IE921186A1 - Novel trindene compounds - Google Patents

Description

Novel trindene compounds The invention relates to novel trindene compounds of formula wherein X is methylene or carbonyl, is hydrogen, acyl or unsubstituted or substituted alkyl, and R2 is carboxy or functionally modified carboxy, and salts thereof, to a process for the preparation of those compounds, to pharmaceutical compositions comprising those compounds and the preparation thereof, and to the use of those compounds and compositions for the therapeutic treatment of the human or animal body.

Within the scope of this description, the definitions used hereinbefore and hereinafter have preferably the following meanings and, unless indicated to the contrary, organic radicals referred to as lower contain from one to seven, and preferably from one to four, carbon atoms.

Acyl R| is an acyl radical derived from a free or functionally modified carboxylic acid and is characterised especially by the partial formula Z-C(=W)-, wherein W is oxygen or sulfur and Z is hydrogen, hydrocarbyl, hydrocarbyloxy, an amino group, especially one of I the formula R3-N-R4, or chlorine. -2IE 921186 Hydrocarbyl Z in such an acyl radical has a total of preferably not more than 30, and especially not more than 19, carbon atoms and is an aliphatic hydrocarbon, aryl or heteroaryl radical, or also an araliphatic or heteroaraliphatic radical.

An aliphatic unsubstituted hydrocarbon radical Z is saturated or unsaturated. Unsaturated hydrocarbon radicals Z are those which contain one or more, especially conjugated and/or non-conjugated multiple bonds (double and/or triple bonds). There is preferred as an aliphatic hydrocarbon radical Z a straight-chain or branched lower alkyl, lower alkenyl or lower alkynyl radical. Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl; lower alkenyl is e.g. allyl, propenyl or isopropenyl; lower alkynyl is e.g. propargyl or 2-butynyl. In corresponding unsaturated radicals, the double bond is preferably not situated in the α-position with respect to the free valency.

An aryl radical Z is a carbocyclic radical in which at least one ring is in the form of a 6-membered aromatic ring (i.e. a benzene ring). Preferred are phenyl, naphthyl, such as 1or 2-naphthyl, biphenylyl, such as, especially, 4-biphenylyl, anthryl and fluorenyl and also such ring systems having one or more fused saturated rings.

An araliphatic radical Z is an aryl-substituted alkyl radical. Preferred are aryl-lower alkyl and aryl-lower alkenyl radicals, e.g. phenyl-lower alkyl or phenyl-lower alkenyl having a terminal phenyl radical, e.g. benzyl, 1- or 2-phenethyl, 1-, 2- or 3-phenylpropyl, diphenylmethyl (benzhydryl), trityl and cinnamyl, and also 1- or 2-naphthylmethyl.

Tbe term heteroaryl embraces heterocyclic compounds of aromatic character, e.g. those in which at least one 5- or 6-membered heterocyclic ring contains the maximum number of non-cumulative double bonds.

A heteroaryl radical Z is especially a monocyclic, but also a bicyclic, aza-, thia-, oxa-, thiaza-, oxaza-, diaza-, triaza- or tetraza-cyclic radical of aromatic character the free valency of which must extend from one of its carbon atoms. More especially, it is a monocyclic radical containing one nitrogen, oxygen or sulfur atom, such as pyrrolyl, e.g. 2-pyrrolyl or 3-pyrrolyl, pyridyl, e.g. 2-, 3- or 4-pyridyl, thienyl, e.g. 2- or 3-thienyl, or furyl, e.g. 2-furyl; analogous bicyclic radicals containing one nitrogen, oxygen or sulfur atom are e.g. indolyl, such as 2- or 3-indolyl, quinolyl, such as 2- or 4-quinolyl, isoquinolyl, such as 3- or 5-isoquinolyl, benzofuranyl, such as 2-benzofuranyl, chromenyl, such IE £21186 - 3 as 3-chromenyl, or benzothienyl, such as 2- or 3-benzothienyl; preferred monocyclic and bicyclic radicals containing several hetero atoms are e.g. imidazolyl, such as 2-imidazolyl, pyrimidinyl, such as 2- or 4-pyrimidinyl, oxazolyl, such as 2-oxazolyl, isoxazolyl, such as 3-isoxazolyl, or thiazolyl, such as 2-thiazolyl, and benzimidazolyl, such as 2-benzimidazolyl, benzoxazolyl, such as 2-benzoxazolyl, or quinazolyl, such as 2-quinazolinyl, respectively.

Heteroaraliphatic radicals Z are preferably derived from aliphatic radicals having not more than 7, and preferably not more than 4, carbon atoms, e.g. those mentioned above, such as lower alkyl, especially methyl or ethyl, and may carry one, two or more heteroaryl radical(s), e.g. those mentioned above, it also being possible for the ring to be bonded to the aliphatic radical by a nitrogen atom.

Hydrocarbyl Z can be substituted by one, two or more identical or different substituents, especially by two or three substituents. Suitable substituents are especially the following: free, etherified and esterified hydroxy groups; mercapto, lower alkylthio and unsubstituted or substituted phenylthio groups; halogen atoms, such as chlorine and fluorine, but also bromine and iodine; oxo groups that are also in the form of corresponding acetals or ketals; azido and nitro groups; primary, secondary and, preferably, tertiary amino groups, primary or secondary amino groups protected by conventional protecting groups, acylamino groups and diacylamino groups, and free or functionally modified sulfo groups, such as sulfamoyl groups or sulfo groups in salt form. Preferably, the functional groups are not situated at the carbon atom from which the free valency extends but are separated therefrom by two or even more carbon atoms. The hydrocarbyl radical can also be substituted by free and functionally modified carboxy groups, such as carboxy groups in salt form or esterified carboxy groups, by carbamoyl, ureido or guanidino groups each unsubstituted or carrying one or two hydrocarbon radicals, such as lower alkyl, and by cyano groups. Other substituents of aryl or heteroaryl radicals Z are, for example, lower alkyl, such as methyl, ethyl, n-propyl, n-butyl and isobutyl, and halo-substituted lower alkyl, e.g. trifluoromethyl.

An etherified hydroxy group present as a substituent in the hydrocarbyl radical Z is e.g. a lower alkoxy group, such as a methoxy, ethoxy, propoxy, isopropoxy, butoxy or tertbutoxy group, which may also be substituted. For example, such a lower alkoxy group may be substituted by halogen atoms, e.g. by one, two or more halogen atoms, especially in the 2-position, such as in the 2,2,2-trichloroethoxy, 2-chloroethoxy or 2-iodoethoxy IE' : 1186 -4radical, or by hydroxy or lower alkoxy radicals, preferably by one in each case, especially in the 2-position, such as in the 2-methoxyethoxy radical. An especially preferred form of etherified hydroxy group is an oxaalkyl radical, in which, in a preferably linear alkyl, one or more carbon atoms are replaced by oxygen atoms which are preferably separated from one another by several (especially 2) carbon atoms so that they form a group Y-(O-CH2CH2-)n- wherein n - 1 to 14 and Y is hydrogen or lower alkyl, such as methyl or ethyl. Such etherified hydroxy groups are also unsubstituted or substituted phenoxy radicals and phenyl-lower alkoxy radicals, such as especially benzyloxy, benzhydryloxy and triphenylmethoxy (trityloxy), and heterocyclyloxy radicals, such as especially 2-tetrahydropyranyloxy. A special etherified hydroxy group is the grouping methylenedioxy or ethylenedioxy; the former as a rule bridges 2 adjacent carbon atoms, especially in aryl radicals, and the latter is bonded to one and the same carbon atom and is to be regarded as a protecting group for oxo. Etherified hydroxy groups are also to be understood in this context as including silylated hydroxy groups, such as, for example, in tri-lower alkylsilyloxy, such as trimethylsilyloxy and dimethyl-tert-butylsilyloxy, or phenyl-di-lower alkylsilyloxy or lower alkyl-diphenylsilyloxy.

An esterified hydroxy group present as a substituent in the hydrocarbyl radical Z carries an acyl radical characterised above, especially an acyl radical having not more than 12 carbon atoms, or is lactonised by a carboxy group also present in the hydrocarbyl radical Z.

An esterified carboxy group present as a substituent in the hydrocarbyl radical Z is one in which the hydrogen atom has been replaced by one of the hydrocarbon radicals characterised above, especially by a lower alkyl or phenyl-lower alkyl radical; as examples of an esterified carboxy group there may be mentioned lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl which is unsubstituted or substituted in the phenyl moiety, especially the methoxy-, ethoxy-, tert-butoxy- or benzyloxy-carbonyi group, and also a lactonised carboxy group.

A primary amino group -NH2 as a substituent of the hydrocarbyl radical Z may also be in protected form as an acylamino group corresponding to that amino group. A secondary amino group carries instead of one of the two hydrogen atoms a hydrocarbyl radical, preferably an unsubstituted hydrocarbyl radical, such as one of those mentioned above, especially lower alkyl, and may also be in a protected form as an acylamino group derived therefrom and having a monovalent acyl radical characterised hereinbelow. It is characIE £21186 •5teristic of protecting groups that they can be removed readily, i.e. without undesired side-reactions taking place, for example by solvolysis, reduction, photolysis or under physiological conditions. Amino-protecting groups and their introduction and removal are known per se and described, for example, in T.W. Greene Protective Groups in Organic Syntheses, Wiley, New York 1984.

An acyl radical serving as an amino-protecting group is preferably derived from a carbonic acid semi-derivative and is preferably lower alkoxycarbonyl or aryl-lower alkoxycarbonyl each of which is unsubstituted or substituted, especially by lower alkyl, lower alkoxy, nitro and/or by halogen, such as methoxycarbonyl, ethoxycarbonyl, tertbutoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-iodoethoxycarbonyl, lower alkenyloxycarbonyl, e.g. allyloxycarbonyl, benzyloxycarbonyl, 4-nitro- or 4-methoxy-benzyloxycarbonyl, 2-phenyl-2-propoxycarbonyl, 2-p-tolyl-2-propoxycarbonyl, 2-(p-biphenylyl)-2propoxycarbonyl or 9-fluorenylmethoxycarbonyl.

A tertiary amino group occurring as a substituent in the hydrocarbyl radical Z carries two different or, preferably, identical hydrocarbyl radicals (including the heteroaryl radicals), such as the unsubstituted hydrocarbyl radicals characterised above, especially lower alkyl.

A preferred amino group as a substituent of a hydrocarbyl radical Z is one of the formula I R3-N-R4, wherein each of R3 and R4 independently of the other is hydrogen, unsubstituted aliphatic C]-C7hydrocarbyl, such as, especially, CrC4alkyl or Cj-C4alkenyl, or monocyclic unsubstituted or Cj-C4alkyl-, Cj-C4alkoxy-, halo- and/or nitro-substituted aryl, aralkyl or aralkenyl having not more than 10 carbon atoms, it being possible for carbon-containing radicals R3 and R4 to be bonded to each other by a carbon-carbon bond or by an oxygen atom, by a sulfur atom or by a nitrogen atom which is unsubstituted or substituted by hydrocarbyl, such as lower alkyl. In such a case, they form together with the nitrogen atom of the amino group a nitrogen-containing heterocyclic ring. The following may be mentioned as examples of especially preferred amino groups: lower alkylamino, such as methylamino or ethylamino, di-lower alkylamino, such as dimethylamino or diethylamino, pyrrolidino, piperidino, morpholino, thiomorpholino, piperazino or 4-methylpiperazino, or phenylamino, diphenylamino, benzylamino and dibenzylamino each unsubstituted or substituted, especially in the phenyl moiety, e.g. by lower alkyl, lower alkoxy, halogen and/or by nitro; protected amino groups are preferably in the form of lower alkoxycarbonylamino, e.g. tert-butoxycarbonylamino, phenyl-lower alkoxyIE ’ .:1186 -6carbonylamino, e.g. 4-methoxybenzyloxycarbonylamino, and 9-fluorenylmethoxycarbonylamino.

In an acyl of the formula Z-C(=W)- wherein Z is an aliphatic hydrocarbon radical characterised above, the latter may carry especially from one to three substituents selected from tbe following: a carboxy group, which may also be in salt form or in the form of a cyano group or a Cj^alkyl ester (C1-C4alkoxycarbonyl group) and which is preferably in the I ω-position, an amino group of the formula R3-N-R4 defined above, preferably one in which each of R3 and R4 is hydrogen and which is then preferably in the 1-position, or one or more halogen atoms, especially fluorine or chlorine, which are preferably situated in the vicinity of the carbonyl group.

A preferred acyl is a bicyclic or, especially, a monocyclic aroyl, especially benzoyl, which may also carry one or more of the following substituents: halogen atoms, especially chlorine or fluorine, nitro groups, CpQalkyl radicals, especially methyl, hydroxy groups and etherified hydroxy groups, especially CrC4alkoxy, such as methoxy, phenoxy and methylenedioxy, and carboxy groups which may also be in salt form or in the form of a cyano group or a Cj-C^alkyl ester (C]-C4alkoxycarbonyl). The aroyl radicals carry preferably not more than two and especially only one of such substituents. Also preferred are analogous heteroaroyl radicals Ac0, especially those that are derived from pyridine, furan, thiophene and imidazole and the analogues thereof having a fused benzene ring (such as quinoline, isoquinoline, benzofuran, benzothiophene and benzimidazole) and that are unsubstituted or also substituted as indicated above. Other preferred acyl radicals are derived also from monocyclic aryl-alkyl or aryl-alkenyl, e.g. benzyl and styryl (i.e. phenacetyl and cinnamoyl). These too may be substituted in the manner indicated above. For example, corresponding acyl radicals Ac0 are derived from the following carboxylic acids: aliphatic monocarboxylic acids having not more than 10 carbon atoms, such as lower alkanecarboxylic acids, e.g. propionic, butyric, isobutyric, valeric, isovaleric, caproic, trimethylacetic, oenanthic and diethylacetic acid and, especially, acetic acid, but also corresponding halogenated lower alkanecarboxylic acids, such as chloroacetic acid, trifluoroacetic acid or trichloroacetic acid, bromoacetic acid or α-bromoisovaleric acid, aromatic carbocyclic carboxylic acids, e.g. benzoic acid, which may be mono- or polysubstituted as indicated above; aryl- or aryloxy-Iower alkanecarboxylic acids and analogues thereof that are unsaturated in the chain, e.g. phenylacetic or phenoxyacetic acids, phenylpropionic acids and cinnamic acids each unsubstituted or substituted as -7IE '186 indicated above for benzoic acid; and heteroaryl acids, e.g. furan-2-carboxylic acid, -tert-butylfuran-2-carboxylic acid, thiophene-2-carboxylic acid, nicotinic or isonicotinic acid, 4-pyridinepropionic acid, and pyrrole-2- or -3-carboxylic acids which are unsubstituted or substituted by lower alkyl radicals; also corresponding α-amino acids, especially naturally occurring α-amino acids, e.g. glycine and the α-amino acids of the L series, such as phenylglycine, alanine, phenylalanine, proline, leucine, isoleucine, serine, threonine, valine, tyrosine, arginine, histidine, lysine, aspartic acid, glutamic acid, glutamine and asparagine, preferably in an N-protected form, i.e. in a form in which the amino group is substituted by a conventional amino-protecting group, e.g. one of those mentioned above, and also dicarboxylic acids, such as oxalic acid, malonic acid, mono- or di-lower alkylmalonic acids, succinic acid, glutaric acid, adipic acid, maleic acid, or phthalic acid which is unsubstituted or substituted by halogen, such as fluorine, chlorine or bromine, lower alkyl, hydroxy, lower alkoxy and/or by nitro. As mentioned, the second carboxy group not only may be free but also may be functionally modified, for example may be present in the form of a C1-C4alkyl ester group or in the form of a salt.

Hydrocarbyl in a hydrocarbyloxy radical Z has the same general and preferred meanings as those indicated above.

A corresponding preferred acyl is derived from monoesters of carbonic acid (hydrocarbyloxycarbonyl). This acyl accordingly forms with the basic structure of the compounds of formula I corresponding N-disubstituted urethanes. Among especially preferred hydrocarbyl radicals in those derivatives there may be mentioned, for example, the following: aliphatic hydrocarbyl, especially a Cj-Qoalkyl, preferably a linear C1-C2oalkyl, that may be substituted by a carboxy group which is preferably in a functionally modified form, such as in the form of a salt, cyano or a C1-C4alkyl ester, and is preferably situated in the ω-position, a branched lower alkyl, e.g. tert-butyl, or unsubstituted or substituted phenyl and benzyl radicals, e.g. those mentioned above as being preferred.

Another preferred acyl R] is derived from amides of carbonic acid (or also thiocarbonic acid) and is characterised by the formula wherein R3 and R4 are as defined above and W is sulfur or, especially, oxygen. This acyl radical accordingly forms with the basic structure of the compounds of formula I corresIE ‘1186 -8ponding ureas or thioureas. Among preferred compounds according to the invention that carry this acyl, prominence is to be given especially to those wherein W is oxygen, one of the radicals R3 and R4 is hydrogen and the other is phenyl or C]-C7alkyl each of which may be substituted by hydroxy, mercapto, methylthio, phenyl, p-hydroxyphenyl, p-methoxyphenyl and, especially, by carboxy (in free form or in a functionally modified form, such as C|-C4alkoxycarbonyl, carbamoyl or amidino). Prominence is also to be given to compounds wherein W is sulfur, one of the radicals R3 and R4 is hydrogen and the other is CrC7alkyl or, especially, CrC7alkenyl in which the free valency extends from a carbon atom other than that from which the double bond extends, such as allyl.

Prominence is also to be given to the compounds of formula I according to the invention wherein X and R2 are as defined above and Rj is chloroformyl or thiochloroformyl, which compounds are distinguished especially by being advantageous intermediates for the preparation of modified carbonic acid acyl esters.

Especially preferred are acyl groups of the partial formula Z-C(=W)- wherein W is oxygen and Z is CrC7alkyl, especially CpC^alkyl, such as methyl, propyl or tert-butyl, which may also be substituted by halogen, such as fluorine or chlorine, carboxy or by Cj-C4alkoxycarbonyl, such as methoxycarbonyl, such as trifluoromethyl or trichloromethyl, 2-carboxy- or 2-methoxycarbonyl-ethyl, or phenyl or benzyl each of which may be unsubstituted or substituted by CrC4alkyl, C1-C4alkoxy, halogen, such as fluorine or chlorine, nitro, trifluoromethyl, carboxy, C]-C4alkoxycarbonyl, methylenedioxy and/or by cyano.

Especially preferred as the radical Rj is a Cj-C7alkoxycarbonyl, especially a C1-C4alkoxycarbonyl, radical or a phenyloxycarbonyl radical which is unsubstituted or substituted by Cj-C4alkyl, Ci-C4alkoxy, halogen, nitro, trifluoromethyl, carboxy, C1-C4alkoxycarbonyl, methylenedioxy and/or by cyano.

R\ . .

Especially preferred are acyl radicals of the partial formula yN-C(-W)-5 wherein W is sulfur or, especially, oxygen, R3 is hydrogen and R4 is C^-C-yalkyl, especially C1-C4alkyl, or phenyl each of which is unsubstituted or substituted by Cj-C4alkyl, C]-C4alkoxy, halogen, nitro, trifluoromethyl, carboxy, Q-C^alkoxycarbonyl, methylenedioxy and/or by cvano.

IE' 186 -9Especially preferred as the radical Rj are acyl radicals that are derived from an a-amino acid, especially a naturally occurring α-amino acid of the L series.

Especially preferred are acyl radicals that are derived from an α-amino acid selected from glycine, phenylglycine, alanine, phenylalanine, proline, leucine, isoleucine, serine, threonine, valine, tyrosine, arginine, histidine, lysine, glutamine, glutamic acid, aspartic acid and asparagine.

Especially preferred are those acyl radicals Rj that are derived from an α-amino acid in which the α-amino group is protected by an amino-protecting group, e.g. tert-butoxycarbonyl.

Alkyl Rj is an unsubstituted or substituted radical that has a total of not more than 19 carbon atoms, especially a straight-chain or branched lower alkyl radical. Lower alkyl is e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl or tert.-butyl. Alkyl Rt can be substituted by one, two or more identical or different substituents, e.g. those mentioned above for bydrocarbyl. Preferred alkyl radicals Rj are Cj-C7alkyl, C2-C7hydroxyalkyl in which the hydroxy group is in any position other than the 1-position and is preferably in the 2-position, cyano-lCrC7]alkyl in which the cyano group is preferably in the 1- or the ω-position, or carboxy-[C]-C7]alkyl in which the carboxy group is preferably in the 1- or the ω-position and may also be in salt form or in the form of a Cj-C4alkyl ester (C!-C4alkoxycarbonyl) or benzyl ester (benzyloxycarbonyl).

A functionally modified carboxy group R2 preferably means that the carboxy group may also be in the form of esterified carboxy that can be cleaved under physiological conditions or in the form of cyano, or that the hydroxyl radical of the carboxy group has been replaced by amino (carbamoyl) or the hydrogen atom of the carboxy group has been replaced by alkyl (alkoxycarbonyl).

Esterified carboxy groups R2 that can be cleaved under physiological conditions (i.e. metabolisable esterified carboxy groups R2) are known from the chemistry of antibiotics. Suitable groups are especially acyloxymethoxycarbonyl groups wherein acyl is, for example, the radical of an organic carboxylic acid, especially an unsubstituted or substituted lower alkanecarboxylic acid, or wherein acyloxymethyl forms the radical of a lactone. Such groups are e.g. lower alkanoyloxymethoxycarbonyl, e.g. acetoxymethoxycarbonyl or pivaloyloxymethoxycarbonyl, amino-lower alkanoyloxymethoxycarbonyl, ΙΕ 186 - 10especially α-amino-lower alkanoyloxymethoxycarbonyl, and 4-crotonolactonyl. Other esterified carboxy groups R2 that can be cleaved under physiological conditions are e.g. -indanyloxycarbonyl, phthalidyloxycarbonyl, 1-lower alkoxycarbonyloxy-lower alkoxycarbonyl, 1-lower alkoxy-lower alkoxycarbonyl, e.g. 1-ethoxycarbonyloxyethoxycarbonyl or also 2-oxo-l,3-dioxolan-4-ylmethoxycarbonyl that in the 5-position of the dioxolene ring is unsubstituted or is substituted by lower alkyl or by phenyl.

In an alkoxycarbonyl group R2 alkyl has the same general and preferred meanings as those given above.

Preferred as the radical R2 is carboxy or functionally modified carboxy that is in the form of an alkoxycarbonyl group, especially a lower alkoxycarbonyl group, for example ethoxycarbonyl and, especially, methoxycarbonyl.

The compounds according to the invention may also be in the form of salts, especially pharmaceutically acceptable, i.e. physiologically tolerable, salts. For isolation or purification it is also possible to use pharmaceutically unsuitable salts. Only pharmaceutically acceptable salts are used therapeutically and are preferred.

For example, compounds having free acid groups, for example a free sulfo or carboxy group, especially one in the acyl radical Ac0 or one that acts as the substituent R2, may be in the form of salts, preferably physiologically tolerable salts, with a salt-forming basic component. Suitable salts are especially metal or ammonium salts, such as alkali metal and alkaline earth metal salts, e.g. sodium, potassium, magnesium or calcium salts, and ammonium salts with ammonia or suitable organic amines, especially tertiary monoamines and heterocyclic bases, e.g. triethylamine, tri-(2-hydroxyethyl)-amine, N-ethylpiperidine or Ν,Ν’-dimethylpiperazine. Such an acid group can also form an internal salt with the amino nitrogen of the staurosporin basic structure or with another amino group that may be present.

Compounds according to the invention of basic character may also be in the form of addition salts, especially in the form of acid addition salts with inorganic or organic acids. For example, compounds of formula I that carry in the radical Rj or R2 a basic group, such as an amino group, as substituent can form acid addition salts with common acids. Special prominence is to be given to addition salts that are formed by acid addition to the 9-amino group of the compounds of formula I, with physiologically tolerable salts being preferred.

IE ! 1186 -11 The following common acids, for example, are suitable for salt formation: hydrohalic acids, e.g. hydrochloric and hydrobromic acid, sulfuric acid or phosphoric acid, and aliphatic, alicyclic, aromatic or heterocyclic carboxylic or sulfonic acids, such as formic, acetic, propionic, succinic, glycolic, lactic, malic, tartaric, citric, fumaric, maleic, hydroxymaleic, oxalic, pyruvic, phenylacetic, benzoic, p-aminobenzoic, anthranilic, p-hydroxybenzoic, salicylic, 4-aminosalicylic, embonic, methanesulfonic, ethanesulfonic, hydroxyethanesulfonic, ethylenedisulfonic, halobenzenesulfonic, toluenesulfonic or sulfanilic acid, and also amino acids, such as methionine, tryptophan, lysine or arginine, and ascorbic acid.

Compounds of formula I may contain one or more further chiral centres in the radicals Rj and R2. Accordingly, the invention relates to mixtures of diastereoisomers and especially to the novel diastereoisomers of compounds of formula I that have additional chiral centres in the radicals R] and/or R2.

The invention relates especially to compounds of formula I wherein X is methylene or carbonyl, Rj is hydrogen, acyl of the partial formula Z-C(=Wj-, wherein W is oxygen or sulfur and Z is CpCyalkyl, especially CpC^alkyl, such as methyl, propyl or tert-butyl, which may be unsubstituted or substituted by phenyl, phenyloxy, amino, halogen, such as fluorine or chlorine, carboxy, cyano and/or by C1-C4alkoxycarbonyl, such as methoxycarbonyl, such as aminomethyl, 2-aminoethyl, trifluoro- or trichloro-methyl, 2-carboxy- or 2-methoxycarbonyl-ethyl, or 3-carboxypropyl, phenyl which is unsubstituted or substituted by C1-C4alkyl, C]-C4alkoxy, halogen, such as fluorine or chlorine, nitro, trifluoromethyl, carboxy, CrC4alkoxycarbonyl, methylenedioxy and/or by cyano, Q-C^alkoxy, especially tert-butoxy, phenyloxy or benzyloxy each of which is unsubstituted or substituted by C1-C4alkyl, C]-C4alkoxy, halogen, such as fluorine or chlorine, nitro, trifluoromethyl, carboxy, Cj-C4alkoxycarbonyl, methylenedioxy and/or by cyano, acyl of the partial formula '>N-C(=W)-j wherein W is sulfur or, especially, oxygen, R3 is hydrogen and R4 is C,-C7alkyl, especially CrC4alkyl, or phenyl each of which is unsubstituted or substituted by Cj-Qalkyl, Q-Qalkoxy, halogen, nitro, trifluoromethyl, carboxy, CpQalkoxycarbonyl, methylenedioxy and/or by cyano, IE; 1186 - 12or is an acyl radical derived from an a-amino acid, especially an acyl radical derived from glycine, phenylglycine, alanine, phenylalanine, proline, leucine, isoleucine, serine, threonine, valine, tyrosine, arginine, histidine, lysine, glutamine, glutamic acid, aspartic acid or asparagine, in which the α-amino group is free or protected by an amino-protecting group and it being possible, in corresponding amino acids having an additional carboxy group, for the carboxy group also to be esterified, or wherein Rj is Cj-C7alkyl, C2-C7hydroxyalkyl in which the hydroxy group is in any position other than the 1-position and is preferably in the 2-position, cyano-[Ci-C7Jalkyl in which the cyano group is preferably in the 1- or the ω-position or carboxy-[Cj-C7]alkyl in which the carboxy group is preferably in the 1- or the ω-position and may also be in salt form or in the form of a C^C^ilkyl ester (Ci-C4alkoxycarbonyl) or a benzyl ester (benzyloxycarbonyl), and R2 is carboxy, CrC7alkoxycarbonyl, carbamoyl, cyano or esterified carboxy that can be cleaved under physiological conditions; or a salt thereof.

The invention relates chiefly to compounds of formula I wherein X is methylene or carbonyl, Rj is hydrogen, acyl of the partial formula Z-C(=O)-, wherein Z is CpC-^alkyl, such as methyl, ethyl or n-propyl, which is unsubstituted or substituted by phenyl, phenyloxy, halogen, such as fluorine or chlorine, carboxy and/or by Cj-C4alkoxycarbonyl, such as methoxycarbonyl or ethoxycarbonyl, or phenyl, CrC7alkoxy, such as methoxy, ethoxy, n-propoxy, isobutoxy or tert-butoxy, or phenyloxy each of which is unsubstituted or is substituted by halogen, such as fluorine or chlorine, carboxy, C1-C4alkoxycarbonyl, such as methoxycarbonyl, C1-C4alkoxy, such as methoxy, CpC^alkyl, such as methyl, and/or by nitro, or the acyl radical of a naturally occurring α-amino acid, such as glycine, alanine, serine or phenylalanine, in which the amino group may be protected by an amino-protecting group, such as lower alkoxycarbonyl, e.g. tert-butoxycarbonyl, or wherein Rj is CpQalkyl, cyano-Cj-Qalkyl, such as cyanoethyl, carboxy-Cj-C4alkyI, such as carboxymethyl, and R2 is carboxy or lower alkoxycarbonyl; or a salt thereof.

The invention relates more especially to compounds of formula I wherein X is methylene or carbonyl, R! is hydrogen, benzoyl, C1-C4alkoxycarbonyl, such as tert-butoxycarbonyl, or glycyl or L-alanyl in each of which the amino group may be protected by CrC4alkoxycarbonyl, and R-> is carboxy or Cj-C4alkoxycarbonyl; or a salt thereof.

IE £ 1186 -13The invention relates most especially to the compounds of formula I described in the Examples and their salts.

The compounds of formula I are prepared by a novel process which comprises subjecting a compound of formula II OH wherein X is methylene or carbonyl, to the conditions of a Beckmann rearrangement and, if desired, converting a compound of formula I obtainable according to the process wherein Rj is hydrogen and R2 is methoxycarbonyl into a different compound of formula I according to a process known per se, and/or separating a resulting mixture of diastereoisomeric compounds of formula I into the individual diastereoisomers, and/or converting a compound of formula I obtained in free form into a salt thereof or a compound of formula I obtained in the form of a salt into its free form or into a different salt.

The process according to the invention is carried out under the conditions conventionally used for a Beckmann rearrangement by reacting an oxime of formula II with an organic or inorganic acid or an acid chloride at room temperature or at slightly reduced or, preferably, slightly elevated temperature, e.g. in a temperature range of from approximately 0 to approximately 150°C, preferably in a temperature range of from approximately 25 to approximately 100°C, in an inert solvent, such as a protic solvent, e.g. water or glacial acetic acid, an aprotic solvent, e.g. dioxane, THF, acetonitrile or diethyl ether, or in expedient mixtures of such solvents.

Suitable acids are, especially, concentrated mineral acids, e.g. sulfuric acid, and also IE K '· 186 - 14 Lewis acids, for example boron trifluoride. Boron trifluoride can also be used in the form of adducts, for example as an acetic acid or ether adduct. A suitable acid chloride is, for example, phosphoryl chloride.

In compounds of formula II wherein X is as defined, under the conditions of a Beckmann rearrangement there is surprisingly neither an enlargement of the ring to form the corresponding lactam nor a fragmentation to form the corresponding nitriloaldehyde, but, with a contraction of the ring, a compound of formula I wherein X is methylene or carbonyl, Rj is hydrogen and R2 is methoxycarbonyl is formed.

A compound of formula I obtained according to the invention wherein X is methylene or carbonyl, Rt is hydrogen and R2 is methoxycarbonyl can, if desired, be converted into a different compound of formula I according to methods known per se. For example, an acyl or alkyl group can be introduced into a compound of formula 1 wherein Rj is hydrogen and X and R2 are as defined above.

Acylation of the primary amino group is carried out, advantageously in the presence of an acid-binding agent, with a reagent of the formula Ac-Υμ wherein Ac has the meanings given above for acyl Rb and Yj is a hydroxy group or a reactively activated hydroxy group, under process conditions that are generally customary in organic chemistry for the substitution of amines, usually at temperatures between the freezing point and the boiling point of the reaction mixture, such as in a temperature range of from approximately -10 to approximately + 160°C, especially from approximately +20 to approximately +50°C, at atmospheric or elevated pressure, in heterogeneous phase (such as suspension), with stirring or rotary shaking, or especially in homogeneous liquid phase, such as in an excess of liquid reagent or, especially, in the presence of solvents, especially organic solvents, and, where appropriate, in the presence of acid-binding inorganic or organic agents. Suitable solvents are, for example, aprotic organic solvents, such as aliphatic and aromatic hydrocarbons of the hexane and benzene type, respectively, and 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 dioxane and tetrahydrofuran, respectively, lower aliphatic esters and amides, such as ethyl acetate and Ν,Ν-dimethylacetamide and dimethylformamide, respectively, and also acetonitrile, dimethyl sulfoxide and hexamethylphosphoric acid triamide. The solvents may also be used in advantageous combinations, e.g. in order to increase the solubility of components. - 15 IE‘186 It is possible in principle to use any basic compound as an acid-binding agent, such as, on the one hand, an organic nitrogen-containing base, e.g. a tertiary amine of the type triethylamine, ethyldiisopropylamine, Ν,Ν-dimethylaniline, N-ethylpiperidine or N,N’dimethylpiperazine, or aromatic heterocyclic bases of the type pyridine, collidine, quinoline or 4-dimethylaminopyridine, or, on the other hand, inorganic compounds giving a basic reaction, especially alkali metal hydroxides, carbonates and hydrogen carbonates, and alkali metal salts of carboxylic acids, such as sodium or potassium acetate.

A reactively activated hydroxyl group will already be present in the free carboxy group of a carboxylic acid of the formula Ac-COOH if, owing to the particular nature of its structure, such as in trifluoroacetic acid or, especially, formic acid, it has a sufficient reactivity, but especially if it is temporarily activated by the action of activating reagents, e.g. carbodiimides, such as, especially, dicyclohexylcarbodiimide or carbonyl-di-(2-imidazolyl), and analogous compounds and, where appropriate, in the presence of auxiliaries that form active esters, such as substituted phenols and especially N-hydroxyamino compounds of the type 1-hydroxybenzotriazole, N-hydroxyphthalimide and N-hydroxymaleimide or -succinimide.

If the acyl radical is derived, for example, from one of the α-amino acids defined at the beginning, or from one of their N-protected derivatives, there is used as starting material especially the relevant amino acid or a salt, which is treated with one of the conventional activating agents, for example one of those mentioned above, thus enabling the carboxy group to be temporarily activated. The reaction is advantageously carried out in situ without isolating the activated intermediate stages. Preferred activating agents are dicyclohexylcarbodiimide and N-hydroxysuccinimide.

An activated hydroxyl group that is advantageous for the acylation is a reactive hydroxyl group esterified by strong acids that forms with the acyl radical a mixed acid anhydride. Particular prominence is to be given to mixed anhydrides with hydrohalic acids, especially with hydrobromic acid and more especially hydrochloric acid, i.e. acid bromides and acid chlorides, e.g. those of the formula Z-C(=W)-Hal, wherein Hal is bromine and preferably chlorine, and Z and W are as defined above.

In acyl radicals Ac of carboxylic acids (including the acyl radical of a functionally modified carbonic acid), the reactive esterified hydroxyl group may also be esterified IE t :1186 - 16either by the radical of a different carboxylic acid, especially a stronger carboxylic acid, such as formic acid, chloroacetic acid or, most especially, trifluoroacetic acid, (mixed anhydride) or, alternatively, by the same acyl radical and form a symmetrical carboxylic acid anhydride of the formula Ac-O-Ac.

The preparation of a compound of formula I wherein X and R2 are as defined above and Rj is acyl of the partial formula Z-(C=S)-, wherein Z is as defined above, is effected in a manner known per se.

The removal of acyl groups that are not a component part of the desired end product of formula I but serve as amino-protecting groups is effected in a manner known per se, e.g. by means of solvolysis, especially hydrolysis.

In a compound of formula I obtainable according to the invention wherein R2 and X are as defined above and Rt is hydrogen, the primary amino group can be convened in known manner into an N-alkylated secondary amino group.

In order to prepare compounds of formula I wherein X and R2 are as defined above and Rj is unsubstituted or substituted alkyl, a compound of formula I wherein Rj is hydrogen is reacted, for example, with a reagent of the formula Y2-Alk wherein Alk is unsubstituted or substituted alkyl as defined above and Y2 is a reactively esterified hydroxy group.

Y2 is a reactive esterified hydroxyl group (as a special form of the above-mentioned reactively activated hydroxyl group), i.e. one that is esterified by a strong inorganic acid, such as a hydrohalic acid (e.g. hydrochloric, hydrobromic or hydriodic acid), an oxygencontaining mineral acid, such as phosphoric acid and, especially, sulfuric acid, or a strong organic, such as aliphatic or aromatic, sulfonic acid (e.g. methane- and ethane-sulfonic acid and benzene-, ρ-toluene-, p-nitrobenzene- and p-chlorobenzene-sulfonic acid, respectively). The reaction is carried out in the presence of one of the acid-binding agents mentioned above. In order to prevent alkylation of the desired N-alkylated secondary amine to the tertiary amine, it may be advisable to protect the primary amino group in a compound of formula I wherein X and R2 are as defined and Rj is hydrogen by introducing a monovalent protecting group, e.g. an acyl group, especially one of those mentioned above, and to remove the protecting group in a manner known per se after the alkylation.

IE S : 186 - 17A functional group present in the radical Rj can be converted into a different functional group, e.g. a protected amino group can be converted into its free form, or a reactive chlorine atom (such as that in the chloroformyl radical) can be replaced by the radical Z-Ο-, wherein Z is as defined above, or by R3-N(-R4)-, wherein R3 and R4 are the substituents defined above. The freeing of the amino group is effected in a manner known per se, e.g. by solvolysis, especially hydrolysis, preferably in an acid medium. The conversion of a chloroformyl (C1-CO-) group into a hydrocarbyloxycarbonyl group (Z-O-CO-) or an aminocarbonyl-(carbamoyl) group (R3-N(-R4)-CO-) is effected under conditions known per se by, for example, reacting 9-chloroformylamino-9-methoxycarbonyl-cyclooctatrinden-l-one with an alcohol of the formula Z-OH- or with an amine (including ammonia) of the formula R3-NH-R4, respectively, preferably in the presence of an acid-binding agent, such as an organic base (e.g. one of the tertiary amines mentioned above).

In a compound of formula I wherein Rj and X are as defined above and R2 is a methoxycarbonyl group, the latter can be converted into the free carboxy group or into a different functionally modified form defined above. The conversion into the free carboxy group is generally effected by conventional hydrolysis, especially under the action of bases, especially alkali metal hydroxides, carbonates or hydrogen carbonates. A corresponding acid amide can be produced from the methoxycarbonyl compound by ammonolysis, and an alkyl ester, especially a C2-C2alkyl ester or a compound of formula I wherein X and Rj are as defined and R2 is an esterified carboxy group that can be cleaved under physiological conditions is obtained by alcoholysis (transesterification) of the methoxycarbonyl compound. On the other hand, compounds of formula I wherein R2 is carboxy can also be converted into compounds of formula I wherein R2 is an esterified carboxy group that can be cleaved under physiological conditions. Such esters can be prepared, for example, by reacting a salt of the acid, which may be formed in situ, with a reactive ester of a corresponding alcohol and a strong inorganic acid, such as sulfuric acid, or a strong organic sulfonic acid, such as 4-toluenesulfonic acid. The preparation of a compound of formula I wherein X and Rt are as defined and R2 is cyano is effected in a manner known per se, e.g. by dehydration of the corresponding acid amide.

Furthermore, a compound of formula I wherein R[ and R2 are as defined and X is methylene can be converted with a suitable oxidising agent into a corresponding compound of formula 1 wherein X is carbonyl. Such an oxidising agent is one of the customary oxidising agents suitable for the oxidation of an activated methylene group, IE €21186 - 18such as a benzyl group, to a carbonyl group, for example a compound of hexavalent chromium, such as an alkali metal chromate or dichromate, e.g. potassium chromate or potassium dichromate, and anhydrides of chromic acid, e.g. chromium trioxide, and complexes thereof, such as the chromium trioxide-pyridine complex, chromyl chloride or chromyl acetate, and esters of chromic acid, e.g. chromic acid tri-tert-butyl ester, a compound of quadrivalent to heptavalent manganese, e.g. manganese dioxide and potassium permanganate, ruthenium tetroxide and the like. Other suitable oxidising agents are peracids, their salts and hydroperoxides, e.g. tert-butyl hydroperoxide and potassium peroxodisulfate, which are to be used in the presence of catalytic amounts of manganese(II) or manganese(III) salts, and, in a photooxidation, atmospheric oxygen in the presence of catalytic amounts of titanium(IV) oxide.

The oxidation is carried out in a manner known per se in an inert solvent, such as a protic solvent, such as water or glacial acetic acid (e.g. when using chromium trioxide or an oxidising salt), an aprotic solvent, such as benzene, pyridine, acetone, diethyl ether, carbon tetrachloride, methylene chloride, carbon disulfide and the like (e.g. when using chromyl chloride, chromium trioxide-pyridine complex etc.), or in mixtures of such solvents, and, when using two immiscible solvents, such as water and benzene, also in the presence of a phase-transfer catalyst, such as a quaternary ammonium compound, e.g. benzykrimethylammonium chloride, tetrabutylammonium chloride or cetyltrimethylammonium bromide, and, when using an oxidising salt, e.g. potassium permanganate, also in the presence of a crown ether, e.g. dicyclohexyl-18-crown-6, and, where appropriate, for example when using an oxidising salt, e.g. potassium dichromate, also in the presence of an equimolar amount of a strong inorganic acid, e.g. sulfuric acid, and, depending upon the nature of the oxidising agent used, at room temperature or at reduced or elevated temperature, e.g. in a temperature range of from approximately 0° to approximately 10()°C. When using chromyl chloride or chromyl acetate as oxidising agent, the initially formed adduct must, when reaction is complete, be hydrolysed with water to form the desired compound of formula II.

Mixtures of diastereoisomeric compounds obtainable according to the process are separated by means of physico-chemical methods known per se into the individual diastereoisomers. Such methods include, for example, fractional crystallisation, liquid chromatography and adsorption chromatography.

The formation of salts and the freeing of the fundamental forms of the compounds of IE (a'1186 - 19formula I from their salts, which may be carried out if desired, is effected in a conventional manner that is known per se. For example, compounds of formula I carrying carboxy are converted into corresponding salts, especially alkali metal salts, by treatment with a corresponding base, especially a compound giving an alkaline reaction, such as an alkali metal hydroxide, carbonate or hydrogen carbonate; the salts can be converted into free carboxy compounds by acidification, e.g. with inorganic acids, such as, especially, hydrohalic acids. Compounds of formula I containing primary, secondary or tertiary amino groups can be converted into their salts with acids, e.g. by treatment with an acid suitable for forming salts, such as one of those mentioned above; conversely, by treatment with agents giving a basic reaction, such as with inorganic alkali metal hydroxides, carbonates and hydrogen carbonates, organic bases or ion-exchangers, such a basic fundamental form of an amine of formula I is freed.

Suitable compounds of the present invention may also form internal salts, e.g. by conventional titration to the neutral point or to the isoelectric point.

The latter or other salts of the novel compounds, e.g. the picrates, can also be used to purify the resulting compounds, by converting the free compounds into salts, separating the latter and recovering the free compounds from the salts again. In view of the close relationship between the compounds in free form and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds should be understood as including also the corresponding salts, as appropriate and expedient.

The invention relates also to those forms of the process according to which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining steps are carried out or a starting material is used in the form of a derivative, e.g. a salt, or is formed under the reaction conditions.

In the processes of the present invention, there are used starting materials that are known or that can be obtained by known methods, preferably those which result in the compounds described at the beginning as being especially valuable.

The reactions described above can be carried out under reaction conditions known per se, in the absence or, usually, in the presence of solvents or diluents, preferably those which are inert towards the reagents used and are solvents thereof, in the absence or presence of catalysts, condensation agents or neutralising agents, and, depending upon the nature of IE 221186 -20the reaction and/or the reactants, at reduced, normal or elevated temperature, e.g. in a temperature range of from approximately -80°C to approximately 190°C, preferably from approximately -20° to approximately 150°C, e.g. at the boiling point of the solvent used, under atmospheric pressure or in a closed vessel, where appropriate under pressure, and/or in an inert atmosphere, e.g. under a nitrogen atmosphere.

The starting compound of formula II wherein X is methylene (staurosporin-4’-one oxime) is known from Japanese Patent Application No. 1246288 and can be isolated in the manner described (see also Tanida, S. etal., J. Antibiot. (1989) 42, 1619-1630). The starting compound of formula II wherein X is carbonyl can be prepared from the latter by oxidation analogously to the oxidation described for compounds of formula I.

The compounds of the present invention exert a pronounced inhibiting action on protein kinase C. Protein kinase C, which is dependent upon phospholipids and calcium, occurs in cells in several forms and participates in various fundamental processes, such as signal transmission, proliferation and differentiation, and in the release of hormones and neurotransmitters. These enzymes are known to be activated either by receptor-mediated hydrolysis of phospholipids of the cell membrane or by direct interaction with certain tumourpromoting substances. The sensitivity of a cell to receptor-mediated signal transmission is considerably influenced by the inhibition of the activity of protein kinase C (as the signal transmitter).

The protein kinase C inhibiting action is determined using protein kinase C from pigs’ brains, which is purified by the procedure described by T. Uchida and C.R. Filbum in J. Biol. Chem. 259, 12311-4 (1984). The protein kinase C inhibiting action of the compounds of formula I is determined according to the method of D. Fabro et al.. Arch. Biochem. Biophys. 239, 102-111 (1985). In that test, the compounds of formula I inhibit protein kinase C at a concentration IC50 of as little as approximately from 0.01 to 0.2 μιηοΐ/litre.

The compounds of formula I also exhibit good inhibiting action (IC50 approximately from 0.005 to 0.2 pmol/litre) on protein phosphorylase kinase. Other enzymes, e.g. protein tyrosine kinase, on the other hand, are inhibited by the compounds of formula I only at a far higher, e.g. from 10 to 100 times higher, concentration.

Accordingly, the compounds of formula I and their pharmaceutically acceptable salts can -21 be used e.g. as medicaments, especially for the treatment of tumour diseases. In addition, the compounds of formula I possess anti-inflammatory, immuno-modulating, especially immunosuppressive, and antibacterial properties and can further be used as compositions against AIDS, arteriosclerosis and diseases of the cardiovascular system and the central nervous system.

The immunosuppressive properties of the compounds of the formula I and their pharmaceutically acceptable salts can be demonstrated by various biological tests, e.g. the inhibition of T lymphocyte proliferation. For example, human peripheral blood lymphocytes (PBL) from donors which are sensitive to an antigen, like purified protein derivative (PPD) from M. tuberculosis, are separated by Ficoll method and incubated with PPD in the presence or absence of a compound of the formula I for 6 days in culture. In order to measure antigen induced T cell proliferation, the cultures are pulsed with 3H-thymidine for the last 20 hours of the culture period. In this assay, the compounds of the formula I show IC50-values between about 0.005 and 0.1 μΜ, e.g. the compound of the formula I, wherein Rj is hydrogen, R2 is methoxycarbonyl and X is methylene shows an IC50-value of 0.04 μΜ.

When tested in a similar assay in the mouse which utilizes lymphocytes from antigen (ovalbumin) sensitized animals, said test being described in detail in Eur. J. Immunol. 8 (1978) 112, the compounds of the formula I show ICso-values between about 0.00001 and 0.001 μΜ, e.g. the compound of the formula I, wherein Rj is hydrogen, R2 is methoxycarbonyl and X is methylene shows an IC50-value of 0.0001 μΜ. In the same test cyclosporine A has an IC50-value of 0.03 μΜ and dexamethasone has an IC50-value of 0.003 μΜ.

Therefore the present invention relates also to a method of suppressing the immune system by administering to a warm-blooded animal in need of such treatment, e.g. when transplanting organs, an immunosuppressing effective amount, especially an amount suppressing the proliferation of T lymphocytes, of a compound of the formula I or of a pharmaceutically acceptable salt thereof.

The present invention further relates to the use of the compounds according to the invention for the preparation of medicaments, e.g. for the applications described above, for the therapeutic and prophylactic treatment of the human, and also the animal, body. •22In view of the above-described pharmacological properties of the novel compounds, the present invention also includes the use of the active ingredients according to the invention on their own, where appropriate together with excipients, or in combination with other active ingredients, e.g. antibiotics or chemotherapeutic drugs, as compositions for the treatment of diseases in which, as described above, cell growth is of importance, both prophylactically and curatively. When used as medicaments, the active ingredients according to the invention are administered in prophylactically or curatively effective amounts, preferably in the form of pharmaceutical compositions together with conventional pharmaceutical carriers or excipients. There will be administered, for example, to a warm-blooded animal weighing approximately 70 kg, depending upon the species, body weight, age and individual condition, and depending upon the method of administration and especially also the particular syndrome, daily doses of approximately from 0.1 to 5000 mg, which, in acute cases, may be exceeded, especially from 70 mg to 5000 mg, preferably from 70 to 700 mg. The invention also includes accordingly the corresponding method of medical treatment.

The invention relates further to pharmaceutical compositions comprising the compounds of the present invention as active ingredients, and to processes for the preparation of those compositions.

The pharmaceutical compositions according to the invention are, for example, for enteral, such as peroral or rectal, and for parenteral administration to warm-blooded animals. Corresponding unit dose forms, especially for peroral administration, e.g. dragees, tablets or capsules, preferably comprise approximately from 5 to 500 mg, especially approximately from 10 to 100 mg, of active ingredient together with pharmaceutically acceptable carriers or excipients.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, and binders, such as starch pastes (using, for example, corn, wheat, rice or potato starch), gelatin, gum tragacanth, methylcellulose and/or, if desired, disintegrators, such as the above-mentioned starches, also cyclodextrins, carboxymethyl starch, crosslinked polyvinylpyrrolidone, agar or alginic acid or a salt thereof, such as sodium alginate. Excipients are especially flow conditioners and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol. Dragee cores can be provided with suitable -23coatings which may be enteric coatings, there being used, inter alia, concentrated sugar solutions which may comprise gum arabic, talc, polyvinylpyrrolidone, polyethylene glycols and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the preparation of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colourings or pigments may be added to the tablets or dragee coatings, for example for identification purposes or to indicate different doses of active ingredient.

Other orally administrable pharmaceutical compositions are dry-filled capsules consisting of gelatin, and also soft sealed capsules consisting of gelatin and a plasticiser, such as glycerol or sorbitol. The dry-filled capsules may contain the active ingredient in the form of granules, for example in admixture with fillers, such as lactose, binders, such as starches, and/or glidants, such as talc or magnesium stearate, and, where appropriate, stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.

Suitable rectally administrable pharmaceutical compositions are, for example, suppositories that consist of a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. There may also be used gelatin rectal capsules that comprise a combination of the active ingredient with a base; suitable bases are, for example, liquid triglycerides, polyethylene glycols and paraffin hydrocarbons.

For parenteral administration there are suitable, especially, aqueous solutions of a form of the active ingredient that is soluble in water, e.g. a water-soluble salt, or aqueous injection suspensions comprising viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, where appropriate, stabilisers. The active ingredient, where appropriate together with excipients, may also be in the form of a lyophilisate and may be dissolved by the addition of suitable solvents prior to parenteral administration.

The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, confectioning, dissolving or lyophilising processes. For example, pharmaceutical compositions for oral -24administration can be obtained by combining the active ingredient with solid carriers, if desired granulating a resulting mixture and processing the mixture or granules, if desired or necessary after the addition of suitable excipients, to form tablets or dragee cores.

The following Examples illustrate the invention described above, but do not imply any limitation of the scope thereof. Temperatures are given in degrees Celsius. The following abbreviations are used: TFA = trifluoroacetic acid, BOC = tert-butoxycarbonyl.

The product of formula Ia H which falls within the formula I is called in accordance with IUPAC rules (8R,9S,11S)9amino-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11 -epoxy-1 H,8H, 11H2,7b, 1 la-triazabenzo[a,g]cycloocta[cde]trinden-l-one.

In the text of the priority document belonging to the present Application, the (8R,9S, 11 S)-8-methyl-2,3,9,10-tetrahydro-8,11 -epoxy- 1H,8H, 11 H-2,7b, 11 a-triazabenzo(a,glcycloocta[c,d,e]trinden-l-one structure was called, in short, cyclooctatrinden-l-one. In order to avoid confusion with the unsubstituted cyclooctatrindene, in the present text of the Application, the latter term is placed in quotation marks.

Example 1: 9-amino-9-methoxvcarbonyI-''cyclooctatrinden- 1-one Staurosporin-4’-one oxime is isolated from the culture supernatant of Streptomyces sp. C-71799 as described in Tanida, S. ct al. J. Antibiot. (1989) 42, 1619-1630. The strain Streptomyces sp. C-71799 has been deposited with the Fermentation Research Institute -25(FRI), Japan, under No. P-9714.

In a 50 ml round-bottom flask, 250 mg of staurosporin-4’-one oxime are dissolved in 20 ml of dioxane (Merck; for spectroscopy; 99.5 %) by briefly heating. After the addition of 56 μΐ of sulfuric acid (cone.; 96 %) the reaction mixture is stirred under reflux for 40 minutes, during which, after about 10 minutes, a light-yellow precipitate begins to form. The precipitate is dissolved with a small quantity of methanol and methylene chloride, then 50 ml each of methylene chloride and saturated Na2CO3 solution are added to the reaction mixture, and the aqueous phase is extracted twice with 25 ml of methylene chloride. The organic phases are washed with a small quantity of water, combined and dried with a silicone folded filter. After removal of the solvent, a yellow-brown crude product is obtained which, upon chromatography on silica gel (LiChroprep Si 60, -25 μηι; methylene chloride (indust.), H2O saturated; 130 ml column), is eluted in the fractions from 200 ml to 600 ml. Depending upon the quality of the methylene chloride, it is necessary to add 0.5 % isopropanol to the eluant. Removal of the solvent and recrystallisation from 0.5 ml of methylene chloride and 6 ml of methanol yield the title compound of m.p. 283-290° (with decomp.).

Example 2: 9-amino-9-methoxycarbonyl-cyclooctatrinden-1 -one The title compound is obtained analogously to Example 1 by adding 3.2 ml of dioxane, μΐ of H2O and 0.32 ml of boron trifluoride-acetic acid (36 %) to 40 mg of staurosporin-4’-one oxime and stirring under reflux for 100 minutes.

Example 3: 9-amino-9-methoxycarbonyl-’’cyclooctatrinden-l-one The title compound is obtained analogously to Example 1 by dissolving 30 mg of staurosporin-4'-one oxime in 2.4 ml of dioxane and adding, to 400 μΐ of that solution, 50 μΐ of boron trifluoride etherate (48 %). The reaction batch is stirred under reflux for 2 hours. -26Example 4: 9-amino-9-methoxycarbonyI-cyclooctatrinden-l-one The title compound is obtained analogously to Example 1 by dissolving 30 mg of staurosporin-4’-one oxime in 2.4 ml of dioxane and adding, to 400 μΐ of that stock solution, 4.5 mg of phosphoryl chloride. The reaction batch is stirred under reflux for 30 minutes.

Example 5: 9-benzoylamino-9-methoxycarbonyl-,,cyclooctatrinden-l-one In a 5 ml pointed flask under argon equipped with a magnetic stirrer, 3.8 μΐ of triethylamine and 15 μΐ of benzoyl chloride are added to 10 mg of 9-amino-9-methoxycarbonyl”cyclooctatrinden-l-one in 2.5 ml of methylene chloride and 100 μΐ of pyridine. The reaction mixture is stirred at room temperature for 1 hour, then 25 ml of methylene chloride and 5 ml of saturated Na2CO3 solution are added, and the aqueous phase is extracted twice with 25 ml of methylene chloride. The organic phases are washed with a small quantity of water, combined and dried with a silicone folded filter. Removal of the solvent and final purification by semi-preparative HPLC on silica gel (Nucleosil 100-5, μην, 8x250 mm; methylene chloride / isopropanol 99.5:0.5, H2O saturated; 6 ml/min; detection: 310 nm; retention times: product: 11.8 min, educt: 24 min) yield the title compound in the form of a colourless substance, m.p. 205-208°.

Example 6: 9-amino-9-carboxy-''cyclooctatrinden-l-one A solution of 9 mg of 9-amino-9-methoxycarbonyl-cyclooctatrinden-l-one in dioxane (1 ml) and 400 μΐ of 0. IN NaOH is stirred at 55° for 30 minutes. The reaction is stopped by the addition of 5 μΐ of TFA and the solvent is almost completely driven off with a stream of nitrogen. The mixture is dissolved by the addition of 300 μΐ of methanol. Purification is carried out by semi-preparative HPLC on a reversed-phase column (Nucleosil 100-5 C-18,5 pm; 8x250 mm; eluant A: 0.1 % TFA, eluant B: acetonitrile/water/TFA 80:20:0.08; gradient of 35 % eluant B to 47 % B in 12 minutes; 5 ml/min; detection: 310 nm; retention time: 8.4 min.) and yields the colourless title compound, m.p. >300°.

Example 7: 9-BOC-amino-9-methoxycarbonyl-cyclooctatrinden-1 -one In a 50 ml flask under argon equipped with a magnetic stirrer 33 μΐ of triethylamine and 58 mg of di-tert-butyl dicarbonate are added to 50 mg of 9-amino-9-methoxycarbonyl”cyclooctatrinden”-l-one in 25 ml of methylene chloride. The reaction mixture is stirred under reflux for 4 hours. The mixture is adjusted to pH 2 with 2N HC1, 25 ml of methylene chloride and 5 ml of water are added and the aqueous phase is extracted twice with 25 ml of methylene chloride. The organic phases are combined and dried with a -27silicone folded filter. Removal of the solvent yields the title compound which can be used directly in the next Example. EI-MS: 566 (M+), 466, 406, 353, 311.

Example 8: 9-(BOC-glycylamino)-9-methoxyearbonyl-cycIooctatrinden-l-one 23.2 mg of dicyclohexylcarbodiimide in 2 ml of methylene chloride are added to 54 mg of 9amino-9-methoxycarbonyl-cyclooctatrinden-l-one and 21.6 mg of BOC-glycine in 4 ml of methylene chloride. After stirring overnight at room temperature, the urea is removed by filtration and the filtrate is diluted with methylene chloride. The organic phase is washed with IN HCI and saturated Na2CO3 solution and dried with a silicone folded filter, and the solvent is removed. Chromatography on silica gel (LiChroprep Si 60, 15-25 pm; first methylene chloride, then methylene chloride / acetone 90:10, 50 ml column) yields the title compound. FAB-MS: 623 (M+H), 524, 450, 406.

Example 9: 9-amino-9-methoxycarbonyl-3-oxo-cyclooctatrinden-1 -one ml of TFA are added dropwise at 0°C to 520 mg of 9-BOC-amino-9-methoxycarbonyl-3-oxo-cyclooctatrinden-l-one (Example 10) in 10 ml of methylene chloride.

After 60 minutes, the reaction mixture is neutralised with 100 ml of saturated Na2CO3 solution and is extracted twice with 100 ml of methylene chloride. The combined organic phases are dried with a silicone folded filter. Removal of the solvent yields the title compound.

Example 10: 9-BOC-amino-9-methoxycarbonyl-3-oxo-cyclooctatrinden-l-one In a 250 ml round-bottom flask, 2.8 g of chromium trioxide-pyridine complex in 40 ml of CH2C12 are added at 4°C to 60 mg of 9-BOC-amino-9-methoxycarbonyl-cyclooctatrinden-l-one in 25 ml of methylene chloride and the mixture is stirred overnight. 100 ml of water are added to the mixture which is then extracted twice with 100 ml of methylene chloride. The combined organic phases are dried with a silicone folded filter. Removal of the solvent yields the title compound in the form of a yellow substance. EI-MS: 580 (M+), 480, 420, 351,325.

Example 11: 9-amino-9-methoxyearbonyl-3-oxo-cyclooctatrinden-l-one In a 25 ml round-bottom flask, 66 mg of chromium trioxide-pyridine complex (Fieser & Fieser, Reagents for Organic Synthesis, vol. 1, Wiley, 1967, page 145) are added at 0°C to mg of 9-amino-9-methoxycarbonyl-cyclooctatrinden-l-one in 10 ml of methylene chloride. The reaction mixture is stirred at room temperature for 19 hours. 5 ml of water are added to the mixture which is then rendered basic with 1 ml of saturated Na2CO3 - 28 solution and extracted twice with 25 ml of methylene chloride. The organic phases are washed with a small quantity of water, combined and dried with a silicone folded filter. Removal of the solvent, drying under a high vacuum and final purification by semipreparative HPLC (Nucleosil C]8, 5 pm, 8 x 250 mm, methylene chloride/isopropanol 199.5/0.5], H2O saturated, 6 ml/minute, 300 nm, 3 runs) yield the title compound; retention time: 4.6 minutes (educt: 19 minutes), EI-MS: 480 (M+), 437,420, 367, 351, 325.

The NMR data of some of the compounds of formula I are indicated in Table 1.

Table 1: ’H-NMR chemical shifts (in ppm) Proton Example 1 Example 5 Example 6 1 8.03* d 8.04 d 8.08 d 2 7.47 t 7.49 =t 7.49 m 3 7.27* t =7.3 m 7.28* t 4 9.23 d 9.22 d 9.22 d 6 8.29 s br 8.65* s br 8.70 s br 7 4.98 =d 5.0 =d 5.02 =d 8 8.06* d 7.88 d 8.16 d 9 7.35* t =7.4* m 7.40* 10 7.47 t 7.42 t 7.49 m 11 7.83 d 7.86 d 7.92 d 2'-CH3 2.15 s 2.66 s 2.26 s 3-COOCH3 3.92 s 3.80 s 3'-NH2 2.10 s br 3'-NH 8.47* s br 4'a 3.36 dd 3.42 dd 3.47 m 4'b 2.04 dd 2.79 dd 2.15 dd 5' 7.07 dd 7.25 m 7.18 dd C6H5COO 7.4-7.25 Solvent: DMSO-d6. Allocations marked with an asterisk may be exchanged. -29Example 12: 9-methylamino-9-methoxvcarbonyl-cvclooctatrinden-l-one A solution of 233 mg of 9-amino-9-methoxycarbonyl-cyclooctatrinden-l-one and 87 μΐ of trifluoroacetic anhydride in 2 ml of dry pyridine is stirred for 2 hours. After the addition of 100 ml of methylene chloride, the organic phase is washed in succession with 0.1 normal hydrochloric acid, cold, saturated potassium hydrogen carbonate solution and ι small quantity of water and is dried with a silicone folded filter, and the solvent is removed. 40 μΐ of methyl iodide and 28 mg of potassium hydroxide are added to a solution of the resulting product in 5 ml of acetone and the mixture is stirred overnight. For hydrolysis, 1 ml of aqueous 0.5 normal potassium hydroxide solution is added and stirring is continued for 30 minutes. After the addition of 100 ml of methylene chloride, the organic phase is washed with water and dried with a silicone folded filter and the solvent is removed. HPLC chromatography (Nucleosil C18, 5 pm, 16 x 250 mm, eluant A water, eluant B: acetonitrile/water [80/20], 70 % B [isocratic], 10 ml/minute, 290 nm, runs) yields the title compound; retention time: 23 minutes, m.p. 154-156°.

Example 13: Tablets each comprising 20 mg of active ingredient (e.g. 9-amino-9methoxycarbonyl-cyclooctatrinden-l-one) are prepared in the customary manner, for example in the following composition: Composition: active ingredient 20 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 mg 145 mg Preparation: The active ingredient is mixed with a portion of the wheat starch, with lactose and colloidal silica and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained. '[’he plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the -30resulting dry granules are forced through a sieve once more. Then, the remainder of the wheat starch, the talc and the magnesium stearate are admixed and the mixture is pressed to form tablets each weighing 145 mg and having a breaking notch.

Example 14: Tablets each comprising 1 mg of active ingredient (e.g. 9-amino-9methoxycarbonyl-cyclooctatrinden-l-one) are prepared in the customary manner in the following composition: Composition: active ingredient 1 mg wheat starch 60 mg lactose 50 mg colloidal silica 5 mg talc 9 mg magnesium stearate 1 mg 126 mg Preparation: The active ingredient is mixed with a portion of the wheat starch, with lactose and colloidal silica and the mixture is forced through a sieve. A further portion of the wheat starch is made into a paste with 5 times the amount of water on a water bath and the powder mixture is kneaded with the paste until a slightly plastic mass is obtained.

The plastic mass is pressed through a sieve of about 3 mm mesh size and dried, and the resulting dry granules are forced through a sieve once more. Then, the remainder of the wheat starch, the talc and the magnesium stearate are admixed and the mixture is pressed to form tablets each weighing 126 mg and having a breaking notch.

Example 15: Capsules each comprising 10 mg of active ingredient (e.g. 9-amino-9methoxycarbonyl-cyclooctatrinden-l-one) are prepared in the customary manner as follows: Composition: active ingredient talc 2500 mg 200 mg -31 colloidal silica 50 mg Preparation: The active ingredient is homogeneously mixed with talc and colloidal silica, and the mixture is forced through a sieve of 0.5 mm mesh size and introduced in portions of 11 mg into hard gelatine capsules of a suitable size.

Example 16: It is also possible to prepare pharmaceutical compositions comprising as active ingredient another of the compounds of formula I described in Examples 1 to 12 instead of the compositions described in Examples 13 to 15.

Claims (22)

What is claimed is:
1. l. A compound of the formula I R 1 wherein X is methylene or carbonyl, Rj is hydrogen, acyl or unsubstituted or substituted alkyl, and R 2 * s carboxy or functionally modified carboxy, or a salt thereof.
2. 2. A compound of formula I according to claim 1, wherein X is methylene or carbonyl, R.) is hydrogen, acyl of the partial formula Z-C(=W)-, wherein W is oxygen or sulfur and Z is C!-C 7 alkyl which is unsubstituted or substituted by phenyl, phenyloxy, carboxy, cyano, Cj-C 4 alkoxycarbonyl, amino and/or by halogen, phenyl which is unsubstituted or substituted by C r C 4 alkyl, C r C 4 alkoxy, halogen, nitro, trifluoromethyl, carboxy, CpQalkoxycarbonyl, methylenedioxy and/or by cyano, C 1 -C 2 oitlkoxy, phenyloxy or benzyloxy each of which is unsubstituted or substituted by Cj-C 4 alkyl, C 1 -C 4 alkoxy, halogen, nitro, trifluoromethyl, carboxy, C r C 4 alkoxycarbonyl, methylenedioxy and/or by cyano, acyl of the partial formula C(=W)-, wherein W is sulfur or oxygen, R 3 is hydrogen and R 4 is C^-Cjalkyl or phenyl each of which is unsubstituted or substituted by Cj-C 4 alkyl, C r C 4 alkoxy, halogen, nitro, trifluoromethyl, carboxy, C 1 -C 4 alkoxycarbonyl, methylenedioxy and/or by cyano, -33or is an acyl radical derived from an α-amino acid selected from glycine, phenylglycine, alanine, phenylalanine, proline, leucine, isoleucine, serine, threonine, valine, tyrosine, arginine, histidine, lysine, glutamine, glutamic acid, aspartic acid and asparagine, in which the α-amino group is free or protected by an amino-protecting group and it being possible, in corresponding amino acids having an additional carboxy group, for the carboxy group also to be esterified, or wherein Rj is Cj-Cyalkyl, C 2 -C 7 hydroxyalkyl in which the hydroxy group is in any position other than the 1-position, cyano-fCj-C^alkyl or carboxy-fCj-C 7 ]alkyl in which the carboxy group is in the form of a Cj-C4alkyl ester or a benzyl ester, and R 2 is carboxy, alkoxycarbonyl, carbamoyl, cyano or esterified carboxy that can be cleaved under physiological conditions; or a salt thereof.
3. 3. A compound of formula I according to claim 1, wherein X is methylene or carbonyl, R) is hydrogen, acyl of the partial formula Z-C(=O)-, wherein Z is Cj-C 7 alkyl which is unsubstituted or substituted by phenyl, phenyloxy, halogen, carboxy and/or by C4-C4alkoxycarbonyl, or phenyl, C]-C 7 alkoxy or phenyloxy each of which is unsubstituted or is substituted by halogen, carboxy, Cj-C^tlkoxycarbonyl, C[-C 4 alkoxy, Ci-C 4 alkyl and/or by nitro, or the acyl radical of a naturally occurring α-amino acid selected from glycine, alanine, serine and phenylalanine in which the amino group may be protected by an amino-protecting group, or wherein R! is Ci-C4alkyl, cyano-C[-C 4 alkyl or carboxyC]-C 4 alkyl, and R 2 is carboxy or Ci-C 7 alkoxycarbonyl; or a salt thereof.
4. 4. A compound of formula I according to claim 1, wherein X is methylene or carbonyl, R t is hydrogen, benzoyl, C 1 -C 4 alkoxycarbonyl, or glycyl or L-alanyl in each of which the amino group may be protected by Cj^alkoxycarbonyl, and R 2 is carboxy or Q-C4alkoxycarbonyl; or a salt thereof.
5. 5. A pharmaceutically acceptable salt of a compound of formula 1 according to claim 1.
6. 6. y-Amino-9-methoxycarbonyl-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
7. 7. 9-Benzoylamino-9-methoxycarbonyl-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1. S. 9-Amino-9-carboxy-cyclooctatrinden-l-one or a pharmaceutically acceptable salt - 34thereof according to claim 1.
8. 8. 9. 9-BOC-amino-9-methoxycarbonyl-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
9. 9. 10. 9-(BOC-glycyl)-amino-9-methoxycarbonyl-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
10. 10. 11. 9-Amino-9-methoxycarbonyl-3-oxo-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
11. 11. 12. 9-BOC-amino-9-methoxycarbonyl-3-oxo-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
12. 12. 13. 9-Methylamino-9-methoxycarbonyl-cyclooctatrinden-l-one or a pharmaceutically acceptable salt thereof according to claim 1.
13. 13. 14. A pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 together with a pharmaceutical carrier.
14. 14. 15. A method for the treatment of warm-blooded animals, including humans, suffering from abnormally increased cell proliferation, wherein a compound of formula I or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 13 is administered to such a warm-blooded animal at a dosage that retards said cell proliferation.
15. 15. 16. A method of suppressing the immune system of warm-blooded animals comprising administering to a warm-blooded animal in need of such treatment an immunosuppressing effective amount of a compound of the formula I according to any one of claims 1 to 13 or of a pharmaceutically acceptable salt thereof.
16. 16. 17. A process for the preparation of a compound of formula I as defined in claim 1, which comprises subjecting a compound of formula OH wherein X is methylene or carbonyl, to the conditions of a Beckmann rearrangement and, if desired, converting a compound of formula I obtainable according to the process wherein Rj is hydrogen and R 2 is methoxycarbonyl into a different compound of formula I, and/or separating a resulting mixture of diastereoisomeric compounds of formula I into the individual diastereoisomers, and/or converting a compound of formula I obtained in free form into a salt thereof or a compound of formula I obtained in the form of a salt into its free form or into a different salt.
17. 17. 18. A process according to claim 17 for the preparation of a compound of formula I, which comprises treating a compound of formula II with sulfuric acid, boron trifluoride or phosphoryl chloride.
18. 18. 19. A compound obtainable by the process according to claim 17. -3620. A compound of the formula (I) given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.
19. 19. 21. A pharmaceutical composition according to claim 14, substantially as hereinbefore described and exemplified.
20. 20. 22. A process for the preparation of a compound of the formula (I) given and defined in claim 1, or a salt thereof, substantially as hereinbefore described and exemplified.
21. 21. 23. A compound of the formula (I) given and defined in claim 1, or a salt thereof, whenever prepared by a process claimed in any one of claims 17, 18 or
22. 22.