CA2069857A1 - Substituted diaminophthalimides and analogues - Google Patents

Abstract

Substituted diaminophtha1imides and analogues Abstract Compounds of formula I

Description

2~8~7 Substituted diaminophthalimides and analo~ues The invention relates to compounds of formula I

Arl /
Al- N ~,~ C
IJ M~
A2- N ~ C
- Ar2 X -, wherein Al and A2 are each independently of the other hydrogen, lower alkyl, lower aLIcerlyl, lower alkynyl, aryl, acyl, lower alkylsulfonyl or arylsulfonyl; or wherein Al and A2 together form unsubstituted or lower alkyl- or hydroxy-substituted lower alkylene; Arl and Ar2 are each independently of the other aryl, heteroaryl or unsubstituted or substituted cycloalkyl; the group -C(=X)- is -C(-O)-, -C(=S)-, -CH2- or -C(=CRlR2)- wherein Rl and R2 are each îndependently of the other hydrogen or lower alkyl; and R is hydrogen, lower alkyl, aryl-lower aLkyl, aryl, amino, hydroxy or lower alkoxy; with the proviso that R is other than phenyl when Al and A2 are hydrogen, Arl and Ar2 are phenyl and the group -C(--X)- is -C(=O)-; and to salts thereof when salt-forrning groups are present, to processes for the preparation of those compounds, to pharmaceutical compositions comprising those compounds, and to the use of those compounds for the therapeutic treatment of the human or animal body or for the preparation of pharmaceutical compositions.

The general terms used hereinbefore and hereinafter preferably have the following meanings within the scope of this Application:

The term "lower" denotes a radical having up to and including 7, especially up to and including 4, and more especially having 1 or 2, sarbon atoms.

: , . ~ . , :
- : . . - , ~ ..
.. .. . ~ .

: ,:, :~, . ,. ;, : .

20~8~7 Lower alkyl is preferably n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl or n-heptyl, preferably ethyl and especially methyl.

L,ower alkenyl has from 2 to 7, preferably from 2 to 4, carbon atoms and is, for example, allyl or crotyl.

Lower alkynyl has from 2 to 7, preferably from 2 to 4, carbon atoms and is, for example, propyn-l-yl or propyn-2-yl or 2-bntyn-1-yl.

Lower alkyl substituted by halogen is, for example, trifluoromethyl.

Aryl is preferably phenyl or naphthyl, such as 1- or 2-naphthyl. The phenyl and naphthyl radicals can be unsubstituted or substituted, especially as indicated below for phenyl. Aryl is preferably phenyl that is unsubstituted or substituted by one or more, especially one or two, substituents from the group consisting of: hydrocarbyl, for example lower alkyl, lower alkenyl, lower aLI~ynyl, lower alkylene (linked to two adjacent carbon atoms), cyclo-alkyl, phenyl-lower alkyl or phenyl; substituted hydrocarbyl, for example lower alkyl substituted, for example, by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyl-oxy, halogen, amino, lower alkylamino, di-lower alkylamino, mercapto, lower aL~ylthio, lower alkylsulfinyl, lower aL~cylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl andlor by cyano; hydroxy; etheri~led hydroxy, for example lower alkoxy, halo-lower aLt~oxy, phenyl-lower alkoxy, phenoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy or lower allcylenedioxy (linked to two adjacent carbon atoms); esterified hydroxy, for example lower alkanoyloxy, phenyl-lower alkanoyloxy or phenylcarbonyloxy ( - benzoyloxy); mercapto; etherified mercapto, which is optionally oxidised, for example lower aLIcyl,hio, phenyl-lower aLIcyl-thio, phenylthio, lower alkylsulfinyl [-S(=O)-lower aL~yl], phenyl-lower al~ylsulfinyl, phenylsulfinyl, lower alkylsulfonyl [-S(02)-lower aLIcyl], phenyl-lower aLI~ylsulfonyl or phenylsulfonyl; halogen; nitro; amino; monohydrocarbylamino, for example lower alkyl-amino, cycloalkylamino, phenyl-lower alkyl~unino or phenylamino; dihydrocarbylamino, for example di-lower alkylarnino, N-lower alkyl-N-phenylamino, N-lvwer alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, or lower alkyleneamino interrupted by -O-, -S- or -NR" (wherein R" is hydrogen, alkyl or acyl~; acylamino, ~or example lower alkanoylamino, phenyl-lower alkanoylamino or phenylcarbonylamino ( - benzoylamino);
acyl, for example lower alkanoyl, phenyl-lower aLIcanoyl or phenylcarbonyl ( = benzoyl);
carboxy; esteri~led carboxy, for example lower aL~coxycarbonyl; amidated carboxyi for , ~ . .. . . . . . ..
, ~
::
..

.

2 ~ 7 example carbamoyl, N-lower aL~ylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxy-carbamoyl or N-phenylcarbamoyl; cyano; sulfo (SO3H); esterified sulfo, for example lower alkoxysulfonyl; and amidated sulfo, for example sulfamoyl (SO2NH2), N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl or N-phenylsulfamoyl; phenyl groups occurring in the substituents each being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen andlor by trifluoromethyl.

R is preferably selected from all the above-mentioned definitions except aryl.

Heteroaryl is a heterocyclic radical of aromatic character and is preferably linked via a ring carbon atom. It is especially a 5- or 6-membered ring, for example imidazolyl, tri-azolyl, pyridyl, pyrimidinyl or triazinyl, and especially pyridyl. Those radicals may be unsubstituted or substituted, for example, by lower alkyl, hydroxy, lower aLkoxy, halogen, cyano and/or by trifluoromethyl.

Pyridyl is, for example, 2-, 3- or 4-pyridyl.

Imidazolyl is, for example, 2- or 4(5)-imidazolyl.

Triazolyl is, for example, 1,2,4-triazol-3- or -4-yl or 1,2,3-triazol-4-yl.

Pyrimidinyl is, for example, 2-, 4- or 5-pyrimidinyl.

Triazinyl is, for example, 1,3,5-triazin-2-yl.

Lower alkylene, formed from Al and A2 together, is unbranched and is especially a (CH2)n group wherein n is from 1 to 4, preferably 2 or 3. It ;s preferably unsubstituted but may also be substituted by lower aLIcyl or hydroxy.

Lower alkylene, linked to two adjacent carbon atoms of a benzene ring, is preferably C3-C4aLkylene, for example 1,3-propylene or 1,4-butylene.

Lower alkylenedioxy, linked to two adjacent carbon atoms, is preferably Cl-C~alkylene-dioxy, for example methylene- or 1,2-ethylene-dioxy.

Lower alkyleneamino is preferably C4-C7- and especially C4-Cs-alkyleneamino, for 2~8~7 example piperidino. Lower alkyleneamino interrupted by -O-, -S- or -NR"- is preferably C4-C7- and especially C4-C5-alkyleneamino in which a ring carbon atom has been replaced by the corresponding hetero group, and is especially morpholino, thiomorpholino, piperazino or 4-lower allcyl- or 4-lower alkanoyl-piperazino.

~cyl is preferably lower alkanoyl, halo-lower alkanoyl, aryl-lower allcanoyl or aryl-carbonyl. Acyl is especially lower alkanoyl.

Lower aL~canoyl is preferably formyl, acetyl, propionyl, n-butyryl, pivaloyl or valeroyl, especially acetyl.

~ryl-lower alkyl is preferably phenyl-lower aL~cyl and especially benzyl.

Cycloalkyl is preferably C3-C8- and especially Cs-C7-cycloaL~yl, which is intended to indicate that it contains from-3 to 8 and from 5 to 7 ring carbon atoms, respectively. It may, however, also be substituted, for example by lower alkyl or hydroxy.

Halogen is especially fluorine, chlorine and bromine, but may also be iodine.

Salts of compounds according to the invention having salt-forming groups are especially pharmaceutically acceptable, non-toxic salts. For example, compounds of formula I
having basic groups may forrn acid addition salts, for example with inorganic acids, such as hydrochloric acid, sulfuric acid or phosphoric acid, or with suitable organic carboxylic or sulfonic acids, for example acetic acid, fumaric acid or methanesulfonic acid, or with amino acids, such as arginine or lysine. Compounds of formula I having an acidic group, for example carboxy, form, for example, metal or ammonium salts, such as aLI~ali metal and alkaline earth metal salts, for example sodium, potassium, magnesium or calcium salts, and also ammonium salts with ammonia or suitable organic amines, such as lower alkylamines, for example triethylarnine, hydroxy-lower aLI~yl~nines, for example 2-hydroxyethylamine, bis(2-hydroxyethyl)amine or tris(2-hydroxyethyl)amine, basic aliphatic esters of carboxylic acids, for example 4-arninobenzoic acid 2-diethylaminoethyl ester, lower alkyleneamines, for example 1-ethylpiperidine, cycloalkylamines, for example dicyclohexylamine, or benzylamines, for example N,N'-dibenzylethylene-diamine, dibenzylamine or benzyl-~-phenethylamine. Compounds of formula I having an acidic group and a basic group can also be in the form o~ internal salts, that is to say in zwitterionic form ,~

2~8~7 The salts of compounds according to the invention also include complexes of compounds of formula I (Al, A2 = hydrogen) with transition metal ions, for example copper, cobalt or man~anese.

For the purposes of isolation or purification it is also possible to use pharmaceutically un-acceptable salts, for example picrates or perchlorates. Only the pharmaceutically acceptable, non-toxic salts are used therapeutically and these are therefore preferred.

The compounds according to the invention have valuable, especially pharrnacologically acceptable, properties. Ln particular they exhibit specific inhibitory activities that are of pharmacological interest. They act especially as tyrosine protein kinase inhibitors and exhibit, for example, a potent inhibition of the tyrosine kinase activity of the receptor for the epidermal growth factor (EGF) and the c-erbB2 kinase. These receptor-specific enzyme activities play a key role in the signal transmission in a large number of mammal cells, including human cells, especially epithelial cells, cells of the immune system and cells of the central and peripheral nervous system. The EGF-induced activation of the receptor-associated tyrosine protein kinase (EGF-R-PTK) is in various cell types a pre-requisite for cell division and thus for the proliferation of a cell population. The addition of EGF-receptor-specific tyrosine kinase inhibitors therefore inhibits the reproduction of those cells.

The inhibition of EGF-receptor-specific tyrosine protein kinase (EGF-R-PTK) can be demonstrated, for example, using the method of C. House et al., Europ. J. Biochem. 140, 363-367 (1984). The compounds according to the invention inhibit the enzyme activity by 50 % (IC50) 0.1 - 10 ~lM concentration. Furthermore, in the micromolar range too, for example, they also exhibit an inhibition of the cell growth of an ~GF-dependent cell line, for example the epidermoid mouse keratinocyte cell line. In order to measure this inhibition of cell growth, the EGF-stimulated cell proliferation of epidermal Balb/~IK
keratinocytes is used (description of the method in Meyer, T., et al., Int. J. Cancer 43, 851 ~1989)~. Those cells are to a high degree dependent upon the presence of E~F forproliferation (Weissmann, B. E., Aaronson, S. A., Cell 32, 599 (1983)). In order to carry out the test, Balb/MK cells (10 000/well) are transferred to 9~-well microti~e plates and incubated overnight. The test substances (dissolved in DMSO) are added in various concentrations (in dilution series) so that the final concentration of D~SO is no greater than 1 %. After the addition, the plates are incubated for three days, during which time the :

.

2 ~3 control cultures without the test substance are able to undergo at least three cell division cycles. The growth of the MK cells is measured by means of methylene blue staining.
The XCso value is defined as that concentration of the ~est substance in question which results in a 50 % decrease in comparison with the control cultures without inhibitor.

In addition to inhibiting EGF-R-PTK, the compounds according to the invention also inhibit other tyrosine kinases that are involved in signal transmission mediated by trophic factors, for example the abl-kinase, kinases from the family of src-kinases and the c-erbB2 kinase (HER-2), and also serine/threonine kinases, for example protein kinase C, all of which have a role to play in growth regulation and transformation in the cells of mammals, including humans.

The inhibition of the c-erbB2 tyrosine kinase aIER-2) can be demonstrated, for example, analogously to the method of C. House et al., Europ. J. Biochem. 140, 363-367 (1984) used for EGF-R-PTK. The c-erbB2 kinase can be isolated, and its activity determined, in accordance with known protocols, for example in accordance with T. Akiyama et al., Science 232, 1644 (1986).

The compounds according to the invention are therefore also suitable for the inhibition of processes mediated by these and related tyrosine kinases.

The compounds according to ~he invention are therefore useful, for example, in the treatment of benign or malignant tumours. They are able to bring about the regression of tumours and to prevent the formation of tumour metastases and the growth of micro-metastases. In particular, they can be used in epidermal hyperproliferation (psoriasis), in the treatment of neoplasias of epithelial character, for example mammary carcinoma, and in leukaemias. In addition, the compounds can be used in the treatment of diseases of the immune system and in the ~eatment of inflammation insofar as protein kinases areinvolved in those disorders. The compounds can also be used in the treatment of disorders of the central or peripheral nervous system inso-far as signal transmission by protein kinases is involved.

The compounds according to the invention can be used both on their own and in combination with other pharmacologically active substances, for example together with (a) inhibitors of enzymes of polyamine synthesis, (b) inhibitors of prolein kinase C, (c) inhibitors of other tyrosine kinases, (d) cytokines, (e) negative growth regulators, for example TGF-~ or IFN-~, (f) aromatase inhibitors, (g) anti-oestrogens or (h) cytostatics.

The invention relates especially to compounds of formula I wherein Al and A2 are each independently of the other hydrogen, lower alkyl, aryl, acyl, lower alkylsulfonyl or aryl-sulfonyl; or wherein Al and A2 together are unsubstituted or lower alkyl- or hydroxy-substituted lower alkylene; ~rl and Ar2 are each independently of the other aryl, hetero-aryl or unsubstituted or substituted cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -C~I2- or -C(=CRlR2)- wherein Rl and R2 are each independently of the other hydrogen or lower alkyl; and R is hydrogen, lower alkyl, aryl-lower alkyl, aryl, amino, hydroxy or lower alkoxy; with the proviso that R is other than phenyl when Al and A2 are hydrogen, Arl and Ar2 are phenyl and the group -C(=X)- is -C(=O)-, and salts thereof when salt-forrning groups are present.

The invention preferably relates to compounds of forrnula I wherein Al and A2 are each independently of the other hydrogen, lower alkyl; lower alkenyl; phenyl or l-naphthyl or 2-naphthyl, the three last-mentioned radicals being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; lower alkanoyl, lower alkylsulfonyl or phenylsulfonyl wherein the phenyl ~roup is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or wherein A
and A2 together are Cl-C4alkylene; wherein Arl and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from tbe group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent carbon atoms), C3-C8cycloalkyl, phenyl-lower alkyl, phenyl; lower alkyl substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower aLkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower aL~oxycarbonyl, carba~
moyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano, hydroxy, lower aLkoxy, halo-lower aLkoxy, phenyl-lower aLI~oxy, phenoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy (linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower aLIcylsul~myl, phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsul~onyl, phenylaLkylsulfonyl, phenylsul~onyl, halogen, nitro, arnino, lower alkylamino, C3-C8cycloalkylamino, phenyl-lower aLkyl-amino, phenylamino, di-lower alkylamino, N-lower aL1cyl-N-phenylarnino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, lower alkyleneamino intermpted by -O-, -S- or -NR" (wherein R" is hydrogen, lower aL~yl or lower aLkanoyl), lower aL~anoyl-,, ' ~
' ~

8 ~ ~

amino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl, phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkylcarbamoyl, ~-hydroxycarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkyl-sulfamoyl and N-phenylsulfamoyl (phenyl groups occurring in the substituents each being unsubstituted or substituted by lower allcyl, lower alkoxy, hydroxy, halogen and/or by tri-fluoromethyl); pyridyl or pyrimidinyl that is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CRlR2)- wherein Rl and R2 are each independently of the other hydrogen or lower alkyl, and R is hydrogen, lower aLIcyl, phenyl-lower aL~cyl, phenyl, 1-naphthyl or 2-naphthyl, in the four last-mentioned radicals the phenyl or naphthyl group being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or R is amino, hydroxy or lower alkoxy, with the proviso that R is other than phenyl when Al and A2 are hydrogen, Arl and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; and salts thereof when salt-forming groups are present.

Of those last-mentioned compounds of formula I, very special preference is given to those wherein R is as de~med except for phenyl, and the other radicals are as de~med, and salts thereof when salt-forming groups are present.

The invention relates more especially to compounds of formula I wherein A1 and A2 are each independently of the other hydrogen, lower aLkyl; phenyl or 1-naphthyl or 2-naphthyl, the three last-mentioned radicals being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; lower alkanoyl, lower alkylsulfonyl or phenylsulfonyl wherein the phenyl group is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or wherein A
and A2 together are Cl-C4alkylene; wherein Arl and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or mole substituents from the group consisting of: lower alkyl, lower alkenyl, lower aLkynyl, lower alkylene (linked to two adjacent carbon atoms), C3-C8cycloaL~yl, phenyl-lower alkyl, phenyl; lower alkyl substituted by hydroxy, lower alkoxy, phenyl-lower aLkoxy, lower alkanoyloxy, halogen, amino, lower aLkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower aLIcoxycarbonyl, carba-moyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy, lower alkoxy, halo-lower alkoxy, phenyl-lower aLt~oxy, phenoxy, lower alkenyloxy, halo-.

- 20~8~7 lower aL~cenyloxy, lower alkynyloxy, lower alkylenedioxy (linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylalkylsulfonyl, phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C3-C8cycloalkylamino, phenyl-lower alkyl-amino, phenylamino, di-lower alkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, lower alkyleneamino interrupted by -O-, -S- or -NR" (wherein 1~" is hydrogen, lower alkyl or lower alkanoyl), lower aLt~anoyl-amino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl, phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarb-amoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkylsulfonyl, sulfamoyl, N-lower aLkylsulfamoy', N,N-di-lower alkyl-sulfamoyl and N-phenylsulfamoyl (phenyl groups occurring in the substituents each being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by tri-fluoromethyl); pyridyl that is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl; the group -C(=X)-is -C(=O)-, -C(=S)-, -CH2- or -C(=CRIR2)- wherein Rl and R2 are each independently of the other hydrogen or lower alkyl, and R is hydrogen, lower aLkyl; phenyl-lower alkyl, phenyl, l-naphthyl or 2-naphthyl, in the four last-mentioned radicals the phenyl or naphthyl group being unsubstituted or substituted by lower allsyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or R is amino, hydroxy or lower aLkoxy, with the proviso that R is other than phenyl when Al and A2 are hydrogen, Arl and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; and salts thereof when salt-forming groups are present.

The invention relates especially preferably to the compounds of formula I mentioned in the preceding paragraph wherein Al and A2 are each independently of the other hydrogen or lower alkyl, the group -C(=X)- is -C(=O)-, -C~=S)- or -C(=C~H2)-, and R is hydrogen or lower aLkyl, and salts thereof.

The invention relates more especially to compounds of formula I wherein Al and A2 a~e each independently of the other hydrogen; lower alkyl; lower aLkenyl; or lower aLkanoyl;
or wherein Al and A2 together are Cl-C4aLkylene; wherein Arl and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substi-tuted by one or more substituents from the group consisting of: lower alkyl, lower alkylene (linked to two adjacent carbon atoms), hydroxy, phenoxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower aLkanoylamino, carboxy, lower aLkoxy-2 ~ 7 carbonyl, carbamoyl, N-lower aLIcylcarbamoyl, N,N-di-lower alkylcarbamoyl and cyano pyridyl; pyrimidinyl; or C3-C8cycloalkyl; the group -C(=X)- is -C(=O)- or -C(=S)-, and R
is hydrogen, lower alkyl, phenyl-lower alkyl, amino or hydroxy; and salts thereof when salt-forming groups are present.

The invention relates even more especially to compounds of forTnula I wherein A1 and A2 are each independently of the other hydrogen or methyl; or wherein A1 and A2 together are -(CH2)2- or -(CH2)3-; Arl and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from the group consisting of: lower alkyl, lower aL~oxy, phenyl-lower alkoxy, hydroxy, lower alkanoyloxy, nitro, amino, lower aLt~ylamino, di-lower aL~ylamino, lower aL'canoylarnino, halogen, trifluoromethyl, carboxy, lower aLIcoxycarbonyl, carbamoyl, N-lower aLlcyl-carbamoyl, N,N-di-lower aL~ylcarbamoyl, cyano, lower aL~canoyl, benzoyl, lower aLlcyl-sulfonyl and sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower alkylsulfamoyl; cyclo-pentyl; cyclohexyl; or pyridyl; the group -C(--X)- is -C(=O)-, -C(=S)- or -C(=CH2)-, and R
is hydrogen or lower alkyl; and pharrnaceutically acceptable salts thereof.

The invention relates most especially to compounds of formula I wherein A1 and A2 are hydrogen; Arl and Ar2 are each independently of the other phenyl that is unsubstituted or substituted by lower alkyl, trifluoromethyl, phenyl, hydroxy, lower aLtcoxy, benzyloxy, amino, di-lower alkylarnino, lower alkanoylamino, halogen, carboxy, lower alkoxy-carbonyl, carbamoyl, N,N-di-lower alkylcarbamoyl or by cyano; or cyclohexyl; the group -C(=X)- is -C(=O)-, -C(=S)- or -C(=CH2)-, and R is hydrogen; and pharmaceutically acceptable salts thereof.

The invention relates more especially to the specific compounds described in theExamples and pharmaceutically acceptable salts thereof.

The compounds of formula I can be prepared in a manner known ~r se, for example by (a) reacting a compound of forrnula II

, ~
`.

2 ~

, . .

Arl Al--N ~ COOR3 Ar2 wherein Arl, Ar2, Al and A2 are as defined under formula I and R3 and R4 are each independently of the other aryl or lower aLkyl, with a compound of formula III
H2N-R (III) wherein R is as defined under formula I, or (b) reacting a compound of formula IV

Arl O -~O (IV) A2--N~
Ar2 wherein Ar and A are as defined under formula I, with a compound of formula III
H2N-R (III) wherein R is as defined under formula I;

and, if desired, or converting a resulting compound of formula I into a different compound of formula I, and/or converting a resulting salt into the free compound or into a different salt, and/or converting a resulting free cumpound I into a salt andlor separating a resulting mixture of isomeric compounds of fonnula I into the individual isomers.

In the following, more detailed description of the processes, the symbols Arl, Ar2, Al, A2, X, R, R3 and R4 are each as defined under formulae I and II unless indicated to the contrary.

.
~, - -.. .

-: , . . :

`

2~857 Process (a): The reaction according to process (a) corresponds to the aminolysis, known se, of phthalic acid diesters with ammonia or primary amines. The reaction with acti-vated phthalic acid diesters, for example the di(p-nitrophenyl) ester, normally takes place at room temperat~lre, b-lt the reaction with di-lower alkyl esters generally takes place only at high temperatures. Preferably the dimethyl ester is used. Preferred is the reaction of di-lower alkyl esters in a solvent, especially in a high-boiling alcohol, for example a diol, such as ethylene glycol, at temperatures of from 100 to 150C, for example approximately 120C, or the reaction of the lower alkyl esters with ammonia or the respective amine of formula II is carried out a~ the same temperatures in the presence of a solvent, for example an alcohol, such as a lower aLlcanol, for example methanol or ethanol, or in the absence of a solvent, in an autoclave at elevated pressure.

The starting compounds of formula II are prepared, for example, by reacting a cyclohexa-diene of formula V -Me3SiO CO(~R3 ~1 11 (V) Me3SiO ~ COOR4wherein Me is methyl, with an aniline of formula VI
AHN Ar (VI) wherein A is especially hydrogen or lower alkyl, under acid catalysis [see Matlin, Stephen A. and Barron, Kenneth, J. Chem. Res. Synop. 8, 246-247 (1990)].

The preparation of the compounds of formula V is effected, for example, by means of a Diels-Alder reaction and is likewise described in the literature mentioned.

For the preparation of asymmetrical compounds of forrnula II, wherein Al and A2 and/or Ar1 and Ar2 are different, for example compounds of formula V can be reacted - for example stepwise - with two different compounds of forTnula VI and the desired com-pounds of formula II can be isolated by chromatographic separation.

: ; . .. , .; ,.
. : ~ ' -............................... ~ .

. .

.

2~8~

Furthermore, for exarnple, compounds of forrnula II wherein A1 = A2 = H can be reacted in a ratio of 1:1 with a lower aLlcyl-introducing agent, for example methyl iodide, yielding asymmetrical compounds of formula II wherein Al = lower alkyl and A2 = H. If the lower alkyl-introducing agent is used in excess, for example 10:1, then symmetrical compounds of formula II wherein Al = A2 = lower alkyl are obtained.

Process (b): The reaction according to process (b) corresponds to the aminolysis, known se, of phthalic acid anhydrides, for example with ammonia or primary amines at relatively high temperatures or with hexamethyldisilazane and methanol at room tempera-ture [Davis, Peter D. and Bit, Rino A., Tetrahedron Lett. 31, 5201-5204 (1990)].
The starting compounds of formula IV are prepared, for example, by reacting a compound of tormula VII

Arl Al--N~ COOH
ll (VII) A2--N ~ COOH
Ar2 with an acid anhydride of formula VIII, (RsCO)(Rs'CO)O, wheIein Rs and Rs' are each independently of the other hydrogen or lower allcyl, but are not both hydrogen.

The compounds of formula VII can be obtained, for example, by hydrolysis, for example in an acidic or al~aline medium, of a corresponding compound of formula ~I.

Compounds of formula I can be converted into different compounds of formula I in a manner known ~ se.

For example, a compound of formula I wherein the group -C(=X)- is -C(=O3- can bereacted with a suitable reagent in order to obtain a different compound of formula I
wherein the group -C(=X)- is -C(=S)-, -CH2- or -C(=CR1R2)-. A suitable reagent for the conversion of -C(=~)- into -C(=S)- is, for example, the Lawesson reagent (= 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiaphosphetane), the reaction being carried out, for example, in a halogenated hydrocarbon, such as dichloromethane, at temperatures of from 30C to the reilux temperature, especially at reflux temperature. Suitable systems .

'. ' '-2~8~7 for the conversion of -C(=O)- into -CH2- are, for example, LiAlH4/tetrahydrofuran or zinc amalgam/HCl/ethanol. The conversion of -C(=O)- into -C(=CR,R2)- is effected, forexample, by reaction with a strong base, for example LDA (lithium diisopropylamide) and then with a Grignard reagent of the formula HCRlR2MgHal (~Ial = halogen, for example iodine).

Furthermore, for example, compounds of formula I wherein R is hydrogen can be converted by alkylation, for example with lower aLIcyl or aryl-lower aL~yl halides, after treatment with suitable bases, for example sodium hydride or potassium tert-butoxide, into different compounds of formula I wherein R is lower alkyl or aryl-lower alkyl.

Moreover, for example, compounds of formula I wherein Al and/or A2 are hydrogen can be converted by reaction with suitable reagents into different compounds of forrnula I
wherein Al and/or A2 are lower alkyl, aryl, acyl, lower alkylsulfonyl or arylsulfonyl.

A suitable method for the introduction of Al and/or A2 = lower alkyl is, for example, treatment with the base LDA and subsequent reaction with a di-lower aL~cyl ether or a lower alkyl halide. Under those conditions a group -N(-R)- = -NH- which may be present in the molecule is aL~ylated only slightly or not at all.

For the introduction of Al and/or A2 = acyl, lower alkylsulfonyl or arylsulfonyl, the s~arting compound can be reacted, for exarnple, again first with LDA and then with an acylating agent, for example acetyl chloride, or with an agent that introduces the lower alkylsulfonyl or arylsulfonyl group, for example methylsulfonyl chloride or p-toluene-sulfonyl chloride.

Compounds of formula I wherein Arl andlor Ar2 are aryl, especially phenyl or naphthyl, substituted by halogen, preferably by bromine, can be conver~ed into the corresponding derivatives in which one or all of the halogen atoms present in aryl Arl and/or Ar2 have been replaced ~y cyano, for example by reaction with a cyanide salt of a transition metal, especially CuCN, at temperatures of from 50 to 15()C, preferably from 60 to 140C, in an inert polar solvent, such as an N,N-di-lower aLkyl-lower aL~anecarboxylic acid amide, for example dimethylformamide, with or without the subsequent addition of a catalyst, for example a transition metal halide, such as iron(lII) chloride, in aqueous solution (see also Rosenmund et al., Ber. 52, 1749 (1916); von Braun et al., Ann. 488, 111 (1931)~.

: ~, . .. . .

," ~ ' , 2~6~7 In compounds of formula I, the radicals Arl and/or Ar2 that are unsubstituted orsubstituted aryl, prefeMbly unsubstituted phenyl or naphthyl, can be nitrated independently of one another, with the introduction of one or more nitro groups, for example under conditions customary for the introduction of a nitro group into aromatic compounds, for example with concentrated or 100 % nitric acid at temperatures of from 0 to 100C, preferably from 10 to 40C, in an inert solvent, for example an organic acid anhydride, such as acetic anhydIide. If the nitration results in several different products in which thc number of nitro groups and their position(s) are different, they can be separated according to customary methods, for example by column chromatography.

Nitro substituents in radicals Arl and/or Ar2 can be reduced to amino groups, for example by hydrogenation under customary conditions, for example hydrogenation in the presence of a hydrogenation catalyst suitable for the selective reduction of nitro groups, such as Raney nickel, in an inert solvent, for example a cyclic or acyclic ether, such as tetrahydro-furan, under normal pressure or under elevated pressure of up to ~ bar.

Compounds of the formula I with etherified hydroxy groups, for example, with lower alkoxy residues as substituents within Arl and/or Ar2, can be converted into thecorresponding hydroxy-substituted compounds of the formula I by ether cleavage. The ether cleavage takes place under conditions known ~ se, for exarnple in the presence of hydrohalic acids, such as hydrobromic or hydroiodic, in the presence or absence of solvents, such as carbonic acids, for example, lower alkyl-carboni acids, such as acetic acid, at temperatures between 20 C and the reflux temperature of the reaction mixture, or preferentially under mild conditions with boron halides, especially boron tribromide, in an inert solvent, for example a halogenated hydrocarbon, such as methylen cloride or chlorofo~n, at temperatures between -80 and 0 C, preferably between -50 and 20 C.

Free compounds of formula I obtainable in accordance with the process having salt-forming properties can be converted into their salts in a manner known ~r se; compounds having basic properties can be converted into their salts, for example, by treatment with acids or suitable derivatives thereof, and compounds having acidic properties can be converted into their salts, for example, by treatment with bases or suitable derivatives thereof.

Mixtures of isomers obtainable in accordance with the invention can be separated into the ~6~8~7 individual isomers in a manner known ~ se; racemates can be separated, for example, by the formation of salts with optically pure salt-forming reagents and separation of the dia-stereoisomeric mixture so obtaillable, for example by fractional crystallisation.

The above-mentioned reactions can be carried out under reaction conditions known ~ se, in the absence or, usually, in the presence of solvents or diluents, preferably those solvents or diluents which are iner$ towards the reagents used and are solvents therefor, in the absence or presence of catalysts, condensation agents or neutralising agents, and, depending upon the nature of the reaction and/or the reactants, at reduced, norrnal or elevated temperature, for exarnple in a temperature range of from approximately -80C to approximately 200~, preferably from approximately -20C to approximately 150C, for example 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, for example under a nitrogen atmosphere.

As a result of the close relationship between the compounds of formula I in free forrn and in the form of their salts, hereinbefore and hereinafter any reference to the free compounds or their salts should be understood as meaning also the corresponding salts or free compounds, respectively, when the compounds contain salt-forming groups, for example basic groups, such as amino or imino groups, and also those groups which contain no more than one unsaturated carbon atom, such as the groups -NA1Ar1 and/or -NA2Ar2 at the carbon atom of the central phenyl ring, wherein Ar1 and Al and/or Ar2 and A2 are not bonded via an unsaturated carbon a$om, and/or acidic groups, such as carboxy or sulfo (SO3H).

The compounds, including their salts, can also be obtained in the forrn of hydrates, or their crystals may include, for example, the solvent used for crystallisation.

In the processes of this invention it is preferable to use those starting materials which result in the compounds described at the beginning as being especially valuable.
The invention relates also to those forms of the process in which a compound obtainable as intermediate at any stage of the process is used as starting material and the remaining process steps are carried out, or in which a starting material is formed under the reaction conditions or is used in the forrn of a derivative, for exarnple a salt, thereof.

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The present invention relates also to pharmaceutical compositions that comprise one of the co1npounds of formula I as active ingredient. Compositions for enteral, especially oral, and for parenteral administration are especially preferred. The compositions comprise the active ingredient on its own or, preferably, together with a pharrnaceutically acceptable carrier. The dosage of the active ingredient clepends upon the disease to be treated and upon the species, its age, weight and individual condition, and also upon the mode of administration.

Preferred is a pharmaceutical composition suitable for adrninistration to a warm-blooded animal, especially a human, suffering from a disease responsive to the inhibition of a pro~ein kinase, i~or example psoriasis or a tumour, comprising a compound of forrnula I, or a salt thereof when salt-forming groups are present, in an amount effective for the inhibition of the protein kinase, together with at least one pharrnaceutically acceptable carrier.

The pharmaceutical compositions comprise from approximately 5 % to approximately95 % active ingredient, dosage forms in single dose form preferably comprising from approximately 20 % to approximately 90 % active ingredient and dosage forrns that are not in single dose form preferably comprising from approximately 5 % to approximately 20 % active ingredient. Unit dose forrns, such as dragées, tablets or capsules, comprise from approximately 0.05 g to approximately 1.0 g of active ingredient.

The pharmaceutical compositions of this invention are prepared in a manner known E~ se, for example by means of conventional mixing, granulating, confectioning, dissolving or Iyophilising processes. For exampie, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with one or more solid ca~Tiers, optionally granulating a resulting mixture, and, if desired, processing the mixture or granules, if appropriate with the addition of additional excipients, to form tablets or dragée cores.

Suitable carriers are especially fillers, such as sugars, for example lactose, saccharose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tri-calcium phosphate or calcium hydrogen phosphate, also binders, such as starches, for example corn, wheat, rice or potato starch, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose andlor polyvinylpyIrolidone, andlor, if desired, disintegrators, such as the above-mentioned starches, also carboxymethyl starch, cross-lirlked polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodiurn alginate.

2~8~7 Additional 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 poly-ethylene glycol, or derivatives thereof.

Dragée cores can be provided with suitable, optionally enteric, coatings, there being used inter alia concentrated sugar solutions which may contain gum arabic, talc, polyvinyl-pyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions in suitable organic solvents or solvent mixtures, or, for the production of enteric coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethyl-cellulose phthalate. Colourings or pigments may be added to the tablets or dragée coatings, for example for identification purposes or to indicate different doses of active ingredient.

Qrally administrable pharmaceutical compositions also include 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 corn starch, binders and/or glidants, such as talc or magnesium stearate, and optionally stabilisers. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as fatty oils, paraffin oil or liquid polyethylene glycols, to which stabilisers may also be added.

Other oral dosage forms are, for example, syrups prepared in customary manner which comprise the active ingredient, for example, in suspended form and in a concentration of about 5 % to 20 %, preferably about 10 %, or in a similar concentration that provides a suitable single dose, for example, when administered in measures of S or 10 ml. ~Iso suitable are, for example, powdered or liquid concentrates for the preparation of shakes, for example in milk. Such concentrates may also be packaged in single dose quantities.

Suitable rectally administrable pha~naccutical compositions are, for example, suppositories that consist of a combination of the active ingredient and a suppository base.
Suitable suppository bases are, ~or example, natural or synthetic triglycerides, paraffin hydrocarbons, polye~hylene glycols or higher aL~anols.

For parenteral administration there are especially suitable aqueous solutions of an active ingredient in water-soluble form, for example in the form of a water-soluble salt, or .~ ~ . . . , .~ .. , ~, . :..
.

: . ~, 2Q&~7 ,9 aqueous injection suspensions that contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if desired, stabilisers. The active ingredient, optionally together with excipients, can also be in the form of a lyophilisate and can be made into a solution prior to parenteral administration by the addition of suitable solvents.

Solutions such as are used, for example, for paren~eral administration can also be used as infusion solutions.

I`he invention relates also to a method of treating the above~mentioned pathological conditions, especially those conditions responsive to the inhibition of protein kinases. The compounds of this invention can be administered prophylactically or therapeutically, preferably in an amount effective against the said diseases, to a warm-blooded animal, for example a human, requiring such treatment, the compounds preferably being used in the forrn of pharmaceutical compositions. In the case of an individual having a body weight of about 70 kg the daily dose administered is from approximately 0.1 g to approximately 5 g, preferably from approximately 0.5 g to approximately 2 g, of a compound of this invention.

The following ~xamples illustrate the present invention; temperatures are given in degrees Celsius. The following abbreviations are used: ether ^ diethyl ether; THF = tetrahydro-furan; DMF = N,N-dimethylformamide; MS ~ mass spectrum; FAB ^ Fast Atom Bombardment.

Exam~le 1: 4.5-Bis(anilino~phthalimide A suspension of 230 mg (0.7 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 23 ml of ethylene glycol is heated at 120; ammonia gas is passed through the suspension, with stirring, for 24 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three tirnes with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloro-methane/methanol 40:1 and the product fractions are combined and concentrated byevaporation, yielding the title compound in the form of yellow crystals, m.p. 215-217, FAB-MS: 330 [M++H].

.
~;

2~8~7 a) 4,5-Bis(trimethylsilYloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester Under argon, a solution of 7.1 g (50 mmol) of acetylenedicarboxylic acid dimethy] ester in 30 ml of toluene is added dropwise to 12.5 g (50 mmol) of 2,3-bis(trimethylsilyloxy)-1,3-butadiene (95 %) and then boiled under reflux for 19 hours. The reaction mixture is cooled, the solvent is evaporated off and the residue is distilled under a high vacuum (0.1 mbar, 124-127), yielding the title compound in the form of a yellow, highly v;scous oil, lH-NMR (CDCl3): ~ - 0.18 (s, 18H), 3.09 (s, 4H), 3.78 (s, 6H).
..
b) 4,5-Bis(anilino)phthalic acid dimethYI ester A solution of 5.6 g (~5 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-di-carboxylic acid dimethyl ester and 5.5 ml (60 mmol) of aniline in 60 ml of glacial acetic acid is boiled under reflux for 4 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of lN HCl, 50 ml of saturated Na~ICO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The crude product is recrystallised from ethanol, yielding the title compound in the form of yellow crystals, m.p. 178, FAB-MS: 377 [M++H].

Example 2: 5.8-Diphenyl-5.8-diaza-5~6.7.8-tetrahYdronaPhthalene-2.3-dicarboxYlic acid imide Analogously to Example 1, 40 mg (0.1 mmol~ of 5,8-diphenyl-5,8-diaza-5,6,7,8-tetra-hydronaphthalene-2,3-dicarboxylic acid dimethyl ester in 4 ml of ethylene glycol are heated at 120, ammonia gas being passed through the mixture, with stirring, for 24 hours.
The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated so~ium chloride solution, dried with sodium sulfate and concentrated by evaporation. ~he evaporation residue is chromatographed on silica gel with dichloromethane/methanol 20:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, FAB-MS: 356 [~I+~H].

a) 5.8-DiphenYl-5.8-diaza-5.6~7.8-tetrahydronaphthalene-2.3-dicarboxYlic acid dimethvl ester - ~ . . -~

I
.

2~8~7 A solution of 2.24 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-di-carboxylic acid dimethyl ester (Example la) and 5.1 g (24 mmol) of N,N'-diphenyl-ethylenediamine in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. 'rhe reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 20 ml of lN
HCI, 50 ml of saturated Na~lCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The crude product is chromatographed on silica gel with hexane/ethyl acetate 3:1 and the product fractions are concentrated by evaporation and the residue is recrystallised from ethanol, yielding the title compound in the forrn of orange crystals, FAB-MS: 402 [M+], 403 [M++H].

2 ~ 7 F,xample 3: 4,5-Bis(4-fluoroanilino)phthalimide ~nalogously to Example 1, 290 mg (0.7 mmol) of 4,5-bis(4-fluoroanilino)phthalic acid climethyl ester in 22 ml of ethylene glycol are heated at 120 and, with stilring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. I~e evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p. > 220C, FAB-MS: 3~6 ~M++H].

a) 4,5-Bis(4-fluoroanilino)phthalic acid dimethyl ester A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-di-carboxylic acid dimethyl ester (Exarnple la) and 2.3 ml (24 mmol) of 4-fluoroaniline in 60 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloro-methane and the solution is washed in succession with 20 ml of lN HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 2:1 and the product fractions are concentrated by evaporation and recrystallised from ethyl acetate/hexane, yielding the title compound in the form of yellow crystals, lH-NMR ((~DCI3): ~ = 7.40 (s, 2H), 7.10-6.80 (m, 8H), 5.70 (br s, 2H), 3.83 (s, 6H).

Example 4: 4,5-Bis(4-benzvloxv-anilino~phthalimide Analogously to Example 1, 294.4 mg (0.5 mmol) of 4,5-bis(4-benzyloxy-anilino)phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120, ammonia gas being passed through the mixture, with stirring, for 16 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. I~he evaporation residue is chromatographed on silica gel with dichloromethane/methanol 50:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the forrn of red crystals, , : ~
.

2~8~

m.p.187-189~, FAB-~S: 542 [M++H].
a) 4.5-Bis(4-benzyloxy-anilino)phthalic acid dimethvl ester A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example la) and 4.8 g (24 mmol) of 4-benzyloxyaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloro-methane and the solution is washed in succession with 20 ml of 1 N ~ICI, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concen-trated by evaporation. The evaporation residue is dissolved while hot in ethyl acetate and filtered, then allowed to crystallise at 0. The crystalline residue is chromatographed on silica gel with ethyl acetate/hexane 3:2 and the product fractions are concentrated by evaporation and recrystallised from ethyl acetate/hexane, yielding the title compound in the form of beige crystals, FAB-MS: 589 [M++H].
~xample 5: 4~5-E~isr4-(N,N-diethylamino)-anilinolphthalimide bishYdrochloride Analogously to Example 1,294.4 mg (0.5 rnmol) of ~,5-bis[4-(N,N-diethylamino)-anilino]phthalic acid dimethyl ester in 22 ml of ethylene glycol are heated at 120, ammonia gas being passed through the mixture, with stirring, for 22 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 30: 1 and the pro~1uct fractions are combined and concentrated by evapora~ion. The red crystalline evaporation residue is dissolved in dichloromethane, and 4. lN HCl (g) in ether is added thereto. The crystalline precipitate is ~lltered off and dried, yielding the title compound in the form of yellow crystals, m.p. 228-230C, FAB-MS: 472 [M++H].
a) 4,5-Bisr4-(N~N-diethylamino)-anilinolphthalic acid dimethYl ester A solution of 2.4 g (6 mmol~ of 4~5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Exarnple la) and 3.94 g (24 mmol) of 4-(N,N-diethyl-amino)-aniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. I he reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is 2~8~7 dissolved in dichloromethane and the solution is washed in succession with 50 ml of saturated Na~ICO3 and twice with 20 ml of water, dried with sodium sulfate and concen-trated by evaporation. The evaporation residue is chromatographed on silica gel with dichloromethane/methanol 400:15 and the product fractions are concentrated by evapora-tion and again chromatographed on silica gel with ethyl acetate/hexane 1: 1. The product fractions are concentrated by evaporation, yielding the title compound in the form of green crystals, FAB-MS: 518 [M+],519 [M+~H~.
Example 6: 4.5-Bis(cyclohexylamirlo)phtllalimide Analogously to Example 1, 194 mg (0.5 mmol) of 4,5-bis(cyclohexylamino)phthalic acid dimethyl ester in 15 ml of ethylene glycol are heated at 120, ammonia gas being passed through the mixture, with stirring, for 12 hours. The reaction mixture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate ansl concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 3:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of orange crystals, m.p. 170-175C, FAB-MS: 342 [M+-~H].
a) 4,5-Bis(cyclohexylamino)phthalic acid dimethvl ester A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa- 1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example la) in 21.5 rnl (188 mmol) of cyclohexylamine and 4.5 ml of glacial acetic acid is boiled under reflux for 3.5 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 100 ml of 2N HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate andconcentrated by evaporation. The evaporation Tesidue is Ghromatographed on silica gel with ethyl acetate/hexane 5:12 and the product fractions are concentrated by evaporation and again chromatographed with ethyl acetate/hexane 1:4, yielding the title compound in the form of a yellow oil, FAB-MS: 38~ [M+~.

4-Cyclohexylaminophthalic acid dimethyl ester is obtained as a secondary product and is converted into ~-cyclohexylaminophthalimide analogously to Example 6, yielding acolourless powder, FAB-MS: 245 [M+], m.p. 217-219C.

Example ~S-Bis(4-methoxyanilino)phthalimide Analogously to Example 1, 393 mg (0.9 mmol) of 4,5-bis(4-methoxyanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol are heated at 120, arnmonia gas being passed through the mixture, with stirring, for 18 hours. The reaction mi~cture is cooled, saturated with sodium chloride and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetatelhexane 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 191-193C, F~B-MS: 3~0 [M++H].

a) 4,5-Bis(4-methoxvanilino)phthalic acid dimethYl ester A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example la~ and 3.0 g (24 mmol) of 4-anisidine in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloromethane and the solution is washed in succession with 2û ml of lN HCI, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/-hexane 1:1 and the product fractions are concentrated by evaporation~ yielding the title compound in the form of a yellow foam, FAB-~S: 437 [M~+H].

Example 8: 4,5-Bis(2-iodoanilino)phthalimide Analogously to Example 1, 1.4~ g (2.36 mmol) of 4,5-bis(2-iodoanilino)phthalic acid dimethyl ester in 25 ml of ethylene glycol are heated at 120 and9 with stirring, ammonia gas is passed through the mixture for 19 hours. The reaction mixture is cooled, diluted with brine and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The residue obtained after concen-tration by evaporation is filtered through silica gel with dichloromethane and the product fractions are combined and concentrated by evaporation. The residue obtained after concentration by evaporation is crystallised from boiling dichloromethane, yielding the .

.

20~8~7 title compound in the form of yellow crystals, m.p. 108-110C, FAB-MS: 582 [M+~H].
a) 4,5-Bis(2-iodoanilino)phthalic acid dimethyl ester A solution of 2.4 g (6 mmol) of 4,5-bis(trimethylsilyloxy)cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example la) and 5.3 g (24 mmol) of 2-iodoaniline in 24 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated off and the dark-brown residue is dissolved in dichloro-methane and the solution is washed in succession with 20 ml of lN HCl, 50 ml of saturated NaHCO3 and twice with 20 ml of water, dried with sodium sulfate and concen-trated by evaporation. The residue obtained after concentration by evaporation is chromatographed on silica gel with ethyl acetate/hexane 2: 1 and the product fiactions are concentrated by evaporation, yielding the title compound in the form of a yellow foam:
lH-NMR (DMSO-d6): ~ = 7.91 (dxd, Jl=8, J2=1, 2H),7.39 (dxdxd, Jl=10, J2=8, J3=1, 2H), 7.32 (br s, 2H), 7.22-7.05 (m, 2H), 7.01 (s, 2H), 6.88 (txd, Jt=8, Jd=1, 2H), 3.73 (s, 6H).
Example 9: 4~5 Bis(2-cvanoanilino)phthalimide A solution of 581 mg (1 mmol) of 4,5-bis(2-iodoanilino)phthalimide and 197 mg (2.2 mmol) of copper(I) cyanide in DMF is stirred for 6 hours at 130-140C, the dark-brown solution changing into a dark-yellow suspension. The reaction mixture is cooled to 80C and diluted with 8 rnl of ethyl acetate. After further cooling to 60-70C, a solution of 467 mg (2.88 mmol) of iron(III) chloride in 1.6 ml of water and 300111 of concentrated hydrochloric acid is added dropwise and the mixture is stirred for 30 minutes. 2 ml of water and Hyflo Super Cel~) (kieselguhr from Fluka, Buchs, Switzerland) are added to the reaction mixture which is then filtered through Hyflo Super Cel~ and the phases are separa~ed. The aqueous phase is extracted once with ethyl acetate and the combined organic phases are washed twice with water, once with saturated sodium hydrogen carbonate solution and twice more with water, dried over magnesium sulfate and concen-trated by evaporation. The resulting oily brown crystal mixture is chromatographed on silica gel with ethyl acetate~exane 2:3. The product fractions are concentrated by evaporation and crystallised from boiling dichloromethane, yielding the title compound in the form of pale-yellow crystals: FAB-MS: 380 (M++H), m.p.: 279-280C.

5-Anilino-4-(2-cyanoanilino)phthalimide is obtained as a secondary product in the forrn of yellow crystals: FAB-MS: 355 (M~+H), m.p.: 115-117C.

- , .
- , ; ; ~ : :

Example 10: 4~5 Bis(2-nitroanilino)phthalimide, 4-(4-nitroanilino)-5-(2~4-dinitroanilino)-phthalimide and 4~5-bis(4-nitroanilino)phthalimide 990 mg t3 mmol) of 4,5-bis(anilino)phthalimide are added to a mixture of 12 mmol of acetic anhydride and 24 mmol of glacial acetic acid and 7.5 mmol of nitric acid (100 %) at temperatures of less than 20C. After stirring for 20 minutes, the reaction mixture is poured onto ice and extracted with ethyl acetate. The organic phases are washed once with saturated NaHCO3 solution and once with water, dried over sodium sulfate and filtered. Chromatography twice on silica gel using a gradient of dichloromethane/ethyl acetate 1:1 to 3:1 yields the following amorphous compounds: 4,5-bis(2-nitroanilino)-phthalimide in the form of a reddish-black powder: m.p. 87-90C; 4-(4-nitroanilino)-5-(2,4-dinitroanilino)phthalimide in the form of a reddish-black powder: m.p. 176-178C, lH-NMR (DMSO-d6): 9.25 (br s,2H), 8.85 (d, J=2.5, lH), 8.16 (dxd, Jl=8, J2-2.5, lH), 8.13 (d, j=9, 2H), 7.88 (s, lH), 7.75 (s, lH),7.17 (d, J=9, 2H), 6.96 (d, J=9.5, lH);
4,5-bis(4-nitroanilino)phthalimide in the form of a led, lustrous powder: m.p. > 250C, decomposition from ~105C, lH-NMR (DMSO-d6): 9.22 (br s, 2H), 8.12 (d, J=9.1, 4H), 7.71 (s, 2H), 7.13 (d, J=9.1, 4H); l3C-NMR (DMSO-d6): 168.9 s, 149.8 s, 139.6 s, 138.2 s, 128.2 s, 125.9 d, 116.~ d, 115.6 d.

Example 11: 4.5-Bis(4-aminoanilino)phthalimide A solution of 38 mg (0.09 mmol~ of 4,5-bis(4-nitroan-ilino~phthalimide in 15 ml of T~IF is hydrogenated with 10 % Raney nickel as catalyst for three hours at normal pressure and room temperature. The catalyst is f~ltered off and the reaction mixture is concentrated by evaporation, yielding the title compound in the form of a slightly yellowish powder:
m.p. 154-157C, F~B-MS: 360 (M+~-H).

Example 12: Analogously to the Example given in parentheses after each compound there are prepared:

(a) 4,5-Bis(4-iodoanilino)phthalimide, FAB-MS: 582 (~I~+H), m.p.: 246-X47C
(analogously to Example 8~
(b) 4,5-Bis(3-iodoanilino)phthalimide, FAB-MS: 582 (M++H), m.p.: 244-245C
(analogously to E~xample 8) (c) 4,5-Bis(2,6-dibromoanilino)phthalimide, FAB-MS: S42 (M++H), m.p.: 235-237C

: . ,.:-, 2~98~7 (analogously to Example 8) (d) 4,5-Bis(3-methoxyanilino)phthalimide, FAB-MS: 390 (M-~+H), m.p.: 169-171C
(analogously to Example 7) (e) 4,5-Bis(2-methoxyallilino)phthalimide, FAB-MS: 390 (M ~H), m.p.: 227-22~C
(analogously to Example 7) (f~ 4,5-Bis(4-trifluoromethylanilino)phthalimide, FAB-MS: 512 (M++H), lH-NMR
(CD30D): 7.7 (s, 2H), 7.5 (d, 4H),7.2 (d, 4H) (analogously to Example 1), (g) 4-Cyanoanilino-5-trifluoromethylanilino-phthalimide, FAB-MS: 423 (M++H), lH-NMR (CDC13): 7.7 (d, 2~1), 7.6 (d, 4H), 7.1 (d, 2H), 7.0 (d, 2H), 6.2 (s, lH), 6.1 (s, lH) (analogously to Example 1) (h) 4,5-Bis(4-biphenylamino)phthalimide, FAB-MS: 482 (M++H), m.p.: 230-231C
(analogously to Example 1) (i) 4,5-Bis(4-cyanoanilino)phthalimide, FAB-MS: 380 (M++H), m.p.: > 250C, lH-NMR
(DMSO-d6): 7.1 (d, 4H),7.6 (d, 4H), 7.7 (s, 2H) (analogously to Example 9) (j) 4,5-Bis(3-cyanoanilino)phthalimide, FAB-MS: 380 (M++H), m.p.: 255-257C
(analogously to Example 9) (k) 4,5-Bis(4-pyridineamino)phthalimide (analogously to Example 1) (1) 4,5-Bis(3-pyridineamino)phthalimide (analogously to Example 1) (m) 4,5-Bis(2-pyridineamino)phthalimide (analogously to Example 1) (n) 4,5-Bis(2-pyrimidineamino)phthalimide (analogously to Example 1) (o) 4,5-Bis(3-pyrimidineamino)phthalimide (analogously to Example 1) (p) 4,5-Bis(4-pyrimidineamino)phthalimide (analogously to Example 1) (q) 4,5-Bis(2-triazineamino)phthalimide (analogously to Example 1) (r) 4,5-Bis(3-fluoroanilino)phthalimide (analogously to Exarnple 3) (s) 4,5-Bis(2-fluoroanilino)phthalimide (analogously to Example 3) (t) 4,5-Bis(pentafluoroanilino)phthalimide (analogously to Example 3) (u) 4,5-Bis(4-hydroxyanilino)phthalimide (analogously to Example 1) (v) 4,5-Bis(3-hydroxyanilino)phthalimide (analogously to Example 1) (w) 4,5-Bis(2-hydroxyanilino)phthalimide (analogously to Example 1) (x) 4,5-Bis(4-ethylanilino)p~thalimide (analogously to Example 1) (y) 4,5-Bis(3-ethylanilino)phthalimide (analogously to Example 1) (z) 4,5-Bis(2-ethylanilino)phthalimide (analogously to Exarnple 1) (aa) 4,5-Bis(4-methylanilino)phthalimide (analogously to Example 1) (ab) 4,5-Bis(3-methylanilino)phthalimide (analogously to Example 1) (ac) 4,5-Bis(2-methylanilino)phthalimide (analogously to :Example 1) (ad) 4,5-Bis(3-trifluoromethylanilino)ph~halimide (analogously to Example 1) - , ; :

, , 2~8~

(ae) 4,5-Bis(2-trifluoromethylanilino)phthalimide (analogously to Example 1) (af) 4,5-Bis[4-(N,N-dimethylamino)-anilino]phthalimide (analogously to Example 5) (ag) 4,5-Bis[4-(N-acetylamino)-anilino]phthalimide (analogously to Example 1) (ah) 4,5-Bis(3-biphenylylamino)phthalimide (analogously to Example 1) (cai) 4,5-Bis(2-biphenylylamino)phthalimide (analogously to Example 1) (aj) 4,5-Bis(1-naphthylamino)phthalimide (analogously to Example 1) (ak) 4,5-Bis(2-naphthylamino)phthalimide (analogously to Example 1) (al) 4,5-Bis(5-tetralinylamino)phthalimide (analogously to Example 1) (am) 4,5-Bis(4-carboxyanilino)phthalimide (analogously to Example 1) (an) 4,5-Bis(3-carboxyanilino)phthalimide (analogously to Example 1) (ao) 4,5-Bis(2-carboxyanilino)phthalimide (analogously to Example 1) (ap) 4,5-Bis(4-rnethoxycarbonyl-anilino)phthalimide (analogously to Example 1) ~aq) 4,5-Bis(3-methoxycarbonyl-anilino)phthalimide (analogously to Example 1) (ar) 4,5-Bis(2-methoxycarbonyl-anilino)phthalimide (analogously to Example 1) (as) 4,5-Bis(4-ethoxycarbonyl-anilino)phthalimide (analogously to Example 1) (at) 4,5-Bis(3-ethoxycarbonyl-anilino)phthalimide (analogously to Example 1) (au) 4,5-Bis(2-ethoxycarbonyl-anilino)phthalimide (analogously to Example 1) (av) 4,5-Bis(4-isopropyloxycarbonyl-anilino)phthalimide (analogously to Example 1) (aw) 4,5-Bis(4-tert-butyloxycarbonyl-anilino)phthalimide (analogously to ~xample 1) (ax) 4,5-Bis(4-carbamoyl-anilino)phthalimide (analogously to Example 1) (ay) 4,5-Bis(4-N,N-dimethylcarbamoyl-anilino)phthalimide (analogously to Example 1) (az) 4,5-Bis(4-hydroxy-3-methylanilino)phthalimide (analogously to Example 1) (ba) 4,5-Bis(2-hydroxy-5-methylanilino)phthalimide (analogously to Example 1).

Example 13: 4.5-Bis(N-methyl-N-phenvlamino~Rhthalimide Analogously to Example 1, 66 mg (0.16 mmol~ of 4,5-bis(N-methyl-N-phenylamino)-phthalic acid dimethyl ester (~xample 14 A) in S ml of ethylene gly~ol are heated at 120 and, with stiTTing, ammonia gas is passed through the mixture for 18 houTs. The reaction mixture is cooled, and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concent~ated by evaporation, yielding the title compound in the form of slightly yellow crystals, F~B-MS: 358 [M++H], lH-NMR (CDCI3): 3.05 (s, 6H).

2~8~7 Example 14: 4-(N-Methyl-N-phenylamino)-5-anilino-phthalimide Analogously to Example 1, 160 mg (0.41 mmol) of 4-(N-methyl-N-phenylamino)-5-anilinophthalic acid dimethyl ester in 12 ml of ethylene glycol are heated at 120 and, with stirring, ammonia gas is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the forrn of slightly yellow crystals, FAB-MS: 344 [M++H], lH-NMR (CDCl3): 3.28 (s, 3H).

a) 4,5-Bis(N-methyl-N-phenylamino)phthalic acid dirnethyl ester (A) and 4-(N-methyl-N-phenYlamino)-5-anilino-phthalic acid dimethyl ester (B) A solution of 564 mg (1.5 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example lb) in 5 ml of acetonit~ile is heated at 80C for 16 hours with 0.93 ml(15 mmol) of methyl iodide and 442 mg (3.2 mmol) of anhydrous potassium carbonate in a bomb tube. The reaction mixture is concentrated to dryness by evaporation, the residue is twice digested in dichloromethane and f~lltered, and the filtrate is concentrated by evaporation. Repeated chromatography on silica gel with hexane/ethyl acetate yields the title compounds in the form of slightly yellowish powders. (A): FAB-MS: 405 [M*+H];
(B): FAB-MS: 391 [M++H].

Example 15: 4,5-Bis(anilino)-N-methyl-phthalimide Analogously to Example 1, 376 mg (1 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester in 33 ml of ethylene glycol are heated at 120 and, with stirring, methylamine is passed through the mixture for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate. The ethyl acetate phases are washed in succession three times with water and once with saturated sodium chloride solution, dried with sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 1:1 and the product fractions are combined and concentrated l)y evaporation, yielding the title compound in the form of slightly yellow crystals, ~AB-MS:
344 ~M++H], m.p. 195-196C.

;

g ~ 7 ~xample 16: 4,5-Bis(anilino)-thiophthalimide r= 5.6-bis(anilino)-isoindol-1-one-3-thionel 138 mg (0.36 mmol) of Lawesson reagent [= 2,4-bis(4-rmethoxyphenyl)-2,4-dithioxo-1,3,2,~-dithiaphosphetane] are added to a solution of 100 mg (0.3 rnmol) of 4,5-bis-(anilino)phthalimide (Example 1) in 15 ml of dichloromethane and the mixture is boiled under re~lux for 4 hours. The reaction mixture is concentrated by evaporation and chromatographed directly on silica gel with hexane/ethyl acetate 2:1. The product fractions are concentrated by evaporation, yielding the title compound in the form of yellow crystals, FAB-MS: 346 [M-~+~U.

Example 17: 4,5-l~is(anilino)-N4.N5-propane-1.3-divlphthalimide In an autoclave, 457 mg (1 mmol) of 4,5-bis(anilino)-N4,Ns-propane-1,3-diyl-phthalic acid dimethyl ester are dissolved in 5 ml of methanol, and 15 ml of ammonia are used for the purpose of amide ~ormation. The autoclave is closed and then heated at 120C for 24 hours, then cooled and opened, and the ammonia is driven off with nitrogen. The residue is rinsed out with ethyl acetate and filtered, and the filtrate is chromatographed on silica gel with hexane/ethyl acetate 3:1. Thc product fractions are concentrated by evaporation and crystallised from hexane/ethyl acetate, yielding the title compound in the form of yellow crystals, FAB-MS: 370 [M+~H].

a) 4,5-Bis(anilino)-N4~N5-propanediyl-phthalic acid dimethvl ester and 4,5-bis(N-allyl-anilino)phthalic acid dimethvl ester 0.6 g (15.4 mmol~ of sodium amide is added at room temperature under argon to a solution of 3.76 g (10 mmol) of 4,5-bis(anilino)phthalic acid dimethyl ester (Example lb) in 15 ml of HMPT (hexamethylphosphoric acid triamide) or DMPU, and the mixture is heated at 60C for 30 minutes. The deep red solution is cooled to room temperature and evacuated for S minutes (1 torr), then a solution of 1.5 ml (15.2 mmol) of 1-bromo-3-chloropropane in 2 ml of TH F is added dropwise and the reaction mixture is stirred for 18 hours at room temperature. The reaction mixture is poured onto ice-water, extracted with ethyl acetate and the organic phases are combined and washed with generous amounts of water, dried over sodium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with hexane/ethyl acetate 5:1, yielding the title compounds:
4,5-bis(anilino)-N4,Ns-propanediyl-phthalic acid dimethyl ester in the form of colourless crystals, FAB-MS: 417 [M+~H]; and 4,5-bis(N-allylanilino)phthal;c acid dimethyl ester in .( .. :
. . ~ ~ . . . . : .... ...

8 ~ 7 the form of a colourless oil, FAB-MS: 457 [M++H].
Example 18: Analogously to Examples 13-17 there are prepared:

ta) 4-(N-Acetyl-N-phenyl)amino-5-anilino-phthalimide, FAB-MS: 372 [M++H], lH-NMR(DMSO-d6): 2.0S (s, 3H) (analogously to Example 14) (b) 4,5-Bis(anilino)-N-benzyl-phthalimide (analogously to Example 15) (c) 4,5-Bis(anilino)-N-amino-phthalimide (analogously to Example 15) (d) 4,5-Bis(anilino)-N-hydroxy-phthalimide (analogously to Example 15) (e) 4,5-Bis(N-allylanilino)phthalimide, FAB-MS: 410 (analogously to Example 17).
Example 19: 5000 capsules are prepared, each comprising 0.25 g of active ingredient, for example one of the compounds prepared in Examples 1 to 16:

Composition active ingredient 1250 g talc 180 g wheat starch 120 g magnesium stearate 80g lactose 20 g Method: The pulvemlent substances are forced through a sieve having a mesh size of 0.6 mm and mixed together. 0.33 g portions of the mixture are filled into gelatin capsules using a capsule-filling machine.
Example 20: 4-Anilino-5-(4-hYdroxv-anilino)-I?hthalimide To a solution of 359.4 mg (1 mmol) of 4-anilino-5-(4-methoxy-anilino)-phthalimide in 5 ml of chloroform, a solution of 186 ,LI (2 mmol) boron tribromide is added dropwise at -40 C to -30 C. The reaction mixture is stirred for 5 hours at -30 C, and is then quenched with 5 ml of water. The reaction mixture is warrned up to room temperature, and the phases are separated. The organic phase is washed twice with water, dried over magnesium sulfate and concentrated by evaporation. Excluding light, the evaporation residue is chromatographed with ethylacetate~exane 1: 1 on a silica gel column that is cooled with ice-water (double jacket), the product fractions are combined and concentrated by evaporation. The title compound is obtained in the form of yellow ' , ,.

2 ~ 7 crystals, FAB-MS: 346 [M++H].
a) 4-Anilino-5-(4-methoxY-anilino)pthalimid ~nalogously to Example 1, 0.7 g (1.7 mmol) 4-anilino-5-(4-methoxy-anilino)-phthalic acid dimethyl ester are heated at 120 , ammonia gas being passed through the mixture, with stirring, for 18 hours. The reaction mixture is cooled and extracted with ethyl acetate.
The ethyl acetate phases are washed in succession twice with water and once withsaturated sodium chloride solu~ion and dried with magnesium sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethylacetate/hexane 1: 1 and the product fractions are combined and concentrated by evaporation, yielding the title compound in the form of yellow crystals, m.p. 266-7 C, FAB-MS: 360 [M~+H].

b) 4-Anilino-5-(4-methoxv-anilino)-phthalic acid dimethvl ester and 4~5-Bis(4-methoxy-anilino)-phthalic acid dimethyl ester A solution of 4.8 g (12 mmol) 4,5-Bis(trimethylsilyloxy)-cyclohexa-1,4-diene-1,2-dicarboxylic acid dimethyl ester (Example 1 a), 2.6 g (24 mmol) p-anisidine and 2.2 ml (24 mmol) aniline in 48 ml of glacial acetic acid is boiled under reflux for 2 hours. The reaction mixture is cooled, the solvent is evaporated and the dark-brown residue is dissolved in ethyl acetate and the solution is washed in succession with 40 ml of lN HCl, 100 ml of saturated NaHCO3 and twice with water, dried with magnesillm sulfate and concentrated by evaporation. The evaporation residue is chromatographed on silica gel with ethyl acetate/hexane 1 :3 and the product fractions are concentrated by evaporation. This way, in the first product fractions 4,5-bis-(4-methoxy-anilino)-phthalic acid dimethyl ester is obtained in the fo~n of a yellow foam: FAB-MS:
437 [M++H]. The evaporation residue of the product fractions following thereafter is recrystallized, and 4-anilino-~-(4-methoxy-anilino)-phthalic acid dirnethyl ester is obtained in the form of yellow crystals, m.p. 122-4 C, FAB-MS: 407 [M~+H].

Claims (25)

1.A compound of formula I

(I) wherein A1 and A2 are each independently of the other hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aryl, acyl, lower alkylsulfonyl or arylsulfonyl; or wherein A1 and A2 together form unsubstituted or lower alkyl- or hydroxy-substituted lower alkylene; Ar1 and Ar2 are each independently of the other aryl, heteroaryl or unsubstituted or substituted cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CR1R2)- wherein R1 and R2 are each independently of the other hydrogen or lower alkyl; and R is hydrogen, lower alkyl, aryl-lower alkyl, aryl, amino, hydroxy or lower alkoxy; with the proviso that R1 is other than phenyl when A1 and A2 are hydrogen, Ar1 and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; or a salt thereof when salt-forming groups are present.

2. A compound of formula I according to claim 1 wherein A1 and A2 are each independently of the other hydrogen, lower alkyl, aryl, acyl, lower alkylsulfonyl or aryl-sulfonyl; or wherein A1 and A2 together are unsubstituted or lower alkyl- or hydroxy-substituted lower alkcylene; Ar1 and Ar2 are each independently of the other aryl, hetero-aryl or unsubstituted or substituted cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CR1R2)- wherein R1 and R2 are each independently of the other hydrogen or lower alkyl; and R is hydrogen, lower alkyl, aryl-lower alkyl, aryl, amino, hydroxy or lower alkoxy; with the proviso that R is other than phenyl when A1 and A2 are hydrogen, Ar1 and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; or a salt thereof when salt-forming groups are present.

3. A compound of formula I according to claim 1 wherein A1 and A2 are each independently of the other hydrogen lower alkyl; lower alkenyl; phenyl or l-naphthyl or 2-naphthyl, the three last-mentioned radicals being unsubstituted or substituted by lower alkyl, lower alkoxy hydroxy, halogen and/or by trifluoromethyl; lower alkanoyl, lower alkylsulfonyl or phenylsulfonyl wherein the phenyl group is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or wherein A
and A2 together are C1-C4alkylene; wherein Ar1 and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent carbon atoms), C3-C8cycloalkyl, phenyl-lower alkyl, phenyl; lower alkyl substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkylsulfinyl, lower alkylsulfonyl, carboxy, lower alkoxycarbonyl, carba-moyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy, lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy (linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylalkylsulfonyl, phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C3-C8cycloalkylamino, phenyl-lower alkyl-amino, phenylamino, di-lower alkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-lower alkylamino, lower alkyleneamino, lower alkyleneamino interrupted by -O-, -S- or -NR" (wherein R" is hydrogen, lower alkyl or lower alkanoyl), lower alkanoyl-amino, phenyl-lower aLkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl, phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkylsulfonyl, sulfamoyl, N-lower aLkylsulfamoyl, N,N-di-lower alkyl-sulfamoyl and N-phenylsulfamoyl (phenyl groups occurring in the substituents each being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by tn-fluoromethyl); pyridyl or pyrimidinyl that is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CR1R2)- wherein R1 and R2 are each independently of the other hydrogen or lower alkyl, and R is hydrogen, lower alkyl;
phenyl-lower alkyl, phenyl, 1-naphthyl or 2-naphthyl, in the four last-mentioned radicals the phenyl or naphthyl group being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or R is amino, hydroxy or lower alkoxy, with the proviso that R is other than phenyl when A1 and A2 are hydrogen, Ar1 and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; or a salt thereof when salt-forming groups are present.

4. A compound of formula I according to claim 3 wherein R is as defined except for phenyl, and the other radicals are as defined, or a salt thereof when salt-forming groups are present.

5. A compound of formula I according to claim 1 wherein Al and A2 are each independently of the other hydrogen, lower alkyl; phenyl or l-naphthyl or 2-naphthyl, the three last-mentioned radicals being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; lower alkanoyl, lower ]
or phenylsulfonyl wherein the phenyl group is unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl; or wherein Al and A2 together are C1-C4alkylene; wherein Ar1 and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from the group consisting of: lower alkyl, lower alkenyl, lower alkynyl, lower alkylene (linked to two adjacent carbon atoms), C3-C8cycloalkyl, phenyl-lower alkyl, phenyl; lower alkyl substituted by hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkanoyloxy, halogen, amino, lower alkylamino, di-lower alkylamino, mercapto, lower alkylthio, lower alkyl-sulfinyl, lower alkylsulfonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkyl-carbamoyl, N,N-di-lower alkylcarbamoyl and/or by cyano; hydroxy, lower alkoxy, halo-lower alkoxy, phenyl-lower alkoxy, phenoxy, lower alkenyloxy, halo-lower alkenyloxy, lower alkynyloxy, lower alkylenedioxy (linked to two adjacent carbon atoms), lower alkanoyloxy, phenyl-lower alkanoyloxy, phenylcarbonyloxy, mercapto, lower alkylthio, phenyl-lower alkylthio, phenylthio, lower alkylsulfinyl, phenyl-lower alkylsulfinyl, phenylsulfinyl, lower alkylsulfonyl, phenylalkylsulfonyl, phenylsulfonyl, halogen, nitro, amino, lower alkylamino, C3-C8cycloalkylamino, phenyl-lower alkylamino, phenylamino, di-lower alkylamino, N-lower alkyl-N-phenylamino, N-lower alkyl-N-phenyl-lower alkyl-amino, lower alkyleneamino, lower alkyleneamino interrupted by -O-, -S- or -NR"
(wherein R" is hydrogen, lower alkyl or lower alkanoyl), lower alkanoylamino, phenyl-lower alkanoylamino, phenylcarbonylamino, lower alkanoyl, phenyl-lower alkanoyl,phenylcarbonyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, N-hydroxycarbamoyl, N-phenylcarbamoyl, cyano, sulfo, lower alkylsulfonyl, sulfamoyl, N-lower alkylsulfamoyl, N,N-di-lower alkylsulfamoyl and N-phenylsulfamoyl (phenyl groups occurring in the substituents each being unsubstituted or substituted by lower alkyl, lower alkoxy, hydroxy, halogen and/or by trifluoromethyl);
pyridyl that is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy, halogen, cyano and/or by trifluoromethyl; or C3-C8cycloalkyl; the group -C(=X)- is -C(=O)-, -C(=S)-, -CH2- or -C(=CR1R2)- wherein R1 and R2 are each independently of the other hydrogen or lower alkyl, and R is hydrogen, lower alkyl; phenyl-lower alkyl, phenyl, 1-naphthyl or 2-naphthyl, in the four last-mentioned radicals the phenyl or naphthyl group being unsubstituted or substituted by lower alkyl, lower alkoxy hydroxy, halogen and/or by trifluoromethyl; or R is amino, hydroxy or lower alkoxy, with the proviso that R is other than phenyl when A1 and A2 are hydrogen, Ar1 and Ar2 are phenyl and the group -C(=X)- is -C(=O)-; or a salt thereof when salt-forming groups are present.

6. A compound of formula I according to claim 2 wherein A1 and A2 are each independently of the other hydrogen or lower alkyl, the group -C(=X)- is -C(=O)-, -C(=S)-or -C(=CH2)-, and R is hydrogen or lower alkyl; or a salt thereof.

7. A compound of formula I wherein A1 and A2 are each independently of the otherhydrogen; lower alkyl; lower alkenyl; or lower alkanoyl; or wherein A1 and A2 together are C1-C4alkylene; wherein Ar1 and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from the group consisting of: lower alkyl, lower alkylene (linked to two adjacent carbon atoms), hydroxy, phenoxy, halogen, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl,N,N-di-lower alkylcarbamoyl and cyano; pyridyl; pyrimidinyl; or C3-C8cycloalkyl; the group -C(=X)- is -C(=O)- or -C(=S)-, and R is hydrogen, lower alkyl, phenyl-lower alkyl, amino or hydroxy; or a salt thereof when salt-forming groups are present.

8. A compound of formula I according to claim 1 wherein A1 and A2 are each independently of the other hydrogen or methyl; or wherein A1 and A2 together are-(CH2)2- or -(CH2)3-; Ar1 and Ar2 are each independently of the other phenyl or naphthyl, each of which is unsubstituted or substituted by one or more substituents from the group consisting of: lower alkyl, lower alkoxy, phenyl-lower alkoxy, hydroxy, lower alkanoyl-oxy, nitro, amino, lower alkylamino, di-lower alkylamino, lower alkanoylamino, halogen, trifluoromethyl, carboxy, lower alkoxycarbonyl, carbamoyl, N-lower alkylcarbamoyl, N,N-di-lower alkylcarbamoyl, cyano, lower alkanoyl, benzoyl, lower alkylsulfonyl and sulfamoyl, N-lower alkylsulfamoyl and N,N-di-lower alkylsulfamoyl; cyclopentyl; cyclo-hexyl; or pyridyl; the group -C(=X)- is -C(=O)-, -C(=S)- or -C(=CH2)-, and R is hydrogen or lower alkyl; or a pharmaceutically acceptable salt thereof.

9. A compound of formula I according to claim 1 wherein A1 and A2 are hydrogen; Ar1 and Ar2 are each independently of the other phenyl that is unsubstituted or substituted by lower alkyl, trifluoromethyl, phenyl, hydroxy, lower alkoxy, benzyloxy, amino, di-lower alkylamino, lower alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, carbamoyl, N,N-di-lower alkylcarbamoyl or by cyano; or cyclohexyl; the group -C(=X)- is -C(=O)-, -C(=S)- or -C(=CH2)-, and R is hydrogen; or a pharmaceutically acceptable salt thereof.

10. 4,5-Bis(anilino)phthalimide according to claim 1.

11. 4,5-Bis(4-fluoroanilino)phthalimide according to claim 1.

12. 4,5-Bis(cyclohexylamino)phthalimide according to claim 1 or a pharmaceutically acceptable salt thereof.

13.5,8-Diphenyl-5,8-diaza-5,6,7,8-tetrahydronaphthaleene-2,3-dicarboxylic acid amide according to claim 1.

14. 4,5-Bis(2-nitroanilino)phthalimide according to claim 1.

15. 4,5-Bis(4-aminoanilino)phthalimide according to claim 1 or a pharmaceutically acceptable salt thereof.

16. 4,5-Bis(2-pyridincamino)phthalimide according to claim 1 or a pharmaceutically acceptable salt thereof

17. 4,5-Bis(2-pyrimidineamino)phthalimide according to claim 1 or a pharmaceutically acceptable salt thereof.

18. 4-(N-Methyl-N-phenylamino)-5-anilinophthalimide according to claim 1.

19. 4,5-Bis(anilino)-N4,NS-propane-1,3-diyl-phthalimide according to claim 1.

20. 4,5-Bis(N-allylanilino)phthalimide according to claim 1.

21. A pharmaceutical composition comprising a compound according to any one of claims 1 or 10 and at least one pharmaceutically acceptable carrier.

22. A compound of formula I, or a salt thereof, according to any one of claims 1 or 10 for the inhibition of tyrosine protein kinases or serine/threonine kinases.

23. The use of a compound of formula I according to any one of claims 1 or 10 for the preparation of a pharmaceutical composition.

24. The use of a compound according to any one of claims 1 or 10 for the preparation of a pharmaceutical composition for the treatment of diseases responsive to the inhibition of tyrosine protein kinases or serine/threonine kinases.

25. A process for the preparation of a compound of formula I according to claim 1, which process comprises (a) reacting a compound of formula II

(II) wherein Ar1, Ar2, A1 and A2 are as defined under formula I and R3 and R4 are each independently of the other aryl or lower aLkyl, with a compound of formula III
H2N-R (III) wherein R is as defined under formula I, or (b) reacting a compound of formula IV

(IV) wherein Ar and A are as defined under formula I, with a compound of formula III
H2N-R (III) wherein R is as defined under fonnula I;

and, if desired, converting a resulting cornpound of formula I into a different compound of formula I, and/or converting a resulting salt into the free compound or into a different salt, and/or converting a resulting free compound I into a salt and/or separating a resulting mixture of isomeric compounds of formula I into the individual isomers.