| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | July 15, 2003 |
| PATENT TITLE |
Dervatives of quinoline as alpha-2 antagonists |
| PATENT ABSTRACT | A compound of formula I, ##STR1## wherein A, Ra, Rb, R.sub.1 to R.sub.5, m and t are as defined as disclosed, or a pharmaceutically acceptable salt or ester thereof, useful as an alpha-2 antagonist. The compounds I can be used for the treatment of diseases or conditions where alpha-2 antagonists are indicated to be effective |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 28, 2001 |
| PATENT REFERENCES CITED |
Sathi et al., "New Quinolines as Potential CNS Agents," Arch. Pharm. 316, 767-772 (1983). Radzikowski et al., "New Antitumor Compounds. Biological studies. IV. Antitumor properties of 21 new acridine derivatives," Acc. No. 1967: 401919 XP 002901810. Kozyreva et al., "Synthesis and Study of the Anthelmintic Acttivity of Some N-Heterocycles Containing 4-(4'-Diethylcarbamoyl-1'-Piperazinyl) Phenylamine Substituents," Acc. No. 1972: 400153 XP 002901811. Klopman et al., "Computer-Automated Structure Evaluation of Antileukemic 9-Anilinoacridines," Acc. No. 1987:628423 XP 002901812. Mikailitsyn F.S. et al., Medicinskaja Parazitologija 1 parazitarnye bolezni, vol. 5, pp. 55-57 (1991). Anti Haapalinna et al., "Evaluation of the effects of a specific .alpha..sub.2 -adrenoceptor antagonist, atipamozole, on .alpha..sub.1 - and .alpha..sub.2 -adrenoceptor subtype binding, brain neurochenistry and behaviour in comparison with yohimbine", Naunyn-Schmiedeberg's Arch Pharmacol, vol. 356, pp. 570-582 (1997). Bruce Cain et al., "Potential Antitumor Agents. 23. 4'-(9-Acridinylamino)alkanesulfonanilide Congeners Bearing (Hydrophilic Functionality", Journal of Medicinal Chemistry, vol. 20, No. 8, pp. 987-996 (1977). Adrienne Adams et al., "Interaction of DNA-Intercalating Antitumor Agents with Andrenoceptors", Molecular Pharmacology, vol. 27, pp. 480-491 (1985). William Denny et al., "Pontetial Antitumor Agents. 36. Quantitative Relationships between Experimental Antitumor Activity, Toxicity, and Structure for the General Class of 9-Anilinoacridine Antitumor Agents", J. Med. Chem., vol. 25, pp. 276-315 (1982). Anne Marjamaki et al., "Stable expression of recombinant human .alpha..sub.2 -adrenoceptor subtypes in two mammalian cell lines: characterization with [.sup.3 H]rauwolscine binding, inhibition of adenylate cyclase and RNase protection assay", Biochimica et Biophysica Acta, vol. 1134 pp. 169-177 (1992). Jeffrey Jasper et al., "Ligand Efficacy and Potency at Recombinant .alpha..sub.2 Adrenergic Receptors", Biochemical Pharmacology, vol. 55, pp. 1035-1043 (1998). Katariina Pohjanoksa et al., ".alpha..sub.2 -Adrenoceptor regulation of adenylyl cyclase in CHO cells: dependence on receptor density, receptor subtype and current activity of adenylyl cyclase", Eur. Journal of Pharmacology, vol. 335, pp. 53-63 (1997). Harry Scheinin et al., "Behavioural and neurochemical effects of antipamezole, a novel .alpha..sub.2 -adrenoceptor antagonist", Eur. Journal of Pharmacology, vol. 151, pp. 35-42 (1988). Jukka Sallinen et al., "Genetic Alteration of .alpha..sub.2c -Adrenoceptor Expression in Mice: Influence on Locomotor, Hypothermic, and Neurochemical Effects of Dexmedetomine, a Subtype-Nonselective .alpha..sub.2 -Adrenoceptor Agonist", Molecular Pharmacology, vol. 51 pp. 36-46 (1997). Sallinen et al., "Genetic alteration of the .alpha..sub.2 -adrenoceptor subtype c in mice effects the development of behavioral despair and stress-induced increases in plasma corticosterone levels", Molecular Psychiatry, vol. 4, pp. 443-452 (1999). Timo Kauppila et al., "Effects of atipamezole, a novel .alpha..sub.2 -adrenoceptor antagonist, in open-field, plus-maze, two compartment exploratory, and forced swimming tests in the rat", Eur. Journal of Pharmacology, vol. 205 pp. 117-182 (1991). Steven Southwick et al., "Noradrenergic and Serotonergic Function in Posttraumatic Stress Disorder", Arch Gen. Psychiatry, vol. 54, pp. 749-758 (1997). Crawley et al., "Baseline Exploratory Activity Predicts Anxiolytic Responsiveness to Diazepam in Five Mouse Strains", Brain Research Bulletin, vol. 8, pp. 609-612 (1982). Sallinen et al., "D-Amphetamine and L-5-Hydroxytryptophan-Induced Behaviours in mice with Genetically-Altered expression of the .alpha..sub.2c -Adrenergic Receptor Subtype", Neuroscience, vol. 86, No. 3, pp. 959-965 (1998). Jukka Sallinen et al., "Adrenergic .alpha..sub.2c -Receptors Modulate the Acoustic Startle Reflex, Prepulse Inhibition, and Aggression in Mice", The Journal of Neuroscience, vol. 18 (8), pp. 3035-3042 (1998). Markus Bjorklund et al., ".alpha..sub.2c -Adrenoceptor-Overexpressing Mice Are Impaired in Excuting Nonspatial Escape Strategies", Molecular Pharmacology, vol. 54, pp. 569-576 (1998). |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
We claim: 1. A compound of formula II, ##STR20## or a pharmaceutically acceptable salt or ester thereof, wherein, R.sub.1 is H or (C.sub.1 -C.sub.6)alkyl; each R.sub.2 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S- or hydroxy(C.sub.1 -C.sub.6)alkyl; A is a benzene ring or (C.sub.5 -C.sub.7)cycloalkyl; when A is a benzene ring each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO-, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl, (C.sub.1 -C.sub.6)alkyl-S-, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; when A is (C.sub.5 -C.sub.7)cycloalkyl each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 --C.sub.6)alkyl; R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR21## wherein X is O or .dbd.NR.sub.6 ; R.sub.6 is H, OH, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, CN-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO-(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO-, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)cycloalkyl or benzyl, wherein the said benzyl is optionally substituted with one to three substituent(s) each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or halo-(C.sub.1 -C.sub.6)alkyl; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR22## wherein n=1 or 2; R.sub.6 is as defined above; and r=0 to 3; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, 1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three substituent(s) R.sub.7 each independently being (C.sub.1 -C.sub.6)alkyl or NH.sub.2 ; Ra is H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino or (C.sub.1 -C.sub.6)alkyl-S--; Rb is H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; m is 0 to 3; and t is 0 to 3, with the provisos, that when A is a benzene ring, then Ra and Rb are not at the same time H; and the compound is not 4-[4-[(7-Chloro-2-methyl-4-quinolinyl)amino]phenyl]-1-diethylcarbamoylpipe razine. 2. A compound according to claim 1, which is a compound of formula IIB, ##STR23## or a pharmaceutically acceptable salt or ester thereof, wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m and t are as defined in claim 1; and Ra is H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino or (C.sub.1 -C.sub.6)alkyl-S--; and Rb is H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or ON. 3. A compound according to claim 2, wherein A is a benzene ring. 4. A compound according to claim 3, wherein m is 0 or 1. 5. A compound according to claim 3, wherein R.sub.3 is (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy. 6. A compound according to claim 3, wherein Ra and Rb are independently H or (C.sub.1 -C.sub.3) alkyl, wherein the (C.sub.1 -C.sub.3) alkyl includes both straight and branched chain radicals of up to carbon atoms. 7. A compound according to claim 2, wherein the compound is (3-Ethyl-2,8-dimethylquinolin-4-yl)-[4-(4-methylpiperizin-1-yl)phenyl]amin e, (2-Methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, (3-Ethyl-2,6-dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amin e, (3-Ethyl-6-methoxy-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)pheny l]amine, (3-Ethyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, 3-Isopropyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine , (2,3-Dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine or (3-Ethyl-2-methylquinolin-4-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]a mine. 8. A compound according to claim 1, wherein R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR24## wherein R.sub.6 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkenyl, (C.sub.3 -C.sub.6)cycloalkyl or hydroxy(C.sub.1 -C.sub.6)alkyl. 9. A compound according to claim 8, wherein R.sub.6 is (C.sub.1 -C.sub.6)alkyl. 10. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable diluent, carrier and/or excipient. 11. A method for the antagonism of alpha-2 adrenoceptors, which comprises administering to a mammal in need thereof an effective amount of at least one compound according to claim 1. 12. A method for the treatment of a disorder of the central nervous system, male sexual impotence, orthostatic hypotension, non-insulin dependent diabetes, or obesity, which comprises administering to a mammal in need of the treatment an effective amount of at least one compound according to claim 1. 13. A method for reversing alpha-2 agonistic effects, which comprises administering to a mammal in need thereof an effective amount of at least one compound according to claim 1. 14. The method according to claim 12, which comprises treating a disorder of the central nervous system. 15. The method according to claim 14, wherein the disorder of the central nervous system is depression, anxiety, post-traumatic stress disorder, schizophrenia, Parkinson's disease, or another movement disorder. |
| PATENT DESCRIPTION |
FIELD OF THE INVENTION The present invention relates to therapeutically active derivatives of quinoline, including the pharmaceutically acceptable salts and esters thereof, and their use as alpha-2 antagonists. BACKGROUND Some compounds exhibiting alpha adrenergic activity are well known in the art. Those compounds may be used for the treatment of a wide variety of diseases and conditions of the peripheric system and the central nervous system (CNS). The alpha adrenergic receptors are divided into alpha-1 and alpha-2 adrenoceptors, each of which are further divided into subtypes. Accordingly, alpha-2 adrenoceptors in humans have been subdivided into three pharmacological subtypes known as alpha-2A, alpha-2B and alpha-2C adrenoceptors. A fourth subtype, alpha-2D, is known in rat, bovine and porcine and it corresponds to alpha-2A in man. These subtypes have a distinct distribution in human and animal tissues. For instance, alpha-2C adrenoceptors are concentrated in the CNS, and they appear to play a role in the modulation of various CNS-mediated behavioural and physiological responses. Compounds that are non-specific to any of the above-mentioned alpha-2 subtypes, and compounds that are specific to certain alpha-2 subtypes, are already known. For example, atipamezole is a non-specific alpha-2 antagonists. Atipamezole has been described in, for example, EP-A-183 492 (cf. p.13, compound XV) and A. Haapalinna et al., Naunyn-Schimiedeberg's Arch. Pharmacol. Vol. 356, 1997, p.570-582. U.S. Pat. No. 5,902,807 describes compounds that are selective antagonists for the alpha-2C subtype and may be used in the treatment of mental illnesses, e.g. mental disturbances induced by stress. Such compounds include, for example, MK-912 and BAM-1303. Furthermore, WO-A-99 28300 discloses substituted imidazole derivatives having agonist-like activity for alpha-2B or 2B/2C adrenoceptors. The disclosures of all documents cited above in this paragraph are incorporated by reference herein. As to the derivatives of quinoline, Medicinskaja parazitologija I parazitarnye bolezni, vol.5, 1991, 55-7 (Mikhailitsyn F. S. et al.) and J. Med. Chem., vol.20(8), 1977, 987-996 (Cain F. C. et al.) describe, for example, acridine derivatives as anticancer and/or antiparasitic agents. In addition, a publication by Adams et al in 1985 (Mol. Pharm. 27, 480-491) reports on the binding of diquinolines, diacridines and a number of monoacridines on rat brain alpha-1-, alpha-2- and beta-adrenoceptors. SUMMARY OF THE INVENTION An object of the present invention is to provide further antagonists of alpha-2 adrenoceptors that can be used for the treatment of diseases or conditions of the pheripheric or central nervous system where alpha-2 antagonists are indicated to be useful. Accordingly, an object of the present invention is to provide further compounds to be used as alpha-2 antagonist agents in the treatment of mammals, including humans and animals. Another object of the present invention is to provide further compounds useful as selective alpha-2C antagonist agents for the treatment of various disorders or conditions of the central nervous system where alpha-2C antagonists are indicated to be useful. BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 shows the effects of atipamezole and compound 1 on dexmedetomidine-induced hypolocomotion. FIG. 2 shows the effects of atipamezole and compound 1 in a forced swimming test in Balb/c mice. DETAILED DESCRIPTION OF THE INVENTION One embodiment of the present invention covers a method of treatment using compounds of formula I: ##STR2## wherein, R.sub.1 is H or (C.sub.1 -C.sub.6)alkyl; each R.sub.2 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or hydroxy(C.sub.1 -C.sub.6)alkyl; A is a benzene ring or (C.sub.5 -C.sub.7)cycloalkyl; when A is a benzene ring each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl, (C.sub.1 -C.sub.6)alkyl-S--, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; when A is (C.sub.5 -C.sub.7)cycloalkyl each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR3## wherein X is O or .dbd.NR.sub.6 ; R.sub.6 is H, OH, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, CN--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl, phenyl, naphthyl or benzyl, wherein the said phenyl, naphthyl or benzyl is optionally substituted with one to three substituent(s) each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or halo-(C.sub.1 -C.sub.6)alkyl; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR4## wherein n=1 or 2; R.sub.6 is as defined above; and r=0 to 3; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, 1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three substituent(s) R.sub.7 each independently being (C.sub.1 -C.sub.6)alkyl or NH.sub.2 ; or one of R.sub.4 and R.sub.5 is --SO.sub.2 R.sub.8 and the other of R.sub.4 and R.sub.5 is H or (C.sub.1 -C.sub.6)alkyl; R.sub.8 is (C.sub.1 -C.sub.6)alkyl, phenyl, naphthyl or benzyl, wherein the said phenyl, naphthyl or benzyl is optionally substituted with one to three substituent(s) R.sub.9 each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or mono- or di(C.sub.1 -C.sub.6)alkylamino; Ra and Rb are independently H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring optionally substituted with one to three substituent(s) R'.sub.3 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl or (C.sub.1 -C.sub.6)alkyl-S--, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to four substituent(s) R.sub.10 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four substituent(s) each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five or six membered heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which heterocyclic ring is optionally substituted with one to three substituent(s) R.sub.10 as defined above; R.sub.11 is H or (C.sub.1 -C.sub.6)alkyl, or R.sub.11 is phenyl optionally substituted with one to three substituents R.sub.12 each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or mono- or di(C.sub.1 -C.sub.6)alkylamino; m is 0 to 3; and t is 0 to 3, or pharmaceutically acceptable salts and esters thereof. Those compounds can be used for the treatment of diseases or conditions where alpha-2 antagonists are indicated to be effective, and for the manufacture of a medicament for such treatment. The following subgroups (1) to (18) of compounds of formula I taken alone or in any combination with each other are possible: (1) A is a benzene ring; (2) A is a (C.sub.5 -C.sub.7)cycloalkyl; (3) Ra and Rb are independently H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; e.g. H, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy or halo(C.sub.1 -C.sub.6)alkyl; such as H, halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; e.g. H or (C.sub.1 -C.sub.3)alkyl, wherein the (C.sub.1 -C.sub.3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms; (4) Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring unsubstituted or substituted with one to three, e.g. one or two, such as one, substituent(s) R'.sub.3 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, (C.sub.1 -C.sub.6)alkyl-S or hydroxy(C.sub.1 -C.sub.6)alkyl; e.g. OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl or (C.sub.1 -C.sub.6)alkoxy; such as halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; e.g. (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; (5) Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to four, e.g. one or two, such as one, substituent(s) R.sub.10 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; such as (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; e.g. (C.sub.1 -C.sub.6)alkyl; (6) Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four, e.g. one or two, such as one, substituent(s) each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; e.g. (C.sub.1 -C.sub.6)alkyl (7) Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five or six membered heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which heterocyclic ring is optionally substituted with one to three, e.g. one or two, such as one substituent(s) R.sub.10 as defined above; and R.sub.11 is H or (C.sub.1 -C.sub.6)alkyl, or R.sub.11 is phenyl optionally substituted with one to three, e.g. one or two, such as one, substituents R.sub.12 each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy or mono- or di(C.sub.1 -C.sub.6)alkylamino; (8) R.sub.4 and R.sub.5 form, together with the N-atom, 1-piperazinyl which is 4-substituted with R.sub.6, wherein R.sub.6 is as defined above; e.g. (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, CN--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl or optionally substituted benzyl; such as (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl; e.g. (C.sub.1 -C.sub.6)alkyl; (9) R.sub.4 and R.sub.5 form, together with the N-atom, a morpholino ring; (10) R.sub.4 and R.sub.5 form, together with the N-atom, a 1-piperidinyl or 1-pyrrolidinyl optionally substituted with R.sub.6, wherein R.sub.6 is as defined above, possibly (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, CN--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1 -C.sub.6)alkyl or (C.sub.3 -C.sub.6)cycloalkyl; such as (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl; e.g. (C.sub.1 -C.sub.6)alkyl; (11) R.sub.4 and R.sub.5 form, together with the N-atom, 1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three, e.g. one or two, such as one, substituent(s) R.sub.7 each independently being (C.sub.1 -C.sub.6)alkyl or NH.sub.2 ; e.g. R.sub.4 and R.sub.5 form, together with the N-atom, 2-amino-imidazol-1-yl or 2-amino-imidazolin-1-yl; (12) one of R.sub.4 and R.sub.5 is --SO.sub.2 R.sub.8 and the other of R.sub.4 and R.sub.5 is H or (C.sub.1 -C.sub.6)alkyl; R.sub.8 is independently (C.sub.1 -C.sub.6)alkyl, phenyl, naphthyl and benzyl, wherein the said phenyl, naphthyl or benzyl is optionally substituted with one to three, e.g. one or two, such as one, substituent(s) R.sub.9 each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or mono- or di(C.sub.1 -C.sub.6)alkylamino; (13) m is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1; such as 0; (14) t is 0 to 3; e.g. 0, 1 or 2; e.g. 0 or 1; such as 0; (15) R.sub.1 is H; (16) R.sub.1 is (C.sub.1 -C.sub.6)alkyl; (17) R.sub.2 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or hydroxy(C.sub.1 -C.sub.6)alkyl; such as OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or hydroxy(C.sub.1 -C.sub.6)alkyl; e.g. (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy; and/or (18) R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl, (C.sub.1 -C.sub.6)alkyl-S--, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; such as OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl; e.g. halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy. A possible subgroup of the compound of formula I is a compound of formula IA: ##STR5## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.10 ; m and t are as defined above; i is 1 to 3; and j is 0 to 4. Another possible subgroup of the compound of formula I is a compound of formula IB: ##STR6## wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, Ra, Rb, m and t are as defined above; and Ra and Rb are independently H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to three substituent(s) R.sub.10 ; each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl. Another possible subgroup of the compound of formula I is a compound of formula IC: ##STR7## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.10, R.sub.11, m and t are as defined above; i is I or 2;and j is 0 to 3. Another possible subgroup of the compound of formula I is a compound of formula ID: ##STR8## wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3, R.sub.4, R.sub.5, m and t are as defined above and p is 0 to 3; for example wherein m is 1 and R.sub.3 is (C.sub.1 -C.sub.6)alkoxy. In a possible subgroup of the compound of formula I, IA, IB, IC or ID, R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR9## wherein X is .dbd.NR.sub.6 ; R.sub.6 is as defined above under formula I; such as (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, hydroxy(C.sub.1 -C.sub.6)alkyl or (C.sub.3 -C.sub.6)cycloalkyl; e.g. (C.sub.1 -C.sub.6)alkyl. Another possible subgroup of the compound of formula I is, wherein, when one of R.sub.4 and R.sub.5 is --SO.sub.2 R.sub.8 and the other of R.sub.4 and R.sub.5 is H or (C.sub.1 -C.sub.6)alkyl; then R.sub.8 is not (C.sub.1 -C.sub.6)alkyl. Another possible subgroup of the compound of formula ID is, wherein, when one of R.sub.4 and R.sub.5 is --SO.sub.2 R.sub.8 and the other of R.sub.4 and R.sub.5 is H or (C.sub.1 -C.sub.6)alkyl; then R.sub.8 is not (C.sub.1 -C.sub.6)alkyl. Another embodiment of the invention provides new compounds of formula II and a method of treatment using the compounds of formula II: ##STR10## wherein, R.sub.1 is H or (C.sub.1 -C.sub.6)alkyl; each R.sub.2 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or hydroxy(C.sub.1 -C.sub.6)alkyl; A is a benzene ring or (C.sub.5 -C.sub.7)cycloalkyl; when A is a benzene ring each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl, (C.sub.1 -C.sub.6)alkyl-S--, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; when A is (C.sub.5 -C.sub.7)cycloalkyl each R.sub.3 is independently OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR11## wherein X is O or .dbd.NR.sub.6 ; R.sub.6 is H, OH, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, CN--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy-CO--(C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkyl-CO--, NH.sub.2 --CO--, mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl, hydroxy(C.sub.1 -C.sub.6)alkyl, (C.sub.3 -C.sub.6)cycloalkyl or benzyl, wherein the said benzyl is optionally substituted with one to three substituent(s) each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or halo-(C.sub.1 -C.sub.6)alkyl; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR12## wherein n=1 or 2; R.sub.6 is as defined above; and r=0 to 3; or R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, 1-imidazolyl, 1-imidazolinyl or 1-triazolyl, each of which can optionally be substituted with one to three substituent(s) R.sub.7 each independently being (C.sub.1 -C.sub.6)alkyl or NH.sub.2 ; Ra and Rb are independently H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring optionally substituted with one to three substituent(s) R'.sub.3 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.1 -C.sub.6)alkoxy, halo-(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-CO--, mono- or di(C.sub.1 -C.sub.6)-alkylcarbamoyl or (C.sub.1 -C.sub.6)alkyl-S--, hydroxy(C.sub.1 -C.sub.6)alkyl or NH.sub.2 --CO--; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to four substituent(s) R.sub.10 each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed bicyclo[2.2.1]-heptane ring optionally substituted with one to four substituent(s) each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five or six membered heterocyclic ring with one ring heteroatom .dbd.NR.sub.11, which heterocyclic ring is optionally substituted with one to three substituent(s) R.sub.10 as defined above; R.sub.11 is H or (C.sub.1 -C.sub.6)alkyl, or RI 1 is phenyl optionally substituted with one to three substituents R.sub.12 each independently being OH, halogen, NO.sub.2, NH.sub.2, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or mono- or di(C.sub.1 -C.sub.6)alkylamino; m is 0 to 3; and t is 0 to 3, or of a pharmaceutically acceptable salt or ester thereof, with the provisos, that a) when A is a benzene ring, m is 0 or 1, t is 0, R.sub.1 is H, R.sub.3 is Cl or NO.sub.2, and Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring, and X is NR.sub.6, then R.sub.6 is not H, --CH.sub.3, --CH.sub.2 CH.sub.3, --COCH.sub.3, or --CO--NH.sub.2 ; b) when A is a benzene ring, then Ra and Rb are not at the same time H; c) when A is a benzene ring, m is 1, t is 0, R.sub.1 is H, and Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed benzene ring, which is optionally substituted with Br, and X is 0, then R.sub.3 is not NO.sub.2 or --OCH.sub.3 ; d) when A is a benzene ring, m is 0, t is 0, R.sub.1 is H, and Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed nonsubstituted benzene ring, then X is not 0; e) the compound is not 4-[4-[(7-Chloro-2-methyl-4-quinolinyl)amino]phenyl]-1-diethylcarbamoylpipe razine, 4-[4-[(6-Chloro-2-methoxy-9-acridinyl)amino]phenyl]-1-diethylcarbamoylpipe razine, 6-amino-4-[[3-chloro-4-(1H-imidazol-1-yl)phenyl]amino]-7-metoxy-3-quinolin ecarbonitrile or 4-[[3-chloro-4-(1H-imidazol-1-yl)phenyl]amino]-7-methoxy-6-nitro-3-quinoli necarbonitrile. A possible subgroup of the compound of formula II is a compound of formula IIA, ##STR13## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.10, m and t are as defined in formula II; i is 1 to 3; and j is 0 to 4; for example wherein i is 2, j is 0 or 1 and R.sub.10 is (C.sub.1 -C.sub.3)alkyl, wherein the (C.sub.1 -C.sub.3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms; or wherein m is 0 or 1 and R.sub.3 is (C.sub.1 -C.sub.3)alkyl or halogen, wherein the (C.sub.1 -C.sub.3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms; or wherein the compound is [4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4-tetrahydroacridin-9-yl)amine, 2-{4-[4-(1,2,3,4-Tetrahydroacridin-9-yl)aminophenyl]piperazin-1-yl}ethanol , [4-(4-Methylpiperazin-1-yl)phenyl]-(2-methyl-1,2,3,4-tetrahydro-acridin-9- yl)amine, (8-Fluoro-1,2,3,4-tetrahydroacridin-9-yl)-[4-(4-methylpiperazin-1-yl)pheny l]amine, [4-(4-Methylpiperazin-1-yl)phenyl]-(2,7-dimethyl-1,2,3,4-tetrahydroacridin -9-yl)amine, [4-(4-Methylpiperazin-1-yl)phenyl]-(7,8,9,10-tetrahydro-6H-cyclohepta[b]qu inolin-11-yl)amine or [4-(4-Methylpiperazin-1-yl)phenyl]-(1,1,3,3-tetramethyl-1,2,3,4-tetrahydro acridin-9-yl)amine. Another possible subgroup of the compound of formula II is a compound of formula IIB, ##STR14## wherein A, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m and t are as defined in formula II; and Ra and Rb are independently H, OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.1 -C.sub.6)alkoxy, halo(C.sub.1 -C.sub.6)alkyl, NO.sub.2, NH.sub.2, mono- or di(C.sub.1 -C.sub.6)alkylamino, (C.sub.1 -C.sub.6)alkyl-S-- or CN; or Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring optionally substituted with one to three substituent(s) R.sub.10 ; each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy, mono- or di(C.sub.1 -C.sub.6)alkylamino or hydroxy(C.sub.1 -C.sub.6)alkyl; for example wherein A is a benzene ring; or wherein m is 0 or 1; or wherein R.sub.3 is (C.sub.1 -C.sub.6)alkyl or (C.sub.1 -C.sub.6)alkoxy; or wherein Ra and Rb are independently H or (C.sub.1 -C.sub.3)alkyl, wherein the (C.sub.1 -C.sub.3)alkyl includes both straight and branched chain radicals of up to 3 carbon atoms; or wherein A is a six membered carbocyclic ring and Ra and Rb form, together with the carbon ring atoms to which they are attached, a condensed five to seven membered carbocyclic ring, wherein the carbocyclic ring can optionally be substituted with one to three substituent(s) each independently being OH, halogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkoxy or hydroxy(C.sub.1 -C.sub.6)alkyl; or wherein the compound is (3-Ethyl-2,8-dimethylquinolin-4-yl)-[4-(4-methylpiperizin-1-yl)phenyl]amin e, (2-Methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, (3-Ethyl-2,6-dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amin e, (3-Ethyl-6-methoxy-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)pheny l]amine, (3-Ethyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, 4-[4-(4-Methylpiperazin-1-yl)phenylamino]quinoline-3-carbonitrile, 3-Isopropyl-2-methylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine , (2,3-Dimethylquinolin-4-yl)-[4-(4-methylpiperazin-1-yl)phenyl]amine, [4-(4-Methylpiperazin-1-yl)phenyl]-(1,2,3,4,5,6,7,8-octahydroacridin-9-yl) amine or (3-Ethyl-2-methylquinolin-4-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]a mine. Another possible subgroup of the compound of formula II is a compound of formula IIC, ##STR15## wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.10, R.sub.11, m and t are as defined in formula II; i is 1 or 2; and j is 0 to 3. Another possible subgroup of the compound of formula II is a compound of formula IID, ##STR16## wherein R.sub.1, R.sub.2, R.sub.3, R'.sub.3, R.sub.4, R.sub.5, m and t are as defined in formula II; and p is 0 to 3; for example wherein m is 1 and R.sub.3 is (C.sub.1 -C.sub.6)alkoxy; or wherein the compound is 2-{4-[4-(Acridin-9-yl)aminophenyl]piperazin-1-yl}-ethanol, (4-Methoxyacridin-9-yl)-[4-(4-methylpiperazin-1-yl)-phenyl]amine, Acridin-9-yl-[4-(piperidin-1-yl)phenyl]amine, Acridin-9-yl-[4-(4-benzylpiperazin-1-yl)phenyl]amine, Acridin-9-yl-[4-(4-methylpiperidin-1-yl)phenyl]amine, Acridin-9-yl-[4-(3-hydroxymethylpiperidin-1-yl)-phenyl]amine, Acridin-9-yl-[4-pyrrolidin-1-yl)phenyl]amine, Acridin-9-yl-[4-(4-cyclopropylpiperazin-1-yl)phenyl]amine, Acridin-9-yl-[4-(4-isopropylpiperazine-1-yl)phenyl]amine, (Acridin-9-yl)-methyl-[4-(4-methylpiperazin-1-yl)phenyl]amine or Acridin-9-yl-[2,5-diethoxy-4-(morpholin-4-yl)phenyl]amine. In a possible subgroup of the compound of Formula II, IIA, IIB, IIC, or IID, R.sub.4 and R.sub.5 form, together with the N-atom to which they are attached, ##STR17## wherein R.sub.6 is (C.sub.1 -C.sub.6)alkyl, (C.sub.1 -C.sub.6)alkenyl, (C.sub.3 -C.sub.6)cycloalkyl or hydroxy(C.sub.1 -C.sub.6)alkyl, for example, R.sub.6 is (C.sub.1 -C.sub.6)alkyl. The compounds of formulae I and II and the subgroups IA, IB, IC, ID, IIA, IIB, IIC, and IID thereof, as well as the pharmaceutically acceptable esters and salts thereof, are referred to below as the compounds of the invention, unless otherwise indicated. The compounds of the invention may have chiral carbon atom(s) in their structure. The invention includes within its scope all the possible stereoisomers of the compounds, including geometric isomers, e.g. Z and E isomers (cis and trans isomers), and optical isomers, e.g. diastereomers and enantiomers. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms of the starting material or they may be separated after the preparation of the end compound according to conventional separation methods. For the separation of, for example, optical isomers, e.g. enantiomers, from the mixture thereof the conventional resolution methods, e.g. fractional crystallisation, may be used. Physiologically acceptable salts, e.g. acid addition salts with both organic and inorganic acids are well known in the field of pharmaceuticals. Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbates. Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Non-limiting examples of those esters include esters of aliphatic or aromatic alcohols, e.g. lower alkyl esters, e.g. methyl, ethyl and propyl esters. Terms employed herein have the following meanings: A halogen or halo refers to fluorine, chlorine, bromine or iodine, e.g. fluorine or chlorine. The term (C.sub.1 -C.sub.6)alkyl as employed herein as such or as part of another group includes both straight, and branched chain radicals of up to 6 carbon atoms, for example of 1 to 4 carbon atoms, e.g. methyl, ethyl, n-propyl, 1-propyl, n-butyl, 1-butyl or s-butyl. The term (C.sub.1 -C.sub.6)alkoxy as such or as part of another group refers to --O--(C.sub.1 -C.sub.6)alkyl, wherein (C.sub.1 -C.sub.6)alkyl is as defined above. The term (C.sub.2 -C.sub.6)alkenyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2 to 4 carbon atoms, containing (a) double bond(s). The term (C.sub.2 -C.sub.6)alkynyl includes both straight and branched chain radicals of up to 6 carbon atoms, for example of 2 to 4 carbon atoms, containing (a) triple bond(s). The term halo-(C.sub.1 -C.sub.6)alkyl refers to (C.sub.1 -C.sub.6)alkyl radical, as defined above, that is substituted by one or more halo radicals as defined above, for example trifluoromethyl, difluoromethyl etc. The term mono- or di(C.sub.1 -C.sub.6)alkylcarbamoyl refers to a carbamoyl radical which is N-substituted with one or two (C.sub.1 -C.sub.6)alkyl radical(s), as defined above. The compounds of the invention can be prepared analogously or according to a variety of synthetic routes known in the literature using suitable starting materials, for example, according to or analogous to methods described by B. F. Cain et al. in J. Med. Chem., vol.20(8), 1977, pp. 987-996, and by W. A. Denny et al. in J. Med. Chem., vol.25, 1982, p.276-315, the contents of which are hereby incorporated by reference. In general, the compounds of the invention can be prepared e.g. analogously or according to the following reaction scheme 1: ##STR18## wherein Ra, Rb, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, m and t are as defined above. The above reaction is a conventional acid-catalyzed coupling of the chloro-compound of formula III with a substituted aromatic amine of formula IV. The reaction is carried out at room or elevated temperature in a suitable solvent, e.g. alcohol, such as methanol, in acidic conditions, to obtain the compound of formula I' which is then isolated from the reaction mixture in a usual manner. The starting compounds III and IV are commercially available or can be prepared according to or analogously to the methods described in the literature (see e.g. J. Med. Chem., vol.20(8), 1977, pp. 987-996, and J. Med. Chem., vol.25, 1982, p.276-315, as mentioned above). Accordingly, a substituted aromatic NR.sub.1 -amine IV can e.g. be prepared starting from the corresponding nitro compound which is reduced with a reducing agent, e.g. in the presence of SnCl.sub.2.H.sub.2 O, in a suitable solvent, e.g. DMF, and optionally alkylated with R.sub.1 in a manner known in the art, when R.sub.1 =(C.sub.1-6)alkyl is desired. The starting material III can be prepared e.g. according to following scheme 2: ##STR19## wherein Ra, Rb, R.sub.3, and m are as defined above. In scheme 2 a compound V is reacted e.g. with thionyl chloride in the presence of a small amount of DMF, to obtain the 9-chlorinated reactant III. The reaction is carried out at room or elevated temperature. It is obvious for a skilled person that, in the above reactions, any starting material or intermediate can be protected, if necessary, in a manner well known in the chemical field. Any protected functionality can subsequently be deprotected in a manner known in the art. The above disclosed synthetic routes are meant to illustrate the preparation of the compounds of the invention, and the preparation is by no means limited thereto, i.e. other synthetic methods that are within the general knowledge of a skilled person are also possible. The compounds of the invention may be converted, if desired, into their pharmaceutically acceptable salt or ester form using methods well known in the art. The following examples are meant only for illustrating purposes and do not limit the scope of the invention defined in claims |
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