH2 (II) (meaning of the residue (Stau) see above), as the basis of the process of the invention, was isolated as early as 1977 from the cultures of Streptomyces staurosporeus AWAYA, TAKAHASHI and OMURA, sp. nov. AM 2282, cf.

Omura, S.; Iwai, Y.; Hirano, A.; Nakagava, A.; Awaya, J.; Tsuchiya, H.; Takahashi, Y. and Masuma, R.: J. Antibiot.

30, 275-281 (1977) and tested for antimicrobial efficacy. The compound was also found to be effective against yeast and fungal microorganisms (MICs of about 3 to 25 mcg / tnl), with LDL = 6.6 mg / kg (mouse, intraperitoneal) as the hydrochloride. Recently, extensive screening has shown a cf. Tamaoki, T.;

Nomoto, H.; Takahashi, I; Kato, Y; Morimoto, M. and Toraita,

F.: Biochem. and Biophys. Research Commun. 135 (No. 2), 397-402 (1986) that the compound has a potent inhibitory effect on protein kinase C (from rat brain).

Phospholipid- and calcium-dependent protein kinase occurs in the cell in several forms and is involved in its various basic pathways, such as signal transduction, proliferation and differentiation, as well as hormone and neurotransmitter delivery. Activation of these enzymes occurs, as is known, either by hydrolysis of receptor-mediated cell membrane phospholipids or by direct interaction with certain effective agents that promote tumors. The sensitivity of a cell to receptor-mediated signal transduction can also be affected by the conversion of protein kinase C activity (as a signal transducer). Compounds capable of selectively converting protein kinase C activity can be used as effective agents that inhibit tumors and inflammation, modulate immunization because they have antibacterial properties, and are also interesting as agents for atherosclerosis and diseases of the cardiovascular and central nervous systems.

Although Stavrosporin has a potent inhibitory effect on protein kinase C (see above), it also potently inhibits other protein kinases and therefore lacks the selectivity required for therapeutic use.

Stavrosporine derivatives substituted with methylamine nitrogen of formula (I), defined below, are novel, and therefore a process for their preparation has not yet been described.

- 3 Description of a solution to a technical problem with implementation examples

However, we have now established a process for the preparation of new stavrosporine derivatives substituted by methylamine nitrogen of the general formula / Stau / -N (CH ₃ ) -R (I) where / Stau / represents a residue of the partial formula% / \

N '\ /' / \ / \ / \ \ f \ / \ f

Y _A V \ / \ z • ·! · “

II '· \ / \' CH ₃ och ₃ tStau J and R represent hydrocarbyl R ° or aoyl Ac containing preferably up to 30 carbon atoms, as well as salts of compounds of formula I with soluble properties. Surprisingly, it has now been shown that the removal of hydrogen in the methylamine group of stavrosporine by substitution makes such N-substituted derivatives selectively retain the inhibitory activity of stavrosporin against protein kinase C, against other pro tein kinases P ^{a s0} significantly less effective. Due to this significantly increased selectivity, the compounds of the invention are thus also an important condition for therapeutic use in the aforementioned indicative domains, primarily for influencing cell proliferation.

To determine the inhibitory effect on protein kinase C, we first obtain protein kinase C from pigs' brains and purify them in the manner described in T. Uchida and C.R. Philburn in J. Biol. Chem. 259, 1231 1-4 (1984). To determine the inhibitory effect of compounds of formula I on protein kinase, we work based on the methodology of D. Fabro et al. Arch.

Biochem. Biophys. 239, 102-111 (1985). Significant inhibition of protein kinase C occurred above a concentration of about 0.01 / U / l.

Accordingly, compounds of formula I and their pharmaceutically useful salts can be used e.g. as medicines, in particular for the suppression of tumors and inflammations, modeling of immunization, against bacteria, further as agents for arteriosclerosis, diseases of the cardiovascular system and central nervous system.

The compounds of formula (I) are useful for the preparation of medicaments, e.g. for the above use, for therapeutic and prophylactic treatment of the human as well as the animal body.

The market formulation of active substances is also included.

Hydrocarbyl (hydrocarbon residue) R ° is an acyclic (aliphatic), carbocyclic or carbocyclic cyclic hydrocarbon residue having a total of preferably not more than 30, in particular not more than 18, carbon atoms and may be saturated or unsaturated, unsubstituted or substituted. It may also contain, instead of one, two or more carbon atoms, the same as different heteroatoms, such as in particular oxygen, sulfur and nitrogen, in the acyclic and / or cyclic moiety; in the latter case, it is referred to as a heterocyclic residue (heterocyclyl residue) or as a heterocycliccyclic residue.

Unsaturated residues are those containing one or more, in particular conjugated and / or isolated multiple bonds (double and / or triple bonds). The importance of cyclic residues also encompasses aromatic residues, e.g. such that at least one 6-membered carbocyclic or 5- to 8-membered heterocyclic ring contains the maximum number of non-cumulative double bonds. Carbocyclic residues where at least one ring acts as a 6-membered aromatic ring (i.e., a benzene ring) are designated as aryl residues.

Unless otherwise stated, in the present disclosure, organic residues designated by lower, maximum 7, preferably maximum 4 carbon atoms.

The acyclic, unsubstituted hydrocarbon radical is in particular a straight or branched lower alkyl, lower alkenyl lower alkadienyl or lower alkynyl radical.

Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further also n-pentyl, isopentyl, n-hexyl, isohexyl and n-heptyl; lower alkenyl is e.g. allyl, propenyl, isopropenyl, 2- or 3-raetallyl and 2- or 3-butenyl; lower alkadienyl is e.g.

1- penta-2,4-dienyl; lower alkynyl is e.g. propargyl or

2- butynyl. In the corresponding unsaturated residues, the double bond is localized, in particular, to a higher than the Jv -lega.

The carbocyclic hydrocarbon residue is in particular a mono-, bi- or polycyclic cycloalkyl, cycloalkenyl or cycloalkadienyl radical, or a corresponding aryl radical. Preference is given to residues of up to 14, in particular 12, ring carbon atoms and 3- to 8-, preferably 5- to 7-, especially 6-membered rings, but may carry one or more, e.g. two acyclic residues, e.g. the above and in particular lower alkyl radicals or further carbocyclic radicals. Carbocyclic-acyclic moieties are those wherein the acyclic moiety, in particular one with up to 7, preferably up to 4 carbon atoms, such as methyl, ethyl and vinyl, bears one or more carbocyclic, optionally aromatic moieties of the above definition. Mention should be made in particular of cycloalkyl-lower alkyl and aryl alkyl radicals, as well as their ring and / or chain unsaturated analogues, which carry the ring on the terminal C-atom of the chain.

Cycloalkyl preferably has from 3 to 10 C atoms inclusive and is e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl, as well as 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 residues, in particular methyl residues; cycloalkenyl is e.g. one of the monocyclic cycloalkyl residues already mentioned having a double bond in position 1, 2 or 3. Cycloalkyl-loweralkyl or-loweralkenyl is e.g. with one of the above cycloalkyl radicals substituted -methyl, -1- or -2-ethyl, -1- or -2-vinyl, -1-,

-2- or -3-propyl resp. -alyl, preferred are those substituted at the end of the linear chain.

The aryl residue is primarily phenyl, further naphthyl, such as 1- or 2-naphthyl, biphenyl, such as 4-biphenyl, in particular, anthryl, fluorenyl and azulenyl, as well as their aromatic analogs with one or more saturated rings. Preferred aryl-lower alkyl and lower alkenyl radicals are e.g. phenylalkyl or phenylalkylalkyl having a terminal phenyl radical, such as e.g. benzyl, phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, furthermore 1- or 2-naphthylmethyl. Under the aryl radicals bearing acyclic radicals as lower alkyl, we should mention in particular the β, m- and p-tolyl and xylyl radicals with differently substituted methyl radicals.

Heterocyclic residues, including heterocyclic acyclic residues, are in particular monocyclic, but also bi- 'or polycyclic, aza-, thia-, oxa-, thiaza-, oxase-, diaza-, triaza- or tetrazacyclic aromatic character residues, as well as corresponding partially or primarily fully saturated heterocyclic residues of this type, wherein such residues may optionally be e.g. as the above carbocyclic or aryl radicals, carry further acyclic, carbocyclic or heterocyclic radicals and / or may be mono-, di- or polysubstituted by functional groups. The acyclic moiety in heterocycliccyclic moieties has e.g. meaning given for the corresponding carbocyclic-acyclic residues. To the extent that heterocyclyl

- 8 found as a direct substituent of R ° on the methylamino group of stavrosporine, its free valence must originate from one of its C atoms. It is primarily unsubstituted or substituted monocyclic moieties with a nitrogen, oxygen or sulfur atom such as 2-aziridinyl, and in particular aromatic moieties of this type as pyryl, e.g. 2-pyryl or

3- pyryl, pyridyl, e.g. 2-, 3- or 4-pyridyl, further thienyl, e.g. 2- or 3-thienyl or furyl, e.g. 2-furyl; analogous bicyclic residues with a nitrogen, oxygen or sulfur atom are e.g. indolyl, such as 2- or 3-indolyl, quinolyl as

2- or 4-quinolyl, isoquinolyl as 3- or 5-isoquinolyl, benzofuranyl as 2-benzofuranyl, chromenyl as 3-chromenyl or benzothienyl as 2- or 3-benzothienyl; preferred monocyclic or bicyclic residues with multiple heteroatoms are e.g. imidazolyl as 2-imidazolyl, pyrimidinyl as 2- or

4- pyrimidinyl, oxazolyl as 2-oxazolyl, isoxazolyl as

3- isoxazolyl _; or thiazolyl as 2-thiazolyl, resp. benziraidazolyl as 2-benzimidazolyl, benzoxazolyl as 2-benzoxazolyl, or quinazolyl as 2-quinazolinyl < RTI ID = 0.0 >" suitable < / RTI > or partially saturated analogues, such as 2-tetrahydrofuryl, 2- or 3-pyrrolidyl,

2- or 3- or 4-piperidyl as well as 2- or 3-morpholinyl,

2- or 3-thiomorpholinyl, 2-piperazinyl and N, N'-bis-lower alkyl 2-piperazinyl residues. However, these residues may also carry one or more acyclic, carbocyclic or heterocyclic residues, in particular the above. Heterocyclic-acyclic residues are in particular derived from acyclic residues of not more than 7, preferably not more than 4, carbon atoms, e.g. of the above, and may carry one, two or more heterocyclic residues, e.g. above, wherein the ring may also be linked to the chain by one of its nitrogen atoms.

As mentioned earlier, hydrocarbyl (including heterocyclyl) may be substituted by one, two or more identical or different substituents (functional groups); in particular, the following substituents are preferred: free, ethereal and esterified hydroxyl groups; mercapto as well as lower alkylthio and optionally substituted phenylthio groups; halogen atoms such as chlorine and fluorine, as well as bromine and iodine; oxo groups, which are in the form of formyl (i.e., aldehyde) and keto groups, as well as the corresponding acetals or. ketals; azido and nitro groups; primary secondary and preferably tertiary amino groups, with conventional protecting groups protected primary or secondary amino groups, acylamino groups and diacylamino groups, as well as optionally functionally converted sulfo groups as sulfamoyl, or salt-forming sulfo groups. However, all these functional groups must not be located on the C-atom from which the free valence is derived, but preferably are separated from it by two or more carbon atoms. The hydrocarbyl moiety may also carry free and functionally converted carboxyl groups, such as salt-forming or esterified carboxyl groups, optionally carbamoyl, ureido or guanidine groups bearing, if appropriate, one or two carbon atoms, and cyano groups.

The ethereal hydroxyl group, which acts as a substituent on hydrocarbyl, is e.g. a lower alkoxy group such as methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert.butoxy group which may also be substituted. Thus, such a lower alkoxy group may be substituted by halogen atoms, e.g. once, twice or more, especially in position 2, such as e.g. in 2,2,2-trichloroethoxy, 2-chloroethoxy or 2-iodoethoxy radicals, or with hydroxy resp. lower alkoxy residues, preferably once, especially in position 2, as in the 2-methoxyethoxy residue. A particularly preferred form of the ethereal hydroxyl groups is in the oxaalkyl radicals, where in one, preferably linear, alkyl, one or more carbon atoms are replaced by oxygen atoms, which are preferably separated from each other by more (especially two) carbon atoms, to form a group - (-0. CH ₂ CH ₂ -) _n ~, where n is 1 to 14, with this group repeating itself several times in the given case. Further, such ethereal hydroxyl groups are also optionally substituted by phenoxy and phenylalkyloxy moieties, such as, in particular, benzyloxy, benzhydryloxy and triphenylmethoxy (trityloxy), as well as heterocyclyloxy moieties such as, in particular, 2-tetrahydropyranyloxy. As particular etherified hydroxyl group to mark the grouping methylenedioxy and ethylenedioxy, wherein the first bridge in general two ^- adjacent carbon atoms, in particular in aryl radicals, and the latter is bound to one and the same carbon atom, and it is considered as a protective group for oxo. Among the ethereal hydroxyl groups, silylated hydroxyl groups are also understood in this connection, such as e.g. in trinylalkylsilyloxy such as trimethylsilyloxy and dimethyl-tert.butylsilyloxy, or phenyldinylalkylsilyloxy or. lower alkyl-diphenylsilyloxy.

The esterified hydroxyl group, which acts as a substituent on the hydrocarbyl, bears the acyl residue Ac defined below, in particular one with a maximum of 12 carbon atoms, or is lactonized with a carboxyl group also present in the hydrocarbyl.

The esterified carboxyl group acting as a substituent on the hydrocarbyl is one in which the hydrogen atom is replaced by one of the hydrocarbon radicals defined above, preferably by a lower alkyl or phenyl lower alkyl radical; as an example of a esterified carboxyl group, e.g. lower alkoxycarbonyl or optionally substituted phenylbutyloxycarbonyl, in particular the methoxy, ethoxy, tert.butoxy and benzyloxy carbonyl group, as well as the lactonized carboxyl group.

The primary amino group -NH ₂ as the hydrocarbyl substituent may also be present in the protected form as the corresponding acylamino group of the formula -NH-Ac ° in which Ac ° has the meaning indicated hereinafter. The secondary amino group carries, instead of one of the two hydrogen atoms, a hydrocarbyl residue, preferably unsubstituted, as one of the foregoing, especially lower alkyl, but may also be present in a protected form, such as the acylamino group derived therefrom, referred to as the monovalent acyl residue Ac ° .

The acyl acyl residue used as the amino protecting group is preferably derived from a carbon dioxide derivative and is preferably optionally substituted by lower alkoxycarbonyl or aryl zyalkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, ethoxycarbonyl, or ethoxycarbonyl, in particular. .butoxycarbonyl,

2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, benzyloxycarbonyl, 2-phenyl-2-propoxycarbonyl, 2-p-tolyl-2-propoxycarbonyl, 2- (p-biphenyl) -2 ~ propoxycarbonyl or 9-fluorenylmethoxycarbonyl.

The tertiary amino group, which acts as a substituent on hydrocarbyl, bears two different or preferably identical hydrocarbyl residues (including heterocyclic residues) such as the unsubstituted hydrocarbyl residues indicated above, especially lower alkyl.

The preferred amino group is the one of formula 12 12

R-NR, where R and R are each independently hydrogen, unsubstituted acyclic C 1-6 hydrocarbyl (such as in particular C 1 -C 6 -alkyl or C 1-4 -alkenyl) or monocyclic, optionally with C 1-6 -alkyl, C 1-4 alkoxy, halogen and / or nitro, substituted aryl, aralkyl or aralkenyl with a maximum of 10 carbon atoms, the carbon-containing residues of which may be linked to a carbon-carbon bond or oxygen sulfur or optionally a hydrocarbyl substituted nitrogen atom. In this case, together with the nitrogen atom of the amino group, they form a heterocyclic ring containing nitrogen. As an example of particularly preferred free amino groups, the following are mentioned: dicycloalkylamino such as dimethylamino, diethylamino, pyrrolidino, piperidine, morpholino, thiomorpholine and piperazine or 4-methylpiperazine, optionally in the phenyl moiety, e.g. lower alkyl, lower alkoxy, halogen and / or nitro substituted diphenylamino and dibenzylamino; of the protected then especially lower alkoxycarbonylamino than tert-butoxycarbonylamino, phenylbenzoxycarbonylamino such as 4-methoxybenzyloxycarbonylamino as well as 9-fluorenylmethoxycarbonylamino.

Unless otherwise stated, the aromatic, carbocyclic and heterocyclic hydrocarbyl moieties above and below may be substituted once or more than twice or thrice, in particular by alkyl having 1 to 4 carbon atoms, alkoxyl having 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, further carboxyl, alkoxycarbonyl having 1 to 4 carbon atoms, methylenedioxyl and / or cyan. The aforementioned, reduced substituent information should be considered as a priority.

Preferred compounds of the invention are e.g. such that R represents hydrocarbyl R ° with the following preferred meanings of acyclic hydrocarbyl: C ₁ -C ₄ -alkyl, C ₂ -C ₂ Q-hydroxyalkyl, whose hydroxyl group is in any position other than position 1 and preferably in position 2 , cyano-C 1 -C ₂₀ -alkyl, the cyano group of which is preferably in the 1-position or, or carboxy- (C ₁ -C 2 _O ) alkyl, the carboxyl group of which is preferably in the 1-position or b /, and in where appropriate, also in the form of a salt or as a C1-C4-alkylester (CC4-alkoxycarbonyl) or benzyl ester (benzyloxycarbonyl), as well as C3-C2Q-alkenyl, the free valence of which is not located on the same carbon atom as the double bond, wherein all of the above residues, with the exception of those with a basic C 1 -C 4 -alkyl structure, have a linear (unbranched) alkyl chain; furthermore linear (mono-, di- to hexa) -oxaalkyl having 4 to 20 ring members, wherein one or more carbon atoms, counted from C-3, is linear C 1 -C 2 C-alkyl substituted by oxygen atoms which are separated from each other by at least two carbon atoms and preferably located in positions 3, 6, 9, 12, 15 and 18.

Preferred compounds of the invention are also those wherein R represents hydrocarbyl R ° with the following preferred meanings of carbocyclic or heterocyclic as well as carbocyclic-acyclic or. heterocyclic-acyclic hydrocarbyl: bicyclic or preferably monocyclic aryl, especially phenyl, further naphthyl, which may carry one or more of the following substituents: halogen atoms, in particular fluorine, chlorine and bromine, -C1-6alkyl radicals, in particular methyl, CC4- alkoxy groups, in particular methoxy, methylenedioxy, nitro groups and / or carboxylic groups, which may be free, in salt form or as C 1-6 alkyl esters, in particular methoxycarbonyl or ethoxycarbonyl. Preferably, the aryl residues do not carry more than two substituents, in particular of the same nature, or only one; above all, they are unsubstituted. As a preferred heterocyclic hydrocarbyl (heterocyclyl), e.g. one analogous to the aryl moieties mentioned above and containing, instead of one or two carbon atoms, one heteroatom each, in particular nitrogen, such as pyridyl or quinolyl, respectively. quinazolyl, wherein the free valence is localized to the carbon atom and may also be suitably substituted. Preferred carbocyclic-acyclic and heterocyclic-acyclic hydrocarbyl moieties are those having C 1 -C 4 -alkyl 2 or 3, and preferably only one of the above-defined cyclic moieties, preferably unsubstituted, all preferably located on one carbon atom, preferably at final; unsubstituted benzyl is most preferred.

Particularly preferred compounds of formula I are those wherein R is C ^ -C ^ alkyl, in particular C ^ alkyl, hydroxy-C2-C ₁ g alkyl, especially hydroxy-C, _{p-C 1} alkyl, cyano-C 1 -C 4 -alkyl, in particular cyano-C ₁ -C 4 -alkyl, carboxy-C ₁ -C 6 alkyl, in particular carboxy-C ₁ -C 4 -alkyl, -C 1 -alkoxy-carbonylC 1 -C 4 -alkyl, in particular C C 1 -C 4 -alkoxy-carbonyl-C 1 -C 4 -alkyl, benzyloxy-carbonyl-C 1 -C 4 -alkyl, in particular benzyloxy-carbonylC 1 -C 4 -alkyl, C 1 -C 4 -alkenyl, phenyl, naphthyl, pyridyl, quinolyl, resp. quinazolyl, or phenyl-C 1 -C 6 -alkyl, in particular phenyl-C 1 -C 4 -alkyl, wherein the aromatic moieties in question may further be substituted by alkyl of 1 to 7 carbon atoms, in particular alkyl of 1 to 4 carbon atoms , alkoxyl of 1 to 7 carbon atoms, and in particular 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, further carboxyl, C 1 -C 4 -alkoxycarbonyl, methylenedioxyl and / or cyano, the hydroxyl group being positioned in a suitably substituted alkyl residue, in particular in position 2, cyano-, carboxy-, alkoxy-carbonyl, benzyloxy-carbo

nil or . the phenyl group, however v accordingly substituted alkyl the remainder especially in position 1 or o '. Particularly preferred compounds with formula I are such where is C 1 -C 4 -alkyl, as methyl or ethyl, hydroxy-

C1-C4-alkyl, such as 2-hydroxy-propyl, -hexyl, -deyl or -tetradecyl cyano-C1-C4-alkyl, such as 2-cyano-ethyl, carboxy C1-C4-alkyl, such as carboxymethyl , C 1 -C 4 -alkoxycarbonyl-C 1 -C alkyl, such as methoxycarbonyl-methyl or -ethyl, C 1 -C 4 -alkenyl, such as allyl or phenyl, wherein the hydroxyl group is in a suitably substituted alkyl, preferably in position 2 and cyano-, carboxy- or. an alkoxycarbonyl group especially in position 1 or W.

The acyl residue Ac is derived from a functionally converted carboxylic acid, an organic sulfonic acid, or optionally esterified phosphoric acid as pyro or orthophosphoric acid, optionally having a maximum of 30 carbon atoms.

Acyl derived from the functionally converted carboxylic acid, hereinafter referred to as

Ac1 is particularly one of the partial formula Z-C (= W) -, wherein W may represent oxygen, sulfur or imino, and Z is hydrogen, hydrocarbyl R °, hydrocarbioxy R ° 0, an amino group, especially with

1 * 2 v (formula R -NR, or when W stands for oxygen or sulfur, also chlorine. The meanings for R °, R ^ and R ^ correspond to the above, the general and the foregoing, the latter being the generally preferred choice here .

The acyl derived from organic sulfonic acid, denoted by Ac ^ is particularly one of the partial formula R ° -SO ₂ -, where R ° is hydrocarbyl having the above mentioned general meanings, the latter being generally preferred here.

The acyl derived from the esterated phosphoric acid, which is referred to as Ac, is, in particular, the partial formula

R ^r 0

7 (= 0) R ^z 0 ^Z

2 where R and R are each independently of the above, generally m

2 stressed meanings. Preferably, R and R have the same meaning.

Preferred acyl residues Ac ¹ are acyl residues of carboxylic acid, designated by the partial formula R ° -CO-, where R 4 stands either for hydrogen (and thus forms a formyl residue), or has one of the above general and preferred meanings for the hydrocarbyl radical R <0>, and are thereby optionally substituted

- 18 acyclic, carbocyclic, carbocyclic-acyclic, heterocyclic or heterocyclic-acyclic monocarboxylic acids. Preferred hydrocarbyl in such acyl is e.g.

-C1-g-alkyl, especially C 1 -C 6 - or C 1 -C 6 -alkyl, in particular having a linear chain at more than 5 carbon atoms, p

and which may also carry the following substituents: a carboxyl group which may optionally also be present in the form of a salt or as a cyano group or as a C 1-6 -alkyl ester (a C 1 -C 6 -alkoxycarbonyl group) and which is preferably in the eq position) , an amino group of the above-defined 1-12 formula R -NR, preferably in which R and R are each hydrogen and are then preferably in position 1, or one or more halogen atoms, in particular fluorine or chlorine, preferably located in the carbonyl group neighborhood. ;

A further preferred acyl is bicyclic or especially monocyclic aroyl, especially benzoyl, which may also carry one or more of the following substituents; halogen atoms, in particular chlorine or fluorine, nitro groups, -C1-6alkyl radicals, in particular methyl, hydroxyl groups and tetrahydroxyl groups, in particular -C1-6alkoxy as methoxy, phenoxy or methylenedioxy, as well as carboxyl groups which may also occur in the form of a salt or as a cyano group or -C 1 -alkyl ester (-C 1 -alkoxycarbonyl). Preferably, the aroyl moieties carry a maximum of 2, and in particular only one such substituent. Analogous heteroaryl residues are also preferred, especially those derived from pyridine, furan, thiophene and imidazole and their analogs with a fused benzene ring (such as quinoline, isoquinoline, benzofuran and benzimidazole) and optionally substituted as indicated above . Preferred acyl residues of this type are also derived from monocyclic aryl-alkenyl, e.g. of the corresponding aryl-C 1 -C 4 alkenyl as benzyl and styryl (i.e. phenacetyl and cinamoyl), but may also be substituted as indicated above. Such acyl residues form corresponding acylamides with the basic structure of stavrosporine, with those with the above meanings of Ac ¹ being particularly preferred. So e.g. the Stavrosporine amides derived from the following carboxylic acids should be mentioned: aliphatic monocarboxylic acids with a maximum of 20 carbon atoms as lower alkanecarboxylic acids, e.g. propionic, butyric, isobutyric, valeric, isovaleric, capric, trimethylacetic, enanth and diethylacetic acids, in particular acetic as well as lauric, myristic, palmitic and stearic acids, as well as olive, elaidic, linoleic and linolenic acids, as well as lower alkaline acids, but also acids such as chloroacetic, trifluoro- or trichloroacetic, bromoacetic or N, N-bromoisovaleric acid, carbocyclic or carbocyclic-acyclic monocarboxylic acids, e.g. cyclopropanoic, cyclopentanoic and cyclohexane-carboxylic acids, resp. cyclopentane- or cyclohexane-acetic or -propionic acid; aromatic carbocyclic carboxylic acids, e.g. benzoic acid, which may be substituted one or more times as indicated above; aryl or aryloxy-lower alkanecarboxylic acids and their, in the unsaturated chain, analogs, e.g. optionally, as indicated above for benzoic acid, substituted phenylacetic or phenoxyacetic acids, phenylpropionic acids and cinnamic acids; further heterocyclic acids, e.g. furan-2-carboxylic, 5-tert-butyl-furan-2carboxylic, thiophene-2-carboxylic, nicotinic or isonicotinic acid, 4-pyridinpropionic acid and optionally lower alkyl residues of substituted pyrrole 2- or -3-carboxylic acids; furthermore, the associated cC-amino acids, especially the naturally occurring L-type c2-amino acids, e.g. glycine, phenylglycine, alanine, phenylalanine, proline, leucine, serine, valine, tyrosine, arginine, histidine and asparagine, preferably in the N-protected form, that is, in which the amino group is substituted by a conventional, e.g. one of the foregoing amino protecting groups; furthermore dicarboxylic acids such as oxalic, malonic, mono- or di-lower alkylmalonic acids, succinic, glutaric, adipic, erucic acid, maleic acid, with halogen as fluorine, chlorine or bromine and / or lower alkyl, hydroxyl, lower alkoxyl and nitro optionally substituted t-isoquinoline or phenylsulphuric acid, as well as glutamic and aspartic acids, with both of the latter acids being preferably represented by protected amino groups. As mentioned, the second carboxyl group may be present not only in free form but also functionally converted, e.g.

as a C 1 -C 4 -alkyl ester or as a salt, preferably as a physiologically acceptable salt, with a soluble, basic component. Thus, metal or ammonium salts are preferably used as alkali and alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts,

oz. ammonium salts with ammonia or appropriate organic amines. Further preferred acyl Ac ^ se implemented from

carbon monoester and is denoted by the partial formula R ° -O-CO-. With the basic structure of stavrosporine, this acyl then forms the corresponding N-disubstituted urethanes. Among the particularly preferred hydrocarbyl residues R <0> in these derivatives, e.g. the following: acyclic hydrocarbyl, in particular -C 1-6 alkyl, preferably linear, which may be substituted by a carboxyl group, preferably in a functionally converted form, such as a salt, cyano or -C 1-6 alkyl ester, preferably in position (X >, or a linear (mono- to hexa-) - oxaalkyl analogue having 4 to 20 linkages in the chain, especially those designated above as being particularly preferred, with phenyl and benzyl radicals being optionally substituted for the meaning of R °, e.g., the ones mentioned above as preferred.

Still further, the preferred acyl Ac ^ is derived from amides of carbonic acid (or also thiocarbonic acid) and is designated by the formula

Rl \ -C (= W) R ^{z /}

2 where R and R have the meanings given above and W stands for sulfur and especially oxygen. With the basic structure of stavrosporine, this acyl residue then forms the corresponding urea, respectively. thioureas.

Under the preferred compounds of formula I bearing this acyl, in particular those where W is 1 2 for oxygen, one of R and R is hydrogen and the other is C 1 -C ₇ -alkyl which may be substituted by hydroxyl , mercapto, methylthio, phenyl, p-hydroxyphenyl, p-methoxyphenyl, 2-indolyl, 2-imidazolyl and, in particular, carboxyl (in free or functionally converted form as C 1 -C 4 alkoxycarbonyl, carbamoyl or amidino), wherein one of which is preferably in position 1, and preferably corresponds to the radical whose free valence stands in place of the amino group in the usual amino acid such as (D -alanine, t-amino-butyric acid or norvaline, and in particular one ·

J is a naturally occurring L-type amino acid component of the peptide or its antipode. We should also emphasize compounds with acyl of the last listed species, where W 1 2 stands for sulfur, one of the residues R and R being hydrogen and the other C 1 -C 6 -alkyl, or in particular CC ₇ ~ alkenyl, where the free valence is derived from another atom carbon as a double bond, like allyl.

Also highlighted are the compounds (I) of the invention wherein R stands for chloroformyl or thiochloroformyl, which are particularly distinguished as suitable intermediates for the preparation of modified carbonic acid acyl esters.

The acyl residue Ac is derived from acyclic, carbocyclic or heterocyclic, further carbocyclic · acyclic or heterocyclic-acyclic sulfonic acid, and corresponds to the above-mentioned partial formula R ° -SO ₂ -, where R ° stands for hydrocarbyl with the above mentioned general and especially preferred meanings. Of the compounds of the invention bearing the Ac ² residue, in particular those where R ° is (C 1 -C 6 -alkyl, in particular linear, bicyclic or in particular monocyclic aryl such as phenyl, which may be analogously substituted as above Analogously constructed, bicyclic and monocyclic, aroraatic heterocyclyl residues, wherein one or two of the carbon atoms is replaced by hetero atoms such as pyrimidyl, eg 2- or 4-pyrimidyl, quinolyl or isoquinolyl, are also mentioned. may carry substituents, especially those emphasized for aroyl (wherein, for example, a hydroxyl derivative with a tautomeric double bond displacement is equal to a dihydro-oxo derivative).

The acyl residue Ac derived from phosphoric acid is e.g. derived from pyrophosphoric acid, in particular orthophosphoric acid, which may also occur in a functionally converted form, e.g. as salt. hydrocarbylester or amide. Among the compounds (I) obtained according to the invention, wherein R

3 stands for Ac, in particular those whose Ac corresponds to the partial formula leo / (= 0) R ² 0 ^Z

2 wherein R and R have the above meanings and especially the meanings, and preferably both are identical and represent hydrogen or unsubstituted alkyl of 1 to 7 carbon atoms, in particular linear alkyl, in particular methyl or ethyl, or optionally, in particular alkyl with 1 to 4 carbon atoms, alkoxyl with 1 to 4 carbon atoms, halogens and / or nitro, substituted phenyl.

Particularly preferred are those compounds of formula I wherein R is acyl of the partial formula ZC (= W) -, where W is oxygen, further sulfur, and Z alkyl of 1 to 7 carbon atoms which may be substituted by halogen, carboxy or C 1 -C 4 alkoxy-carbonyl.

Particularly preferred are those compounds of formula I, wherein R is acyl of the partial formula ZC (= W) -, where W is oxygen, further sulfur, and Z is phenyl, further pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl, or benzimidazolyl, which is in each case unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxyl of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, carboxyl, C 1-4 alkoxycarbonyl, methylenedioxyl and / or cyan.

Particularly preferred are those compounds of formula I wherein R is acyl of the partial formula R ° -CO-, wherein R 1 is alkyl of 1 to 7 carbon atoms, in particular alkyl of 1 to 4 carbon atoms such as methyl or tert-butyl, which may also be substituted by halogen such as fluorine or chlorine, carboxy or

-C 1 -alkoxycarbonyl such as methoxycarbonyl such as CF 3 or C 1-3 -methyl, 2-carboxy- or 2-methoxycarbonyl-ethyl.

Particularly preferred are such compounds of formula o o

I, wherein R is acyl of the partial formula R _b -CO-, wherein R 1 is phenyl, which may be unsubstituted or further substituted by alkyl of 1 to 4 carbon atoms, alkoxyl of 1 to 4 carbon atoms, halogen as fluorine or chlorine, nitro, trifluoromethyl, carboxyl or C1-C4-alkoxy-carbonyl.

Particularly preferred are those compounds of formula I, wherein R is acyl of the partial formula R ° -SO 2 -, wherein R ° is alkyl of 1 to 7 carbon atoms, in particular alkyl of 1 to 4 carbon atoms,

Particularly preferred are those compounds of formula I wherein R is acyl of the partial formula Ηθ-δΟ ^ -, wherein R ° is phenyl, further pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, which is in each case unsubstituted or substituted with Cl-Cjj alkyl, --C -alkoksilom, halogen, nitro, trifluoromethyl, carboxyl, C ₁ -Cjj-alkoxy-carbonyl, metilendioksilom and / or cyano.

Particularly preferred are those compounds of formula I, wherein R is acyl of the partial formula R 1 -C 5 - -, wherein R ° is phenyl or alkyl having 1 to 4 carbon atoms or halogen substituted phenyl or isoquinolyl as 5-isoquinolyl.

Particularly preferred are those compounds of formula I, wherein Racyl is of the partial formula R ° -O-C0-, wherein R ° is alkyl of 1 to 7 carbon atoms, especially alkyl of 1 to 4 carbon atoms.

Particularly preferred are those compounds of formula I 'wherein R is acyl of the partial formula R ° -O-CO-, where R ° is phenyl, further pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofurani or benzimidazolyl, which is each unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxyl of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, carboxyl, C ₁ -C 4 -alkoxycarbonyl, methylenedioxyl and / or cyano.

Particularly preferred is a compound of formula I, wherein R is acyl of the partial formula R ° -O-CO-, where R ° is unsubstituted phenyl.

Particularly preferred are those compounds of formula I, wherein R is acyl of the partial formula ^R 1 -C (= W) - wherein W stands for sulfur or in particular oxygen,

R ^z

R 1 is hydrogen and R ₂ is C 1 -C 4 -alkyl, in particular -C 1 -alkyl, C 1 -C 4 -alkenyl or phenyl, further pyridyl, furyl, thienyl, imidazolyl, quinolyl, isoquinolyl, benzofuranyl or benzimidazolyl, which is may in each case be unsubstituted or substituted by alkyl of 1 to 4 carbon atoms, alkoxyl of 1 to 4 carbon atoms, halogen, nitro, trifluoromethyl, carboxyl,

-C 1 -alkoxy-carbonyl, methylenedioxyl and / or cyano.

Particularly preferred are such compounds of formula I, wherein R is derived from the <RTI ID = 0.0> A-amino </RTI> amino acid, especially the naturally occurring <A-amino acid L-species.

Particularly preferred are those compounds of formula I wherein R is derived from a cC-amino acid selected from glycine, phenylglycine, alanine, phenylalanine, proline, leucine, serine, valine, tyrosine, arginine, histidine and asparagine. ------------------ Particularly preferred are those compounds of formula I, wherein R is derived from the N-amino acid selected from glycine, alanine, phenylalanine, serine, arginine and of histidine.

Depending on their nature, compounds of formula (I) may occur, to the extent that they contain solvate groups, including in the form of salts, in particular pharmaceutically useful, i.e. of physiologically tolerated salts. Pharmaceutically acceptable salts may also be used for isolation or purification. For therapeutic use, however, only pharmaceutically useful salts are preferred.

So e.g. there are compounds with free acidic moieties such as e.g. a free sulfo, phosphoryl or carboxyl group, in particular in the acyl residue Ac, in the form of a salt, preferably as a physiologically acceptable salt, with a soluble basic component. Preferably metal or ammonium salts are preferred as alkali and alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, respectively. ammonium salts with ammonia or suitable organic amines, in particular tertiary monoamines and heterocyclic bases, e.g. triethylamine, tri- (2-hydroxyethyl) -amine, N-ethylpiperidine or N, N'-dimethylpiperazine. When such an acid group is present in the hydrocarbyl moiety R °, it may also form, with the amine nitrogen of the basic structure of stavrosporine, or with another, optionally present amino group, an internal salt.

Compounds of formula (I) with a basic character may also act as addition salts, in particular as acid addition salts with inorganic or organic acids, as well as quaternary salts. Thus, e.g. Compounds of formula I which, in the residue Ac, have a basic group as an amino group, as a substituent, form acid addition salts with conventional acids. Particular emphasis should be given to the addition salts of the formula

(IA) where (Stau) and R ° have the meanings given above, represents hydrogen or unsubstituted, preferably linear, C 1 -C 4 -alkyl, in particular ethyl or, in particular, methyl, or benzyl, and is the X 'anion of inorganic or organic acid, or a carboxyl occurring in the R <0> moiety, with physiologically acceptable salts being preferred. Under quaternary salts of formula IA, those in hydrocarb are preferred

R 0 represents the first carbon atom as methylene.

For anion formation

X are suitable e.g. inter alia, the following common acids: hydrohalic acids, e.g. hydrochloric and hydrobromic acid, sulfuric, phosphoric, hydrochloric or perchloric acid, respectively. aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyrogrotic, benzoic, benzoic, acetic anthranilic, p-hydroxybenzoic, salicylic, p-aminosalicylic, embonic, methanesulfonic, ethansulfonic, hydroxyethanesulfonic, ethylene-disulfonic, halogenbenzenesulfonic, toluenesulfonic and naphthalenesulfonic acid, or sulfonyl acid, further methionine, arginine, or ascorbic acid In quaternary salts, the anions of strong inorganic acids, such as hydrohalic acids, especially bromides and iodides, or organic sulfonic acids, such as methanesulfonates (mesylates), p-toluenesulfonates (tosylates), p-bromobenzenesulfonates (brosylates) and p-nitrobenzols, are preferred as X.

Particularly preferred compounds of formula I or IAs are described in the examples.

The compounds of formula I and their salts are prepared according to the invention by treating stavrosporine of formula (Stau (II), wherein (Stau) has the above meaning _; or its acid addition salt is reacted with a reagent of formula

R-Y (III) wherein R has the above meanings and Y represents a reaction-capable activated hydroxyl group or an additional single bond, the other end of which replaces hydrogen in the residue

R, and optionally the resulting compound of formula I is converted into another compound of formula I and / or in free form the resulting compound of formula I is converted into a salt thereof, and / or a compound of formula I obtained as a salt is converted into its free form or some other salt.

The metabolism of stavrosporine according to the invention with the type III reagent defined by Formula III is carried out under the conditions of methods generally customary in organic chemistry for the substitution of amines, usually at temperatures between freezing and boiling of the reaction mixture, such as in the temperature range of about -10 to about + 100 ° C, in particular about +20 to about + 50 ° C, at atmospheric or elevated pressure, in a heterogeneous phase (as a suspension) with stirring or shaking, or in particular in a homogeneous liquid phase, such as in excess liquid reagent, or in particular in the presence of solvents, in particular organic solvents, and optionally in the presence of inorganic or organic acid binding agents. Suitable solvents are e.g. low polarity aprotic organic solvents such as aliphatic and aromatic hydrocarbons such as pentane, hexane, heptane and cyclohexane, respectively. benzoics, toluene and xylenes as well as halogenated, chlorinated, aliphatic hydrocarbons such as chloroform and dichloromethane, and in particular polar aprotic solvents such as aliphatic and cyclic ethers, e.g. diethyl ether, 1,2-dimethoxyethane and diisopropylether, resp. dioxane and tetrahydrofuran, lower aliphatic esters and amides, such as ethyl acetate or. formamide, acetamide, Ν, Ν-dimethylacetamide and dimethylformamide, as well as acetonitrile, dimethylsulfoxy-d and hexamethylphosphorriamide; under certain conditions, water is also useful as the solvent, e.g., me is tanol, ethanol, an organic solvent such as lower alkanol, e.g. ethanol, isopropyl alcohol and tert-butyl alcohol, as well as glycols diglycolmonoether, e.g. 2-methoxyethanol. In this case, it is often convenient to accelerate the reaction rate with elevated pressure, i.e. by working in closed containers to raise the boiling point and the reaction temperature. The solvents can also be used in suitable combinations, e.g. to increase the solubility of the components.

In principle, any basic compounds can be used as an acid-binding agent, such as an organic nitrogen-containing base, e.g. tertiary amines such as triethylamine, ethyldiisopropylamine, N, N-dimethylaniline, N-ethylpiperidine or N, N'-dimethylpiperazine, or aromatic heterocyclic bases such as pyridine, collidine, quinoline or 4-dimethylaminopyridine, and, in turn, inorganic compounds and also inorganic compounds , in particular alkali metal hydroxides, carbonates and hydrogen carbonates, as well as carboxylic acid salts such as sodium or potassium acetate.

Finally, N-containing neutral compounds may also take on this role, often also simultaneously being suitable solvents, e.g. carboxylic acid amides, in particular lower aliphatic carboxylic acid amides, such as

- 32 above, and cyclic amides such as N-methylpyrrolidone, as well as carbonic acid amide derivatives such as urethanes and urea.

Although the exchange reaction is always based on the same principle i, n is carried out according to a single basic scheme, for the optimum result it is necessary to take into account the properties of the reaction components, in the first instance, of the reaction agent of formula III in the practical embodiment.

For the purposes of the above definition, the residue R may be hydrocarbyl R with the meanings given above, general and emphasized. In this case, Y is primarily a reaction capable, esterified hydroxyl group (as a particular form of the above reaction of a capable activated hydroxyl group), i.e. those which are esterified with a strong inorganic acid such as hydrochloric acid (eg hydrochloric, hydrobromic, and hydrofluoric acid), an oxygen-containing mineral acid such as phosphoric and in particular sulfuric acid, or strong organic as aliphatic or aromatic sulfonic acid (eg. and ethane- or benzene-, ρ-toluene-, p-nitrobenzene- and p-chlorobenzenesulfonic acid). If R ° is an aliphatic character, i.e. if its free valence arises from a carbon atom bound only by the adjacent C atom or by a single bond. H, ga. can be freely selected from the ester hydroxyl groups mentioned above as an example; however, if R ° has an aromatic character, i.e. if its free valence is derived from a carbon atom that is an integral part of an aromatic carbocyclic or heterocyclic ring, halogenated esters of hydrochloric acids, in particular bromides and iodides, are preferred.

A reagent of formula III, wherein Y represents an additional single bond to the hydrocarbyl radical R ° (when one of its hydrogen is replaced) is e.g. an alkene, especially one whose double bond is additionally activated by a structural specificity, such as in 2-methylpropene, or a substitution, such as in acrylonitrile in particular. The definition of Y also includes a single bond, the other end of which is not directly bonded to the carbon atom of the hydrocarbyl radical R ° but to the heteroatom acting as a substituent, such as oxygen (i.e. oxygen of the hydroxyl group) or nitrogen (amino group) (replacing it) hydrogen of this group); Particularly preferred are reagents of the formula R ° Y containing the group c / · '-epoxide (oxiran) or -imine (aziridine) and used as a convenient source of R 2 residues with 2-hydroxy- or. 2-aminoalkyl group. The digestion of these reagents is preferably carried out in the presence of lower alkanols at elevated temperature, e.g. at about +100 to about 150 ° C and optionally (to raise the boiling point of the reaction mixture) at elevated pressure, or in a basic medium, and in particular with excess reagent.

For the purposes of the above definition, the residue R may be acyl Ac and thus form the basis of an acylating agent of the formula AcY, in which both Ac and Y have the same general and emphasized meanings as 1 2 3 given for Ac, Ac and Ac. Preferably, Y is halogen, in particular chlorine, bromine and iodine.

- 34 In acylating agents derived from the acyl carboxylic acid acyl residue defined above, Y may be e.g. for the reaction-capable activated hydroxyl group. Such a reaction is already present in the free carboxylic carboxylic acid group of the formula R ° -COOH if, due to the peculiarities of the structure, such as trifluoroacetic acid and especially formic acid, it has sufficient reactivity, especially if it is pre-activated by the action of activating reagents, e.g. carbodiimides, such as in particular dicyclohexylcarbodiimide or di- (2-imidazolyl) -carbodiimide and other analogous compounds, and optionally in the presence of excipients which form active esters such as substituted phenols, and in particular N-hydroxyamine compounds of type 1-hydroxy-benzotriazole, N-hydroxyphthalimide and N-hydroxymaleinimide or -succinimide.

An activated hydroxyl group suitable for 1 2 3 acyl residues of all kinds, e.g. for Ac, Ac and Ac, the reaction is a hydroxyl group, esterified with strong acids, as defined above with respect to the hydrocarbyl R ° defined to form an acidic anhydride with an acyl residue.

Of these, particular emphasis should be placed on mixed hydrochloric acid anhydrides, in particular with hydrochloric acid and especially hydrochloric acid, i.e. acid bromides or. acid chlorides, e.g. those with formulas

R ^l 0; P (= O) -Hal,

R ^Z O

ZC (= W) -Hal, R ° -SO ₂ -Hal and where Hal represents bromine and preferably chlorine and have Z, W,

R °, R ¹ and R ^{2 are} as defined above; with particular reference to phosgene and thiophosgene.

'For acyl residues of Ac carboxylic acids (including acyl residues of functionally converted carbonic acid), the reaction is capable, the esterified hydroxyl group may also be esterified, either by the residue of another carboxylic acid, in particular more powerful carboxylic acid than formic, chloroacetic or in particular trifluoroacetic acid, for the mixed anhydride, or may be esterified with the same acyl residue to form a symmetric 1,1 L carboxylic acid anhydride of the formula Ac -O-Ac, in particular one of the formulas R ° -CO-O-CO-R ° or R ° -O- CO-O-CO-OR ° (or its sulfur analogue).

For acylations with the acylation ones mentioned above. the agents are preferably used in the presence of an acid-binding agent such as the above, which is used primarily in an equivalent amount or a small excess (not normally exceeding two equivalents).

The acylating agents of the formula AcY, wherein Y represents an additional bond to the Ac residue, are derived, in particular, from acyl residues of Ac carboxylic acids, especially those bearing on the adjacent atom a carbonyl group, i.e. on the adjacent carbon or nitrogen atom), hydrogen; belong to the category of ketenes or. isocyanates and corresponding

R ° = 0z0 oz '. R ¹ -N = C = O, a 'f ormulam where R ° has the meaning of a divalent hydrocarbide of aliphatic character corresponding to the residue R ° (ie one in which a functionalized single-bonded carbon atom is bonded to adjacent carbon atoms and / or hydrogen) and R has the above meanings and meanings, with the exception of hydrogen. Mention should also be made of an analogous, sulfur-containing acylating agent, an isocyanate of the formula R-N = C = S, wherein R has the above-mentioned general and emphasized meanings, except for hydrogen. Depending on their nature, acylation with this type of agent can be carried out, even without acid binding agents, with the exclusion of moisture and / or protic solvents, which is advisable.

According to the invention, the resulting compound of formula I can be optionally converted to another compound of formula I; in particular, the functional group in the residue R is transformed into another, e.g. the functionally converted, especially protected, hydroxyl, carboxyl or amino group is converted into their free forms, or the reaction-capable chlorine atom, such as that in the chloroformyl residue, is replaced by a residue R0-O- or R4-N (-R4) - . The release of a functionally converted group is, for example, the conversion of a esterified carboxyl group into a free carboxyl group which can be surface-washed by conventional hydrolysis, in particular by the action of bases (in particular alkali metal hydroxides, carbonates or hydrogen carbonates), or also in suitable esters such as esters tertiary alcohols (e.g. tert.butyl alcohol), by acidolysis, e.g. using hydrofluoric or trifluoroacetic acid. Esters of benzyl alcohol can also be cleaved by conventional hydrogenolysis. Considering esterification is one of the most common methods for protecting carboxyl groups, the above conversion is at the same time an effective method for removing carboxyl protecting groups.

The groups and cleavage methods used for the transient protection of hydroxyl groups are also generally known, e.g. from peptide synthesis. In particular, hydroxyl groups are protected in the form of esters with carboxylic acids, such as lower alkanoic acids or carboxylic acid monoesters (eg formates or acetates on the one hand, or tert-butoxy or benzyloxy carbonates on the other), or in the form of ethers, in particular such with tertiary alcohols (eg tert-butyl alcohols), or also in the form of acetals (eg, in particular as 2-tetrahydropyranylether). The first protecting groups are typically cleaved by analogy as the esterified carbonyl groups; both of which are eliminated mainly by acidolysis.

The protecting groups useful for the transient protection of the primary and secondary amino groups correspond to those which have been extensively investigated in peptide synthesis and are most widely used; preferably, the aforementioned amino protecting groups are used - their cleavage, which generally follows their specific nature, takes place under commonly known hydrolysis conditions (especially basic hydrolysis), acidolysis or. hydrogenolysis ..

In particular, we select the general conditions for the normal cleavage of functionally converted groups so that neither the bond between the R moiety and the stavrosporin methyl group nor its basic structure is affected; since these structural characteristics are generally characterized by good stability, normal reaction conditions can be used without special precautions.

If desired, the subsequent conversion of the reaction of a capable chlorine atom of the invention is carried out, in particular by the conversion of the chloroformyl group (C1-CO-) to a hydrocarboxycarbonyl group (R ° -O-CO-) or aminocarbonyl- (carbamoyl) group / R-N ( -R) -C0- /. This conversion takes place under known conditions, by treating the N-chloroformylstavrosporine with an alcohol of the formula R ° -OH or. with an amine (including ammonia) of the formula R -NH-R, preferably in the presence of an acid-binding agent, as an organic base (e.g., one of the above, tertiary amines). The general reaction conditions are analogous to those described above for the metabolism of reagents with a reaction-capable esterified hydroxyl group (especially for acid chlorides).

Optionally, the feasible formation of salts and the release of the basic forms of a compound of formula I from its salts is carried out in a generally known, conventional manner. - In this way, the acyl derivatives of the carboxyl-bearing formula I are converted into the corresponding salts with bases, in particular alkali metal salts, by treatment with a suitable base, in particular with a reactive alkali compound such as hydroxide, carbonate or bicarbonate; to free carboxylic compounds by acidification, e.g. with inorganic acids, such as in particular hydrohalic acids. - Finished base reacting substances,

- 40 tertiary and quaternary amines of Formula I or. IA, can be converted to their salts with acids, e.g. by treatment with an acid suitable for forming salts such as one of the above. Conversely, by treating with basic reacting agents such as inorganic hydroxides, carbonates and bicarbonates, or organic bases and ion exchangers, this basic tertiary amine formula of formula I is released.

Suitable compounds of the present invention may also form internal salts, e.g. with normal acid-base filtration to a neutral point or. to the isoelectric point, or e.g. by treatment with a quaternary agent corresponding to the residue R ° as reaction esters of the corresponding hydroxyl compound with a strong acid, such as halogen acid, sulfuric acid or strong organic sulfonic acid, quaternary ammonium salts of formula IA.

These and other salts of novel compounds, such as e.g. picrates can also be used to purify the compounds obtained by converting the free compounds into salts, removing them and recovering the free compounds from the salts. Due to the narrow relationship between the free and in the form of the salts, the corresponding salts (including quaternary salts) are understood to be meaningful and expedient, as appropriate, in the foregoing and hereinafter referred to as the free compounds.

Certain carbonyl functions can be e.g. with suitable reagents that cause the exchange of 0 with S, to be converted to the corresponding thio-form. Thus, e.g. by reaction with Lawesson's reagent / 2,4-bis- (4-methoxyphenyl) -2,4-dithioxo-1,3,2,4-dithiadiphosphethane / in compounds ^of formula I and their salts having carbonyl function, e.g. carboxamide, ketone and lactone grouping, replace oxygen atom with sulfur atom.

The invention also relates to those embodiments of the process by which a compound obtained at any stage of the process is obtained as an intermediate and the missing steps are carried out or a starting material is used in the form of a derivative, e.g. salts, but is formed under the reaction conditions.

In the process of the present invention, known or known starting materials are available, preferably those which lead to the introduction as particularly valuable compounds described.

In view of the pharmacological properties of the novel compounds described above, we also describe the use of the active substances obtained by the invention themselves, optionally together with excipients, or in combination with other active substances, e.g. antibiotics or chemotherapeutics, as agents for the treatment of diseases in which, as described above, cell growth is important, both prophylactically and curatively. When used as a medicament, the active ingredients of formula (I) are administered prophylactically or.

curatively effective amounts, preferably in the form of pharmaceutical compositions, together with conventional pharmaceutical carriers or excipients. In doing so, we give e.g. to warm-blooded creatures weighing about 70 kg, depending on the species, body weight, age and individual condition, as well as the route of administration, and in particular depending on the disease picture in question, daily doses of about 1 to 1000 mg, which in acute cases also exceed. The invention also encompasses, by analogy, an appropriate method of nursing.

We further describe pharmaceutical compositions containing the compounds obtained by the present invention as an effective substance, as well as a process for the preparation of these compositions.

The pharmaceutical compositions provided are

And e.g. for those intended for enteral or oral or rectal administration, as well as for parenteral administration to warm-blooded beings. Suitable dosage units, especially for oral administration, e.g. dragees, tablets or capsules preferably contain about 5 to 500 mg, in particular about 10 to 100 mg, of the active substance together with pharmaceutically useful carriers or excipients.

Suitable carriers are in particular fillers such as sugars, e.g. lactose, sucrose, mannitol or sorbitol, cellulosic preparations and / or calcium phosphates, e.g. tricalcium phosphate or calcium hydrogen phosphate, further binders such as starch adhesives (using, for example, corn, wheat, rice or potato starch), gelatin, tragacanth, methylcellulose

- 43 and / or optionally disintegrants such as the abovementioned starches, further carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, alginic acid or a salt thereof as sodium alginate. The auxiliaries are, first and foremost, flow-control agents and lubricants, e.g. silica, talc, stearic acid or a salt thereof as magnesium or calcium stearate, and / or polyethylene glycol. Dragee cores may be provided with suitable gastric juice-resistant coatings, using, inter alia, concentrated sugar solutions, which may optionally contain Arabic gum, talc, polyvinylpyrrolidone, polyethylene glycols and / or titanium dioxide, or varnish solutions in suitable organic solvents or solvent mixtures, or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulosic preparations such as acetylcellulose phthalate or hydroxypropyl methylcellulose phthalate. Dyes or coatings of dragees may be added to dyes or pigments, e.g. to identify or label different doses of the active substance.

Further pharmaceutical preparations for oral use include gelatin capsule capsules as well as soft, closed gelatin and plasticizer capsules such as glycerin or sorbitol. The plug capsules may contain an active substance in the form of a granulate, e.g. in admixture with lactose fillers, binders as starches and / or glidants, as talc or magnesium stearate, and optionally stabilizers

- 44 In soft capsules, the active substance is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, stabilizers may also be added.

As pharmaceutical preparations for rectal use, e.g. suppositories existing from a combination of an active substance with a base mass for suppositories. Suitable excipients, for example, are the base mass for suppositories. natural or synthetic triglycerides, paraffinic hydrocarbons, polyethylene glycols or higher alkanols. Furthermore, gelatin rectal capsules containing a combination of an active substance with a basic weight can also be used; as a base mass, e.g. liquid triglycerides, polyethylene glycols or paraffinic hydrocarbons.

For parenteral use, aqueous solutions of the water-soluble form of the active substance, e.g. water-soluble salts or aqueous injectable suspensions containing viscosity enhancers, e.g. sodium carboxymethylcellulose, sorbitol and / or dextran, and optionally stabilizers. In this case, the active substance, together with the excipients, may be present, also in the form of lyophilisate and before parenteral

by giving translate to solution z by the addition of suitable solvents. Pharmaceutical compositions, which contain compounds (I) _? we can prepare on alone by Yourself a known way, e.g. s

through the usual mixing, granulating and irritation processes

- 45 dissolving or lyophilizing. Thus, pharmaceutical preparations for oral administration can be obtained by combining the effective substance with solid carriers, granulating the resulting mixture as appropriate, and the mixture, respectively. The granulate can be processed as desired or necessary after the addition of suitable excipients to the tablets or cores of the dragees.

The following examples illustrate the invention described above, but are by no means limited in scope. Temperatures are given in degrees Celsius.

The product nomenclature is derived from the complete structure of stavrosporine (/ StauZ-NH-CH2)

H

II

II) wherein the N-labeled substituent is on the nitrogen of the methylamino group.

EXAMPLE 1

N-methoxycarbonylmethyl-stavrosporine

A mixture of 233 mg (0.5 mmol) of stavrosporine, 0.1 ml (0.59 mmol) of Ν, di-diisopropyl-ethylamine and 2 ml of dimethylformamide was added at room temperature 0.056 ml (0.6 mmol) of methyl bromoacetic acid. The reaction mixture was stirred in a closed flask for 48 hours at room temperature; Add 1 ml of water to precipitate the product and then recrystallize from methanol. Mp. ^ 210 ° (decay, over 170 ° brown coloration).

• · .A ___ / A___A.

II I \ Z II •. · = · · · ^In vay ⁱⁿ • Jícha ₃ h ₃ co-§-H ₂ C-Z

OCH:

H ₃

EXAMPLE 2

N-carboxymethyl-stavrosporine

269 mg (0.5 mmol) of N-methoxycarbonylmethyl-sporine (Example 1) was boiled in 15 ml of methanol and 0.3 ml of 2 N sodium hydroxide for 18 hours at reflux. After cooling to room temperature, neutralize with 0.1 ml of acetic acid and precipitate the product by adding 15 ml of water. Tal. above 2J3O ° (decays, above about 220 ° brown in color).

- 47 EXAMPLE 3

N- (1-methoxycarbonylethyl) -storprosporine

A mixture of 233 mg (0.5 mmol) of stavrosporine, 0.12 ml (0.71 mmol) of N, N-diisopropyl-ethylamine and 2 ml of dimethylformamide was added at room temperature to 0.085 ml (0.75 mmol) of methyl bromo-propionic acid. The reaction mixture was stirred in a closed flask for 20 hours at room temperature. After addition of a further 0.044 ml (0.038 mmol) of cZ - bromopropionic acid methyl ester, it is heated to 80 ° for 20 hours. After cooling to room temperature, precipitate the product by adding 2 ml of water. The crude product was purified by chromatography on silica gel (eluent: methylene chloride / ethanol 9: 1). Tal./vi50° (decay).

EXAMPLE 4

N-benzyl-stavrosporine

Mixtures of 116.5 mg (0.25 mmol) of stavrosporine,

0.06 ml (0.35 mmol) of N, N-diisopropyl-ethylamine and 1 ml of dimethylformamide are added at room temperature to 0.048 ml (0.38 mmol) of benzyl bromide and the reaction mixture is stirred in a closed flask for 6 hours at room temperature. The product was precipitated by the addition of one ml of water, filtered off and recrystallized from methanol. Tal ^ x.170 ° (decay).

EXAMPLE 5

N-allyl-stavrosporine

Mixtures of 116.5 mg (0.25 mmol) of stavrosporine,

0.06 ml (0.35 mmol) of N, N-diisopropyl-ethylamine and 1 ml of dimethylformamide are added at room temperature to 0.032 ml (0.38 mmol) of allyl bromide and the reaction mixture is stirred in a closed flask for 6 hours at room temperature. The product was precipitated by the addition of 1 ml of water and filtered. Purification is performed by chromatography on silica gel with methylene chloride / ethanol 9: 1 as eluant. Tal. 160 ° (decay).

EXAMPLE 6

N, N-dimethyl-stavrosporine iodide (N-methyl-stavrosporineodomethylate)

A mixture of 233 mg (0.5 mmol) of stavrosporine, 0.12 ml (0.71 mol) of N, N-diisopropyl-ethylamine and 2 ml of dimethylformamide was added at room temperature to 0.046 ml (0.75 mmol) of methyl iodide and the reaction mixture was stirred in sealed flasks at room temperature. After about 1 hour, a precipitate forms. After addition of a further 0.023 ml (0.038 mmol) of methyl iodide and 0.06 ml (0.038 mmol) of N, N-diisopropyl-ethylamine were stirred for 4 hours at room temperature and filtered after addition of 2 ml of water; the solid crude product was washed in warm methanol and, after cooling, filtered and dried again. Tal. 260 ° (decay).

EXAMPLE 7

N-ethyl-stavrosporine

Mixtures of 116.5 mg (0.25 mmol) of stavrosporine,

O, 06 ml (0.35 mmol) of N, N-diisopropyl-ethylamine and 2 ml of dimethylformamide are added at room temperature to 0.029 ml (0.38 mmol) of ethyl iodide and stirred in a closed flask for 24 hours

- 49 at room temperature. The product was precipitated by addition of 2 ml of water and filtered off. Tal. 170 ° (decay).

EXAMPLE 8

N, N-ethyl-methyl-stavrosporine iodide (N-ethylstroporinodomethylate)

A mixture of 115 mg (0.2 mmol) of N-ethyl-stavrosporine (Example 7) and 2 ml of dimethylformamide was added at room temperature to 0.018 ml (0.3 mmol) of methyl iodide. After 16 hours at room temperature and 16 hours at 50 °, more were added

O, 018 ml (0.3 mmol) of methyl iodide and stirred at 80 DEG C. for 6 hours. The crude product is obtained by precipitation with 2 ml of water and recrystallized from dimethylformamide / chloroform. Tal. 265 ° (decay).

EXAMPLE 9

N- (2-hydroxyhexyl) -storprosporine

A suspension of 116.5 mg (0.25 mmol) of stavrosporine and 0.054 ml (0.45 mmol) of 1-hexenoxide in 3.5 ml of absolute ethanol was heated at 110 ° for 36 hours in a bomb tube. The cooled reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated and chromatographed on silica gel (eluent methylene chloride / ethanol 9: 1); recrystallization from ether / petroleum ether gives us the product of m.p. 110 ° (decay).

EXAMPLE 10

N- (2-hydroxytetradecyl) -storprosporine

A suspension of 116.5 mg (0.25 mmol) of stavrosporine and 0.075 ml (0.30 mmol) of 1-tetradeeenoxide in 3.5 ml of absolute ethanol was heated at 110 ° C for 68 hours. The cooled reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated and chromatographed on silica gel (eluent methylene chloride / ethanol 9: 1). Recrystallization from ether / petroleum ether gives the product m.p. 120 ° (decay).

EXAMPLE 11

N- (2-Hydroxydecyl) -ustrosporine

A suspension of 116.5 mg (0.25 mmol) of stavrosporine and 0.055 ml (0.30 mmol) of 1-decenoxide in 3.5 ml of absolute ethanol was heated for 43 hours in a bomb tube at 110 °. The cooled reaction mixture was diluted with water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate, evaporated and chromatographed on silica gel (eluent methylene chloride / ethanol 9: 1). Recrystallization from ether / petroleum ether gives us the product of m.p. 140 °.

EXAMPLE 12

N- (2-cyanoethyl) -storprosporine

A suspension of 116.5 mg (0.25 mmol) of stavrosporine in 2.5 ml (38 mmol) of acrylonitrile was heated in a bomb tube for 70 hours at 140 °. After cooling, the reaction mixture was evaporated and chromatographed on silica gel (eluent, methylene chloride / ethanol 9: 1). · Recrystallization from chloroform / methanol afforded the product from mp 210 °.

EXAMPLE 13

N-qcetyl-stavrosporin

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform were added at room temperature 0.03 ml (0.3 mmol) of acetic anhydride and stir for 2 hours in a sealed flask. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The product was recrystallized from chloroform / methanol; m.p. 240 °.

EXAMPLE 14

N- (3-carboxypropionyl) -storprosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 40 mg (0.4 mmol) of succinic anhydride and stirred 28 hours in a closed flask. The reaction mixture was diluted with chloroform, washed with 0.1 N hydrochloric acid solution, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel (eluent methylene chloride / ethanol 9: 1); m.p. 140 °.

EXAMPLE 15

N- (5-isoquinolinsulfonyl) -stosteroporin

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.118 ml (0.69 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 105 mg (0.4 mmol)

- 52 5-isoquinolinesulfonyl chloride and stirred for 29 hours in a sealed flask. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The product was recrystallized from chloroform / methanol. Tal. 240 ° (on decay).

EXAMPLE 16

N / -methylsulfonyl-staurosporine

A solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature to 0.023 ml (0.38 mmol) of methanesulfochloride and stirred for 24 hours in closed zucchini. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel (eluting agent methylene chloride / ethanol 9: 1) and recrystallized from chloroform / methanol; m.p. 230 °.

EXAMPLE 17

N- (p-sued) -storprosporin

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 57 mg (0.3 mmol) of p-toluenesulfoxide and stirred 68 hours in a closed flask. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated.

The crude product is chromatographed on silica gel (eluting agent methylene chloride / ethanol 9: 1) and recrystallized from chloroform / methanol; m.p. 245 °.

EXAMPLE 18

N-benzoyl-stavrosporine

A solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (O; 38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature to 0.035 ml (0.3 mmol) of benzoyl chloride and stirred for 10 minutes. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 30: 1); m.p. 235 to 247 ° with brown color.

EXAMPLE 19

N-Trifluoroacetyl-stavrosporine

To a solution of 233 mg (0.5 mmol) of stavrosporine and 0.13 ml (0.6 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.5 ml (3.57 mmol) of trifluoroacetic anhydride and stir for 15 minutes. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (eluent methylene chloride / ethanol 20: 1; m.p. 220 ° C.

EXAMPLE 20

N-phenoxycarbonyl-stavrosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.035 ml (0.28 mmol) of hydrochloric acid phenyl ester 'and stirred 30 minutes in a sealed flask. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The residue was triturated with hot methanol and filtered and dried after cooling. Tal. above 210 ° (decay).

EXAMPLE 21

N-methoxycarbonyl-stavrosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.025 ml (0.32 mmol) of hydrochloric acid methyl ester and stirred 1 hour in a sealed flask. The reaction mixture was diluted with chloroform, washed with sodium bicarbonate solution, dried over magnesium sulfate and evaporated. The crude product was recrystallized from methanol; m.p. above 220 ° (during decay).

EXAMPLE 22

N-allylaminothiocarbonyl-stavrosporine (N-allylthiocarbamoylstavrosporin)

To a solution of 116.5 mg (0.25 mmol) of stavrosporine in 2.5 ml of chloroform was added 0.029 ml (0.3 mmol) of allylisothio55 cyanate and stirred in a closed flask at room temperature for 12 hours. The reaction mixture was evaporated and the crude product was recrystallized from chloroform / methanol; m.p. 220 °.

EXAMPLE 23

N-methylaminothiocarbonyl-stavrosporine (N-methylthiocarbamoylstavrosporin)

To a solution of 116.5 mg (0.25 mmol) of stavrosporine in 2.5 ml of chloroform was added 0.022 mg (0.3 mmol) of methylisothiocyanate and stirred for 12 hours in a closed flask at room temperature. The reaction mixture was evaporated and the crude product was recrystallized from chloroform / methanol; m.p. 235 to 238 °.

EXAMPLE 24

N-Phenylcarbamoyl-stavrosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine in 2.5 ml of chloroform was added 0.033 ml (0.3 mmol) of phenylisocyanate and stirred at room temperature for 15 minutes. The reaction mixture was evaporated and the crude product was recrystallized from chloroform / methanol; m.p. 225 to 229 ° (brown color).

EXAMPLE 25

N-trichloroacetyl-stavrosporin

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.1 ml (0.58 mmol) of N, N-diisopropyl-ethylamine in 1 ml of chloroform was added at room temperature 0.04 ml (0.35 mmol) of trichloroacetyl chloride and stirred for 1 hour. The reaction mixture was diluted with methylene chloride and washed with sodium bicarbonate solution, dried over magnesium sulfate

- 56 and evaporate.

The crude product is chromatographed on silica gel (eluent ethyl acetate); IR: 1682 (strong); FAB-MS: 661.

EXAMPLE 26

N- (3-chlorobenzoyl) -storprosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.038 ml (0.38 mmol) of 3-chlorobenzoyl chloride and stirred 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p. 240 ° (dec.).

EXAMPLE 27

N- (2-chlorobenzoyl) -storprosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.038 ml (0.38 mmol) of 2-chlorobenzoyl chloride and stirred 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p.

255 ° (dec.).

EXAMPLE 28

N- (3-Nitrobenzoyl) -storprosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporin and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 55.5 mg (0.30 mmol) of 3-nitrobenzoyl chloride and stirred for 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p. 230 °.

EXAMPLE 29

N- (4-methoxybenzoyl) -storprosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.083 ml (0.38 mmol) of 58% solution 4 -methoxybenzoyl chloride in toluene and stirred for 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution of 1 N hydrochloric acid and saturated sodium chloride solution, dried over magnesium sulfate and evaporated.

- 58 The crude product is chromatographed on silica gel (eluent methylene chloride-ethanol 95: 5); m.p. 220 °.

EXAMPLE 30

N - (4-fluorobenzoyl) -stavesporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine and 0.065 ml (0.38 mmol) of N, N-diisopropyl-ethylamine in 2 ml of chloroform was added at room temperature 0.036 ml (0.30 mmol) of 4-fluorobenzoyl chloride and stirred 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p. 225 ° (dec.).

EXAMPLE 31

N- (4-chlorobenzoyl) -storprosporine

A solution of 233 mg (0.5 mmol) of stavrosporine and 0.13 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform was added at room temperature, 0.077 ml (0.6 mmol) of 4-chlorobenzoyl chloride and stirred. 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p.

220 ° (dec.).

EXAMPLE 32

N- (3-fluorobenzoyl) -storprosporine

To a solution of 233 mg (0.5 mmol) of stavrosporine and 0.13 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform was added at room temperature 0.072 ml (0.6 mmol) of 3-fluorobenzoyl chloride and stirred 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p.

240 ° (dec.).

EXAMPLE 33

N- (4-Nitrobenzoyl) -storprosporine

To a solution of 233 mg (0.5 mmol) of stavrosporine and 0.13 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform was added at room temperature 0.11 ml (0.6 mmol) of 4-nitrobenzoyl chloride and stirred for 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); tal.255 ^ bO

EXAMPLE 34

N- (4-methoxycarbonylbenzoyl) -stavesporine

To a solution of 466 mg (1 mmol) of stavrosporin and 0.26 ml (1.52 mmol) of N, N-diisopropyl-ethylamine in 8 ml of chloroform was added at room temperature 237 mg (1.2 mmol) of 4-methoxycarbonylbenzoyl chloride and stirred for 1 hour at room temperature. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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); m.p. 240 ° (dec.).

EXAMPLE 35

N-Thiobenzoyl-stavrosporine

A mixture of 180 mg (0.31 mmol) of N-benzoyl-stavrosporine (Example 18) and 132 mg (0.326 mmol) of Lawesson's reagent (Fluka AG) in 2 ml of toluene was stirred for 48 hours at room temperature. For treatment, they are diluted with methylene chloride, washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The crude product is chromatographed on silica gel (ethyl acetate eluting agent); FD-MS: 586; H-NMR (300 MHz in CDC1 _3): 2.99 s (3H); 2.62 s (3H); 2.56 s (3H).

EXAMPLE 36

N-tert.butoxycarbonyl-stavrosporine

To a solution of 116.5 mg (0.25 mmol) of stavrosporine in 2 ml of tetrahydrofuran was added at room temperature a solution of 65 mg (0.297 mmol) of di-tert-butyl dicarbonate in 1 ml of tetrahydrofuran and stirred for 9 hours. The reaction mixture was evaporated and chromatographed on silica gel (methylene chloride / ethanol 95: 5 eluting agent); m.p. 160 °.

EXAMPLE 37

N- (4-carboxybenzyl-stavrosporine) salt

A mixture of 314 mg (0.5 mmol) of N- (4-methoxycarbonylbenzoyl) -strosporine (Example 34), 10 ml of methanol and 0.3 ml of 2 N sodium hydroxide was heated at reflux for 24 hours. After cooling, it is filtered, diluted with 10 ml of water and neutralized with 0.1 ml of acetic acid; this precipitates the title compound as an acid (mp 275 °). To prepare the sodium salt, suspend the acid in 10 ml of methanol and add 1 equivalent (5 ml) of 0.1 N sodium hydroxide. The resulting solution was evaporated and the residue was recrystallized from methanol / ether; FAB-MS: 637 (M + M) &lt; + &gt;; 659 (M + Na) &lt; + &gt;.

EXAMPLE 38

N- (3,5-dinitrobenzoyl) -storprosporin

To a solution of 233 mg (0.5 mmol) of stavrosporine and

0.13 ml (0.76 mmol) of N, N-diisopropyl-ethylamine in 4 ml of chloroform were added at room temperature to 138 mg (0.6 mmol) of 3,5-dinitrobenzoyl chloride and stirred for 1 hour. The reaction mixture was diluted with chloroform and washed with sodium bicarbonate solution, 1 N 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 ° (dec.).

EXAMPLE 39

N - [(tert-butoxycarbonylamino) -acetyl] -estrosporine

699 mg (1.5 mmol) of stavrosporine in 40 ml of dry chloroform was added 264 mg (1.5 mmol) of BOC-glycine (Eluka AG) and 340 mg (1.65 mmol) of dicyclohexylcarbodiimide and stirred at room temperature for 1.5 hours. The reaction mixture was then diluted with chloroform and washed with sodium bicarbonate solution and saturated sodium chloride solution, dried over magnesium sulfate and evaporated. The residue was taken up in some methylene chloride and filtered (removal of dicyclohexylurea). The filtrate was evaporated and dried; m.p. 190 °.

EXAMPLE 40

N- (2-aminoacetyl) -storprosporine

To a solution of 187 mg (0.3 mmol) of N - [(tert-butoxycarbonylamino) -acetyl] -estrosporine (Example 39) in 1 ml of acetic acid ethyl ester was added at room temperature 1 ml of saturated hydrochloric acid in ethyl acetate. This immediately produces a precipitate. The suspension was stirred for another 10 hours, the product was filtered off and washed with ethyl ester

- 63 acetic acid; m.p. 280 ° (dec.).

EXAMPLE 41

N- (2-hydroxy-propyl) -storprosporine

A mixture of 23.3 mg (50 µmol) of stavrosporine in 1 ml of dioxane, 0.5 ml (0.05 M) of borate buffer (pH 10.0) and 100 / Ul (1.5 mmol) of propylene oxide was stirred for 13 days. The mixture was extracted twice with dichloromethane. The organic phase was dried over sodium sulfate and the solvent removed in vacuo. The reaction product was purified by semi-preparative HPLC (Lichrosorb Si 60.5 μm, 8 x 250 mm) using water-saturated dichloromethane / 2-propanol (98: 2, v / v) at a flow rate of 5 ml / rainuto and a detector with 295 nm. Perform 20 injections. The product retention time is 15.4 minutes. The structure was confirmed by El-MS and 1 H-NMR (360 Hz).

EXAMPLE 42

N-phenyl-stavrosporine

A solution of 2.4 mg (51 Uraols) of stavrosporine in 0.5 ml of dioxane and 50 µl of 1 N phenyldiazonium chloride solution (Organikum, 13th ed., Deutscher Verlag der Wissenschaften, Berlin, 1974, p. 583) was stirred for 1 hour and to the mixture is added 1 ml of 1 N sodium bicarbonate, 50 ml of dichloromethane and 5 ml of methanol. The organic phase was dried over sodium sulfate, the solvent removed and the product purified by semi-preparative HPLC under the conditions of Example 41. The product retention time was 5.1 minutes. The structure was confirmed by El-MS and ¹ H-NMR (360 Hz).

EXAMPLE 43

In an analogous manner as described in the above embodiments, we can prepare:

N-alanyl-stavrosporine,

N-arginyl-stavrosporine,

N-phenylalanil-stavrosporine,

N-histidyl-stavrosporine,

N-seryl-stavrosporine.

EXAMPLE 44

Tablets containing 20 mg of active substance, e.g. N-methoxy-carbonylmethyl-stavrosporine is prepared in the following composition and in the usual way:

Composition:

effective substances 20 mg wheat starch 60 mg milk sugar 50 mg colloidal flint 5 mg talc 9 mg of magnesium stear ta 1 mg

145 mg

Preparation:

The active substance is mixed with a portion of wheat starch, milk sugar and colloidal silica, and the mixture is passed through a sieve. Remove the further portion of cornstarch with 5 times the amount of water in a water bath and knead the powder mixture with this adhesive until a weak plastic mass is formed.

- 65 The plastic mass is pushed through a sieve with a loop width of about 3 mm, dried and the dry granulate obtained is again pushed through the sieve. The remaining kotiiziii starch, talc and magnesium stearate are then mixed and the mixture compressed into 145 mg tablets and a notch.

EXAMPLE 45

Tablets containing 1 mg of active substance, e.g. N-methoxy-carbonylmethyl-stavrosporine is prepared in the following composition and in the usual way:

Composition:

effective substances 1 mg wheat starch 60 mg milk sugar 50 mg colloidal flint 5 mg talc 9 mg of magnesium stearate 1 mg

126 mg

Preparation:

The active substance is mixed with a portion of wheat starch, milk sugar and colloidal silica, and the mixture is passed through a sieve. Remove the further part of the wheat starch with 5 times the amount of water in a water bath and knead the powder mixture with this adhesive until a weak plastic mass is formed.

The plastic mass is pushed through a sieve with a loop width of about 3 mm, dried and the dry granulate obtained is again pushed through the sieve. Then the remaining corn66 starch, talc and magnesium stearate are mixed and the mixture is compressed into 126 mg tablets and a notch.

EXAMPLE 46

Capsules containing 10 mg of active substance, e.g. N-methoxy-carbonylmethyl-stavrosporine is prepared as follows in the usual way:

Composition:

effective substances 2500 mg talc 200 mg colloidal flint 50 mg

Preparation:

The active substance is thoroughly mixed with talc and colloidal quartz, the mixture is passed through a sieve with a mesh width of 0.5 mm, and in 11 mg portions each is filled into hard gelatin capsules of suitable size.

EXAMPLE 47

Instead of the compound described in Examples 44 to 46, pharmaceutical compositions containing one of the compounds described in Examples can be prepared as an effective substance

Claims (1)

A process for the preparation of N-substituted stavrosporine derivatives of the general formula '/ Stau / -N (CH ₃ ) -R (I), where / Stau / represents a residue of the partial formula s / \' aa \ / · = · · - - · · = · / \ / \ / \ \ // \ / // ^x · - · '· = · · - ·' V.O.V • 'CH3 OCH j [Stau] and R hydrocarbyl R ° or acyl Ac having not more than 30 carbon atoms, as well as salts of compounds of formula I with soluble properties, characterized in that stavrosporine of formula (Stau) -NH-CH ₃ (II) _f where (Stau) has the above meaning, or an acid addition salt thereof, is reacted with a reagent of the formula R-Y (III) wherein R has the above meanings and Y represents a reaction-capable activated hydroxyl group or an additional single bond, the other end of which replaces hydrogen in the residue R. and, if desired, the resulting compound of formula I is converted to another compound of formula I and / or in free form the resulting compound of formula I is converted into a salt thereof, and / or a compound of formula I obtained as a salt is converted into its free form or some other salt.