97993 ff

SUBSTITUTED ANTHRANILAMIDES AND ANALOGUES, MANUFACTURING AND USE THEREOF AS MEDICAMENTS

The present invention relates to new substituted anthranilamides and the analogues thereof of general formula (I)

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, which have valuable properties.

The compounds of the above general formula (I) as well as the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases, and the stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity and a factor Xa-inhibiting activity.

The present application relates to new compounds of the above general formula (I), the preparation thereof, the pharmaceutical compositions containing the pharmacologically effective compounds, the preparation and use thereof.

A 1 st embodiment of the present invention encompasses those compounds of general formula (I) wherein

D denotes one of the following groups Ma or Mb

wherein

K ¹ and K ⁴ each independently of one another denote a bond, a -CH ₂ , -CHR 7a CR ^7b R ^7c or a -C(O) group, and wherein

_R 7a _/R 7b _/R 7c each independently of one another denote a fluorine atom, a hydroxy, Ci _-5 -alkyloxy or a Ci _-5 -alkyl group which may be substituted by 1 -3 fluorine atoms, while the two groups R ^7b /R ^7c cannot both simultaneously denote a hydroxy group, or two groups R ^7b /R ^7c together with the ring carbon atom may form a

3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group, and

K ^z and K ³ each independently of one another denote a -CH ₂ , -CHR ^8a , -CR ^8b R ^8c or a -C(O) group, wherein

_R 8a _/R 8b _/R 8c each independently of one another denote a Ci _-5 -alkyl group which may be substituted by 1-3 fluorine atoms, a hydroxy-Ci _-5 - alkyl, Ci _-5 -alkyloxy-Ci- ₅ -alkyl, carboxy-Co- ₅ -alkyl, Ci _-5 - alkyloxycarbonyl-Co- ₅ -alkyl, aminocarbonyl-Co- ₅ -alkyl, Ci- ₅ -alkylaminocarbonyl-C ₀ - ₅ -alkyl, di-(Ci _-5 -alkyl)-aminocarbonyl- Co- ₅ -alkyl or a C _4-7 -cycloalkyleneiminocarbonyl-Co- ₅ -alkyl group,

or two groups R ^8b /R ^8c together with the ring carbon atom may form a 3-, 4-, 5-, 6- or 7-membered saturated carbocyclic group, and

R ¹ denotes a hydrogen atom or a Ci _-5 -alkyl, C _2-5 -alkenyl-CH ₂ ,

C2-5-alkynyl-CH ₂ , Cs-6-cycloalkyl, benzyl group,

and

A ¹ denotes either N or CR ¹⁰ ,

A ² denotes either N or CR ¹¹ ,

A ³ denotes either N or CR ¹² ,

A ⁶ denotes either N or CR ¹³ , and

A ⁴ denotes either N or CR ¹⁴ ,

A ⁵ denotes either N or CR ¹⁵ ,

wherein R ¹⁰ , R ¹¹ , R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ each independently of one another denote

a hydrogen, fluorine, chlorine, bromine or iodine atom, or a Ci _-5 - alkyl, CF ₃ , C2-5 -alkenyl, C2-5-alkynyl, a cyano, carboxy, Ci _-5 - alkyloxycarbonyl, hydroxy, Ci _-3 -alkyloxy, CF ₃ O, CHF ₂ O, CH ₂ FO, amino, Ci _-5 -alkylamino, di-(Ci _-5 -alkyl)-amino or C _4-7 - cycloalkyleneimino group, and

R ² denotes a hydrogen atom or a Ci _-3 -alkyl group, and

R ³ denotes a hydrogen, fluorine, chlorine or bromine atom or an amino, Ci _-3 - alkyloxy, Ci _-3 -alkyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and

R ⁴ denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, amino, Ci _-3 -alkyloxy, Ci _-3 -alkyl or a hydroxy group, and

R ⁶ denotes a hydrogen atom or a Ci _-3 -alkyl group, and

M denotes a phenyl or pyridyl ring optionally substituted by R ⁷ and R ⁸ , wherein

R ⁷ denotes a fluorine, chlorine, bromine or iodine atom or a methyl, ethyl, vinyl, methoxy, ethynyl, cyano Or -C(O)NH ₂ group, and

R ⁸ denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a hydroxy, methoxy, Ci _-3 -alkyl, cyano, amino, or NH ₂ C(O) group,

and while the alkyl, alkenyl, alkynyl and alkyloxy groups with more than two carbon atoms contained in the previous definitions, unless stated otherwise, may be straight-chain or branched and the alkyl groups in the previously mentioned dialkylated groups, for example the dialkylamino groups, may be identical or different,

and the hydrogen atoms of the methyl or ethyl groups contained in the foregoing definitions, unless stated otherwise, may be wholly or partly replaced by fluorine atoms,

the tautomers, the enantiomers, the diastereomers, the mixtures thereof and the salts thereof.

Examples of the Ci-6-alkyl groups mentioned hereinbefore in the definitions are the methyl, ethyl, 1 -propyl, 2-propyl, n-butyl, sec-butyl, te/t-butyl, 1 -pentyl, 2-pentyl, 3-pentyl, neo-pentyl, 3-methyl-2-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 3- methyl-2-pentyl, 4-methyl-2-pentyl, 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,2- dimethyl-3-butyl or 2,3-dimethyl-2-butyl group.

Examples of the Ci _-5 -alkyloxy groups mentioned hereinbefore in the definitions are the methyloxy, ethyloxy, 1 -propyloxy, 2-propyloxy, n-butyloxy, sec-butyloxy, te/t-butyloxy, 1 -pentyloxy, 2-pentyloxy, 3-pentyloxy or neo-pentyloxy group.

Examples of the C _2-5 -alkenyl groups mentioned hereinbefore in the definitions are the ethenyl, 1 -propen-1 -yl, 2-propen-1 -yl, 1 -buten-1 -yl, 2-buten-1 -yl, 3- buten-1-yl, 1-penten-1-yl, 2-penten-1 -yl, 3-penten-1 -yl, 4-penten-1 -yl, but-1-en- 2-yl, but-2-en-2-yl, but-1 -en-3-yl, 2-methyl-prop-2-en-1 -yl, pent-1 -en-2-yl, pent- 2-en-2-yl, pent-3-en-2-yl, pent-4-en-2-yl, pent-1 -en-3-yl, pent-2-en-3-yl, 2-

methyl-but-1-en-1 -yl, 2-methyl-but-2-en-1 -yl, 2-methyl-but-3-en-1 -yl or 2-ethyl- prop-2-en-1 -yl group,

Examples of the C2-5-alkynyl groups mentioned hereinbefore in the definitions are the ethynyl, 1 -propynyl, 2-propynyl, 1-butyn-1 -yl, 1-butyn-3-yl, 2-butyn-1-yl, 3-butyn-1 -yl, 1 -pentyn-1-yl, 1 -pentyn-3-yl, 1 -pentyn-4-yl, 2-pentyn-1 -yl, 2- pentyn-3-yl, 3-pentyn-1 -yl, 4-pentyn-1-yl, 2-methyl-1 -butyn-4-yl, 3-methyl-1 - butyn-1-yl or 3-methyl-1-butyn-3-yl group.

A 2nd embodiment of the present invention includes those compounds of general formula (I) wherein M, R ² -R ⁶ and A ⁴ -A ⁵ are defined as described in embodiment 1 and wherein

D denotes one of the following groups Ma or Mb

wherein

K ¹ and K ⁴ each independently of one another denote a bond, a -CH ₂ , -CHR ^7a - or a -CR ^7b R ^7c group, and wherein

_R 7a _/R 7b _/R 7c each independently of one another denote a fluorine atom or a methyl group, or two groups R ^7b /R ^7c together with the ring carbon atom may form a cyclopropyl ring, and

K ^z and K eeaacchh iinnddependently of one another denote a -CH ₂ , -CHR ^8a or -CR ^8b R ^8c - group, wherein

_R 8a _/R 8b _/R 8c

each independently of one another denote a methyl group,

or two groups R ^8b /R ^8c together with the ring carbon atom may form a cyclopropyl ring, and

R ¹ denotes a hydrogen atom or a Ci- ₃ -alkyl, or C ₃ - ₆ -cycloalkyl group,

and

A ¹ denotes CR ¹⁰ ,

A ² denotes CR ¹¹ ,

A ³ denotes CR ¹² ,

A ⁶ denotes either N or CR ¹³ ,

while R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, CF ₃ , cyano, methoxy, CF ₃ O, CHF ₂ O, CH ₂ FO- group.

A 3rd embodiment of the present invention includes those compounds of general formula (I), wherein D and M are defined as described in embodiment 1 or 2 and wherein

A ⁴ denotes CR ¹⁴ ,

A ⁵ denotes CR ¹⁵ ,

while R ¹⁴ and R ¹⁵ each independently of one another represent

a hydrogen atom, or a methyl, group, and

R ² denotes a hydrogen atom, and

R ³ denotes a hydrogen, fluorine, chlorine atom or a methoxy, methyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and

R ⁴ denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, C 1.3- methoxy, methyl or a hydroxy group, and

R ⁶ denotes a hydrogen atom.

A 4th embodiment of the present invention includes those compounds of general formula (I) wherein

D denotes one of the following groups Ma or Mb

wherein

K ¹ and K ⁴ each independently of one another denote a bond, a -CH ₂ , -CHR 7a- or a -CR ^7b R ^7c group, and wherein

_R 7a _/R 7b _/R 7c each independently of one another denote a fluorine arom or a methyl group or two groups R ^7b /R ^7c together with the ring carbon atom may form a cyclopropyl ring, and

K ² and K ³ each independently of one another denote a -CH ₂ , -CHR ^8a or -CR ^8b R ^8c - group, wherein

_R 8a _/R 8b _/R 8c each independently of one another denote a methyl group,

or two groups R ^8b /R ^8c together with the ring carbon atom may form a cyclopropyl ring, and

R ¹ denotes a hydrogen atom or a Ci _-3 -alkyl, or C _3-6 -cycloalkyl group,

and

A ¹ denotes CR ¹⁰ ,

denotes CR 1 1

A ³ denotes CR ¹² ,

A ⁶ denotes either N or CR ¹³ ,

while R ¹⁰ , R ¹¹ , R ¹² and R ¹³ each independently of one another denote

a hydrogen, fluorine or chlorine atom, or a methyl, methoxy, CF ₃ O,

CHF ₂ O, CH ₂ FO- group and

A ⁴ denotes CR ¹⁴ ,

A ⁵ denotes CR ¹⁵ ,

while R ¹⁴ and R ¹⁵ each independently of one another denote

a hydrogen atom, or a methyl group, and

R ² denotes a hydrogen atom, and

R ³ denotes a hydrogen, fluorine, chlorine atom or a methoxy, methyl or a hydroxy group, while the compounds glucuronidated at the hydroxy group may occur in vivo as active metabolites and

R ⁴ denotes a hydrogen, fluorine, chlorine or bromine atom or a cyano, Ci _-3 -

methoxy, methyl or a hydroxy group, and

R ⁶ denotes a hydrogen atom and

M denotes a phenyl or pyridyl ring optionally substituted by R ⁷ and R ⁸ , wherein

R ⁷ denotes a fluorine, chlorine or bromine atom or an ethynyl group, and

R ⁸ denotes a hydrogen or fluorine atom.

A fifth embodiment of the present invention includes those compounds of general formula (I) which are glucuronidated at a hydroxy group.

According to the invention the compounds of general formula (I) are obtained by methods known per se, for example by the following methods:

(a) The preparation of a compound of general formula (I)

wherein D, M, A ⁴ , A ⁵ and R ² to R ⁶ are defined as mentioned in embodiment 1 ,

and which may optionally be protected at any amino, hydroxy, carboxy or thiol groups by common protective groups such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which may be cleaved by methods known from the literature, is described in the examples or may be carried out for example according

to formula scheme 1 or analogously to the methods of synthesis described in WO2002/42270, WO2004/58728, WO2000/09480, US6642224 or in US20030195193.

Diagram 1

i) Acylation

Compound of Formula (I)

(Ia) on

wherein

Q denotes a leaving group or a group which may be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy,

Ci _-4 -alkyloxy, alkyloxycarbonyloxy, 4-nitrophenyloxy, a thchloromethyl or acyloxy group, and components III and/or IV may optionally be derivatised at reactive groups by a protective group known from the literature.

The reaction steps i) -ii) shown in Scheme 1 may be carried out in the manner described in the Examples or according to the conditionsdesc in the literature, for example as follows:

i) acylation of an amine (IV) with an optionally activated carboxylic acid (III) :

The acylation is conveniently carried out with a corresponding halide or anhydride in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether,

tetrahydrofuran, dioxane, benzene, toluene, acetonitrile, dimethylformannide, dimethylsulphoxide, sodium hydroxide solution or sulpholane, optionally in the presence of an inorganic or organic base at temperatures between -20 and 5 200 ⁰ C, but preferably at temperatures between -10 and

100 ⁰ C.

The acylation may however also be carried out with the free acid optionally in the presence of an acid-activating agent or io a dehydrating agent, for example in the presence of ethyl-1 - ethoxy-1 ,2-dihydroquinoline-i -carboxylate, isobutyl chloroformate, thionyl chloride, trimethylchlorosilane, hydrogen chloride, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, is phosphorus pentoxide, propanephosphonic acid cycloanhydride, λ/./V-dicyclohexylcarbodiimide, A/./V-dicyclohexylcarbodiimide/camphorsulphonic acid, λ/,λ/'-dicyclohexylcarbodiimide/λ/-hydroxysuccinimide or 1 -hydroxy-benzotriazole, λ/./V-carbonyldiimidazole,

20 O-(benzothazol-1 -yl)-/V,/V,/V\/V-tetramethyl-uronium tetrafluoroborate/λ/-methylmorpholine, O-(benzotriazol-1 -yl)- A/./V./V./V-tetramethyl-uronium tetrafluoroborate//V- ethyldiisopropylamine, O-(7-azabenzotriazol-1 -yl)- /V,/V,/V',/V'-tetramethyluronium-hexafluorophosphate//V-

25 methylmorpholine, O-pentafluorophenyl-λ/,λ/,λ/',λ/'- tetramethyluronium-hexafluorophosphate/thethylamine, λ/./V-thionyldiimidazole or triphenylphosphine/carbon tetrachloride, optionally with the addition of an auxiliary base such as sodium hydroxide solution, caesium,

30 potassium or sodium carbonate or hydrogen carbonate or an amine base such as pyridine, thethylamine, N- methylmorpholine or diisopropylethylamine at temperatures between -20 and 200°C, but preferably at temperatures between -10 and 160 ⁰ C.

35

The acylation may also be carried out with a carboxylic acid ester (V) or (Vl) and the amine (IVa) by activation with

trimethylal u minium.

Other methods of amide coupling are described for example in P. D. Bailey, I. D. Collier, K.M. Morgan in "Comprehensive 5 Functional Group Interconversions", Vol. 5, page 257ff.,

Pergamon 1995, or in the Houben-Weyl Supplementary Volume 22, published by Thieme, 2003, and the literature cited therein.

io ii) Cleaving a protective group

Any protecting group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. In water, isopropanol/water, tetrahydrofuran/water or is dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at

20 temperatures between 0 and 100 ⁰ C, preferably at temperatures between 10 and 50 ⁰ C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with

25 hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as tetrahydrofuran, methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at

30 temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

However, a protective group may also be cleaved by the 35 methods described by T.W. Greene, P. G. M. Wuts in

"Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

(b) The components of general formula (III)

D-C(=O)-Q III

wherein D is defined as in embodiments 1 to 4,

which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups, such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which can be cleaved by methods known from the literature in the course of the synthesis sequence to produce compounds of formula (I), and

Q denotes a leaving group or a group which can be converted in-situ into a leaving group, such as for example a halogen atom, a hydroxy, Ci _-4 -alkyloxy, alkyloxycarbonyloxy, 4-nitrophenyloxy, a thchloromethyl or acyloxy group, are known from the literature, or their synthesis is described in the Examples, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example in WO2000/09480; S. Komoriya et al. Bioorg. Med. Chem. 2006, 14, 1309,

US2005/0020645.

(c) The components of general formula IV

wherein M, A _\ 4 , A _λ 5 , _D R4 , _D R3 , n R6 and R ^z are defined as described in the embodiments,

which may optionally be protected at any amino, hydroxy, carboxy or thiol groups present by common protective groups, such as for example those described in T.W. Greene, P. G. M. Wuts in "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999, and the protective groups of which can be cleaved by methods known from the literature in the course of the synthesis sequence to produce compounds of formula (I), are known from the literature, or their synthesis is described in the embodiments by way of example, or they may be prepared for example using methods of synthesis known from the literature or analogously to methods of synthesis known from the literature, as described for example in US2003/0195193, WO2002/42270, US6642224.

In the reactions described above any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction.

For example, a suitable protecting group for a hydroxy group may be the methoxy, benzyloxy, trimethylsilyl, acetyl, benzoyl, tert. butyl, trityl, benzyl or tetrahydropyranyl group.

Suitable protecting groups for a carboxyl group might be the trimethylsilyl, methyl, ethyl, tert. butyl, benzyl or tetrahydropyranyl group.

Suitable protecting groups for an amino, alkylamino or imino group might be the acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert.butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, the phthalyl group.

For example, a suitable protective group for an ethynyl group may be a trimethylsilyl, diphenylmethylsilyl, tert.butyldimethylsilyl or a 1 -hydroxy- 1 -methyl - ethyl group.

Other protective groups which may be used and their cleaving are described in T.W. Greene, P. G. M. Wuts, "Protective Groups in Organic Synthesis", Wiley, 1991 and 1999.

Any protective group used may optionally subsequently be cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodothmethylsilane, at temperatures between 0 and 100 ⁰ C, preferably at temperatures between 10 and 50 ⁰ C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved hydrogenolytically, for example, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid, optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50°C, but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, preferably, however, 1 to 5 bar.

A methoxybenzyl group may also be cleaved in the presence of an oxidising agent such as cehum(IV)ammonium nitrate in a solvent such as methylene chloride, acetonithle or acetonitrile/water at temperatures of between 0 and 50 ⁰ C, but preferably at ambient temperature.

A methoxy group is expediently cleaved in the presence of boron tribromide in a solvent such as methylene chloride at temperatures between -35 and -25°C.

A 2,4-dimethoxybenzyl group is preferably cleaved in trifluoroacetic acid in the presence of anisol.

A te/t.butyl or te/t.butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as methylene chloride, dioxane or ether.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50°C.

An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(thphenylphosphine)-palladium(0), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1 ,3-dimedone at temperatures between 0 and 100 ⁰ C, preferably at ambient temperature and under an inert gas, or by treating with a catalytic amount of tris-(thphenylphosphine)-rhodium(l)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1 ,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70 ⁰ C.

Moreover the compounds of general formula (I) obtained may be resolved into their enantiomers and/or diastereomers.

Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and ENeI E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971 ) into their optical antipodes and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartahc acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (-)-menthol and an optically active acyl group in amides may be a (+)- or (-)-menthyloxycarbonyl, for example.

Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonic acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and thethanolamine.

As already mentioned, the compounds of general formula I as well as the tautomers, the enantiomers, the diastereomers and the physiologically acceptable salts thereof have valuable pharmacological properties, particularly an antithrombotic activity, which is preferably based on an effect on thrombin or factor Xa, for example on a thrombin-inhibiting or factor Xa-inhibiting activity, on a prolonging effect on the aPTT time and on an inhibiting effect on related serine proteases such as e.g. urokinase, factor Vila, factor IX, factor Xl and factor XII.

The compounds listed in the experimental section may be investigated for their effect on the inhibition of factor Xa as follows:

Method:

Enzyme-kinetic measurement with chromogenic substrate. The quantity of p- nitroaniline (pNA) released from the colourless chromogenic substrate by human factor Xa is determined photometrically at 405 nm. It is proportional to the activity of the enzyme used. The inhibition of the enzyme activity by the test substance (in relation to the solvent control) is determined at various concentrations of test substance and from this the IC ₅ O is calculated, as the concentration which inhibits the factor Xa used by 50 %.

Material:

Tris(hydroxymethyl)-aminonnethane buffer (10O mMoI) and sodium chloride (150 mMol), pH 8.0 plus 1 mg/ml Human Albumin Fraction V, protease-free.

Factor Xa (Calbiochem), spec. Activity: 217 IU/mg, final concentration: 7 IU/ml for each reaction mixture

Substrate S 2765 (Chromogenix), final concentration: 0.3 mM/l (1 KM) for each reaction mixture

Test substance: final concentration 100, 30, 10, 3, 1 , 0.3, 0.1 , 0.03, 0.01 , 0.003, 0.001 μMol/l

Procedure:

10 μl of a 23.5-times concentrated starting solution of the test substance or solvent (control), 175 μl of TRIS/HSA buffer and 25 μl of a 65.8 U/L Factor Xa working solution are incubated for 10 minutes at 37°C. After the addition of 25 μl of S 2765 working solution (2.82 mMol/l) the sample is measured in a photometer (SpectraMax 250) at 405 nm for 600 seconds at 37°C.

Evaluation:

1. Determining the maximum increase (deltaOD/minutes) over 21 measuring points.

2. Determining the % inhibition based on the solvent control.

3. Plotting a dosage/activity curve (% inhibition vs substance concentration).

4. Determining the IC ₅ O by interpolating the X-value (substance concentration) of the dosage/activity curve at Y = 50 % inhibition.

All the compounds tested had an IC ₅ O value of less than 100 μmol/L.

The compounds prepared according to the invention are generally well tolerated.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the prevention and treatment of deep leg vein thrombosis, thrombophlebitis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases, and for preventing and treating pulmonary embolism, disseminated intravascular coagulation and severe sepsis, for preventing and treating DVT in patients with exacerbation of COPD, for treating ulcerative colitis, for treating and preventing coronary thrombosis, for preventing stroke and the occlusion of shunts.

In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with alteplase, reteplase, tenecteplase, staphylokinase or streptokinase, for preventing long-term restenosis after PT(C)A, for the prevention and treatment of ischaemic events in patients with all forms of coronary heart disease, for preventing metastasis and the growth of tumours and inflammatory processes, e.g. in the treatment of pulmonary fibrosis, for preventing and treating rheumatoid arthritis, for preventing and treating fibrin- dependent tissue adhesions and/or the formation of scar tissue and for promoting wound healing processes.

The compounds specified may also be used as anticoagulants in connection with the preparation, storage, fractionation or use of whole blood or in invasive therapies, e.g. for coating prostheses, artificial heart valves and catheters for reducing the risk of thrombosis.

In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are also suitable for treating Alzheimer's and Parkinson ^' s disease. One rationale for this can be seen for example in the following findings, from which it can be concluded that thrombin inhibitors or factor Xa inhibitors, by inhibiting thrombin formation or activity, could be valuable drugs for treating Alzheimer's and Parkinson ^' s disease. Clinical and experimental studies indicate that neurotoxic mechanisms, for example the inflammation that accompanies the activation of proteases of the clotting cascade, are involved in the dying off of neurones following brain damage. Various studies indicate an involvement of thrombin in neurodegenerative

processes, e.g. following a stroke, repeated bypass operations or traumatic brain injury. An increased thrombin activity was able to be detected for example some days after peripheral nerve damage. It was also shown that thrombin causes neurite retraction and glia proliferation, and apoptosis in primary cultures of neurones and neuroblastoma cells (for an overview see: Neurobiol. Aging, 2004, 25(6), 783-793). In addition, various in vitro studies on the brains of patients with Alzheimer's disease indicate that thrombin plays a part in the pathogenesis of this disease (Neurosci. Lett., 1992, 146, 152-54). An accumulation of immunoreactive thrombin has been detected in neurite plaques in the brains of Alzheimer's patients. It was demonstrated in vitro that thrombin also plays a part in the regulation and stimulation of the production of Amyloid Precursor Protein (APP) as well as in the cleaving of APP into fragments which can be detected in the amyloid plaques in the brains of Alzheimer's patients. It has also been shown that thrombin-induced microglial activation in vivo leads to the degeneration of nigral dopaminergic neurones. These findings lead one to conclude that microglial activation, triggered by endogenous substance(s) such as thrombin, for example, are involved in the neuropathological process of the cell death of dopaminergic neurones, such as occurs in patients with Parkinson's disease (J. Neurosci., 2003, 23, 5877-86).

The new compounds and the physiologically acceptable salts thereof can also be used for the prevention and treatment of arterial vascular diseases in combination therapy with lipid-lowering active substances such as HMG-CoA reductase inhibitors and vasodilators, particularly ACE inhibitors, angiotensin Il antagonists, renin inhibitors, β-receptor antagonists, α-receptor antagonists, diuretics, Ca-channel blockers, or stimulators of soluble guanylate cyclase.

By increasing the antithrombotic activity the new compounds and the physiologically acceptable salts thereof can also be used in combination therapy with other anticoagulants such as, for example, unfractionated heparin, low-molecular heparin, fondaparinux or direct thrombin inhibitors, for example recombinant hirudine or "active-site" thrombin inhibitors.

The new compounds and the physiologically acceptable salts thereof may be used therapeutically in conjunction with acetylsalicylic acid, with inhibitors of platelet aggregation such as fibrinogen receptor antagonists (e.g. abciximab, eptifibatide, tirofiban, roxifiban), with physiological activators and inhibitors of

the clotting system and the recombinant analogues thereof (e.g. protein C, TFPI, antithrombin), with inhibitors of ADP-induced aggregation (e.g. clopidogrel, prasugrel, ticlopidine), with P ₂ T receptor antagonists (e.g. cangrelor) or with combined thromboxane receptor antagonists/synthetase inhibitors (e.g. terbogrel).

The dosage required to achieve such an effect is appropriately 0.01 to 3 mg/kg, preferably 0.03 to 1.0 mg/kg by intravenous route, and 0.03 to 30 mg/kg, preferably 0.1 to 10 mg/kg by oral route, in each case administered 1 to 4 times a day.

For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetylstearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.

Experimental section

The following Examples are intended to illustrate the invention, without restricting its scope.

As a rule, melting points and/or IR, UV, ¹ H-NMR and/or mass spectra have been obtained for the compounds prepared. Unless otherwise stated, Rf values were obtained using ready-made silica gel 60 F ₂ S ₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05714) without chamber saturation. The R _f values obtained under the name Alox were determined using ready-made aluminium oxide 60 F ₂₅₄ TLC plates (E. Merck, Darmstadt, Item no. 1.05713) without chamber saturation. The Rf values obtained under the name Reversed-phase-8 were determined using ready-made RP-8 F ₂₅₄₈ TLC plates (E. Merck, Darmstadt, Item no. 1.15684) without chamber saturation. The ratios given for the eluants refer to units by volume of the solvents in question. Chromatographic purification was done using silica gel supplied by Messrs

Millipore (MATREX™, 35-70 μm). If the configuration is not specified in detail, it is unclear whether the compound in question is a pure stereoisomer or a mixture of enantiomer and diastereomer.

The following abbreviations are used in the descriptions of the tests.

DCM dichloromethane

DIPEA /V-ethyl-diisopropylamine

DMF N, N-ύ imethylformam ide

EtOH ethanol sat. saturated h hour(s)

HATU O-(7-azabenzotriazol-1 -yl)-/V,/V,/V',/V'-tetramethyluronium hexafluorophosphate i. vac. in vacuo cone. concentrated min minute(s)

NMM /V-methyl-morpholine

Rf retention factor

Rt retention time

TBTU O-(benzotriazol-1 -yl)-/V,/V,λλ/V-tetramethyluronium tetrafluoroborate

TEA triethylamine

TFA trifluoroacetic acid

THF tetrahydrofuran

Intermediate:

intermediate A (R)-2,3-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6-carboxylic acid

(a) (Ss,R)-2-methyl-propane-2-sulphinic acid-[2-(5-bromo-2-cyano-phenyl)-1 - methyl-ethyl]-amide

6.0 ml (42.8 mmol) diisopropylamine are dissolved in 80 ml THF, slowly combined with 26.7 ml (42.8 mmol) butyllithium solution (1.6 M in n-hexane) at 0 ⁰ C, stirred for 30 min. Then this solution is cooled to -78°C and a solution of 4.0 g (20.4 mmol) 4-bromo-2-methyl-benzonithle in 15 ml THF is slowly added dropwise. This mixture is stirred for 70 minutes at -78°C and then a solution of 1.5 g (10.2 mmol) (Ss)-ethylidene-N-tert.-butyl-sulphinamide (prepared analogously to J. Ellman et al. J. Org. Chem. 2001 , 66, 8772 from acetaldehyde and (Ss)-tert.-butylsulphinamide) in 15 ml THF is added dropwise. The mixture is stirred for 2.5 hours at -70 to -65°C. The reaction mixture is combined with 5 ml sat. Ammonium chloride solution and after thawing it is combined with water and ethyl acetate. The aqueous phase is extracted three times with ethyl acetate, the combined organic phases are dried on sodium sulphate and evaporated to dryness in vacuo. The residue is purified by column chromatography on silica gel (eluant DCM/MeOH 100:3) Yield: 830 mg (24%) Rt value: 1.45 min (Method B) Mass spectrum: (M+H) ⁺ = 343/345 (bromine isotope)

(b) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as the hydrochloride salt)

830 mg (2.4 mmol) (Ss,R)-2-methyl-propane-2-sulphinic acid-[2-(5-bromo-2- cyano-phenyl)-1 -methyl-ethyl]-amide are dissolved in 10 ml of ethanolic hydrochloric acid (40%) and stirred for 3 hours at 60 ⁰ C and then for 16 hours at

RT. Then the reaction mixture is evaporated to dryness.

Yield: quantitative

Rt value: 0.97 min (Method B)

Ci ₀ HnBrN ₂ x HCI (239.12) Mass spectrum: (M+H) ⁺ = 239/241 (bromine isotope)

(c) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1 -one

480 mg (1.7 mmol) (R)-2-(2-amino-propyl)-4-bromo-benzonitrile (as the hydrochloride salt) are dissolved in 5 ml 10 N sodium hydroxide solution and stirred for 16 hours at 80 ⁰ C. Then the reaction mixture is acidified with hydrochloric acid and extracted three times with ethyl acetate. The combined

organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by RP-HPLC. Yield: 264 mg (63%) Rt value: 1.31 min (Method B) CioHioBrNO (240.10)

Mass spectrum: (M+H) ⁺ = 240/242 (bromine isotope)

(d) (R)-6-bromo-2,3-dimethyl-3,4-dihydro-2H-isoquinolin-1 -one

426 mg (1.7 mmol) (R)-6-bromo-3-methyl-3,4-dihydro-2H-isoquinolin-1 -one are dissolved in 3 ml DMF and at 0 ⁰ C combined with 80 mg (2 mmol) sodium hydride (60% in mineral oil dispersion). After 10 minutes 122 μl (1.9 mmol) methyl iodide are added dropwise, and the mixture is stirred for 16 hours at RT. Then the reaction mixture is mixed with water and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. The residue is purified by flash chromatography on silica gel (eluant DCM/MeOH 20:1 ). Yield: 234 mg (52%) Rt value: 1.40 min (Method B)

Mass spectrum: (M+H) ⁺ = 254/256 (bromine isotope)

(e) methyl (R)-2,3-dimethyl-1 -oxo-1 ,2,3,4-tetrahydroisoquinoline-6- carboxylate

In an inertised autoclave 100 mg (394 μmol) (R)-6-bromo-2,3-dimethyl-3,4- dihydro-2H-isoquinolin-1 -one are dissolved in a mixture of 20 ml MeOH and 5 ml DMF and combined with 20 mg (89 μmol) palladium(ll)-acetate, 70 mg (86 μmol) 1 ,1 '-bis-(diphenylphospino)-ferrocene-dichloropalladium(ll) complex with DCM and with 110 μl (08. mmol) TEA. Then 2 bar carbon monoxide are pressed in and the mixture is shaken for 16 hours. Then the same amount of palladium(ll)-acetate and 1 ,1 '-bis-(diphenylphospino)-ferrocene- dichloropalladium(ll) complex with DCM is added twice more and in each case the mixture is shaken for a further 24 hours at the same temperature. The mixture is left to cool and filtered to remove the catalyst mixture. The filtrate is evaporated down i. vac. The residue thus obtained is purified by flash chromatography on silica gel (eluant PE/EE 1 :1 ). The fractions containing

product are combined and concentrated i. vac. The crude product is purified by RP-HPLC. Yield: 62 mg (68%) Rt value: 1.22 min (Method B) Ci ₃ Hi ₅ NO ₃ (233.26)

Mass spectrum: (M+H) ⁺ = 234

(f) methyl (R)-2,3-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6-carboxylate

60 mg (257 μmol) methyl (R)-2,3-dimethyl-1-oxo-1 ,2,3,4-tetrahydroisoquinoline- 6-carboxylate are dissolved in 2 ml THF under an argon atmosphere and combined with 100 μl (542 μmol) diphenylsilane at RT. Then 20 mg (21 μmol) of carbonylhydridotris(thphenylphosphine)rhodium(l) are added and the mixture is stirred for two hours. A further 50 μl diphenylsilane and 10 mg carbonylhydridotris(triphenylphosphine)rhodium(l) are added and the mixture is stirred for a further 2.5 hours. Then the reaction mixture is evaporated down i. vac. and purified by flash chromatography on silica gel (eluant DCM/MeOH 95:5). Yield: 44 mg (78%) Rt value: 0.93 min (Method B) Ci ₃ Hi ₇ NO ₂ (219.28) Mass spectrum: (M+H) ⁺ = 220

(g) (R)-2,3-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6-carboxylic acid (as the hydrochloride salt)

44 mg (201 μmol) methyl (R)-2,3-dimethyl-1 ,2,3,4-tetrahydroisoquinoline-6- carboxylate are dissolved in 2 ml 6 N hydrochloric acid and stirred at 6O ⁰ C for one day. Then the reaction mixture is concentrated i. vac. and lyophilised. Yield: 47 mg (97%)

Rt value: 0.62 min (Method B)

Ci ₂ Hi ₅ NO ₂ x HCI (205.26)

Mass spectrum: (M+H) ⁺ = 206

intermediate B

2-methyl-2,3-dihydro-1 H-isoindole-5-carboxylic acid

(a) methyl 2,3-dihydro-1 H-isoindole-5-carboxylate

2,3-dihydro-1 H-isoindole-5-carboxylic acid (as the hydrochloride salt; prepared analogously to EP 0 528 369), methanol and thionyl chloride are mixed together while cooling with an ice bath. The ice bath is removed and the mixture is refluxed for three hours. Then the mixture is evaporated down i. vac. and combined with 1 N sodium hydroxide solution. The aqueous phase is extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. Rt value: 0.49 min (Method D) Mass spectrum: (M+H) ⁺ = 178

(b) methyl 2-methyl-2,3-dihydro-1 H-isoindole-5-carboxylate

1.2 g (6.6 mmol) methyl 2,3-dihydro-1 H-isoindole-5-carboxylate are dissolved in 5 ml formic acid, combined with 2 ml formalin solution (37% solution in water), heated to 70 ⁰ C for 3.5 hours and stirred for 16 hours at RT. The reaction mixture is evaporated down i. vac. and combined with 0.1 N sodium hydroxide solution and extracted three times with ethyl acetate. The combined organic phases are dried on sodium sulphate, filtered and evaporated down i. vac. Yield: 530 mg (42%)

Rt value: 0.60 min (Method E)

CiiHi ₃ NO ₂ (191 .23)

Mass spectrum: (M+H) ⁺ = 192

(c) 2-methyl-2,3-dihydro-1 H-isoindole-5-carboxylic acid (as the hydrochloride salt)

Prepared analogously to Example Ag from methyl 2-methyl-2,3-dihydro-1 H- isoindole-5-carboxylate.

Yield: 80%

Rt value: 0.25 min (Method B)

C10H11NO2 x HCI (177.20)

Mass spectrum: (M+H) ⁺ = 178

Example 1

3-methyl-2,3,4,5-tetrahydro-1 /-/-benzo[c/]azepin-7-carboxylic acid-[2-(5-chloro- pyridin-2-ylcarbamoyl)-4-chloro-6-hydroxy-phenyl]-amide

(a) 3-methyl-2,3,4,5-tetrahydro-1 /-/-benzo[c/]azepine-7-carboxylic acid X HCI

0.73 ml 50% NaOH solution are carefully added dropwise to a mixture of 1.65 g (6.9 mmol) 2,3,4,5-tetrahydro-1 H-benzo[d]azepine-carboxylic acid (prepared analogously to V. Austel et al., EP528369) in 2.6 ml formic acid. Then 0.77 ml formalin solution are added and the mixture is heated to 70 ⁰ C for 2 h. Then it is concentrated in vac, the crude product is combined with water and cone. HCI, concentrated in vac. again and washed with cold water. Yield: 84%

Ci ₂ Hi ₅ NO ₂ (205.24) x HCI Rf value: 0.63 (RP-8; methanol / 5% sodium chloride solution 6:4) Mass spectrum: (M+H) ⁺ = 206

(b) 3-methyl-2,3,4,5-tetrahydro-1 H-benzo[c/]azepine-7-carboxylic acid-[2-(5- chloro-pyhdin-2-ylcarbamoyl)-4-chloro-6-hydroxy-phenyl]-amid e

A mixture of 0.10 g (0.41 mmol) 3-methyl-2,3,4,5-tetrahydro-1 /-/- benzo[c/]azepine-7-carboxylic acid X HCI, 0.11 ml NMM, 0.16 g HATU and 5.0 ml THF is stirred for 15 min and then combined with 60 mg (0.201 mmol) 2- amino-3-hydroxy-5-chloro-λ/-(5-chloro-pyhdin-2-yl)-benzamid e and stirred for 18

h. It is concentrated in vacuo, the mixture is taken up in ethyl acetate and washed once each with sat. NaHCO ₃ solution, water and sat. NaCI solution, then dried with Na2SO ₄ and concentrated in vacuo. The crude product is stirred for 2 h with 4.0 ml of methanol and 0.37 ml of 2N NaOH. Then it is concentrated in vacuo, mixed with water, extracted 2x with ethyl acetate, the org. phase is dried with Na ₂ SO ₄ , evaporated down and purified by chromatography (silica gel; Eluant: CH ₂ Cl2/ethanol 9:1 ). C ₂₄ H ₂₂ CI ₂ N ₄ O ₃ (485.36) Rf value: 0.2 (silica gel; CH ₂ CI ₂ /ethanol 95:5) Mass spectrum: (M+H) ⁺ = 485/487/489 chlorine isotope

Example 2

2-methyl-1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid-[2-(5-chloro-pyridin-2- ylcarbamoyl)-4-chloro-6-hydroxy-phenyl]-amide

(a) methyl 2-methyl-1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylate

2.6 ml of 50% NaOH solution are carefully added dropwise to a mixture of 11.3 g (50 mmol) of methyl 1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylate in 22.5 ml formic acid. Then 4.46 ml formalin solution are added and the mixture is heated to 70 ⁰ C for 2.5 h. Then it is concentrated in vacuo, the crude product is combined with water and cone. HCI, concentrated again in vacuo and washed with cold water. Then 170 ml of 6 M HCI were added and the mixture was stirred for 7 days at 20-40 ⁰ C. The reaction mixture was evaporated down in vacuo. Yield: 97%

C _H H _{I 3} NO ₂ (191.22) x HCI

Rf value: 0.69 (RP-8; methanol / 5% sodium chloride solution 6:4)

Mass spectrum: (M+H) ⁺ = 192

(b) 2-methyl-1 ,2,3,4-tetrahydro-isoquinoline-6-carboxylic acid-[2-(5-chloro- pyridin-2-ylcarbannoyl)-4-chloro-6-hydroxy-phenyl]-annide

The title compound was prepared analogously to Example 1 b.

C ₂₃ H ₂₀ CI ₂ N ₄ O ₃ (471.34)

Rf value: 0.25 (silica gel; CH ₂ CI ₂ /ethanol 95:5)

Mass spectrum: (M+H) ⁺ = 471/473/475 chlorine isotope

The following compounds may be prepared analogously to the synthesis steps described above or analogously to methods of synthesis known from the literature, from bicyclic carboxylic acid and anthranilic acid derivatives known from the literature or obtainable by methods of synthesis known from the literature:

The Examples that follow describe the preparation of some pharmaceutical formulations which contain as active substance any desired compound of general formula I:

Example A

Dry ampoule containing 75 mg of active substance per 10 ml

Composition:

Active substance 75.0 mg

Mannitol 50.0 mg water for injections ad 10.0 ml

Preparation:

Active substance and mannitol are dissolved in water. After packaging the solution is freeze-dried. To produce the solution ready for use for injections, the product is dissolved in water.

Example B

Dry ampoule containing 35 mg of active substance per 2 ml

Composition:

Active substance 35.0 mg

Mannitol 100.0 mg water for injections ad 2.0 ml

Preparation:

Active substance and mannitol are dissolved in water. After packaging, the solution is freeze-dried.

To produce the solution ready for use for injections, the product is dissolved in water.

Example C

Tablet containinq 50 mq of active substance

Composition:

(1 ) Active substance 50.0 mg

(2) Lactose 98.0 mg

(3) Maize starch 50.0 mg

(4) Polyvinylpyrrolidone 15.0 mg

(5) Magnesium stearate 2.0 mq 215.0 mg

Preparation:

(1 ), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 9 mm.

Example D

Tablet containing 350 mg of active substance Composition:

(1 ) Active substance 350.0 mg

(2) Lactose 136 .0 mg

(3) Maize starch 80 .0 mg

(4) Polyvinylpyrrolidone 30. 0 mg

(5) Magnesium stearate 4. 0 mq

600.0 mg

Preparation: (1 ), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granulated material. From this mixture tablets are pressed, biplanar, faceted on both sides and with a dividing notch on one side. Diameter of the tablets: 12 mm.

Example E

Capsules containing 50 mg of active substance

Composition:

(1 ) Active substance 50.0 mg

(2) Dried maize starch 58.0 mg

(3) Powdered lactose 50.0 mg

(4) Magnesium stearate 2.0 mg

160.0 mg

Preparation:

(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 3 hard gelatine capsules in a capsule filling machine.

Example F

Capsules containinα 350 mq of active substance

Composition:

(1 ) Active substance 350.0 mg

(2) Dried maize starch 46.0 mg

(3) Powdered lactose 30.0 mg

(4) Magnesium stearate 4.0 mq 430.0 mg

Preparation:

(1 ) is triturated with (3). This trituration is added to the mixture of (2) and (4) with vigorous mixing.

This powder mixture is packed into size 0 hard gelatine capsules in a capsule filling machine.

Example G Suppositories containing 100 mq of active substance

1 suppository contains:

Active substance 100.0 mg

Polyethyleneglycol (M.W. 1500) 600.0 mg Polyethyleneglycol (M.W. 6000) 460.0 mg

Polyethylenesorbitan monostearate 840.0 mq

2,000.0 mg

Preparation:

The polyethyleneglycol is melted together with polyethylenesorbitan monostearate. At 40 ⁰ C the ground active substance is homogeneously

dispersed in the melt. It is cooled to 38°C and poured into slightly chilled suppository moulds.