CA2138167A1 - Use of condensed bis-(3,4-dihydro-1-pyridinyl)methanes for treating crohn's disease, ulcerative colitis, chronic inflammatory processes and as antiproliferative agents - Google Patents

Abstract

Benzo- and thieno-3,4-dihydropyridine derivates having general formula (I), in which D stands for a group having formula (Ia), A and B standing for a benzo- or thieno residue, R2, R3, R5, R6, R7, R11, R12, m and n being as defined in the description, and their pharmaceutically tolerable salts, are used for preparing agents for treating chronic inflammatory processes, colitis ulcerosa and Crohn's disease, and antiproliferative agents.

Description

FILE. rlrd IN THIS A~
TC~T Il~ANSL~AT~ON
S013334J.60 Use of condensed bis-(3.4-dihydro-1-pyridinyl)methanes for treating Crohn's disease. ulcerative col;tis.
chronic inflammatory processes and as antiproliferative agents The invention relates to condensed bis-(3,4-dihydro-1-pyridinyl)methanes and the use thereof for producing pharmaceutical preparations for the treatment of chronic inflammatory processes, ulcerative colitis and Crohn's disease and for producing preparations having an antiproliferative effect.

The compounds mentioned above correspond to general formula I

2 ~3 \~
1 1 )m~ ~ I

wherein A denotes a benzo- or thieno- group;

R2 and R3 independently of each other denote hydrogen or (C15)alkyl or, together with the carbon atom to which they are bound, a 5- or 6-membered carbocyclic group;

R11 denotes (C14)alkyl, halogen (F, Cl, Br, I), hydroxy, (C14)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido, or two adjacent R11 substituents together denote -O-CH2-O- or -0-CH2-CH2-O-;

m denotes 0, 1, 2 or 3, if A is a benzo group, and 0, 1 or 2, if A is a thieno group;

and D denotes a group of formula Ia - 21381~7 ~ N\
1 ~ R6 Ia (Rl~ )n~) ~R7 whilst in the group of formula Ia B denotes a benzo- or thieno- group;

R1 denotes hydrogen, (C11O)alkyl, phenyl, phenyl(C1s)alkyl, (C14)alkoxy or -NHCOX (wherein X is (Cl 5)alkyl);

R5 denotes hydrogen, (C14)alkyl or hydroxymethyl;

R6 and R7 independently of each other denote hydrogen or (C15)alkyl or together with the carbon atom to which they are bound denote a 5- or 6-membered carbocyclic groupi R12 denotes (C14)alkyl, halogen (F, Cl, Br, I), hydroxy, (C14)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido, or two adjacent R12 substituents together denote -O-CH2-O- or -O-CH2-CH2-O-;

and n denotes 0, 1, 2 or 3 if B is a benzo group and 0, 1 or 2 if B is a thieno group;

and the pharmaceutically acceptable salts thereof with lnorganic or organlc acids.

The term "carbocyclic group" formed by R2 and R3 or R6 and R7 and the associated carbon atom to which they are bound, preferably refers to a saturated 5- or 6-membered - 213~167 carbocyclic group.

Compounds of formula I wherein D is the group of formula Ia are hereinafter referred to as compounds of formula VIII

( R 1 1 )r~

~ N ~ VIII

( 12 n ~J R7 Compounds of formula VIII wherein R5 is hydrogen form tautomers of formulae VIIIa and VIIIb, 2`x~'R3 R~ R3 R ) ~ ~ ~ ( ll)~ ~\ N - R ~
~ ~ ~ VIIIa - ~ VIIIb 12 n~ ~ (Rl 2 )n ~ BJ

wherein Rs again denotes hydrogen. The definition of formulae I and VIII also includes the above-mentioned tautomers.

Kobor and Jeno writing in Szegedi Tonarkepzo Foiskola Tud. Kozl. 975, pages 145-153 (cf. Chem. Abstr. 87;
134980Z) described the compound of general formula VIII

_ 21381~7 R2 R~

(Rl,Jm (~,1 ,R5 F~l~ VIII
~I~"R~;
(Rl2)n~ ) R7 and the preparation thereof, wherein R1, R2, R3, R5, R6 and R7 denote hydrogen and the substituted groups A and B
denote the group C~30 C~30 This publication does not contain any information on physiological effects of this compound. In European Patent Application 288 048 the compounds of general formula I are described as compounds having a cardioprotective and cerebroprotective effect.

Of the compounds of formula VIII, the following may be mentioned as having particular interest according to the invention:

-) compounds VIII, wherein Rl denotes hydrogen, (C110)alkyl, phenyl(C15)alkyl or -N~COX (wherein X
is (Cl 5)alkyl);

R11 and R12 independently of each other denote (Cl4)alkyl, hydroxy, (C14)alkoxy, methanesulphonyloxy or methanesulphonamido, or two : 213~167 adjacent substituents Rll and Rl2 together denote -O-CH2-O- or -O-CH2-CH2-O-i -) compounds VIII, wherein Rl is hydrogen, (Cl1O)alkyl or -NHCOX (wherein X is (Cl5)alkyl);

R2, R3, R6 and R7 independently of one another denote hydrogen or R2 together with R3 and/or R6 together with R7 and the associated carbon atom to which they are bound denote a 5- or 6-membered carbocyclic group;

Rll and Rl2 independently of each other denote hydroxy, (Cl4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents Rll and Rl2 together denote -O-CH2-O- or -o-cH2-cH2-o- i -) particularly compounds wherein Rl denotes hydrogen, (Cl6)alkyl or -NHCOCH3 and/or R5 denotes hydrogen, methyl or hydroxymethyl and/or R2, R3, R6 and R7 independently of one another denote hydrogen or R2 together with R3 and/or R6 together with R7 and the associated carbon atom to which they are bound denote a 5-membered carbocyclic group and/or Rll and Rl2 independently of each other denote hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent substituents Rll and Rl2 together represent -O-CH2-O-.

Particular mention should be made of compounds -) wherein Rl and R5 denote hydrogen, and/or wherein R2, R3, R6 and R7 denote hydrogen or wherein R2 and R3 or R6 `- 2138167 and R7 together denote -(CH2) 4-; particularly compounds wherein A and B independently of each other each represent a thieno group, preferably 2,3-thieno, preferably an unsubstituted thieno group or compounds -) wherein A and/or B is a benzo group, wherein m or n represents 2, whilst preferably the two substituents R
and/or Rl2 in the benzo group are in the meta- and para-positions, respectively, to the fusion points of the group A or B and preferably these substituents R11 and R12 independently of each other represent hydroxy, (C14)alkoxy (preferably methoxy) or the 2 adjacent R
and R12 substituents together denote -O-CH2-CH2-O- or Particular mention should be made of compounds wherein R11 and R12 represent methoxy.

Examples of effective compounds according to the invention are listed in the Tables which follow, whilst special mention should be made of `- 2138167 Compound A -~C~

-0~-Compound B

Compound C

Compound D ~

and the pharmaceutically acceptable salts thereof.

The compounds may be prepared by methods known ~ç~ se (e.g. according to EP 288 048).

`_ 21381~7 Acids suitable for salt formation include, for example, hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, nitric acid, acetic acid, propionic acid, butyric acid, oxalic acid, malonic acid, succinic acid, maleic acid, fumaric acid, lactic acid, tartaric acid, citric acid, malic acid, benzoic acid, c; nn~m; C
acid, ascorbic acid and methanesulphonic acid.

The present invention relates to the use of the above-mentioned compounds for the production of agents for treating chronic inflammatory processes, ulcerative colitis and Crohn's disease and for producing agents having an antiproliferative effect. The activity of the compounds can be explained by their inhibition of the unselective cation channels (UCC).

The pathophysiology of chronic bronchial asthma is based on inflammatory processes which are mediated by the activation of inflammatory cells. (BARNES, 1987;
SEIFERT and SCHULTZ, 1991).

The receptor-regulated activation of inflammatory cells (e.g. neutrophilic granulocytes and mast cells or the permanent cell lines HL-60 cells or sensitised RBL
cells, i.e. those charged with gammaglobulin E) is inhibited, irrespective of the nature of the stimulating agonists (e.g. endothelin, PAF, leukotrienes, chemotactical peptide fMLP or antigen against sensitised mast cells) by blockers of unselective cation channels (UCC) (RINK, 1990). Through these channels extracellular calcium, which is responsible for the persistence of receptor-mediated cell activations, enters the cells (PUTNEY, 1990). If this supply of calcium is interrupted this results in a blockade of the activation of inflammatory cells.

Conventional calcium antagonists of the dihydropyridine or phenylalkylamine type do not inhibit either UCCs or inflammatory processes (WELLS et al., 1986).

As a measurement of the cell activation or as a measurement of the inhibition thereof by UCC blockers, the kinetics of the cytoplasmic calcium ion concentration in fura-2-charged cells is quantified fluorometrically using the method described by GRYNKIEWICZ et al. (1985). This procedure has proved a reliable screening method~ within the scope of the invention, for detecting UCC blockers.

So-called functional THAPSIGARGIN inhibition has proved suitable for the specific characterisation of blockers of the unselective cation channels. THAPSIGARGIN is a tumour promoter described by THASTRUP et al. (Proc.
Natl. Acad. Sci. (USA), 87, 2466-2470, 1990) which selectively and irreversibly inhibits the Ca2+-ATPase of intracellular IP3-sensitive Ca2+-stores. Consequently the Ca2+-stores are rapidly depleted. As described by J.
PUTNEY (Calcium, 11, 611-624, 1990) the depletion of these stores constitutes the physiological stimulation for opening up unselective cation channels in the-cell membrane. The result of this is a massive influx of Na+
and Ca2+ into the cell. Because of these properties, Thapsigargin is suitable as an indirect stimulator for agonist- and IP3-independent opening up of the unselective cation channels.

Within the scope of the present invention the Thapsigargin stimulation of unselective cation channels has been carried out successfully on HL 60 cells (human leukaemia cells), on hippocampal and cortical neurone cells and on RBL-cells (rat basophilic lymphoma cells) and in this way the existence of these channels in particular cell lines was demonstrated.

The cytoplasmic Ca2+ concentration ([Ca2+]i) plays an important part in the cell proliferation and in tumour growth (for a summary see L.R. ZACHARSKI, Journal of Medicine 19: 145-177, 1988). In particular, the Ca2+-influx into the cell stimulated by receptor activation with consecutive inositoltriphosphate-(IP3-)-mediation would appear to be of crucial importance for oncogenic cell proliferation (U. KIKKAWA and Y. NISHIZUKA, Ann.
REV. CELL. BIOL. 2: 149-178, 1986). This mechanism also plays a part in the formation of metastases and in "Multi-Drug Resistance". (For a summary see the above-mentioned publication by L.R. ZACHARSKI) J. MED. 19:
145-177, 1980.

This hypothesis is supported by the fact that Thapsigargin, as an indirect stimulator of the unselective cation channels (UCC) not only leads to a Ca2+-overload in the cell but is also a highly effective tumour promoter. (V. THASTRUP et al. Proceedings of the NATL. Acad. Sci: (USA) 87: 2466-2470, 1990).

The blockade of the Ca2+-influx by the UCC leads to normalisation of the intracellular Ca-ion concentration and hence to inhibition of tumour growth etc.

Conventional calcium antagonists do not inhibit these UCC. It has been found, surprisingly, that the compounds according to this invention inhibit the influx of calcium into the cell through the UCC.

As shown by S. H. MURCH et al. (Lancet 339 : 381-385, 15. Febr. 1992) endothelin I plays an important pathophysiological role in inflammatory-intestinal diseases such as ulcerative colitis and Crohn's disease.
Using immunohistochemical methods it has been shown that patients with Crohn's disease in the region of the submucosa and patients with ulcerative colitis in the region of the lamina propria of the epithelium of the large intestine show significantly and greatly increased concentrations of endothelin I compared with healthy normal people. It is assumed that the local secretion of endothelin causes massive vasospasms with consecutive disseminated ischaemia with microinfarcts which are regarded as the actual cause of the above diseases. The vasospasmogenic effectiveness of endothelin is explained by a Ca2+-overload of vascular myocytes. Endothelin primarily triggers an IP3-mediated intracellular release of Ca2~ which is followed by a massive transmembranal Ca2+-entry through dihydropyridine-insensitive channels.
(M. S. Simonson et al. Clin. Invest. Med. 14: 499-507, 1991; T. Masakai, J. Cardiovasc. Pharmacol. 13:Suppl. 5, S1-S4, 1989; D. W. Hay, R. J. Pharmacol. 100: 383-392, 1990). These channels are unselective cation channels which have also been briefly described as existing in cells of the large intestine mucosa. (Chr. Siemer and H. Gogelein, Europ. J. Physiol. 420: 319-328, 1992).

The endothelin-stimulated activation of fura-2-charged human leukaemia cells (HL 60 cells) has proved a suitable screening model for detecting functional endothelin antagonists. In conformity with G.
GRYNKIEWICZ et al. (J. Biol. Chem. 260:340-3450, 1985) the intracellular Ca2~-concentration in the cytoplasm of HL 60 cells (suspensions) can be monitored by spectrofluorometry and quantified as a measurement of cell activation by endothelin. The stimulation was effected by adding 0.1 ~M endothelin and could be inhibited in a dosage-dependent manner by means of the substances according to the invention.

The functional endothelin antagonism of the substances according to the invention is mediated through a blockade of the unselective cation channels.
Consequently, detection of a functional Thapsigargin-21381~7 antagonism on RBL-hml cells is also a suitable screening method for functional endothelin antagonists.

Carrying out the investigation:

For screening purposes, fura-2-charged adhesive RBL-hm 1 cells are stimulated with O.1 ~M Thapsigargin in a Ca2+-free incubation medium. After 4 minutes, extracellular Ca2+ is restored to a concentration of 1.5 mM and, using the fura-2-fluorescence, the excessive increase in the cytoplasmic Ca2+-concentration caused by a massive transmembranal Ca2+-entry through unselective cation channels is recorded.

This entry is to be inhibited solely by unselective cation channel blockers in a dosage-dependent manner.
Neither conventional calcium antagonists nor specific blockers of agonists which stimulate the IP3-turnover are able to inhibit the transmembranal Ca2+-entry triggered indirectly by Thapsigargin. The compounds of the present invention are distinguished by their inhibition of UCC.

The fluorometric calcium measurement in the cytoplasm of individual adhering RBL-hml cells is carried out analogously to the method described by KUDO and OGURA
(1986) for neuronal cells. An AXIOVERT 35 fluorescence microscope made by ZEISS is used in conjunction with an imaging system made by HAMAMATSU, consisting of the ICMS-image processing system, residual light camera with control unit and image intensifier DVS 3000.

The kinetics of the cytoplasmic Ca2+-concentration is recorded continuously as a concentration/time curve after the cell activation stimulated by Thapsigargin (0.1 ~M). The curves of two activated cell cultures are compared in the presence and absence of 10 ~M test `_ 2138167 substance. The area under these curves (area under the curve = AUC) is integrated and recorded as a measurement of cell activation. The inhibitory potency of the UCC-blockers tested is determined using the following equation:

AUCi~,h x 100 ~H = 100 -AUC~ cont rol ) ~H = the percentage inhibition of the calcium entry through unselective cation channels which is stimulated and inhibited by 10 ~M of test substance.

AUCi~ = area under the curve recorded in the presence of the stimulant plus 10 ~M inhibitory test substance.

AUC control = area under the curve which is recorded only after the addition of the stimulant.

Literature relating to the above explanations:

BARNES P.J., I.W. RODGER and N.C. THOMSON
Pathogenesis of asthma, in "ASTHMA, basic mechanisms and clinical management"
ED by P.J. BARNES; ACADEMIC PRESS, LONDON, 1988 GRYNKIEWICZ G., M. POENIE and R.Y. TSIEN
A new generation of Ca2+-indicators with greatly improved fluorescence properties J. BIOL. CHEM. 260: 3440-3450, 1985 .
HIDE, M. and M.A. BEAVEN
Calcium influx in a rat mast cell (RBL-2H3) line J. BIOL. CHEM. 266 15221-15229, 1991 `- 2138167 KUDO, Y. and A. OGURA
Glutamate-induced increase in intracellular Ca2+-concentration in isolated hippocampal neurones BR. J. PHARMACOL. 89: 191-198; 1986 PUTNEY, J.W., jr.
Capacitative Calcium entry revised CELL CALCIUM 11: 611-624, 1990 RINK, T.J.
Receptor-mediated calcium entry FEBS LETT. 268: 381-385, 1990 SEIFERT, R. and G. SCHULTZ
The superoxide forming NADPH oxidase of phagocytes: An enzym system regulated by multiple mechanism REV. PHYSIOL. BIOCHEM. PHARMACOL., Vol. 117, SPRINGER VERL., 1991 WELLS, E., C.G. JACKSON, S.T. HARPER, J. MANN and R.P.
EAOY
Characterization of primate bronchoalveolar mast cells II, inhibition of histamine, LTC4 and PGF2a release from primate bronchoalveolar mast cells and a comparison with rat peritoneal mast cells J. IMMUNOL. 37: 3941-3945, 1986.

`~ 2138167 Results of measurement:
The percentage inhibition of UCC after Thapsigargin stimulation (0.1 ~M Thapsigargin) in RBL-hm 1 cells is given. The uniform concentration of the test substances is 10-5 mol).

RBL - hm 1 cells - Thapsigargin (0.1 ~M)-stimulation Compound A -0 y 0-~H: 44.59 O~=c ~Cl --O
Compound B ~H: 75.75 ~ .HCl Compound C ~H: 73.01 ~,N
~ .HCl Compound D IC50: 9.1.10-7M

~ .HCl ` 21381~7 The functional antiinflammatory effectiveness can be demonstrated by means of the following test:

Individual RBL-2H3-cells (a tumour cell line related to the mast cells) adhering to glass slides are used.

The cultivation and attachment of the RBL-2H3-cells are carried out by the method described by HIDE and BEAVEN
(1991). In order to sensitise the adhesive RBL-2H3-cells the cells are incubated for 2 hours at ambient temperature with a 1:2000 diluted commercial gammaglobulin E-solution against a dinitrophenol-bovine serum albumin complex (DNP-BSA-antigen). The cells are then washed. By the addition of 0.1 ml of DNP-BSA-solution (10 ~g/ml) there is a massive immunological cell activation which is mediated by a cytoplasmic Ca2+-overload. The fluorometric calcium measurement in the cytoplasm of individual adhering RBL-2H3-cells is carried out analogously to the method described by KUDO
and OGURA (1986) for neuronal cells, which is also explained hereinbefore in this specification.

The comparison used in these investigations is (10 ~M) chromoglycate which brings about an approximately 50 inhibition of the antigen-induced cell activation.

In this test the above-mentioned compounds demonstrate ~H values which are comparable with the values specified hereinbefore.

Tests on microcultures of various human tumour cell lines using the tetrazolium assay in order to determine the antiproliferative effect of the substances according to the invention surprisingly showed that the compound tested was 5 to 100 times more potent than the comparison substance Verapamil.

~- 2138167 The antiproliferative effectiveness of the test substances was determined by means of the MTT test described by MOSMANN (J. IMMUNOL. METH. 65: 55-63, 1983), DENIZOT et al. (J. IMMUNOL. METH. 89: 271-277, 1986) and J. ELIASON et al. (INT. J. CANCER 46: 113-117, 1990). (MTT = [3-(4,5-dimethylthiazol-2-yl)2,5-diphenyl-tetrazolium bromide] produced by CHEMICON Inc.
El Segundo, Ca, USA). This indicator is metabolised only by living cells with intact mitochondria into a blue formazane product. The following human tumour cell lines were used in our test: A 549 (adenocarcinoma of the lung), A 431 (epidermal carcinoma of the vulva), PC 3 (adenocarcinoma of the prostate), SK BR 3 (adenocarcinoma of the breast), HT 29 (CXl 1) (adenocarcinoma of the colon) and K 562 (chronic myeloid leukaemia cell). The test was carried out on microtitre plates. Each well contained 100 ~1 of a cell suspension (0.2 x 106 cells per ml). The incubation medium used was RPMI 1640 with 10~ heat-inactivated foetal calves' serum and 50 ~g/ml of gentamycin. The cell suspensions were incubated for 0, 24, 48 or 72 hours in air with a humidity at saturation point in a CO2 (5~)/air (95~) mixture at 37C, incubated in the presence and absence of variable concentrations of antiproliferative test substances. The test substances were dissolved in DMSO
(final dilution: 0.1~). Then 10 ~l of MTT-solution (3 mg/ml) were added, followed after 3 hours by 100 ~1 of an isopropanol solution containing 0.08 N HCl. After a further hour, the light absorption at 570 nm (comparative wavelength 630 nm) was determined in a microplate reader. The light absorption is directly proportional to the number of living cells. The half-m~;mllm inhibitory concentrations of the-substances tested were 1 ~g/ml.

The vasospasmolytic effectiveness of the above-mentioned functional endothelin and Thapsigargin antagonists were _ 21381~7 confirmed on an isolated blood vessel preparation:
coronary perfusion was continuously quantified, on retrogressively perfused, spontaneously beating LANGENDORFF hearts taken from rats, by means of electromagnetic flow measurement (apparatus supplied by Hugo Sachs Elektronik, MARCH). This measuring apparatus could be used to record the extent, duration and pattern of vascular spasms with a high degree of accuracy. If perfusion is carried out with 100 nM endothelin concentration, the coronary perfusion flow is reduced from 11 to 5 ml/min. The restriction in perfusion can be reversed by means of the substances according to the invention. The potencies of the compounds according to the invention with regard to Thapsigargin inhibition on fura-2-charged RBL-hml-cells or the effectiveness of endothelin-inhibition on fura-2-charged HL 60 cells correlates clearly with the vasospasmolytic effectiveness of the test substances detected on the Langendorff preparation. It can be concluded from this that, underlying the vasospasmolytic endothelin antagonism of the substances tested, there is a blockade of the unselective cation channels.

The compounds may be administered both enterally and parenterally. The suggested dose for oral use ranges from 0.1 to 500 mg of active substance per dose and, for intravenous use, from 0.05 to 150 mg per dose. The desired therapeutic dose depends on the indication and form of administration and can be determined experimentally.

Examples of effective compounds are shown in the following Tables:

Table 1 R2 R~
1 1 '~

, R
11' ' ~,N ~
~ R6 i2 ,~" U) m cn ^ m r~
1~ T ~ ~ I ~ 7- ~ I T I ~ ~ t 3C ~
-C~
=

O
- O cn O O O O O o o o o o o o ~ ~ T I ~: ~: O T X ~ X X --' O O --r O O T O

~ .. .. .~
2 _ = T

- O O O O O O O O O O ~ I I O I I O I
~ ~ o o~ ~ o o <~ o I ~ O I ~ ~ T I' r I I 2 o = I I T ~
~; ~t ~) T T ~ ~T ~ I ~ I ~: T

C~ I I I I I T . I T T TT ~ 2 T I ~
_ ~_ ~: ' I I I I T T 2 I T 2 :C :~ 2 _ :~ S S

2 :~ O
~ T I ~ S
C~: S I C C C~ ~ I ~ CC~ ~ ~ C~C~ S T ~ ~) ~
o - o o o ' o o O ~ C v~ o o O O o 0- 0 o o (!) -~
~ ~ ~ ~ I ~ T S . ~ -- T = I ~ Ir T r ~1 0 ~ c~ ~ ~, ~ ~ ~ ~ '~c~ '' ~ ~ ~ ~ ~ " ~ o - o a) O
~ m u ~
X ~

- o o o o o o o o o o o o o o o o I o 1 m ~ ~ ~
-- I = :~ X X -- I :1~ X = X 2 I 2 I X X T

Table 2 S ~, NH

H R

R Salt forn Mp (~C~

H3CO ~

H3CO ~ Cl 218-222 5 ~N Cl 239-235 ~V

21~81~7 Table 3 ~NH

H R

R Salt form Mp(C) Cl 162-172 Cl 237-239 Cl 250-253 Exam~les of Pharmaceutical Pre~arations a) Coated tablets 1 tablet core contains:
Active substance of general formula I30.0 mg Lactose 100.0 mg Corn starch 75.0 mg Gelatine 3.0 mg Magnesium stearate 2.0 mg 210.0 mg Pre~aration The active substance mixed with lactose and corn starch is granulated with a 10~ aqueous gelatine solution through a 1 mm mesh screen, dried at 40~C and rubbed through a screen once more. The granules thus obtained are mixed with magnesium stearate and compressed. The cores produced in this way are coated in the usual manner with a coating consisting of an aqueous suspension of sugar, titanium dioxide, talc and gum arabic. The finished coated tablets are polished with beeswax.

b) Tablets Active substance of general formula I30.0 mg Lactose 100.0 mg Corn starch 70.0 mg Soluble starch 7.0 mg Magnesium stearate 3.0 mg 210.0 mg Preparation The active substance and magnesium stearate are granulated with an aqueous solution of the soluble starch, the granules are dried and intimately mixed with lactose and corn starch. The mixture is then compressed into tablets weighing 210 mg.

c) Capsules Active substance according to claim 1 20.0 mg Lactose 230.0 mg Corn starch 40.0 mg Talc 10.0 mg 300.0 mg Preparation The active substance, lactose and corn starch are first combined in a mixer and then in a grinding machine. The mixture is returned to the mixer, thoroughly combined with the talc and mechanically packed into hard gelatine capsules.

Claims (11)

Claims

1. Use of a compound of general formula I

I

wherein A denotes a benzo- or thieno group;

R2 and R3 independently of each other denote hydrogen or (C1-5)alkyl or, together with the carbon atom to which they are bound, a 5- or 6-membered carbocyclic group;

R11 denotes (C1-4)alkyl, halogen (F, Cl, Br, I), hydroxy, (C1-4)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido, or two adjacent R11 substituents together denote -O-CH2-O- or -O-CH2-CH2-O-;

m denotes 0, 1, 2 or 3, if A is a benzo group, and 0, 1 or 2, if A is a thieno group;

and D denotes a group of formula Ia Ia whilst in the group of formula Ia B denotes a benzo- or thieno- group;

R1 denotes hydrogen, (C1-10)alkyl, phenyl, phenyl(C1-5)alkyl, (C1-4)alkoxy or -NHCOX (wherein X is (C1-5)alkyl);

R5 denotes hydrogen, (C1-4)alkyl or hydroxymethyl;

R6 and R7 independently of each other denote hydrogen or (C1-5)alkyl or together with the carbon atom to which they are bound denote a 5- or 6-membered carbocyclic group;

R12 denotes (C1-4)alkyl, halogen (F, Cl, Br, I), hydroxy, (C1-4)alkoxy, amino, thiomethyl, methanesulphonyloxy or methanesulphonamido, or two adjacent R12 substituents together denote -O-CH2-O- or -O-CH2-CH2-O-;

and n denotes 0, 1, 2 or 3 if B is a benzo group and 0, 1 or 2 if B is a thieno group;

or the pharmaceutically acceptable salt thereof with an inorganic or organic acid for the preparation of an agent for treating chronic inflammatory processes, ulcerative colitis and Crohn's disease and for producing an agent having an antiproliferative effect.

2. Use of a compound according to claim 1, wherein R1 denotes hydrogen, (C1-10)alkyl, phenyl(C1-5)alkyl or -NHCOX (wherein X is (C1-5)alkyl);

R11 and R12 independently of each other denote (C1-4)alkyl, hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent R11 and R12 substituents together denote -O-CH2-O- or -O-CH2-CH2-O-;

wherein preferably R1 denotes hydrogen, (C1-10)alkyl or -NHCOX (wherein X is (C1-5)alkyl);

R2, R3, R6 and R7 independently of one another denote hydrogen or R2 together with R3 and/or R6 together with R7 and the associated carbon atom to which they are bound denote a 5- or 6-membered carbocyclic group;

R11 and R12 independently of each other denote hydroxy, (C1-4)alkoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent R11 and R12 substituents together denote -O-CH2-O- or -O-CH2-CH2-O-;

wherein in particular R1 denotes hydrogen, (C1-6)alkyl or -NHCOCH3 and/or R5 denotes hydrogen, methyl or hydroxymethyl and/or R2, R3, R6 and R7 independently of one another denote hydrogen or R2 together with R3 and/or R6 together with R7 and the associated carbon atom to which they are bound denote a 5-membered carbocyclic group and/or R11 and R12 independently of each other denote hydroxy, methoxy, methanesulphonyloxy or methanesulphonamido, or two adjacent R11 and R12 substituents together represent -O-CH2-O-.

3. Use of a compound according to claim 1 or 2, wherein R1 and R5 denote hydrogen.

4. Use of a compound according to one of claims 1 to 3, wherein R2, R3, R6 and R7 denote hydrogen.

5. Use of a compound according to one of claims 1 to 3, wherein R2 and R3 or R6 and R7 together represent -(CH2)4-.

6. Use of a compound according to one of claims 1 to 5, wherein A and B independently of each other denote a thieno group, preferably 2,3-thieno.

7. Use of a compound according to claim 6, wherein A
and B denote an unsubstituted thieno group.

8. Use of a compound according to one of claims 1 to 5, wherein A and/or B is a benzo group, wherein m or n denotes 2.

9. Use of a compound according to claim 8, wherein, if A and/or B is a benzo group, the two substituents R11 and/or R12 in the benzo group are in the meta- or para-position, respectively, to the fusion points of the group A or B.

10. Use of a compound according to one of claims 1 to 5, 8 and 9, wherein R11 and R12 independently of each other denote hydroxy, (C1-4)alkoxy (preferably methoxy) or the 2 adjacent R11 and R12 substituents together denote -O-CH2-O-.

11. Use of a compound according to claim 1 which is Compound A

Compound B

Compound C

Compound D

or a physiologically acceptable salt thereof.