CA2237997A1 - Antimalarial quinolin derivatives - Google Patents

Abstract

N1-Aralkyl-N2-quinolin-4-yl-diamine derivatives of general formula (I), wherein R1 signifies halogen or trifluoromethyl; R2 signifies hydrogen, halogen or trifluoromethyl; A signifies (a) or (C5-C6)-cycloalkylene; n signifies 1-4; R3 and R4 each independently signify hydrogen or methyl; p signifies 0-3 and B signifies aryl, as well as pharmaceutically acceptable salts of basic compounds of general formula (I), for use as therapeutically active substances, especially as active substances against malaria.

Description

CA 02237997 l998-05-l5 RAN 44~5/22 Quinolin derivatives The invention is concerned with quinoline derivatives, especially Nl-aralkyl-N2-quinolin-4-yl-diamine derivatives of the general formula HN ~ A ~ N~ (CH2)p ~ B

Rj~

o wherein R 1 signifies halogen or trifluoromethyl;
' R2 signifies hydrogen, halogen or trifluoromethyl;
~R3~
A signifies ~ c J or (C5-C6)-cycloalkylene;
\R4 n n signifies 1-4;
15 R3 and R4 each independently signify hydrogen or methyl;
p signifies ~ 1-3 and B signifies aryl, as well as pharmaceutically acceptable salts of basic compounds of general formula 1, with the proviso that when B is 20 unsubstituted phenyl, A does not signify CH(CH3)(CH2)3 and when B is phenyl, trisubstituted by methoxy, A does not signify CH(CH3)(CH2)2 or CH(CH3)(CH2)3.
All possible stereoisomers as well as their racemates are included in formula 1.
A sub-group of compounds of formul~ I comprisas thoso in which p is 1-3 and tho othor substituonts havc thc signific~nccs givcn ~bovc.
These novel compounds have the property that they are active not only against chloroquine-sensitive, but also against 30 chloroquine-resistant malaria pathogens. For this reason they are very well suited for the prophylaxis and treatment of malaria, especially in cases where the malaria pathogens are resistant to chloroquine.

Pop/So 4.9.96 A.M~NDED S~

CA 02237997 1998-0~
WO 97/18193 PCT/Er~)6/0~8CG
Objects of the present invention are the mentioned compounds of formula I as well as their pharmaceutically usable salts thereof per se and as therapeutically active substances, the manufacture of these compounds and salts and their use for 5 therapeutic purposes, especially for the prevention or treatment of malaria, as well as medicaments containing a compound of formula I or a salt thereof and the production of such medicaments.

0 The term "lower-alkyl" used in the present description denotes straight-chain or branched saturated hydrocarbon residues such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl and the like. "Halogen'~ signifies chorine, bromine, fluorine or iodine.

When A in formula I signifies an aliphatic hydrocarbon chain, branched chains, for example -CH(CH3)-Ctlz-, -CHz C~(C~13)- or -CH2C(CH3)2-, are especially preferred.

The term "cycloalkylene" embraces preferably cyclopentyl or cyclohexyl.

The term "aryl" embraces conveniently phenyl or substituted phenyl, with the number of substituents preferably being 1-3 and the substituents befng selected from a group consisting of halogen, hydroxy, lower-alkyl, lower-alkoxy, CF3, cyano, di-lower-alkylamino or their N-oxides, phenyloxy, phenyl or methylsulphanyl.

Furthermore, the term "aryl" conveniently embraces naphthyl, benzo[1,3]dioxol or mono- or bicyclic aromatic hetero-cycles with 1 or 2 hetero atoms, especially N and/or O, for example pyridyl, quinolyl or furyl. Rings such as phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, naphthalen-1-yl, naphthalen-2-35 yl, furan-2-yl, furan-3-yl or quinolin-4-yl are preferred.

Preferred compounds of general formula I are especially those in which R1 signifies chlorine, R2 signifies hydrogen, p --2a-Analo~es of chloroquine derivatives with anl~im~l~rial activities are widely known. In J.Med. Chem., (1971), 14, 183 are described some 7-Chloro-4-(substituted amino)quinolines, having a malaria activity against sensitive malaria strains.
In WO 93/07126 and in J. Med. Chem. (1992), 35,2129 are described bisquinoline derivatives with an activity to chloroquine-resistant strains of malaria.
4-C~loro-7-iodoquinolines are also mentioned in Chemical Abstract, (1980), 92:18031v. Described are some compounds which are not aryl-substituted for melanoma detection.

N~tO Srt~-~

CA 02237997 1998-0~

- signifies 1, A signifies -CH2-C(CH3)2- and B signifies a benzene ring which is unsubstituted, mono-substituted or di-substituted.

Exampies of such compounds are:

N I -(7-Chloro-quinolin-4-YI)-N2-(3-chloro-benzyl)-2-methyl-propane- 1, 2-diamine, N 1 -(7-chloro-quinolin-4-yl)-N2-(benzyl)-2-methyl-propane-1 ,2-diamine, 0 N 1 -(7-chloro-quinolin-4-yl)-N2-(2-hydroxy-3-methoxy-benzyl)-2-methyl-propane-1 ,Z-diamine, N 1 -(7-chloro-quinolin-4-Yl)-N2-(2-hydroxy-5-meth benzyl)-2-methyl-propane-1,2-diamine and N 1 -( 7-chloro-quinolin-4-yl)-N2-(4-hydroxy-3-methoxy-benzyl)-2-methyl-propane- 1, 2-diamine.

Compounds of general formula I in which R1 signifies chlorine, R2 signifies hydrogen, p signifies 1 or 2, A signifies cyclohexane-1 ,2-diyl or cyclohexane-1 ,4-diyl and B signifies a benzene ring which is unsubstituted, mono-substituted, di-substituted or tri-substituted are also preferred.

Examples of such compounds are especially (1 S,2S)-N1-(7-chloro-quinolin-4-yl)-N2-(benzyl)-cyclo-hexane-1 ,2-diamine, ( 1 S,2S)-N 1 -(7-chloro-quinolin-4-yl)-N2-(4-chlorobenzyl)-cyclohexane-1 ,2-diamine, (1 S,2S)-N1-(7-chloro-quinolin-4-yl)-Nz-(4-dimethylamino-benzyl)-cyclohexane-1,2-diamine, cis-N 1 -(7-chloro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane-1 ,4-diamine, cis-N 1 -(7-chloro-quinolin-4-yl)-N4-(benzyl)-cyclohexane-1 ,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(3-chloro-benzyl)-cyclohexane-1 ,4-diamine, cis-N1 -(7-chloro-quinolin-4-yl)-N4-(2-hydroxy-4-methoxy-benzyl)-cyclohexane-1 ,4-diamine, _ CA 02237997 1998-0~

cis-N1 -(7-chioro-quinolin-4-yl)-N4-(3, 5-dimethoxy-benzyl)-cyclohexane-l ,4-diamine, cis-N 1 -(7-chloro-quinolin-4-yl)-N4-(4-methylsulphanyl-benzyl)-cyclohexane- 1 ,4-diamine, s cis-N1-(7-chloro-quinolin-4-yl)-N4-(4-diethylamino-benzyl)-cyclohexane-1 ,4-diamine, cis-N1 -(7-chloro-quinolin-4-yl)-N4-(biphenyl-4-yl)methyl-cyclohexane-l ,4-diamine, trans-N1 -(7-chloro-quinolin-4-yl)-N4-~2-(3,5-dimethoxy-0 phenyl )-ethyl~-cyclohexane- 1 , 4-diamine, cis-N 1 -(7-chloro-quinolin-4-yl)-N4-(4-methoxy-benzyl)-cyclohexane-l ,4-diamine, trans-N1 -(7-chloro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane- 1 ,4-diamine and 1 s trans-N1 -(7-chloro-quinolin-4-yl)-N4-(2,6-difluoro-benzyl)-cyclohexane-l ,4-diamine.

The novel compounds of formula I can be manufactured in accordance with the invention by a) reducing a Schiffls base of the general formula ~A~
R~ L (CH2)p-1 B II

z 5 wherein the substituents have the significance described above, or b) reacting an amine of the formula ~A

R~ E~ NH2 Rl~3 m -CA 02237997 l998-05-l5 WO 97/18193 PC:T/Er~6/0~866 with a compound of the formula X--(CH2)p-B IV

wherein X signifies a leaving group and the other substituents have the significance described above, or c) reacting a compound of the formula ~A~

Rl~ V

with an amine of the formula H2N--(CH2)p-B VI
wherein all substituents have the significance described above, or d) reacting a ketone or an aldehyde of the formula HN--Y

R~ 3 V~

wherein Y signifies - ( c ) - c = o or oxo-(C5-C6)-cycloalkyl 2 5 R4 n-l and R1 and R2 have the significance set forth above, - with an amine of formula Vl and a reducing agent, and 30 e) if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.

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In accordance with process variant a) of the process in accordance with the invention a Schiff's base of formula ll is reduced. Suitabie reducing agents are complex hydrides, diborane, 5 reactive metals or formic acid. The use of complex hydrides such as sodium borohydride is especially preferred. The reduction is carried out in a temperature range of 0 to 30~C, preferably at room temperature. Suitabie solvents are alcohols or mixtures of alcohols with chlorinated hydrocarbons. Ethanol or an ethanol-0 dichloromethane mixture is preferred for the reduction withsodium borohydride. When formic acid is used as the reducing agent, formic acid or another dilute acid can also be used as the solvent.

Compounds of formula I are obtained according to process variant b) by reacting amines of formula lll with compounds of formula IV. Halogen or aliphatic or aromatic sulphonyloxy groups are suitable as the leaving group X in formula IV. Conveniently, the reaction is carried out in a solvent, for example in an alcohol 20 such as methanol or ethanol or in an aprotic solvent such as acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide or 1-methyl-2-pyrrolidone, in a temperature range of 0 to 100~C
within 1 to 24 hours. The precise reaction conditions depend on the corresponding reaction partners.
The reaction of compounds of formula V with an amine of formula Vl is effected in accordance with process variant c).
Halogen or aliphatic or aromatic sulphonyloxy groups are also suitable here as the leaving group X. The reaction is conveniently 30 effected in a temperature range between 120 and 180~C. Phenol, ethoxyethanol, dimethylacetamide or 1-methyl-2-pyrrolidone is suitable as the solvent. The reaction duration can vary between 2 and 28 hours.

The reaction of aldehydes or ketones of formula Vll with an amine of formula Vl according to process variant d) is effected in a manner known per se. Conveniently, Vll and Vl are reacted in a solvent such as alcohol or toluene, with a water-separating agent CA 02237997 1998-0~

such as e.g. molecular sieve optionally being added, and then a reducing agent such as a complex hydride, e.g. sodium borohydride, diborane or a metal, is then added thereto. Vll and Vl can also be reacted in the presence of a reducing agent such as hydrogen and a 5 catalyst or with formic acid.

The conversion into a pharmaceutically usable salt is effected by adding an acid. Hydrochloric acid, methanesulphonic acid or acetic acid are especially preferred because of the 0 physiological compatibility of the corresponding salts.
Especially suitable solvents are conveniently: water, methanol, ethanol, isopropanol, diethyl ether, acetone, N,N-dimethyl-formamide or dioxan.

ts The intermediates required for variants a~-d) of the process can be prepared according to methods known per se. Examples 1 18-124 describe some possibilities for the preparation of the required intermediates.

The Schiffls bases of general formula ll are conveniently obtained by reacting a diamine of formula lll with an aldehyde of the formula (CH2)p-l B vm 25 The reaction is conveniently carried out in an inert ~as atmosphere at a temperature which lies between 20~C and the boiling temperature of the solvent, for example of ethanol, toluene or dichloromethane. The reaction time can be between and 24 hours, conveniently between 2 and 12 hours. The 30 reaction water which is formed can be removed by water-binding agents such as a molecular sieve (preferably 4~), anhydrous sodium sulphate, by evaporation together with the solvent or by azeotropic distillation over a water separator.

As mentioned earlier, the N1-arylalkyl-N2-quinolin-4-yl-diamine derivatives of general formula I in accordance with the CA 02237997 l99X-0~

inven~ion and their pharmaceutically usable salts have extremely vaiuable pharmacological properties.

In particular, they have a very good activity against malaria 5 pathogens. Their activity is equally good against chloroquine-resistant strains of the pathogen as against chloroquine-sensitive strains. Accordingly, the novel compounds can also be used for the prophylaxis and cure of malaria even in those cases where the pathogen does not respond to chloroquine.
The activity of the novel compounds against not only chloroquine-resistant, but also chloroquine-sensitive malaria pathogens shows itself in a strong, in vitro measurable growth inhibition of various strains of the human-patho~enic Plasmodium 15 ~alciparum, as set forth in Table 1 hereinafter. The ratio of the growth inhibition of a strain which is especially resistant to chloroquine and of a strain which is sensitive to chloroquine gives as the "resistance index" a measurement for the absence of a cross-resistance with chloroquine. Since, for all novel 20 compounds the resistance index lies between 0.7 and 2.5, they inhibit the growth of sensitive as well as resistant strains of the malaria pathogen equally effectively. They are accordingly also suitable for the prophylaxis of a malaria disease and also for the treatment of a malaria disease even when chloroquine is 2 5 ineffective. The good activity against malaria pathogens is also shown in animal experiments. The effective doses measured after oral and subcutaneous administration to mice infected with malaria pathogens are shown in Table 2 hereinafter.

Test method for the determination of the activity agains~
PlasmodiL~m falciparum in vitro The preparations are tested on intraerythrocytary stages of Plasmodium falciparum from asynchronous cultures according to the method of Desjardin et al. ~Desjardins, R.E. et al: Quantitative assessment of antimalarial activity in vitro by a semiautomated microdilution technique. Antimicrob. Agents Chemother. 16, 710-718, (1979)).

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The culture medium consists of RPMI 1640 with the addition of 25 mM HEPES, Z5 mM NaHC03, 100 ~Lg/ml neomycin and 105 human serum (A+). Human-A+ erythrocytes are used as 5 the Plasmodium falciparum host cells. The parasites are maintained at 37~C in an atmosphere of 3% ~2, 4% C02, 93% N2 and 95% relative humidity.

In order to determine the activity, the preparations are 0 dissolved in DMSO, pre-diluted in the culture medium to a suitable starting concentration and subsequently titrated-out on to microtitre plates in the 2nd stage over 6-7 steps. After the addition of the parasite culture (0.7% parasitemia in 2.5%
erythrocyte suspension) the test plates are incubated under the conditions given above for 72 h. The parasite growth in the different preparation concentrations is determined using [G-3H]-hypoxanthin incorporation compared to untreated control cultures on the same test plates. The 50% growth inhibition (ICso) is calculated according to logit regression analysis from the 20 resulting dosage-activity curve.

The preparations are tested on at least one chloroquine-resistant and one chloroquine-sensitive Plasmodium falciparum strain. Additional sensitive and resistant strains are included 2 5 for futher characterization.

Test method for the determination of the activity against Plasmodium berghei in vivo The preparations are tested on mice infected with malaria pa.hoger-rs ~P;~smodium bergh~. Maie aibino mice (IBM:MORO~SPF), FUELLINSDORF) weighing about 25 g are used as the test animals. They are kept in climatized rooms at 21-22~C
in groups of 5 animals per cage. They receive ad libitum a diet feed with a low PABA content (NAFAG FUTTER " No. 9009 PAB-45, - PABA content 45 mg/kg) and drinking water. On the first day of the test (D0) the test animals are infected with Plasmodium berghei (strain ANKA). For this there is used heparinized blood of CA 02237997 1998-05-1~

a donor mouse with about 30% parasitemia, which is diluted with physiological saline such that it contains 1 o8 parasitized erythrocytes per ml. 0.2 ml of this suspension is injected intravenousiy (i.v.) into the mice to be treated and into the 5 control mice. In untreated control animals the parasitemia normally reaches 30-40% on the third day after the infection (D+3) and the test animals die between days +5 and +7.

The substances to be tested are dissolved or suspended in 10 distilled water or in a mixture of 7% Tween 80, 3% alcohol (96%) and water. Usually, 0.25 ml of this solution or suspension is administered once subcutaneously and perorally to groups of 5 test animals. Treatment is effected 24 hours after the infection.
10 control animals are treated in the same manner with solvent or suspension medium per test.

All substances are tested in a first test in a single dosage of 10 mg/kg. Only those su~stances which in this test (10 mg/kg) have shown a parasitaemia reduction of 90% are used 20 for the titration. Suitable dilutions of the test substance can be used to obtain an accurate titration of the activity.

48 hours after the treatment (D+3) blood smears are prepared from all animais using blood from tail veins and are 25 stained with giemsa. The average erythrocyte infection rate (parasitemiea in ~/0) in the control groups as well as in the groups which have been treated with the test compounds is determined by counting under a microscope. The difference in the average values of the infection rates of control group (~00%) and treated 30 groups is calculated and expressed as a percentage reduction (Gl%). The EDso or EDgo is determined mathematically by means of the JMP programme (nonlinear fit). The EDso (EDgo) in mg/kg is that dose which after single administration reduces the average erythrocyte infection rate by 50% (90%) in comparison to the 35 control group.

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WO 97/18193 PCT/EP96/0~866 Table 1: Values measured in vitro (IC~o vaqlues in ng/ml) for the growth inhibition of the human-patho~enenic Plasmodium falciparum strain NF54 as an exampie of a chloroquine-sensitive strain and o~ the human-pathogenenic Plasmodium falciparum K1 5 as an example of a chloroquine-resistant strain, as well as the "resistance index", the ratio of the ICso value for the chloro-quine-resistant strain K1 and the ICso value for the chloroquine-sensitive strain NF54, as a measurement of the resistance to the test substance.
1 o ICso (ng/ml) IC50 (ng/ml) Resistance for for index P.falciparum P.falciparum Chloroquine 6.7 95.0 14.2 dipho~ hd~e . Amodiaquine 2.5 3.5 1.4 Example 1 12.6 17.5 1.4 Example 2 7.1 14.8 2.1 Example 3 13.7 18.3 1.3 Example 4 9.1 8.8 1.0 Example 5 49.3 57.2 1.2 Example 6 10.3 14.5 1.4 Example 7 Z4.0 34.9 1.5 Example 8 16. 1 18.9 1.2 Example 9 13.2 16.7 1.3 Example 10 5 1.7 50.4 1.0 Example 11 29.3 48.0 1.6 Example 12 84.7 197.0 2.3 Example 13 2.7 16.1 6.0 Example 14 4.8 28.4 5.9 Example 15 4.3 1 4.7 3.4 Example 16 2.0 1 7.0 8.5 Example 17 6.4 17.4 2.8 Example 18 5.5 21.0 3.8 Example 19 4.9 14.3 2.9 Example 20 4.4 10.8 2.5 CA 02237997 1998-0~
WO 97/18193 PCT/EP96/0~866 Example 21 5.1 9.3 1.8 Example 2Z 11.6 18.9 1.6 Example 23 29.6 32.5 1.1 Example 24 7.9 13.2 1.7 Example 25 17.3 12.9 0.7 Example 26 26.3 37.3 1.4 Example 27 16.0 23.3 1.5 Example 28 4.0 10.7 2.7 Example 29 7.7 16.2 2.1 Example 30 6.7 11.4 1.7 Example 31 6.5 9.9 1.5 Example 32 7.6 14.7 1.9 Example 33 6.3 7.1 1.1 Example 34 7.2 15.0 2.1 Example 35 6.4 13.3 2.1 Example 36 16.2 20.7 1.3 Example 37 11.0 11.0 1.0 Example 38 10.1 15.1 1.5 Example 39 7.8 10.3 1.3 Example 40 3.6 7.1 2.0 Example 41 13.5 18.7 1.4 Example 42 8.7 12.6 1.4 Example 43 16.0 18.1 1.1 Example 44 10.8 15.4 1.4 Exampie 45 12.3 12.5 1.0 Example 46 10.1 12.6 1.2 Example 47 9.4 13.6 1.4 Example 48 12.3 15.9 1.3 Example 49 8.2 12.4 1.5 Example 50 14.2 14.3 1.0 Example 51 12.3 9.1 0.7 Exampie 52 34.6 55.6 1.6 Example 53 15.9 14.9 0.9 Example 54 19.3 29.0 1.5 Example 55 7.8 14.5 1.9 Example 56 31.3 53.7 1.7 Example 57 21.7 28.2 1.3 Example 58 29.3 69.0 2.4 i ~

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WO 97/181g3 PCT/EP96/0 1~C
Example 59 166.4 185.7 1.1 Example 60 7.7 12.2 1.6 Example 61 12.7 11.2 0.9 Example 62 50.8 64.2 1.3 Example 63 10.1 14.6 1.4 Example 64 35.7 82.3 2.3 Example 65 9.9 25.3 2.6 Example 66 5.6 10.5 1.9 Example 67 9.1 23.0 2.5 Example 68 5.9 14.6 2.5 Example 69 3.7 4.6 1.2 Example 70 3.8 6.6 1.7 Example 71 7.1 9.3 1.3 Example 72 11.6 11.2 1.0 Example 73 15.0 19.0 1.3 Example 74 23.3 14.5 0.6 Example 75 25.0 18.0 0.7 Example 76 7.2 6.1 0.8 Example 77 96.6 63.2 0.7 Example 79 4.1 7.7 1.9 Example 80 8.9 18.4 2.1 Example 81 4.3 9.7 2.3 Example 82 5.7 8.5 1.5 Example 83 8.6 5.9 0.7 Example 84 6.9 7.8 1.1 Example 85 4.6 3.9 0.8 Example 86 5.6 7.0 1.3 Example 87 6.2 10.2 1.6 Example 88 7.4 21.4 2.9 Example 89 2.2 17.5 8.0 Example 90 49.7 98.8 2.0 Example 91 3.4 10.9 3.2 Example 92 2.2 8.0 3.6 Example 93 3.4 8.3 2.4 Example 94 2.9 9.8 3.4 Example 95 2.7 9.3 3.4 Example 96 1.6 9.0 5.6 Example 97 4.1 17.8 4.3 CA 02237997 1998-0~

WO 97/18193 PCT/EP9C/~ ~8CC
Example 98 4.5 8.5 1.9 Example 99 3.3 4.2 1.3 Example 1001 .9 4.0 2. 1 Example 10 1 2.7 2.9 1 . 1 Example 1022. 1 3.6 1 .7 Example 1 0 3 2.1 4.6 2.2 Example 1043.6 20.2 5.6 Example I 0 5 3.4 1 5.3 4.5 Example 106 1.5 4.4 2.9 Example 107 1.4 3.4 2.4 Example 108 4.6 18.4 4.0 Example 109 1 .8 3.8 2. 1 Example 1 10 2.8 17.2 6.1 Example 111 Z.9 1 0.4 3.6 Example 11 2 4.3 1 7.2 4.0 Example 11 3 3.0 7.6 2.5 Example 11 4 2.9 8.4 2.9 Table 2: Activity measured in vivo against Plasmodium berghei in mice: Gl% is the percenta~e reduction of the parasitemia after a single, peroral (po) or subcutaneous (sc) administered dose of 5 10 mg/kg of test substance; EDso is the effective perorally administered dose of test substance.

Growth inhibition Growth inhibition in in % after po % after sc administrationadministration Chloroquine 99.9 99.9 diphosphate Amodiaquine 99.9 99.9 Example 3 96.0 8.0 Example 4 68.0 73.0 Example 5 83.0 69.0 Example 6 99.7 95.0 Example 7 96.0 54.0 Example 8 99.0 95.0 Example 9 66.0 74.0 Example 10 99.2 99.3 -CA 02237997 1998-0~

PCT/ErgG~O 1866 Example 11 99.9 99.8 Example 12 98.0 4.0 Example 13 99.9 99.9 Example 14 100.0 100.0 Example 15 600 92.0 Example 16 99.8 99.9 Example 17 3Z.0 87.0 Example 18 100.0 100.0 Example 19 21.0 toxic Example 20 94.0 98.0 Example 21 99.9 100.0 Example 2Z 42.0 84.0 Example 23 97.0 98.0 Example 24 81.0 95.0 Example 25 99.2 99.8 Example 27 99.0 98.0 Example 28 79.0 96.0 Example 29 74.0 99.0 Example 30 70.0 95.0 Exarnple 31 39.0 98.0 Example 33 10.0 97.0 Example 40 84.0 95.0 Example 43 30.0 98.0 Example 44 98.0 99.0 Example 45 98.0 97.0 Example 46 99.7 99-0 Example 47 70.0 79.0 Example 48 99.9 99 9 Example 49 88.0 87.0 Example 50 93.0 96.0 Example 51 82.0 99.0 Example 56 98.0 97.0 Example 57 99.4 99.7 Example 58 72.0 88.0 Example 60 67.0 87.0 Example 61 99.6 99.6 Example 62 99.8 99.8 Example 63 99.9 99.9 I ~

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PCT/EP~GI'~ ~8GG

Example 64 87.0 66.0 Example 66 99.9 99.6 Example 67 99.0 99.0 Example 68 99,9 99.6 Example 69 100-0 100.0 Example 70 99.9 99.9 Example 71 99.8 99.9 Example 72 99.5 99.9 Example 73 23.0 96.0 Example 74 83.0 84.0 Example 75 99.8 99.7 Example 76 96.0 96.0 Example 77 99.0 98.0 Example 78 99.9 100.0 Example 79 99.9 100.0 Example 80 99.9 100.0 Example 81 100.0 100.0 Example 82 99.9 99.9 Example 83 100.0 100.0 Example 84 100.0 100.0 Example 85 99.9 100.0 Example 86 99.9 99 9 Example 87 98.0 94.0 Example 88 66.0 99.9 Example 89 99.8 99.9 Example 90 45.0 60.0 Example 91 88.0 86.0 Example 92 85.0 99.7 Example 93 98.0 99.0 Example 94 99.0 99.9 Example 95 98.0 99.7 Example 96 95.0 98.0 Example 97 49 0 99 0 Example 98 50.0 93.0 Example 99 9~.0 96.0 Example 100 14.0 99.0 Example 101 72.0 84.0 Example 102 72.0 81.0 -CA 02237997 1998-0~
WO 97/18193 PCT/E~r~6/01866 Example 103 89.0 99.8 Example 1Q4 63.0 100.0 Example 105 55.0 99.0 Example 106 98.0 99.5 Example 107 84.0 95.0 Example 108 1 10.0 100.0 Example 109 75.0 9 1 .0 Example 11 0 45.0 99.6 Example 111 25.0 99.8 Example 112 9g.0 99.9 Example 113 99.7 99.9 Example 11 4 99.0 99.9 The compounds of formula I and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical s preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the o form of inJection solutions, or nasally.

The compounds of formula I and the pharmaceutically acceptable acid addition salts of the compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations.
Lactose, corn starch or derivatives thereof, talc, stearic acid or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragées and hard gelatine capsules.
Suitable carriers for soft gelatine capsules are, for example, 20 vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active ingredient no carriers are, however, usually required in the case of soft gelatine capsuies. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oils 25 and the like. Suitable carriers for suppositories are, for example, CA 02237997 1998-0~

natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the ilke.

The pharmaceutical preparations can, moreover, contain 5 preservatives, solubiiizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, coating agents or antioxidants.
They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their manufacture which comprises 15 bringing one or more compounds of formula I and/or pharma-ceutically acceptable acid addition salts thereof into a galenical administration form together with one or more therapeutically inert carriers.

In accordance with the invention compounds o~ general formula I as well as their pharmaceutically acceptable acid addition salts can ~e used for the treatment or prevention of malaria and, respectively, for the production of corresponding medicaments. The dosage can vary within wide limits and will, 2s of course, be fitted to the individual requirements fn each particular case. In the case of oral administration the dosage lies in a range of about 10 mg to about 2.5 g per day of a compound of general hrmula i or the corresponding amount of a pharmaceutically acceptable acid addition salt thereof, although 30 the upper limit can also be exceeded when this is found to be indicated.

In the following Examples, which illustrate the present invention but are not intended to iimit its scope in any manner, 3s all temperatures are given in degrees Celsius. The 250 MHz-1H-NMR spectra were measured at room temperature; chemical shifts ~(ppm) relative to ~(TMS) = 0.0 ppm.

CA 02237997 1998-0~

Example 1 (2R)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-dimethy~amino-benzyl)-propane- 1, 2-diamine trihydrochloride 0.35 g of (2R)-N1-(7-chloro-quinolin-4-yl)-propane-1,2-diamine (see Example 118) and 0.22 g of 4-dimethylamino-benzaldehyde are boiled under reflux in 50 ml of ethanol overnight. After evaporation of the solvent the residue is again 10 taken up in 20 ml of ethanol, 0.05 g of sodium borohydrlde is added thereto and the mixture is left to react at room temperature overnight. The excess sodium borohydride is then decomposed by the addition of 5 ml of glacial acetic acid and the solvent is evaporated. After the addition of 10 ml of methanol the mixture is again evaporated. Addition of methanol and evaporation are repeated again, whereafter the mixture is purified by chromatography on 30 g of siiica gel with a mixture of dichloromethane and methanol in the ratio by volume 10:1. The product-containing fractions are combined and evaporated, and 20 the residue is taken up in 5 ml of ethanol. After the addition of 5 ml of 3N isopropanolic hydrochloric acid the hydrochloride of the product precipitates and is recrystallized from ethanol/diethyl ether.

25 Yield: 0.5 g (70%) of col~urless crystalline (2R)-N1-(7-chlor quinolin-4-yl)-N2-(4-dimethylamino-benzyl)-propane-1 ,2-diamine trihydrochloride; m.p. 220~C.
ISP mass spectrum: peaks at 3 69 (M+H+, 8%), 23 6 ( 58%), 1 34 (100%); lH-NMR in DMSO-d6, d (ppm): 1.44 (d, J = 6.5 Hz, 3H), 2.92 30 (s, 6H), 3.58 (m, 1 H), 3.85 (m, 1 H), 4.0 - 4.5 (m, 3H), 6.95 (m, 2H), 7.07 (d, J = ~ Hz, 1 H), 7.50 ~, J = 8 Hz, 2H), 7.80 (dd, J = 2 ar,d 9 Hz, lH), 8.14 (d, J = 2 Hz, lH), 8.63 (m, lH), 8.63 (m, lH), 8.86 (d, J = 9Hz, 1 H), 9.65 (m, 2H), 9.90 (m, 1 H), 14.65 (br.s, 1 H).

I q -CA 02237997 1998-0~
WO 97/18193 PCT/EP~6/0 1866 Fxamp/e 2 (2S)-N2-(7-Ch~oro-quinolin-4-yl)-N 1 -~4-dimethylamino-benzyl)-propane- 1, Z-diamine trihydrochloride Analogously to Example 1, from 4-dimethylamino-benz-aldehyde and (2S)-N2-(7-chloro-quinolin-4-yl)-propane-1,2-diamine (see Example 119) there is obtained (2S)-N2-(7-chloro-quinol in-4-yl)-N 1 -(4-di methyla m ino-benzyl )-propane- 1,2-0 diamine trihydrochloride, m.p. 189~C (from EtOH/Et20), in a yieldof 57% of theory.
ISP mass spectrum: peaks at 369 (M+H~, 20%), 236 (34%), 134 (100%); 1H-NMR in DMS0-d6, d (ppm): t .34 (d, J = 6.5 Hz, 3H), 2.8~
(s, 6~1), 3.19 (m,1 H), 3.40 (m,1 H), 4.05 (m, 2H), 4.64 (m,1 H), 6.70 15 (d, J = 8 Hz, 2H), 7.04 (d, J = 7 Hz,111), 7.37 (d, J = 8 Hz, 2H), 7.80 (dd, J = 2 and 9 Hz,1 H), 8.09 (d, J = 2 Hz,1 H), 8.61 ~m, 1 H), 8.84 (d, J = 9Hz,1 H), 9.28 (d, J = 8 Hz,1 H), 9.35 (m,1 H), 9.55 (m,1 H~, 14.45 (br.s,1 H).

2~ ~xample 3 N 1 -(7-Chloro-~uinolin-4-yl)-N2-(3,4-dichloro-benzyl)-2-methyl-propane- 1,2-diamine 1.25 g of N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.88 g of 3,4-dichlorobenzaldehyde are heated under reflux in 10 ml of ethanol for 3 hours. In order to complete the reaction, the solvent is evaporated in a vacuum. The resulting Schiff's l~ase is again taken up in 20 ml of ethanol and 30 reduced to the amine by the addition of 0.1 ~3 g of sodium borohydride. Excess reducing agent is decomposed after 2 hours by the addition of 10 ml of glacial acetic acid. The turbid solution is then evaporated on a rotary evaporator. 10 ml of methanol are added to the residue and the mixture is again 35 evaporated. Addition of methanol and evaporation are repeated twice. The evaporation residue is then taken up in 25 ml of water. The pH is adjusted to 10 by the addition of dilute sodium hydroxide solution, with the product separating. It is purified by ~0 CA 02237997 1998-0~

WO 97/18193 PCT/Er96/0186~i recrystaliization from 45 ml of ethyl acetate. Yield: 1.09 g (53%), m.p.178-179~C.
1H-NMR in DMS0-d6, ~ (ppm): 1.17(s, 6H), 3.24 (d, J = 5 Hz, 2H), 3.69 (s, ZH), 6.59 (d, J = 6 Hz,1 H), 6.70 (br. t,1 H), 7.35 (dd, J = 2 5 Hz and 8 Hz,1 H), 7.46 (dd, J = 2 Hz and 9 Hz,1 H), 7.52 (d, J = 8 Hz, 1 H), 7.62 (d, J = 2 Hz,1 H), 7.79 (d, J = 2 Hz,1 H), 8.26 (d, J = 9 Hz, 1H), 8.40 (d, J = 6 Hz, lH).

The following products are obtained as free bases in an 10 analogous manner using the corresponding aromatic aldehydes:

Example 4 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3-chloro-benzyl)-2-methyl-15 propane-1,2-diamine M.p.: 125-126~C (from AcOEt); 1H-NMR in DMS0-d6, ~ (ppm): 1.18 (s, 6H), 3.24 (d, J = 5 Hz, 2H), 3.69 (s, 2H), 6.60 (d, J = 6 Hz,1 H), 6.71 (m,1 H), 7.45-7.74 (m, 3H), 7.43-7.49 (m, 2H), 7.80 (d, J = 21~z, 20 1 H), 8.27 (d, J = 9 Hz,1 H), 8.4t (d, J = 6 Hz,1 H).

~xampl~ 5 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,4-dichloro-benzyl)-2-25 methyl-propane-1,2-diamine M.p.: 138-139~C (from MeCN3; t H-NMR in DMS0-d6, ~ (ppm): 1.19 (s, 6H), 3.25 (d, J = 5 Hz, 2H), 3.73 (s, 2H), 6.59 (d, J = 6 Hz,1 H), 6.72 (m,1 H), 7.39 (dd,J = 2 Hz and 8 Hz, 1 H), 7.46 (dd, J = 2 Hz and 9 30 Hz,1 H), 7.64 (d, J = 8 Hz,1 H), 7.79 (d, J = 2 Hz,1 H), 8.24 (d, J = 9 Hz,1 H), 8.41 (d, J = 6 Hz,1 H).

~ I

WO 97/18193 PCTtEP96/04866 Exam~le 6 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3-chloro-4-fluoro-benzyl)-2-methyl-propane- 1,2-diamine s M~p.: 164-1 ~5~C (from MeCN);lH-NMR in DMS0-d6, ~ (ppm): 1.17 (s, 6H), 3.24 (d, J = 5 Hz, 2H), 3.67 (s, 2H), 6.60 (d, J = 6 Hz, 1 H), 6.69 (m, 1 H), 7.25-7.38 (m, 2 H), 7.46 (dd, J = 2 Hz and 9 Hz, 1 H), 7.56 (dd, J = 2 Hz and 7 Hz, 1 H), 7.80 (d, J = 2 Hz, 1 H), 8.27 (d, J = 9 Hz, 10 1 H), 8.41 (d, J = 6 Hz, 1 H).

Fxample 7 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-chloro-3-trifluoromethyl-15 benzyl)-2-methyl-propane-1,2-diamine M.p.: 158-160~C (from MeCN);~H-NMR in DMS0-d6, â (ppm): 1.23 (s, 6H), 3.36 (s, 2H), 3.89 (s, ZH), 6.68 (d, J = 6 Hz,1 H), 7.48 (dd, J = Z Hz and 9 Hz,7 H), 7.67 (d, J = 8 Hz, 1 H), 7.73 (m,1 H), 7.82 20 (d, J - Z Hz, 1 H), 7.92 (m, 1 H), 8.34 (d, J = 9 Hz, 1 H), 8.43 (d, J = 6 Hz,1 H).

Example 8 25 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3-trifluoromethyl-benzyl)-2-methyl-propane-1,2-diamine M.p.: 156-157~C (from MeCN);~ H-NMR in DMS0-d6, ~ (ppm): 1.19 (s, 6H), 3.25 (d, J = 5 Hz, 2H), 3.78 (s, 2H), 6.61 (d, J = 6 Hz, 1 H), 7.43 30 (dd, J = 2 1 Iz and 9 Hz, 1 H), 7.45-7.74 (m, 3H), 7 80 (d, J = 2 Hz, 1 H), 8.27 (d, J = 9 Hz, 111), 8.41 (d, J = 6 Hz, 1 H).

2~

CA 02237997 1998-0~

WO 97/18193 PCT/EP~)f'01~66 Fxamp/e 9 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-trifluoromethyl-benzyl)-2-methyl-propane-1 ,2-diamine M.p: 145-147~C (from MeCN);lH-NMR in ~MSO-d6, â (ppm): 1.19 (s, 6H), 3.25 (d, J = 5 Hz, 2H), 3.78 (s, 2H), 6.60 (d, J = 6 Hz, 1 H), 6.73 (m, 1 H), 7.47 (dd, J = 2 Hz and 9 Hz, 1 H), 7.55-7.65 (m, 4H), 7.79 (d, J = 2 Hz, 1H), 8.26 (d, J = 9 Hz, lH), 8.41 (d, J = 6 Hz, lH).
Example 1 0:

N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,5-bis-trifluoromethyl-~enzyl)-2-methyl-propane-1 ,2-diamine M.p.: 140-141~C (from AcOEt);~H-NMR in DMS0-d6, ~ (ppm): 1.19 (s, 6H), 2.65 (t, J = 8 Hz, 1 H), 3.26 (d, J = 5 Hz, 2H), 3.89 (d, J = 8 Hz, 2H), 6.62 (d, J = 6 Hz, 1 H), 6.73 (m, 1 H), 7.41 (dd, J = 2 Hz and 9 Hz, 1 H), 7.79 (d, J = 2 Hz, 1 H), 7.91 (s, 1 H), 8.06 (s, 2H), 8.26 (d, 20 J = 9 Hz, 1 H), 8.39 (d, J = 6 Hz, 1 H).

Fxample 1 1:

N 1 -(7-Chloro-quinolin-4-yl)-N2-(pyridin-4-yl-methyl)-2-25 methyl-propane-1,2-diamine M.p.: 1 57-1 59~C (from MeCN);1H-NMR in DMSO-d6, ~ (ppm): 1.17 (s, 6H), 3.25 (m, 2H), 3.73 (s, 2H), 6.61 (d, J = 6 Hz, 1 H), 6.74 (m, H), 7.39 (d, J = 7 Hz, 2H), 7.48 (dd, J = 2 Hz and 9 Hz, 1 H), 7.79 30 (d, J = 2 Hz, lH), 8.28 (d, J = 9 Hz, lH), 8.40 (d, J = 6 Hz, lH), 8.45 (d, J = 7 Hz, ZH).

WO 97/18193 PCT/EP!~6/0181~6 Example 1 2 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,6-dichloro-benzyl)-2-methyl-propane-1,2-diamine M.p.: 154-155~C (from MeCN); lH-NMR in DMS0-d6, ~ (ppm): 1.25 (s, 6H), 2.0 (m,1 H), 3.25 (d, J = 5 Hz, 2H),3.87 (s, 2H), 6.59 (d, J = 6 Hz, lH), 6.61 (m, 1 H), 7.25-7.50 (m, 4H), 7.81 (d, J = 2 Hz, lH), 8.20 (d, J = 9 Hz, lH), 8.42 (d, J = 6 Hz, lH).
Example 1 3 cis -Nl -(7-Chloro-quinolin-4-yl)-N4-phenethyl-cyclohexane-1,4-diamine dihydrochloride ~nalogously to Example 3 using phenylacetaldehyde. Yield: 10%, dec. >250~C.

El mass spectrum: peaks at 380 ((M+H)+,100%), 276 (80%), 219 zo (500/o); 1 H-NMR in DMSO-d6, ~ (ppm): 1.96 (br,9H), 3.08 (br, 4H), 3.32 (br,lH), 4.10 (br,1H), 8,93 (d, J = 7Hz, lH), 7.32 (m,5H), 7.80 (dd, J = 2 and 9Hz,1 H), 8.12 (d, J = 2Hz,1 H), 8.59 (d, J - 7Hz,1 H), 8.72 (d,1 H), 8.87 (d, J = 9Hz,1 H), 9,24 (br, 2H),14.55 (br,1 H).

Fxample 14 cis-Nl -(7-Chloro-quinolin-4-yl)-N4-(Z,4,6-trimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride 30 Analogously to Example 3 using 2,4,6-trimethoxybenzaldehyde.
Yieid: 37% of white crystals (from methanol/diethyl ether), m.p.
195~C.

El mass spectrum: peaks at 455 (M+, 4%),196 (28%), 181 (t 00%);
35 lH NMR in DMSO-d6, ~ (ppm): 1.7-2.2 (m, 8H), 3.14 (br,lH), 3.35 (s,2H), 3.82 (s, 3H), 3,83 (2xs,6H), 4.03 (br, 3H), 6.30 (s, 2H), 6.91 (d, J = 6Hz,1 H), 7.76 (dd, J = 2 and 9Hz, l H), 8.17 (d, J = 2Hz,1 H), CA 02237997 1998-0~

8.60 (br, 3H), 8.75 (d, J = 6Hz,1 H), 8.94 (d, J = 9Hz,1 H), 14.75(br,1 H).

Example 1 5 cis-Nl -(7-Chloro-~uinolin-4-yl)-N4-(2,6-dichloro-benzyl)-cyclohexane-1,4-diamine dihydrochloride ~ nalogously to Example 3 using 2,6-dichlorobenzaldehyde. Yield 43% of 0 white crystals (from methanol/ether). M.p. > 270~C.

ISP mass spectrum: peaks at 434(M+, 100%), 436 ((M+2H)+, 90%);
1 H-NMR of the free base in CDCI3, ~ (ppm): 1.60-2.00 (m, 9H), 2.73 (br,1 H), 3.73 (br, 1 H), 4.09 (s, 2H), 5.05 (d,1 H), 6.43 (d, J =
5.5Hz,1 H), 7.15 (m,1 H), 7.30 (s,1 H), 7.33 (s,1 H), 7.35 (dd, J = 2 and 9Hz, lH), 7.62 (d, J = 9Hz, lH), 7.95 (d, J = 2Hz, lH), 8.51 (d, J
= 5.5Hz,1 H)-~xample 1 6 20cis-N1 -(7-Chloro-quinolin-4-yl)-N4-(2,6-dimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 3 using 2,6-dimethoxybenzaldehyde. Yield 25 58% of beige crystals (from methanol/ether). M.p. 205~C.

ISP mass spectrum: peaks at 426 ((M+H)+, 100%); 1 H-NMR of beige crystals (from base in CD~13, ~ (ppm): 1.60-2.00 (m, 8H), 2.70 (br, 2H), 3.75 (br, lH), 3.82 (s, 6H), 3.94 (s, 2H), 5,20 (d,lH), 6.41 (d, J
30 = 7Hz,1 H), 6.52 (d, J = 9Hz, 2H), 7.17 (t, J = 9Hz,1 H), 7.35 (dd, J =
2 and 1 OHz,1 H), 7.72 (d, J = 1 OHz,1 H), 7.93 (d, J = 2Hz,1 H), 8.51 (d, J = 7Hz,1 H).

2~

WO 97/18193 PCT/Er~6/~1866 Exam,ole 1 7 cis-N, -(7-Chloro-quinolin-4-yl)-N4-~2,3,6-trichloro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 3 using 2,3,6-trichlorobenzaldehyde.
Yield 44% of white crystals (from methanol/ether). M.p. > 270~C.

El mass spectrum: peaks at 469 (M+, 90%)s 467(95%), 258(80%), 0 219(100%), 1 H-NMR of the free base in CDCI3, ~ (ppm): 1.50-2.05 (m,9H), 2.80 (br,1 H), 3.70 (br,1 H), 4.12 (s, 2H), 5.05 (d,1 H), 6.43 (d, J = 5.5Hz,1 H), 7.27 (d, J = 8.5Hz,1 H), 7.34 (d, J = 8.5Hz, 1 H), 7.35 (dd, J = 2 and 9Hz,1 H), 7.63 (d, J = 9Hz,1 H), 7.95 (d, J =
2Hz, lH),8.51 (d, J = 5.5Hz, lH).
Exampfe 7 8 cis-2-{ ~4-(7-Chloro-quinolin-4-ylamino)-cyclohexylamino~-methyl }-3,5 -dimethoxy-phenol dihydrochloride Analogously to Example 3 using 4,6-dimethoxysalicylaldehyde. Yield 23% of beige crystais (from methanol/ether). M.p. 244~C.

ISP mass spectrum: peaks at 442 ((M+H)+, 100%); 1 H-NMR of the 25 free base in CDCI3 ~ (ppm): 1.60-2.00 (m, 9H), 2.90 (br, 1 H), 3.75 (s,3H), 3.76 (s, 3H), 4.03 (s, 2H), 5.00 (d,1 H), 6.00 (d, J = 2Hz, 1 H), 6.06 (d, J = 2Hz,1 H), 6.43 (d, J = 7Hz,1 H), 7.40 (dd, J = 2 and 1 OHz,1 H), 7.70 (d, J = 1 OHz,1 H), 7.95 (d, J = 2Hz,1 H), 8.50 ~d, J -7Hz,1 H)-Example 1 9 cis-Nl -(7-Chloro-quinolin-4-yl)-N4-(2,6-difluoro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 3 using 2,6-difluorobenzaldehyde. Yield 62% of white crystals (from methanoi/ether). M.p. 225~C.

CA 02237997 1998-0~
WO 97/18193 PCT/EP96.'0 1866 ISP mass spectrum: peaks at 402 ((M+H)+,100%), 276 (Z5%), 201 (75%); 1 H-NMR of the free base in CDCI3, o (ppm): 1.50-2.00 (m, gH), 2.75 (m,1 H), 3.70 (m,1 H), 3.92 (s, 2H), 5.05 (d, 1 H), 6.42 (d, J = 5.5Hz,1 H), 6.89 (m, 2H), 7.20 (m,1 H), 7.35 (dd, 1 = 2 and 9Hz, 5 1 H), 7.62 (d, J = 9Hz,1 H), 7.95 (d, J = 2Hz,1 H), 8.50 ~d, J = 5.5Hz, lH).

Example 20 1 0 cis-Nl-(7-Chloro-quinolin-4-yl)-N4-(3-phenyl-propyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to ~xample 3 using 3-phenylpropionaldehyde. Yield 15% of white crystals (from methanol/ether). Dec. from 160~C.

ISP mass spectrum: peaks at 445 ((M+H)+, 100%), 223 (1/2(M+2H)2+; 25%);1 H-NMR of the dihydrochloride in d6-DMSO ~
(ppm): 1.64-2.25 (m,1 OH), 2.69 (t,J = 7Hz, 2H),2.90 (br, 2H), 3.24 (br,1 H), 4.08 (br,1 H), 6.90 (d, J = 7Hz,1 H), 7.26 (m,5H), 7.75 (dd, 20 _1 = 2 and 9Hz,1 H), 8.16 (d, J = 2Hz,1 H), 8.58 (d, J = 7Hz, 1 H), 8.75 (d, br, 2H), 8.88 (d, J = 9Hz,1 H), 9.18 (br,2H),14.4 (br,1 H).

Example 27 25 cis-N~-(7-Chloro-quinolin-4-y~)-N4-(4-methoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to ~xample 3 using anisaldehyde. Yield 34% of white crystals (from methanol/ether). M.p. >185~C.
El mass spectrum: peaks at 395 (M+, 26%), 260 (65%), 219 (34%), 121 (100%); lH-NMR of the dihydrochloride in d6-DMSO ~ (ppm):
1.66-2.25 (m, 8H), 3.18 (br,1 H), 3.77 (s, 3H), 4.11 (br, 3H), 6.90 ~ (d, J = 7Hz,1 H), 6.98 (d, J = 8.6Hz, 2H), 7.55 (d, J = 8.6Hz, 2H), 35 7.78 (dd, J = 2 and 9Hz,1 H), 8.11 (d, 1 = 2Hz,1 H), 8.58 (d, ~ = 7Hz, - 1 H), 8.64 (d, br, 2H), 8.87 (d, J = 9Hz,1 H), 9.32 (br,2H),14.5 (br,1 H).

CA 02237997 l998-0~
WO 97/18~93 PCT/EP9G/~1866 Example Z2 cis-N 1 -(2-Chloro-6-nitro-benzyl)-N4-(7-chloro-quinolin-4-yl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 3 using 2-chloro-6-nitrobenzaldehyde. Yield 23% of white crystals (from methanol/ether). M.p. >260~C.

ISP mass spectrum: peaks at 445 ((M+H)+, 100%), 223 l o (l/2(M+2H)Z+; 25%); 1 H-NMR of the free base in CDCl3, ~ (ppm):
1.50-2.00 (m, 9H), 2.85 (m, lH), 3.71 (m, lH), 4.06 (s, 2H), 5.03 (d, 1 H), 6.43 (d, J = 5.5Hz,1 H),7.37 (m, 2H), 7.68 (m, 3H), 7.95 (d, 1 =
2Hz, IH), 8.51 (d, J = 5.5Hz, lH).

1 5 ~xample 23 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,5-dichloro-benzyl)-2-methylpropane-1,2-diamine dihydrochloride 1.25 g of N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diarnine and 0.88 g of 3,5-dichlorobenzaldehyde are heated ander reflux in 10 ml of ethanol for 3 hours. The solvent is evaporated in a vacuum in order to complete the reaction. The resulting Schiff's base is again taken up in 10 ml of ethanol and zs reduced to the amine by the addition of 0.19 g of sodium borohydride. Excess reducing agent is decomposed after 3 hours by the addition of 10 ml of glaciai acetic acid. The turbid solution is then evaporated on a rotary evaporator. The residue is taken up in 10 ml of methanol, which is again evaporated.
30 Addition of methanol and evaporation are repeated twice. The evaporation residue is then dissolved in 15 ml of hot methanol.
After the addition of 3.6 ml of 3N isopropanolic hydrochloric acid the hydrochloride of the product crystallizes upon cooling. The crude salt (1.1 g) is purified by recrystallization from 30 ml of 35 methanol. Yield: 0.63 g (26%), m.p. >250~C.
1H-NMR in DMS0-d6, ~ (ppm): 1.50 (s, 6H), 4.03 (br.s, 2H), 4.35 (m, 2H), 7.27 (d, J = 7 Hz,1 H), 7.69 (m, 1 H), 7.82 (dd, J = 2 Hz and 9 CA 02237997 1998-0~

Hz), 7.89 (m, 2H), 8.11 (d, J = 2 Hz,1 H), 8.68 (d, J = 7 Hz,1 H~,8.99 (d, J = 9 Hz,1 H), 9.65 (br.,1 H),9.8 ~m, 2H),14.5 (br.s,1 H).

The hydrochlorides of the fol~owing products are obtained in 5 an analogous manner using the corresponding benzaldehydes:

Example 24 N1-(7-Chloro-quinolin-4-yl)-N2-(benzyl)-2-methyl-propane-1,2-0 diamine dihydrochloride M.p.: >250~C (from i-PrOH); El mass spectrum: fragments at 192 (16%),148 (100%3,91 (96%); lH-NMR in DMSO-d6, ~ (ppm): 1.53 (s, 6H),4.06 (m, 2H), 4.29 (m, 2H), 7.28 (d, J = 7 Hz,1 H), 7.40-7.45 15 (m, 3H), 7.70-7.82 (m,3H), 8.17 (d, J = 2 Hz, t H), 8.67 (d, J = 7 Hz,1 H),9.03 (d, J = 9 Hz,1 H), 9.70 (m, 3H),14.65 (br.s, 1H).
Fxamp/e 25 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-chloro-benzyl)-2-methyl-propane- 1,2-diamine dihydrochloride M.p.: >250~C (from i-PrOH); El mass spectrum: fragments at 192 25 (43%),182 (75%),125 (100%); 1H-NMR in DMSO-d6, ~ (ppm): 1.52 (s, 6H), 4.05 (m, 2H), 4.30 (m, 2H),7.28 (d, J = 7 Hz,1 H), 7.51 (d, J e 8.5 Hz, 2H), 7.75-7.80 (m, 3H), 7.70-7.82 (m, 3 H), 8.15 (d, J = 2 Hz,1 H), 8.67 (d, J = 7 Hz,1 H), 9.02 (d, J = 9 Hz,1 H), 9.5-10.0 (m, 3H),14.30 (br.s,1 H).

Examp~e 26 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2.3-dichloro-benzyl)-2-3~ methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from i-PrOH); lH-NMR in DMSO-d6, ~ (ppm): 1.55 (s, 6H), 4.08 (m, 2H), 4.46 (m, 2H), 7.28 (d, J = 7.5 Hz,1 H), 7.48 (t, J =
~.9 CA 02237997 1998-0~

8 Hz, 1 H), 7.70-7.85 (m, 2H), 8.02 (dd,J - 2 Hz and 8 Hz, 1 H), 8.20 (d, J = 2 Hz, lH), 8.70 (d,J = 7.5 Hz, lH), 9.07 (d, J = 9 Hz, lH), 9.70 (m, lH), 10.00 (m, 2H), 14.90 (br.s, lH).

Fxamp/e 27 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-chloro-3-fluoro-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride 10 M.p.: >250~C (from MeOH);1H-~MR in D MSO-d6, ~ (ppm): 1.50 (s, 6H), 4.04 (m, 2H), 4.34 (m, 2H), 7.28 (d, J = 7 Hz, 1 H), 7.60 (dd, J = 2 Hz and 8 Hz, 1 H), 7.70 (t, J = 8 Hz, 1 H), 7.82 (dd, J = 2 Hz and 9 Hz, 1 H), 7.90 (dd, J = 2 Hz and 10 Hz), 8.10 (d, J = 2 Hz, 1 H), 8.68 (d, J = 7 Hz, 1 H), 8.98 (d, J = 9 Hz, 1 H), 9.6 (m, 1 H), 9.85 (m, 2H), 14.5 (br.s, 1 H).
FxampJe 28 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2-hydroxybenzyl)-2-methyl-20 propane-1 ,2-diamine diacetate 1.25 g of N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-1,2-diamine and 0.54 g of salicylaldehyde are stirred ander reflux overnight in the presence of 1.25 g of molecular sieve (E. Merck, 25 3A). Thereafter, the mixture is filtered and the solvent is evaporated. ~rom a small amount of diethyl ether and ethyl acetate there is obtained a crystalline product which is again taken up in 20 ml of ethanol. After the addition of 0.19 g of sodium borohydride the mixture is left to react overnight, 30 thereafter 5 ml of glacial acetic acid are added thereto and the mixture is evaporated to dryness. After the addition of 10 ml of methanol the mixture is again evaporated. Addition of methanol and evaporation are repeated twice. The residue is then crystallized from 10 ml of ethanol. 0.9 g (40%) of colourless 35 crystalline product of m.p. 1 50~C is obtained.
ISP-mass spectrum: peaks at 356 (M+H~, 65 %), 250 (80 %), 1 07 (100%); lH-~IMR in DMSO-d6, ~ (ppm): 1.20 (s, 6H), 1.90 (s, 6H), 3.33 (s, 2H), 3.84 (s, 2H), 6.63-6.74 (m, 3H), 7.03-7.1 3 (m, 2H), CA 02237997 l998-0~
WO 97/t8193 PCT/EP96/04866 7.47 (dd, J = 2 and 9 Hz, 1 H), 7.80 (d, J = 2 Hz, 1 H), 8.31 (d, J =9Hz, 1 H), 8.41 ( d, J = 7 Hz, 1 H).

Example Z9 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2-hydroxy-4-methoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride 1.Z5 g of N1-(7-chloro-quinolin-4-yl)-2-methyl-propane-0 1 ,2-diamine and 0.76 9 of 2-hydroxy-4-methoxy-benzaldehyde are stirred ander reflux overnight in 20 ml of ethanol in the presence of 1.2~ g of molecular sieve (E. Merck, 3A). The mixture is filtered, the solvent is evaporated and the residue is again taken up in 20 ml of ethanol. After the addition of 0.19 9 of sodium borohydride the mixture is stirred at room temperature for 6 hours, thereafter 5 ml of glacial acetic acid are added thereto and the mixture is evaporated to dryness. 10 ml of methanol are added to the residue and the mixture is again evaporated.
Addition of methanol and evaporation are repeated twice. Finally, 20 the residue is taken up in 10 ml of hot ethanol, 10 ml of 3N
isopropanolic hydrochloric acid are added thereto and the product is left to crystallize out as the dihydrochloride. Yield 1.8 9 (78%) of colourless crystalline powder, m.p. 220~C.
ISP mass spectrum: peaks at 386 (M+H+, 20%), 250 (70%), 137 25 (100%); lH-NMR in DMS0-d6, ~ (ppm): 1.48 (s, 6H), 3.71 (s, 3H), 4.02 (m, 2H), 4.10 (m, 2H), 6.44 (dd, J = 2 and 8 Hz, 1 H), 6.59 (d, J = 2 Hz, 1 H), 7.22 (d, J = 7 Hz, 1 H), 7.47 (d, J = 8 Hz, 1 H), 7.80 (dd, J = 2 Hz and 9 Hz, 1 H), 8.21 (d, J = 2Hz, 1 H), 8.67 (d, J = 7 Hz, 111), 9.02 (d, J = 9 Hz, 1 H), 9.30 (m, 2H), 9.57 (m,1 H), 10.40 (m, 30 1 H), 14.94 (br.s, 1 H).

The hydroehlorides of the following products are obtained in an analogous manner using the corresponding aromatic aldehydes:
r CA 02237997 1998-0~

~xample 30 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2-hydroxy-3-methoxy-benzyl)-2-methyl-propane- 1,2-diamine dihydrochloride Yield 82%, m.p.: 210-212~C (from EtOH/i-PrOH); ISP mass spectrum: peaks at 386 (M~H+, 44%), 250 (100%); lH-NMR in DMSO-d6, ~ (ppm): 1.49 (s, 6H), 3.83 (s, 3H), 4.03 (m, 2H), 4.20 (m, 2H), 6.83 (t, J = 8 Hz,1 H), 7.03 (dd, J = 1.S and 8 Hz, 1 H), 7.23 (m, ZH), 10 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.20 (d, J = 2 Hz, lH), 8.66 (d, J = 7Hz, lH), 9.01 (d, J = 9 Hz,1 H), 9.36 (m, 3H), 9.59 (m, 1 H), 14.65 (br.s,1 H).

fxample 3 1 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2-hydroxy-5-methoxy-benzyl)-2-methyl-propane- 1,2-diamine dihydrochloride Yield 44%, m.p.: ~250~C (from EtOH/i-PrOH); ISP mass spectrum:
20 peaks at 386 (M+H+, 67%), 250 (100%); lH-NMR in DMSO-d6, (ppm): 1.50 (s, 6H), 3.71 (s, 3H), 4.03 (m, 2H), 4.17 (m, 2H), 6.80-6.94 (m, 2H), 7.23-7.29 (m, 2H), 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.14 (d, J = 2 Hz, lH), 8.68 (d, J = 7Hz, lH), 8.97 (d, J = 9 Hz, lH), 9.34 (m, 2H), 9.50 (m, lH), 9.75 (m, lH), 14.65 (br.s, lH).
Example 32 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3-hydroxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride Yield 56%, m.p.: >250~C (from EtOH/i-PrOH); ISP mass spectrum:
peaks at 356 (M+H+); 'H-NMR in DMSO-d6, ~ (ppm): 1.50 (s, 6H), 4.04 (m, 2H), 4.18 (m, 2H), 6.83 (m, 1 H), 7.04-7.30 (m, 4H), 7.81 (dd, J = 2 Hz and 9 Hz, lH), 8.19 (d, J = 2 Hz, lH), 8.67 (d, J = 7Hz, 35 lH), 9.02 (d, J = 9 Hz, lH), 9.65 (m, 3H), 9.74 (s, lH), 14.80 (br.s, lH).

3~

CA 02237997 1998-0~
WO 97/~8193 PCT/Er~)6/0~8~;6 Fxamp/e 33 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-hydroxy-3-methoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride Yield 68%, m.p.: >250~C (from EtOH/i-PrOH); lSP mass spectrlJm:
peaks at 386 (M+H+, 100%), 250 (52%); 1H-NMR in DMSO-d6, ~
(ppm): 1.50 (s, 6H), 3.81 (s, 3H), 4.04 (m, ZH), 4.17 (m, 2H), 6.80 (d, J = 8 Hz, 1 H), 7.04 (dd, J = 2 and 8 Hz, 1 H), 7.27 (d, J = 7 Hz, 0 1 H), 7.50 (d, J = 2,1 H), 7.79 (dd, J = 2 Hz and 9 Hz, 1 H), 8.18 (d, J = 2 Hz, 1 H), 8.66 (d, J = 7Hz, l H), 9.04 (d, J = 9 Hz, 1 H), 9.60 (m, 3H),14.83 (br.s, IH).

Fxamp/e 34 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2-methoxy-benzyl)-2-methyl-propane- 1,2-diamine dihydrochloride Yield 68%, m.p.: >250~C (from EtOH/i-PrOH); ISP mass spectrum:
20 peaks at 370 (M+H+, 100%), 250 (75%); 1H-NMR in DMSO-d6, ~
(ppm): 1.50 (s, 6H), 3.82 (s, 3H), 4.05 (m, 2H), 4.20 (m, 2H), 7.00 (t, J = 8 Hz, 1 H), 7.09 (d, J = 8 Hz, 1 H), 7.26 (d, J = 7 Hz, t H3, 7.43 (dt, J = 2 and 8 Hz, 1 H), 7.59 (dd, J = 2 and 8 Hz,1 H), 7.80 (dd, J =
2 Hz and 9 Hz,1 H), 8.20 (d, J = 2 Hz,1 H), 8.68 (d, J = 7Hz, 1 H), 25 9.07 (d, J = 9 Hz,1 H), 9.45 (m, 2H), 9.65 (m, l H),14.83 (br.s, 1 H).

Fxample 35 N 1 -(7-~::hloro-quinolin-4-yl)-N2-(4-methoxy-benzyl)-2-methyl-30 propane- 1,2-diamine dihydrochloride M.p.: >250~C (from EtOH); lH-NMR in DMSO-d6, ~ (ppm): 1.50 (s, 6H), 3.77 (s, 3H), 4.03 (m, 2H), 4.22 (m, 2H), 6.99 (d, J = 9 Hz, 2H), 7.27 (d, J = 7 Hz, 2H), 7.64 (d, J = 9 Hz, 2H), 7.81 (dd, J - 2 Hz and 35 9 Hz), 8.1 4 (d, J = 2 Hz,1 H), 8.68 (d,J = 7 Hz,1 H), 9.01 (d, - J = 9 Hz, lH), 9.63 (m, 3 H), 1 4.65 (br.s, lH).

WO 97/18193 PCT/EP~6/01866 Example 36 N I -(7-Chloro-quinolin-4-yl)-N2-(2,3-dimethoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from ~tOH/i-PrOH); ~H-NMR in DMSO-d6, ~ (ppm): 1.50 (s, 6H), 3.83 (s, 3H), 3.84 (s, 3H), 4.04 (m, 2H), 4.22 (m, 2H), 7.14 (d, J = 5 Hz, 2H), 7.25 (d, J = 7 Hz,1H), 7.35 (t, J = 5 Hz, lH), 7.81 (dd, J = 2 Hz and 9 Hz,1 H), 8.14 (d, J = 2 Hz, lH), 8.69 (d, J = 7 Hz, 10 1 H), 9.00 (d, J = 9 Hz,1 H), 9.54 (m, 3H),14.65 (br.s,1 H).

Exam~le 37 .

N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,4-dimethoxy-benzyl)-2-15 methy~-propane-1,2-diamine dihydrochloride Yield 42%, m.p.: >250~C (from EtOH/i-PrOH); El mass spectrum:
fragments at 301, 208, 191, 151 (100%); lH-NMR in DMSO-d6, (ppm): 1.49 (s, 6H), 3.79 (s, 3H), 3.80 (s, 3H), 4.02 (m, 2H), 4.11 20 (m, 2H), 6.54 -6.63 (m, 2H), 7.24 (d, J = 7 Hz,1 H), 7.52 (d, J = 8 Hz,1 H), 7.80 (dd, J = 2 Hz and 9 Hz,1 H), 8.20 (d, J = 2 Hz, 1 H), 8.67 (d, J - 7Hz,1H), 9.08 (d, J = 9 Hz,1 H), 9.35 (m, 2H), 9.63 (m,1 H), 14.90 (br.s,1 H).

Fxample 38 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,5-dimethoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride 30 Yield 72%, m.p.: >250~C (from EtOH/i-PrOH); ISP mass spectrum:
peaks at 400 (M+H+,100%), 384 (27%), 250 (85%); 'H-NMR in DMSO-d6, ~ (ppm): 1.50 (s, 6H),3.74 (s, 3H), 3.77 (s, 3H), 4.03 (m, 2H), 4.18 (m, 2H), 6.94-7.04 (m, 2H), 7.25 (d, J = 7 Hz,1 H), 7.35 (d, J = 2 Hz, lH), 7.79 (dd, J = 2 Hz and 9 Hz,1H), 8.20 (d, J = 2 Hz, 35 1 H), 8.68 (d, J = 7Hz,1 H), 9.06 (d, J = 9 Hz,1 H), 9.60 (m, 3H), 14.80 (br.s,1 H).

CA 02237997 1998-0~

WO 97/18193 PCT/EP~G,(i l~C
Fx~mp/e 39 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,4-dimethoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride Yield 72%, m.p.: >250~C (from EtOH/i-PrOH); 1H-NMR in DMSO-d6, (ppm): 1.53 (s, 6H), 3.76 (s, 3H),3.81 (s, 3H), 4.06 (m, 2H), 4.20 (m, 2H), 6.97 (d, J = 8.5 Hz,1 H),7.19 (dd, J = 2 Hz and 8.5 Hz,1 H), 7.28 (d, J = 7.5 Hz,1 H), 7.56 (d, J = 2 Hz,1 H), 7.76 (dd, J = 2 and o 8.5 Hz,1 H), 8.23 (d, J = 2 Hz,1 H), 8.65 (d, J = 7.5 Hz,1 H), 9.09 (d, J = 8.5 Hz,1 H), 9.75 (m, 3H),15.00 (br.s,1 H).

Fxample 40 t 5 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,5-dimethoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from EtOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.51 (s, 6H), 3.78 (s, 6H), 4.05 (m, 2H), 4.22 (m, 2H), 6.51 (m, lH), 6.99 (m, 2H), 20 7.28 (d, J = 7 Hz,1 H), 7.81 (dd, J = 2 Hz and 9 Hz), 8.14 (d, J = 2 Hz,1 H) 8.68 (d, J = 7 Hz,1 H), 9.01 (d, J = 9 Hz,1 H), 9.67 (m, 3 H),14.65 (br.s,1 H).
Fxamp/e 41 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,4,5-trimethoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride Yield 60%, m.p.: >250~C (from EtOH/i-PrOH); ISP mass spectrum:
30 peaks at 430 (M+H+); ~H-NMR in DMSO-d6, ~ (ppm): 1.51 (s, 6H), 3.65 (s, 3H), 3.82 (s, 6H), 4.05 (m, 2H), 4.22 (m, 2H), 7.18 (s, 2H), 7.28 (d, J = 7 Hz,1 H), 7.80 (dd, J = 2 Hz and 9 Hz, 1 H), 8.10 (d, J = 2 Hz, 1 H), 8.66 (d, J = 7 Hz, 1 H), 8.97 (d, J = 9 Hz,1 H~, 9.64 (m, 3H),14.55 (br.s,1 H).

Fxam,~/e 42 N 1 -(7-Chloro-quinolin-4-yl)-N2-benzo[1,3 ~dioxol-5-yimethyl-2-methyl-propane-1,2-diamine dihydrochioride Yield 61%, m.p.: >250~C (from EtOH/i-PrOH); ISP mass spectrum:
peaks at 384 (M+H+), 250 (79%); ~H-NMR in C)MSO-d6, ~ (ppm): 1.49 (s, 6H), 4.04 (m, 2H), 4.23 (m, 2H), 6.98 (d, J = 7 Hz, lH), 7.17 (dd, J = 2 Hz and 7 Hz, lH), 7.30 (d, J = 7 Hz, lH), 7.39 (d, J = 2 Hz, lH), 10 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.14 (d, J = 2 Hz, lH), 8.67 (d, J =
7 Hz, 1 H), 9.00 (d, J = 9 Hz, 1 H), 9.63 (m, 3H),1 ~.58 (br.s 1 H).

Example 43 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-phenoxy-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from MeOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.51 (s, 6H), 4.05 (m, 2H), 4.28 (m, 2H), 7.00-7.08 ( m, 4 H), 7.15-7.21 (m, 1 H), Zo 7.28 (d, J = 7.5 Hz, 2H), 7.39-7.46 (m, 2 H), 7.74 (d, J = 9 Hz, 2 H), 7.81 (dd, J = 2 Hz and 9 Hz), 8.14 (d, J = 2 Hz, lH), 8.69 (d, J = 7.5 Hz, 1 H), 9.01 (d, J - 9 Hz,1 H), 9.66 (m, 3 H),14.65 (br.s, lH).

Z5 Fxample 44 N 1 -(7-Chloro-quinoiin-4-yl)-N2-(4-methylsulphanyl-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride 30 M.p.: >250~C (~rom MeOH); lH-NMR in DMSO-d6, o (ppm): 1.50 (s, 6H), 2.50 (s, 3H), 4.03 (m, 2H), 4.25 (m, 2H), 7.28 (d, J = 7 Hz, 1 H), 7.32 (d, J = 9.5 Hz, 2 H), 7.65 (d, J = 9.5 Hz, 2H), 7.80 (dd, J - 2 Hz and 9 Hz, lH), 8.11 (d. J - 2 Hz, lH), 8.69 (d, J = 7 Hz, lH), 8.98 (d, J = 9 Hz, lH), 9.6 (m, 3H), 14.50 (br.s, lH).

Example 45 N 1 -(7-Chloro-quinolin-4-Yl)-N2-(4-dimethylamino-benzyl)-2 methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from MeOH); ~H-NMR in DMSO-d6, ~ (ppm): 1.49 (s, 6H), 2.91 (s, 6H), 4.01 (m, 2H), 4.13 (m, 2H~, 6.74 (d, J = 9 Hz, 2H), 7.25 (d, J = 7.5 Hz,1 H), 7.48 (d, J = 9 Hz, 2H), 7.82 (dd, J = 2 Hz and 9 Hz,1 H), 8.12 (d, J = 2 Hz, 1 H), 8.68 (d, J = 7.5 Hz,1 H), 8.98 (d, 0 J = 9 Hz, 1 H), 9.45 (m, 2H), 9.55 (m, 1 H),14.60 (br.s,1 H).
Fxamp/e 46 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-diethylamino-benzyi)-2-methyl-propane-1,2-diamine trihydrochloride Yieid 21%, m.p.. > 250~C (from EtOH); ISP mass spectrum: peaks at 411 (M+H+, 5%) 250 (24%), 233 (16%), 206 ([M+2H+~ / 2,100%), 162 (98%); ~H-NMR in DMSO-d6, ~ (ppm): 1.05 (t, J = 7 Hz, 6H), 1.51 20 (s, 6H), 3.44 (q, J = 7 Hz, 4H), 4.05 (m, 2H), 4.35 (m, 2H), 7.28 (d, J
= 7.5 Hz, 1 H), 7.82 (dd, J = 2 Hz and 9 Hz,1 H), 7.95, (m, 2H), 8.12 (d, J = 2 Hz, 1 H), 8.68 (d, J = 7.5 Hz, 1 H), 9.00 (d, J = 9 Hz, 1 H), 9.65 (m, 1H), 9.85 (m, lH), 14.58 (br.s, lH).

2 5 Fxamp/e 4 7 N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-nitro-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from EtOH/i-Pr ether; 1H-NMR in DMSO-d6, ~ (ppm):
1 54 (s, 6H), 4.08 (m., 2H), 4.48 (m, 2H), 7.30 ~d,~ = 7 Hz, 2H), 7.81 (dd, J = 2 Hz and 9 Hz), 8.04 (d, J = 8.5 Hz, Z H), 8.13 (d, J = 2 Hz, 1 H), 8.30 (d, J = 8.5 Hz, 2H), 8.68 (d, J = 7 Hz,1 H), 9.00 (d, - J = 9 Hz, lH), 9.66 (m,1 H), 10.0 (m, 2H),14.65 (br.s, lH).

CA 02237997 1998-0~

~xample ~8 N 1 -(7-Chloro-quinolin-4-yl)-N2-(3-cyano-benzyl)-2-methyl-propane- 1,2-diamin e di hydrochloride M.p.: >250~C (from MeOH); lH-NMR in DMSO-d6, â (ppm): 1.51 (s, 6H), 4.04 (m, 2H), 4.38 (m, 2H), 7.28 (d, J = 7 Hz,1 H), 7.67 (t, J = 8 Hz, 1 H), 7.80 (dd, J = 2 Hz and 9 Hz,1 H), 7.92 (d, J = 8 Hz, 1 H), 8.05-8.12 (m, 2H), 8.25 (s, 1 H), 8.69 (d, J = 7 Hz,1 H), 8.97 (d, J = 9 Hz, 10 1 H), 9.6 (m,1 H), 9.8 (m, 2H),14.50 (br.s,1 H).

~xample 4~

N 1 -(7-Chloro-~uinolin-4-yl)-N2-(4-cyano-benzyl)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: >250~C (from EtOH/i-Pr ether; lH-NMR in DMSO-d6, S (ppm):
1.52 (s, 6H), 4.07 (m, 2H), 4.42 (m, 2H), 7.2g (d, J = 7 Hz, 2H), 7.81 (dd, J = 2 Hz and 9 Hz), 7.92-8.00 (m, 4 H), 8.14 (d, J = 2 Hz,1 H), 20 8.69 (d, J = 7 Hz,111), 9.01 (d, J = 9 Hz,1 H), 9.66 (m, 3 H),14.65 (br.s,1 H).

Examp/e 50 25 N 1 -(7-Chloro-quinolin-4-y~)-N2-(4-isopropyl-benzyi)-2-methyl-propane-1,2-diamine dihydrochloride M.p.: 210~C (dec.) (from i-PrOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.20 (d, J = 8,5 Hz, 6H), 1.50 (s, 6H), 2.92 (sept, J = 7 Hz,1 H), 4.03 (m, 30 2H), 4.24 (m, 2H), 7.28 (d, J = 7 Hz,1 H), 7.32 (d, J = 8 Hz, 2H), 7.62 (d, J = 8 Hz, 2H), 7.80 (dd, J = 2 Hz and 9 Hz, 1 H), 8.13 (d, J = 2 Hz, 1 H), 8.68 (d, J = 7 Hz,1 H), 8.98 (d, J = 9 Hz,1 H), 9.60 (m, 3H), 14.60 (br.s,1 H).

3g -CA 02237997 1998-0~

WO 97/181g3 PCT/Er9~/018CC
Example 51 N 1 -(7-Chloro-quinolin-4-yl)-N2-(bipenyl-4-yl-methyl)-2-methyl-propane- 1,2-diamine dihydrochloride M.p.: >250~C (from MeOH); ~H-NMR in DMSO-d6, ~ (ppm): 1.54 (s, 6H), 4.06 (m, 2H), 4.34 (m, 2H), 7.28 (d, J = 7 Hz,1 H), 7.35-7.55 (m, 3H), 7.65-7.85 (m, 7H), 8.t 2 (d, J = 2 Hz, 1 H), 8.69 (d, J = 7 Hz, 1 H), 8.99 (d, J = 9 Hz, I H), 9.60 (m,1 H), 9.70 (m, 2H),14.60 (br.s, 10 1H).

Example 5Z

N 1 -(7-Chloro-quinolin-4-yl)-N2-(naphthalen-1 -yl-methyl)-2-5 methyl-propane-1,2-diamine dihydrochloride M.p.: 180~C (dec.) (from l~eOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.46 (s, 6H), 3.60 (s, 2H), 4.43 (s, 2H), 6.77 (d, J = 6 Hz,1 H), 7.4-7.6 (m, 4H), 7.75-7.95 (m, 4H), 8.23 (d, J = 8 Hz, 1 H), 8.42-8.47 (m, 20 2H).

Ex~mple ~3 N 1 -(7-Chloro-quinolin-4-yl)-N2-(naphthalen-2-yl-methyl)-2-25 methyl-propane-1,2-diamine dihydrochloride M.p.: >250OC (from MeOH/water); lH-NMR in DMSO-d6, ~ (ppm): 1.55 (s, 6H), 4.08 (m, 2H), 4.47 (m, 2H), 7.Z7 (d, J = 7 Hz,1 H), 7.55-7.60 (m, 2H), 7.80-8.05 (m, 5H), 8.12 (d, J = 2 Hz, lH), 8.22 (m, 30 lH), 8.69 (d, J = 7 Hz, lH), 9.00 (d, J = 9 Hz, lH), 9.70 (m, lH), 9.75 (m, 2H),14.60 (br.s,1 H).

~9 -WO 97/18193 PCT/EP96/0~866 Fxam,~/e 54 N 1 -(7-Chloro-quinolin-4-yl)-N2-~furan-2-yl-methyl)-2-methyl-propane- 1,2-diamine dihydrochloride Yield 36%, m.p.: >250~C (from EtOH/i-PrOH); lH-NMR in DMSO-d6, â
(ppm): 1.47 (s, 611), 4.02 (m, 2H), 4.38 (m, 2H), 6.55 (m,1 H), 6.79 (m, 1 H), 7.14 (d, J = 7.5 Hz, 1 H), 7.75-7.85 (m, 2H), 8.21 (d, J = 2 Hz, 1 H), 8.64 (d, J = 7.5 Hz,1 H), 9.07 (d, J = 9 Hz, 1 H), 9.65 10 (m, 1 H), 9.90 (m, 2H),14.90 (br.s,1 H).

Example 55 N 1 -(7-Chloro-quinolin-4-yl)-N2-(furan-3-yl-methyl)-2-methyl-5 propane-112-diamine dihydrochloride Yield 74.5%, m.p.: >250~C (from EtOH/i-PrOH); lH-NMR in DMSO-d6, o (ppm): 1.48 (s, 6H), 4.02 (m, 2H), 4.19 (m, 2H), 6.95 (m,1 H), 7.27 (d, J = 8.5 Hz,1 H), 7.74 (m,1 H), 7.90 (dd, J = 2.5 and 9 Hz, 1 H), 20 7.95 (m, 1 H), 8.15 (d, J = 2.5 Hz,1 H), 8.67 (d, J = 8.5 Hz, 1 H), 9.03 (d, J = 9 Hz,1 H), 9.65 (m, 3 H),14.6 (br.s, 1 H).

Fxample S6 25 N 1 -(7-Chioro-quinolin-4-yl)-N2-(pyridin-2-yl-methyl)-2-methyl-propane-1,2-diamine trihydrochloride M.p.: >250~C (from EtOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.51 (s, 6H), 4.08 (d, J - 6 Hz, 2H), 4.55 (m, 2H), 7.28 (d, J = 7.5 Hz, 1 H), 7.50-30 7.60 (m, 1 H), 7.75-7.87 (m, 2H), 8.0-8.1 (m, 1 H), 8.20 (d, J = 2 Hz, 1 H), 8.60-8.75 (m, 2H), 9.00 (d, J = 9 Hz, 1 H), 9.70 (m, 1 H), 9.90 (m, 21~),14.90 (br.s, 1 H).

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WO 97/18193 PCT/EP~GI'C18C6 Example 57 N 1 -(7-Chloro-quinolin-4-yl)-N2-(pyridin-3-yl-methyl)-2-methyl-propane-1,2-diamine trihydrochloride M.p.: 180~C (dec.) (from EtOH); 1H-NMR in DMSO-d6, ~ (ppm): 1.54 (s, 6H), 4.07 (s, 2H), 4.38 (s, 2H), 7.30 (d, ~ = 7.5 Hz,1 H), 7.49 (dd, J = 6 Hz and 8.5 Hz,11~), 7.78 (dd, J = 2 Hz and 9 Hz,1 H), 8.16 (d, J 0 2 Hz,1 H), 8.23-8.28 (m,1 H), 8.60 (dd, J = 2 Hz and 6 Hz,1 H), 10 8.67 (d, J = 7.5 Hz,1 H), 8.90 (d, J = 2 Hz,1 H), 9.08 (d, J = g Hz, 1 H), 9.70 (m,1 H),10.0 (m, 2H),14.8 (br., 1 H).
Fxample 58 N 1 -(7-Chloro-quinolin-4-yl)-N2-(quinolin-4-yl-methyl)-2-methyl-propane-1,2-diamine trihydrochloride M.p.: 207-209~C (from MeOH); lH-NMR in DMSO-d6, ~ (ppm): 1.66 (s, 6H), 4.25 (d, J = 6.5 Hz, ZH), 5.09 (m, 2H), 7.36 (d, J = 7 Hz, 1 H), 20 7.76 (dd, J = 2 Hz and 9 Hz,1 H), 7.93 (m,1 H), 8.10 (m,1 H), 8.23 (d, J = 2 Hz,1 H), 8.44 (m, 2H), 8.66 (m, 2 H), 9.10 (d, J = 9 Hz, 1 H), 9.34 (d, J = 7 Hz, lH), 9.8~ (m, lH),10.66 (m, 2H),15.00 (br.s, lH).

Exampfe 59 N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,4-bis-trifluoromethyl-benzyl)-2-methyl-propane- 1,2-diamine dihydrochloride M.p.: 260~C (dec.) (from MeOH); tH-NMR in DMSO-d6, ~ (ppm): 1.54 30 (s, 6H~, 4.12 (s, 2H), 4.50 (s, 2H~, 7.30 (d, J = 7.5 Hz,1 H), 7.78 (dd, J = 2 H~7 and 9 Hz,1 H), 8.11 (s,1 H), 8.20 (~!, J = 2 H7, U~), 8.Z3-8.28 (m,1 H), 8.60-8.70 (m, 2 H), 9.08 (d, J = 9 Hz,1 H), 9.75 (m, lH),10.35 (m, 2H),14.80 (br.s,1H).

CA 02237997 1998-0~

Fxamp/e 60 (1 S,2S)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(benzyl)-cyclohexane-1,2-diamine hydrochloride (1 :Z) 0.3 g of N-(7-chloro-~uinolin-4-yl) -cyclohexane- 1,2-diamine and 0.13 ml of benzaldehyde are stirred at 20~C in 3 ml of ethanol for 3 hrs. The solvent is evaporated in order to complete the reaction. The resulting Schiffls base is again 0 dissolved in 3 ml of ethanol, cooled in ice ander argon and then treated portionwise with 0.3 g of sodium borohydride and stirred without cooling for a further 20 hrs. Excess reducing agent is decomposed by the addition of 3 ml of acetone. Thereafter, the mixture is diluted with 30 ml of 0.3N NaOH and extracted twice with 30 ml of dichloromethane each time. The crude product obtained from these extracts is purified by flash chromatography on silica gel with ethyl acetate and ethyl acetate/methanol 5:1.
The purified product is converted into the hydrochloride with ethanolic hydrochloric acid and precipitated by dilution with 20 2-butanone. Yield: 260 mg (54%), m.p. >200~C (dec.).
ISP mass spectrum: peaks inter alia at 366 ~M+H+); 1H-NMR in DMSO-d6, ~ (ppm): 1.25-2.40 (m, 8H), 3.75 (m,1 H), 4.30 (m, 3H), 7.18 (d, J = 7, 2H), 7.37 (m,3H),7.54 (m, 2H), 7.78 (dd, J = 2 Hz and 9 ~Iz, lH), 8.10 (d, lH, J = 2Hz, lH),8.62 (d, J = 7 Hz, lH), 8.88 zs (d, J = 9 Hz, lH), 9.40 (m,lH).

The following compounds are obtained in an analogous manner using the correspondingly substituted benzaldehydes:

3 0 Example 61 ( t S,2S)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-chloro-benzyl)-cycl ohexane- 1,2-diamine dihydrochloride 35 M.p. 210~C (from EtOH/2-butanone); El mass spectrum: fragments at 399 (M+), 274; lH-NMR in DMSO-d6, ~ (ppm): 1.25-2.~0 (m, 8H), 3.75 (m,1 H), 4.30 (m, 3H),7.12 (d, J = 7,2H), 7.43 (d, J = 8.4,2H), 7.59 ~d, J = 8.4, 2H), 7.76 (dd, J = 2 Hz and 9Hz,1 H), 8.09 (d, J =
4 ~

WO 97/18193 PCT/EP~61'~1866 2Hz,1 H), 8.S9 (d, J = 7 Hz,1 H,),8.87 (d, J = 9 Hz,1 H), 9.32 (m, lH).

Examp/e 6Z
(1 S,2S)-N 1 -(7-Chloro-quinoiin-4-yl)-N2-(2,4-dichloro-benzyl)-cyclohexane-1,2-diamine dihydrochloride M.p. 204-220~C (from EtOH/2-butanone); ISP mass spectrum:
0 peaks at 434 (M+H+~; 1H-NMR in DMSO-d6, ~ (ppm): 1.25-2.40 (m, 8H), 3.83 (m,1 H),4.27 (s, 2H),4.40 (m,1 H), 7.12 (d, J = 7 Hz, 2H), 7.43 (dd, J = 2.1 Hz and 8.3 Hz,1 ~1), 7.60 (d, J = 2.1 Hz,1 H), 7.75 (dd, J = 2 Hz and 9 Hz,1 H),7.80 (d, J =8.3 Hz,1 H), 8.14 (d, J = 2 Hz,1 H), 8.60 (d, J c 7 Hz, lH), 8.93 (d, J = 9 Hz,1 H), 9.50 (m, lH~.

Example 63 (1 S,2S)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(3,4-dichloro-benzyl)-20 cyclohexane-1,2-diamine dihydrochloride M.p.: dec. from 210~C (from EtOH/2-butanone); El mass spectrum:
fragments at 433 (M ', 8%), 274 (100%),179 (45%),159 (38%); ISP
mass spectrum: peaks at 434 (M+H+);lH-NMR in DMSO-d6, â (ppm):
25 1.25-2.40 (m, 8H), 3.75 (m, 2H), 4.30 (m, 2H), 7.14 (d, J = 7Hz, 2H), 7.58 (m,1 H),7.64 (m,1 H), 7.78 (dd, J = 2 Hz and 9 Hz,1 H), 7.93 (d, J = ZHz,1 H), 8.1 Z (d, J = 2 Hz,1 H), 8.60 (d, J = 7 Hz,1 H), 8.92 (d, J = 9Hz,1 H), 9.30 (m, 2H),9.50 (d, J - 8 Hz,1 H),10.25 (m, 1 H),14.55 (br.s,1 H).
Fxamp/e 64 (1 S,2S)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(2,4-bis-trifluoro-- methyl-benzyl)-cyclohexane-1,2-diamine dihydrochloride M.p. from 185~C (from ~tOH/2-butanone); dec.; ISP mass spectrum:
peaks at 502 (M+H+); lH-NMR in DMSO-d6, ~ (ppm): 1.25-2.40 (m, 8H), 3.2-3.7 (m, 2H), 4.27 (m,3H), 4.40 (m,1 H), 7.12 ~d, J = 7Hz, ~3 CA 02237997 l998-05-l5 WO 97/18193 PCT/E~G/0 186G
2H), 7.73 (dd, J = 2 Hz and 9 Hz, lH), 7.93 (m, 2H), 8.10 (m, 2H), 8.57 (d, J - 7 Hz,1 H), 8.82 (d, J = 9,1 H), 9.36 (m, 1 H).

Example 65 (1 S,2S)-Nl-(7-Chloro-quinolin-4-yl)-N2-(3,4,5-trimethoxy-benzyl)-cyclohexane-1,2-diamine dihydrochloride M.p. >250~C (from EtOH/2-butanone); ISP mass spectrum: peaks at 0 456 (M+H~); 'H-NMR in DMSO-d6, ~ (ppm): 1.25-2.40 (m, 8H), 3.60 (s, 3H), 3.70 (s, 6H), 3.75-4.50 (m, 4H), 6.97 (s, 2H), 7.14 (d, J =
7Hz, 2H), 7.74 (dd, J - 2 Hz and 9 Hz, lH), 8.14 (d, J = 2 Hz, lH), 8.61 (d, J = 7 Hz,1 H), 8.94 (d, J = 9 Hz,1 H), 9.48 (m,1 H) s Example 66 (1 S,2S)-N 1 -(7-Chloro-quinolin-4-yl)-N2-(4-dimethylamino-benzyl)-cyclohexane-1,2-diamine dihydrochloride 20 M.p. 220-223~C (from EtOH/Et20); ISP mass spectrum: peaks at 409 (M+H~, 50%), 276 (70%),134 (100%); 1H-NMR in DMSO-d6l ~
(ppm): 1.25-2.40 (m, 8H), 2.90 (s, 6H), 3.60 (m, 2H), 4.18 (m, 2H), 4.32 (m,1 H), 6.85 (m, 2H), 7.14 (d, J = 7Hz, 2H), 7,38 (d, J = 8 Hz, 2H), 7.78 (dd, J = 2 Hz and 9 Hz,1H) 8.12 (d, J = 2 Hz,1H), 8.61 (m, 25 1 H), 8.91 (d, J = 9Hz,1 H), 9.05 (m,1 H), 9.45 (d, J = 8 Hz,1 H), 9.75 (m,1 H),14.55 (br.s,1 H).

Fxample 67 30 (1 S,ZS)-N1 -(7-Chloro-quinoiin-4-yl)-N2-(4-cyano-benzyl)-cyclohexane-1,2-diamine dihydrochloride M.p. 2Z6-230~C (from EtOH/Et2O); ISP mass spectrum: peaks at 391 (M+H~,100%), 276 (33%); l H-NMR in DMSO-d6, ~ (ppm): 1.25-35 2.40 (m, 8H), 3.71 (m,1 H), 4.25-4.40 (m, 3H), 7.16 (d, J = 7Hz, 2H), 7.77-7.81 (m, 3H), 7.88 (d, J = 8 Hz, 2H), 8.08 (d, J = 2 Hz, 1 H), 8.62 (d, J = 7 Hz, 1 H), 8.86 (d, J = 9Hz,1 H), 9.41 (d, J = 8 Hz, lH), 9.50 (m, lH),10.5 (m 1 H),14.40 (br.s, lH).

CA 02237997 1998-0~

~xample 68 cis-N 1 -(7-Chloro-quinolin-4-yl)-N3-(4-chloro-benzyl)-5 cyclopentane-1,3-diamine dihydrochloride 0.24 g of cis-N-(7-chloro-quinolin-4-yl)-cyclopentyl-1,3-diamine and 0.21 g of 4-chloro-benzaldehyde are boiled ander reflux in 50 ml of ethanol overnight. After evaporation of the o solvent the residue]is again taken up in 50 ml of ethanol, 0.1 g of sodium borohyride is added thereto and the mixture is left to react at room temperature for 6 hrs. The excess sodium borohydride is then decomposed by the dropwise addition of 5 ml of glaciai acetic acid and the solvent is evaporated. After the addition of 10 ml of methanoi the mixture is again evaporated.
Addition of methanol and evaporation are repeated once more.
The residue is thereafter purified by chromatography on 30 ~ of silica gei with a mixture of dichloromethane and methanol (in the ratio by volume 10:1). The product-containing fractions are 20 combined and evaporated, and the residue is taken up in 5 ml of ethanol. After the addition of 5 ml of 3N isopropano~ic hydrochloric acid the hydrochloride of the product separates and is recrystallized from ethanol/diethyl ether.

zs Yield: 0.55 g (78%) of colourless crystalline cis-N1-(7-chloro-quinolin-4-yl)-N3-(4-chloro-benzyl)-cyclopentane-1,4-diamine dihydrochloride; m.p 191-193~C (from EtOH/Et20).
El mass spectrum with peaks at 385 (M~, 38%), 246 (92%), 205 (98%),178 (44%),125 (100%); lH-NMR in DMS0-d6, ~ (ppm):
30 2.00-2.30 (m, 5H), 2.55-2.65 (m,1 H), 3.34 (m, 2H), 3.58 (m,1 H), 4.20 (s, 2H), 4.36 (m,1 H), 6.91 (d, J = 7Hz, l H), 7.53 (d, J = 8 Hz, 2H), 7.66 (d, J = 8 Hz, 2H),7.75 (dd, J = 2 and 9 Hz,1 H), 8.06 (d, J
= 2 Hz, lH),8.60 (d, J = 7 Hz, lH), 9.06 (d, J = 9Hz, lH), 9.50 (m, 1 H), 9.90 (m,1 H),14.30 (br.s,1 H).

~5 CA 02237997 1998-0~
WO 97/18193 PCT/I~r~/O ~8~;6 Example 69 cis-N1 -(7-Chioro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane-1,4-diamine trihydrochloride 1 g of cis-N-(7-chloro-quinolin-4-yl)-cyclohexyl-1,4-diamine and 0.54 g of 4-dimethylamino-benzaldehyde are boiled on a water separator in 50 ml of toluene overnight. After evaporation of the toluene the residue is taken up in 20 ml of 0 ethanol and 5 ml of dichloromethane, 0.13 g of sodium borohydride is added thereto and the mixture is left to react at room temperature for 6 hours. The excess sodium borohydride is decomposed with 2.5 ml of glacial acetic acid and the solvent is evaporated. After the addition of 10 ml of methanol the mixture 15 iS again evaporated. Addition of methanol and evaporation are repeated once. The residue is thereafter purified by chroma-tography on 50 g of silica gel with a mixture of dichloromethane, methanol and water (in the ratio by volume 8:3:0.6). The product-containing fractions are combined and evaporated, and the residue 20 is taken up in 5 ml of ethanol. After the addition of 5 ml of 3N
isopropanolic hydrochloric acid the hydrochloride of the product separates and is recrystallized from ethanol/diethyl ether.

Yield: 1.5 g (80%) of colourless crystalline trihydrochloride; m.p.
25 228~C. ISP mass spectrum: peaks at 409 (M+H+, 100%), 276 (75%), 134 (76%); 1H-NMR in DMSO-d6, ~ (ppm): 1.70-2.20 (m, 8H), 2.97 (s, 3H), 3.17 (m, 1 H), 4.09 (m, 3H3, 6.92 (d, J = 7Hz, 1 H), 7.05 (m, 2H), 7.57 (m, 2H), 7.78 (dd, J = 2 and 9 Hz, 1H), 8.14 (d, J = 2 Hz, lH), 8.59 (d, J = 7 Hz, 1 H), 8.71 (m, 1 H), 8.90 (d, J = 9Hz, 1 H), 9.35 (m, 30 2H), 14.65 (br.s, lH).

The following compounds are obtained in an analogous manner using the correspondingly substituted benzaldehydes:

L~
-CA 02237997 1998-0~

Example 70 cis-N1-(7-Chloro-quinolin-4-yl)-N4-(benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 68%; m.p. >250~C (from EtOH/EtzO); ISP mass spectrum:
peaks at 366 (M+H+, 100%), 276 (85%); ~H-NMR in DMS0-d6, ~
(ppm): 1.68-1.84 (m, 2H),1.90-2.30 (m, 6H), 3.20 (m, 1 H), 4.08 (m, 1 H), 4.18 (m, 2H), 6.93 (d, J = 7Hz,1 H), 7.40-7.50 (m, 3H), 7.60-10 7.70 (m, 2H), 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.1Z (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz,1 H), ~.69 (m,1 H), 8.89 (d, J = 9Hz,1 H), 9.44 ( m, 2H), 9.32 (m,1 H),14.53 (s, lH).

Fxamp/e 7 1 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(3-chloro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 70%; m.p. 198-200~C (from EtOH/Et20); ISP mass spectrum:
20 peaks at 400 (M~H+, 100%), 276 (62%); lH-NMR in DMS0-d6, ~
(ppm): 1.70-2.24 (m, 8H), 3.25 (m,1 H), 4.08 (m,1 H), 4.21 (m, 2H), 6.92 (d, J = 7Hz,1 H), 7.45-7.53 (m, 2H), 7.61-7.67 (m,1 H), 7.78 (dd, J = 2 and 9 Hz, lH), 7.80 (m, lH), 8.13 (d, J = 2 Hz, lH), 8.59 (d, J = 7 Hz,1 H), 8.70 (m,1 H), 8.89 (d, J = 9Hz,1 H), 9.56 (m, 2H), 25 14.60(br.s,1H).
Fxamp/e 72 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(4-chloro-benzyl)-30 cyclohexane-1,4-diamine dihydrochloride Yield 39%; m.p. 190-195~C (from EtOH/Et20); ISP mass speetrum:
peaks at 400 (M~H+,100%), 276 (90%),125 (100%); 1 H-NMR in :)MS0-d6, ~ (ppm): 1.70-2.23 (m, 8H), 3.16 (m,1 H), 4.08 (m,1 H), 35 4.18 (m, ZH), 6.90 (d, J = 7Hz,1 H), 7.51 (d, J = 8 Hz, 2H), 7.71 (d, J = 8 Hz, 2H), 7.77 (dd, J = 2 Hz and 9 Hz, lH), 8.18 (d, J = 2 Hz, 1 H), 8.58 (d, J = 7 Hz,1 H), 8.73 (m,1 H), 8.92 (d, J = 9Hz,1 H), 9.65 (m, 2H),14.83 (s,1 H).
~7 WO 97/18193 PCT/EP96rO4866 Example 73 cis-N 1 -(7-Chloro-quino~in-4-yl)-N4-(2,4-dichloro-benzyl)-5 cyclohexane-1,4-diamine dihydrochloride Yield 55%; m.p. 204-205~C (from EtOH/~t20); lSP mass spectrum:
peaks at 434 (M+H+,100%),159 (25%); lH-NMR in DMS0-d6, ~
(ppm): 1.74-2.25 (m, 8H), 3.34 (m,1 H), 4.10 (m,1 H), 4.30 (m, 2H), 10 6.95 (d, J - 7Hz,1 H), 7.57 (dd, J = 2 and 8 Hz,1 H), 7.76 (d, J = 2Hz, lH), 7.79 (dd, J = 2 and 9 Hz, lH), 7.92 (d, J = 8 Hz, IH), 8.12 (d, J = 2 Hz, 1 H), 8.59 (d, J = 7 Hz,1 H), 8.70 (m,1 H), 8.88 (d, J = 9Hz, lH), 9.55 (m, 2H),14.53 (br.s, lH).

Exam,c~le 74 cis-N 1 -(7-Chioro-quinolin-4-yl)-N4-(3,4-dichloro-benzyl~-cyclohexane-1,4-diamine dihydrochloride 20 Yield 35%; m.p. 212~C (from EtOH/Et20); lSP mass spectrum: peaks at 434 (M~H+, 100%), 276 (68%), 159 (86%); lH-NMR in DMS0-d6, ~
(ppm): 1.72-2.25 (m, 8H), 3.24 (m, 1H), 4.07 (m, lH), 4.21 (m, 2H), 6.92 (d, J = 7Hz,1 H), 7.67 (dd, J = 1.5 and 8 Hz, 1 H), 7.73 (d, J = Hz, 1 H), 7.7.9 (dd, J = 2 and 9 Hz,1 H), 8.02 (d, J = 1.5 Hz, 1 H), 25 8.12 (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz, 1 H), 8.72 (m,1 H), 8.89 (d, J = 9Hz, 1 H), 9.60 (m, 2H),14.57 (br.s, l H).

Example 75 30 cis-N1-(7-Chloro-quinolin-4-yl)-N4-(3,5-dichloro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 16%; m.p. 204-205~C (from EtOH/Et20); lSP mass spectrum:
peaks at 434 (M+H+, 100%); lH-NMR in DMS0-d6, ~ (ppm): 1.72-2.23 35 (m, 8H), 3.26 (m,1 H), 4.08 (m, 1 H), 4.22 (m, 2H), 6.93 (d, J - 7Hz, 1 H), 7.6g (m, 1 H), 7.77-7.83 (m, 3H), 8.10 (d, J = 2 Hz,1 H), 8.60 ~d, J = 7 Hz,1 H), 8.70 (m, l H), 8.88 ~d, J = 9Hz,1 H), 9.55 (m, 2H), 14.47 (br.s, 1 H).

4g CA 02237997 1998-0~

Example 76 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(4-chloro-3-fluoro-benzyl)-5 cyclohexane-1,4-diamine dihydrochloride Yield 70%; m.p. 158~C (from EtOH/i-PrOH); ISP mass spectrum:
peaks at 418 (M+H+,100%), 276 (88%),143 (61%); 'H-NMR in DMSO-d6, ~ (ppm): 1.70-1.85 (m, 2H),1.90-2.20 (m, 6H), 3.11 (m, 0 1 H), 4.06 (m,1 H), 4.22 (m, 2H), 6.92 (d, J = 7Hz,1 H), 7.53 (m, 1 H), 7.69 (t, J = 8 Hz,1 H), 7.76-7.86 (m, ZH), 8.11 (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz,1 H), 8.68 (m,1 H), 8.87 (d, J = 9Hz,1 H), 9.60 (m, ZH),14.50 (br.s,1 H).
Example 77 cis-N1 -(7-Chloro-quinolin-4-yl)-N4-(3,5-bis-trifluoromethyl-benzyl)-cyclohexane-1,4-diamine dihydrochloride zo Yield 41%; m.p. Z15~C (from EtOHJEt20); ISP mass spectrum: peaks at 502 (M+H+, 67%), Z76 (100%); ~ H-NMR in DMSO-d6, â (ppm):
1.75-Z.25 (m, 8H), 3.36 (m,1 H), 4.09 (m,1 H), 4.43 (m, 2H), 6.94 (d, J = 7Hz, lH), 7.80 (dd, J = 2 and 9 Hz,1 H), 8.13 (d, J = 2 Hz, 1 H), 8.19 (m,1 H), 8.48 (m, ZH), 8.60 (d, J = 7 Hz,1 H), 8.76 (m,1 H), 25 8.89 (d, J = 9Hz,1 H), 9.70 (m, 2H),14.60 (br.s,1 H).
~xample 78 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(2-hydroxy-benzyl)-30 cyclohexane-1,4-diamine dihydrochloride Yield 9Z%; m.p. Z00-202~C (from EtOH/Et20); ISP mass spectrum:
peaks at 382 (M+H+,100%); lH-NMR in DMSO-d6, â (ppm): 1.72-Z.24 (m, 8H), 3.21 (m, lH), 4.11 (m, 3H), 6.85 (t, J = 8 Hz, lH), 6.95 (d, 35 J = 7Hz,1 H), 7.00 (d, J = 8 Hz,1 H), 7.Z4 (dt, J = Z and 8 Hz, 1 H), 7.49 (dd, J = Z and 8 Hz,1 H), 7.80 (dd, J = Z and 9 Hz,1 H), 8.13 (d, J = Z Hz,1 H), 8.59 (d, J = 7 Hz,1 H), 8.69 (m,1 H), 8.88 (d, J = 9Hz, 1 H), 9.00 (m, 2H),10.27 (s,1 H),14.55 (br.s,1 H).

WO 97/18193 PC'r/EP96/04866 Example 79 cis-N 1 -(7-t::hloro-quinolin-4-yl)-N4-(2-hydroxy-4-methoxy-5 benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 75%; m.p. 200~C (from EtOH/Et20); ISP mass spectrum: peaks at 412 (M+H+,100%); ~ H-NMR in DMSO-d6, ~ (ppm): 1.70-2.22 (m, 8H), 3.14 (m,1H), 3.71 (s, 3H), 4.04 (m, 3H), 6.46 (dd, J = 2 and 10 8 Hz,1 H), 6.54 (d, J = 2 Hz,1 H), 6.94 (d, J = 7 Hz,1 H), 7.37 (d, J = 8 Hz,1H), 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.13 (d, J = 2 Hz, 1 H), 8.60 (d, J = 71 Iz, 1 H), 8.70 (m,1 H), 8.86 (d, J = 9 Hz,1 H), 8.88 (m,1 H),10.30 (s,1 H),14.53 (br.s,1 H).

Example 80 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(2-hydroxy-5-methoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride 20 Yield 86%; m.p. 180-185~C (from EtOH/Et20); ISP mass spectrum:
peaks at 412 (M+H+, 4%), 269 ( 49%),187 (83%),165 (100%);
~H-NMR in DMSO-d6, ~ (ppm): 1.70-2.25 (m, 8H), 3.21 (m, lH), 3.70 (s, 3H), 4.09 (m, 3H), 6.80-6.92 (m, 3H), 7.16 (d, J = 2 Hz,1 H), 7.80 (dd, J = 2 Hz and 9 Hz,1 H), 8.09 (d, J = 2 Hz,1 H), 8.59 (d, 2s J = 7 Hz,1 H), 8.61 (s,1 H), 8.85 (d, J = 9Hz,1 H), 9.02 (m, 2H), 9.75 (m, lH),14.45 (br.s, lH).

Fxample 8 1 30 cis-N1-(7-Chloro-quinolin-4-yl)-N4-(2,4-dimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 87%; m.p. >250~C (from EtOH/Et20); ISP mass spectrum:
p~aks at 426 (M+H+,100%), 276 (54%),187 (55%),165 (60%),151 35 (49%); 1H-NMR in DMSO-d6, ~ (ppm): 1.70-2.20 (m, 8H), 3.08 (m, 1 H), 3.79 (s, 3H), 3.83 (s, 3H), 4.05 (m, 3H), 6.59 (dd, J = 2 and 8 Hz,1 H), 6.64 (d, J = 2 Hz,1 H), 6.92 (d, J = 7Hz,1 H), 7.44 (d, J = 8 Hz, 2H), 7.80 (dd, J = 2 Hz and 9 Hz, lH), 8.12 (d, J = 2 Hz, CA 02237997 1998-0~
WO 97/18193 PCT/EP~6/01866 1 H), 8.59 (d, J = 7 Hz,1 H), 8.73 (m,1 H), 8.88 (d, J = 9Hz, ~ H), 8.92 (m, 2H),14.52 (s, lH).

Example 8Z

cis-N1 -(7-Chloro-quinoiin-4-yl)-N4-(3,5-dimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 67%; m.p. 197-198~C (from EtOH/i-PrOH); ISP mass o spectrum: peaks at 426 (M+H+,100%), 276 (90%),151 (93%);
H-NMR in DMSO-d6, ~ (ppm): 1.70-2.23 (m, 8H), 3.20 (m,1 H), 4.11 (m, 3H), 6.53 (t, ~ = 2 Hz,1 H), 6.69 (d, J = 2 Hz, 2H), 6.93 (d, J = 7 Hz,1 H), 7.80 (dd, J = 2 and 9 Hz,1 H), 8.11 (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz,1 H), 8.71 (m,1 H), 8.89 (d, J = 9Hz,1 H), 9.44 (m, 2H),14.50 (br.s,1 H).
Fxamp/e 83 cis-~ 1 -(7-Chloro-quinolin-4-yl)-N4-(4-methylsulphanyl-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 83%; m.p. 181-182~C dec. (from EtOH/Et20); ISP mass spectrum: peaks at 412 (M+H+, 100%), 276 ( 26%); 'H-NMR in DMSO-d6, ~ (ppm): 1.68-1.85 (m, 2H),1.90-2.25 (m, 6H), 3.19 (m, lH), 3.34 (s, 3H), 4.08 (m,1 H), 4.14 (m, 2H), 6.92 (d, J = 7Hz,1 H), 7.31 (d, J = 8 Hz, 2H), 7.57 (d, H = 8 Hz, 2H), 7.79 (dd, J = 2 Hz and 9 Hz,1 H), 8.10 (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz,1 H), 8.64 (m, 1 H), 8.87 (d, J = 9Hz,1 H), 9.38 (m, 2H),14.50 (br.s,1 H).
Fxample 84 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(4-nitro-benzyl)-cyclohexane-1,4-diamine dihydrochioride 35 Yield 52%; m.p. >260~C (from EtOH/Et20); ISP mass spectrum:
peaks at 411 (M+H+,100%), 276 (25%); 1H-NMR in DMSO-d6, ~
(ppm): 1.70-2.24 (m, 8H), 3.25 (m,1 H), 4.09 (m,1 H), 4.34 (m, 2H), 6.92 (d, J = 7Hz,1 H), 7.80 (dd, J = 2 Hz and 9 Hz,1 H), 7.94 (d, J = 8 Hz, 2H), 8.10 (d, J = 2 Hz,1 H), 8.31 (d, J = 8 Hz, 2H), 8.59 (d, J = 7 Hz,1 H), 8.70 (m,1 H), 8.88 (d, J = 9Hz,111), 9.64 (m, 2H), 14.45 (br.s,1 H).
s Example 85 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(4-diethylamino-benzyl)-cyclohexane-1,4-diamine trihydrochloride 0 Yield 52%; m.p. >260~C (from EtOH/Et2O); ISP mass spectrum:
peaks at 411 (M~H+,100%~, 276 (25%); 1H-NMR in DMSO-d6, ~
(ppm): 1.70-2.24 (m, 8H), 3.25 (m,1 H), 4.09 (m,1 H), 4.34 (m, 2H), 6.92 (d, J = 71 Iz,1 H), 7.80 (dd, J = 2 Hz and 9 Hz,1 H), 7.94 (d, J = 8 Hz, 2H), 8.10 (d, J = 2 Hz,1 H), 8.31 (d, J = 8 Hz, 2H), 8.59 (d, J = 7 Hz, 1 H), 8.70 (m,1 H), 8.88 (d, J = 9Hz,1 H), 9.64 (m, 2H), 14.45 (br.s,1 H).
Example 86 20 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(4-cyano-benzyl)-cyclohexane-1,4-diamine dihydrochloride Yield 60%; m.p. >250~C (from EtOH/i-PrOH); ISP mass spectrum:
peaks at 391 (M+H+,100%); lH-NMR in DMSO-d6, ~ (ppm): 1.71-1.87 25 (m, 2H),1.92-2.25 (m, 8H3, 3.22 (m,1 H), 4.08 (m,1 H), 4.29 (m, 2H), 6.93 (d, J = 7Hz,1 H), 7.79 (dd, J = 2 Hz and 9 Hz,1 H), 7.89 (d, J = 8 Hz, 2H), 7.94 (d, J = 8 Hz, 2H), 8.13 (d, J = 2 Hz,1 H), 8.59 (d, J = 7 Hz,1 H), 8.70 (m,1 H), 8.89 (d, J = 9Hz,1 H), 9.71 (m, 2H), 14.56 (br.s,1 H) .
Example 87 cis-N 1 -(7-Chloro-quinolin-4-yl)-N4-(biphenyl-4-yl-methyl)-cyclohexane-1,4-diamine dihydrochloride Yield 86%; m.p. 210-212~C (from E~OH/Et20); ISP mass spectrum:
peaks at 442 (M+H+, 100%),167 (55%); 1H-NMR in DMSO-d6, ~
(ppm): 1.70-1.86 (m, 2H),1.g3-2.30 (m, 6H), 3.25 (m~ 1 H), 4.08 (m, ~2 CA 02237997 1998-0~
WO 97/18193 PCT/Er~)6/0~86C
1 H), 4.23 (m, 2H), 6.93 (d, J = 7Hz, 1 H), 7.40 (m, 1 H), 7.49 ~m, 2H), 7.60-7.83 (m, 7H), 8.13 (d, J = 2 Hz, lH), 8.60 (d, J = 7 Hz, lH), 8.71 (m, 1 H), 8.91 (d, J = 9Hz, 1 H), 9.50 (m, 2H), 14.56 (br.s, 1 H).

Example 88 trans-N~ -(7-Chloro-quinolin-4-yl)-N4-[2-(3 ,4-dimethoxy-pheny~)-ethyl]-cyclohexane-1,4-diamine dihydrochloride 0 275 mg 4-(7-chloroquinolin-4-ylamino)-cyclohexanone (see Example 124) and 181 mg of homoveratrylamine are boiled at reflux for 3 hours in 5 ml of ethanol in the presence of molecular sieve. The solution, which is cooled and freed from the molecular sieve, is concentrated to dryness. The residue is again taken up in 5 ml of ethanol and treated under argon at +5~C with 37 mg of sodium borohydride. After 1 hour the mixture is concentrated and the residue is suspended in dichloromethane.
The excess reducing agent is decomposed by the addition of 2 ml of 3N sodium hydroxide solution. The mixture is diluted with zo water and the dichloromethane is separated. The dried organic phase is concentrated. The residue is chromatographed on silica gel with dichloromethane/methanol (3:1). The free base obtained is crystallized as the dihydrochloride by treatment with 3 N
hydrochloric acid in methanol. Yield: Z80 mg (54%) of white 25 crystals, m.p. 210~C.

ISP mass spectrum: peaks at 440.5 ((M+H)+, 23%), 276.4 (75%), 221 (1 oo1 H NMR of the free base in CDCI3 d (ppm): 1.32 (br, 5H), 2.06 (br,2H), 2.23 (br,2H), Z.55 (br,lH), 2.77 (m,2H), 2.91 (m, 2H), 30 3.87 (s, 1 H), 3,88 (s,1 H), 4.80 (d, 1 H), 6.42 (d, J = 6Hz, 1 H), 6.78 (m, 3H), 7.35 (dd, J = 2 and 9Hz, 1 H), 7.61 (d, J = 9Hz, 1 H), 7.94 (d, J = 2Hz, 1 H), 8.52 (d, J = 6Hz).

CA 02237997 1998-0~

Fxample 89 trans-N,-(7-Chloro-quinoiin-4-yl)-N4-phenethyl-cyclohexane-1,4-diamine dihydrochloride Analo~ously to Exampie 88 using phenethylamine. Yield: 23% of white crystals (from ethanol/ether). Dec. from 210~C.

ISP mass spectrum: peaks at 380 ((M+H)+, 35%), 276 (100%); 1 H
o NMR in DMSO-d6, ~ (ppm): 1.65 (m, 4H), 2.05 (br, 2H), 2.25 (br, 2H), 3.09 (br, 5H), 3.90 (br,1 H),7.05 (d, J - 7Hz,1 H), 7.31 (m,5H), 7.75 (dd, J = 2 and 7.5Hz,1 H), 8.13 (d, J = 2Hz,1 H),8.53 (d, J =
7Hz, l H),8.84 (d, J = 7.5Hz,1 H), 9.15 (d, J = 9Hz,1H), 9.46 (br, 2H),14.6 (br, l H).
1 s Example 90 trans-N1 -(7-Chloro-quinolin-4-yl)-N4-(3,5-dimethoxy-phenyl)-cyclohexane-1,4-diamine hydrochloride 20 Analogously to Example 88 using 3,5-dimethoxyaniline and 72 hours reflux for imine formation. Yield: 8%, Dec. 204~C.
El mass spectrum: peaks at 411 (M+,100%), 258 (35%),1 g2 (30%);
1 H NMR of the free base in C{~CI3 ~ (ppm): 1.66 (br, 4H), Z.05 (br, 4H),3.40 (br,1 H), 3.70 (br,1 H), 3.75 (s, 6H),3.85 (br, l H), 6.52 25 (br,3H), 7.04 (d, J = 7.5 Hz,1 H), 7.76 (dd, J = 2 and 9Hz, l H), 8.10 (d, J = 2Hz, lH), 8.51 (br,lH),8.81 (d, J = 9Hz, lH), 9.09 (d, J =
7.5Hz, l H),14.4 (br,1 H).
Fxample 97 30 trans-Nl-(7-Chloro-quinolin-4-yl)-N4-[Z-(2,4-dichloro-phenyl)-ethyl~-cyclohexane- l ,4-diamine dihydrochloride Analogously to Example 88 using 2,4-dichlorophenethylamine.
Yield: 35% of white crystals (from methanol/ether), dec. 230~C.
35 ISP mass spectrum: peaks at 448 ((M+H)+,100%); 1 H NMR of the free base in CDC13 ~ (ppm): 1.25 (br,4H), 1.75 (br, 1 H), 2.15 (br, 2H), 2.24 (br, 2H), 2.60 (br, ll{), 2.92 (m, 5H),3.55 (br, lH), 4.85 (d,1 H), 6.43 (d, J = 5.5Hz,1 H), 7.19 (m,2H), 7.35 (dd, J = 2 and CA 02237997 1998-0~

WO 97/18193 PCT/Er96/0~6 9Hz,1 H), 7.37(d, J = 2Hz,1 H), 7.62 (d, J = 9Hz,1 H), 7.94 (d J = 2Hz, lH),8.51(d, J = 5.5Hz, lH).

Example 89 trans-N 1 -(7-Chloro-quinolin-4-yl)-N4-[2-(4-methoxy-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 4-methoxyphenethylamine. Yield:
0 48% of white crystals (from methanol/ether), m.p. 220~C.

ISP mass spectrum: peaks at 410 ((M+H)+, 100%);1 H NMR of the free base in CDCI3, ~ (ppm): 1.29 (br,5H), 2.05 (br, 2H), 2.22 (br, 2H), 2.55 (br,lH), 2.77 (m,2H), 2.88 (m, 2H),3.50 (br,lH), 3.80 (s, 15 3H), 4.77 (d,1 H), 6.42 (d, J = 5.5 Hz,1 H), 6.85 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5 Hz, 2H), 7.35 (dd, J = 2 and 9 Hz,1 H), 7.61 (d, J =
9 Hz, lH), 7.94 (d, J = 2 Hz, lH), 8.52 (d, J = 5.5 Hz, lH).

Example 93 trans-N1 -(7-Chloro-quinolin-4-yl)-N4-[2-(4-nitro-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 4-nitrophenethylamine. Yield: 50%
z~ of white crystals (from methanol/diethyl ether), m.p. 2050C.
El mass spectrum: peaks at 424 (M+, 8%), 407 (M-OH,100%), 288 (44%), 259 (72%),179 (48%); 1 H NMR of the free base in CDCI3 ~
(ppm) 1.3 (m, 4H), 2.06 (br, 2H), 2.25 (br, 2H), 2.56 (br,1 H), 2.95 (m, 5H), 3.50 (br,1 H), 4.78 (d,1 H), 6.42 (d, J = 5.4 Hz,1 H), 7.38 (m, 30 3H), 7.61 (d, J = 9 Hz,1 H), 7.95 (d, J = 2 Hz,1 H), 8.17 (d, 2H),8.52 (d, J = 5.4 Hz,1 H).

CA 02237997 l99X - 0.7 - 1.7 Fxamp/e 9~

trans-N1 -(7-Chloro-quinolin-4-yl)-N4-~2-(3,5-dimethoxy-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Examp~e 88 using 3,5-dimethoxyphenethylamine.
Yield: 45% of white crystals (from methanol/diethyl ether), m.p.
210~C.

10 El mass spectrum: peaks at 439 (M+, 8%), 288 (100%), 259 (50%), 179 (20%);

1 H NMR of the free base in CDCI3 ~ (pprn): 1.32 (m, 4H), 2.06 (br, 2H), 2.25 (br, 2H), 2.56 (br,1 H), 2.78 (m, 2H), 2.94 (m, 2H), 3.50 (br,1 H), 3.79 (s, 6H), 4.78 (d,1 H), 6.40 (m, 4H), 7.26( dd, J = 2 and 9 Hz, 1 H), 7.61 (d,J = 9Hz,1 H), 7.95 (d, J = 2Hz,1 H), 8.52 (d, J =
5.4 Hz,1 H).

Fxamp/e 9 trans-N1 -(2-Benzo~ 1,3]dioxol-5-yl-ethyl)-N4-(7-chloro-quinolin-4-yl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 3,4-methylenedioxyphenethyl-25 amine. Yield: 59% of white crystals (from methanol/diethyl ether), m.p. 215~C.

El mass spectrum: peaks at 423 (M+, 8%), 388 (M-CI, 8%), 288 (100%), 259 (68%);
1 H NMR of the free base in CDCI3 ~ (ppm): 1.3 (m, SH), 2.06 (br, 2H), 2.25 (br, ZH), 2.56 (br,1 H), 2.74 (m, 2H), 2.87 (m, 2H), 3.48 (br,1 H), 4.78 (d,1 H), 5.94 (s, ZH), 6.43 (d, J = 5.4 Hz,1 H),6.42 (m, 3H), 7.22 (m, 4H), 7.35 (dd, J = 2 and 9 Hz,1 H), 7.61 (d, J = 9 35 Hz,1H), 7.95 (d, J = 2 Hz, lH), 8.52 (d, J = 5.4 Hz, lH).

5~

CA 02237997 1998-0~

Fxamp/e 96 trans-Nl -~2-(3-Chloro-phenyl)-ethyl~-N4-(7-chloro-quinolin-4-yl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2-(3-chlorophenyl)ethylamine.
Yield: 57% of white crystals (from methanol/diethy~ ether), m.p.
249~C.

o El mass spectrum: peaks at 414 (M+, 5%)1 288 (100%), 259 (48%);
1 H NMR of the free base in CDCI3 ~ (ppm): 1.0-1.5 (m, 4H), 2.07 (br, 2H), 2.23 (br, 2H), 2.55 (br,1 H), 2.80 (m, 2H), 2.90 (m, 2H), 3.50 (br,1 H), 4.78 (d,1 H), 6.43 (d, J = 5.4 Hz,1 H), 7.11 (m, 1 H), 7.22 (m, 4H), 7.35 (dd, J = 2 and 9 Hz,1 H), 7.62 (d, J = 9 Hz,1 H), 7.95 15 (d, J = 2 Hz,1 H), 8.52 (d, J = 5.4 Hz,1 H).
Fxample ~7 trans-Nl -(7-Chloro-q~-inolin-4-yl)-N4-[2-(2,5-dimethoxy-phenyl)-20 ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2,5-dimethoxyphenethylamine.
Yield: 46% of white crystals (from me~hanol/diethyl ether), m.p.
227~C.

El mass spectrum: peaks at 439 (M+, 8%), 288 (100%), 259 (84%), 152 (92%);

1 H NMR of the free base in CDCI3 ~ (ppm): 1.Z-1.6 (m,5H), 30 2.08(br,2H), 2.25(br,2H), 2.58(br,1H), 2.84(m,4H), 3.50(br,1H), 3.77(s,3H), 3.79(s,3H), 4.78(d,1 H), 6.43 (d,J=5.4Hz,1 H), 6.77(m,3H), 7.36(dd,J=2 and 91tz,1 H), 7.60(d,J=9Hz,1 H), 7.95(d,J=2Hz,1 H), 8.52(d,J=5.4Hz,1 H).

WO 97/18193 PCT/EP96/'~, 18CG
Fxample 98 trans-N, -(7-Chloro-quinolin-4-yl)-N4-[2-(4-phenoxy-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 4-phenoxyphenethylamine. Yield:
53% of white crystals (from methanol/diethyl ether), m.p. >250~C.

El mass spectrum: peaks at 471 ((M-H)+, 2%), 288 (100%), 259 0 (44%); 1 H NMR of the free base in CDCI3 ~ (ppm): 1.35 (m, 4H), 1.55 (br,1 H), 2.10 (br, 2H), 2.25 (br, 2H), 2.64 (br,1 H), 2.84 (m, 2H), 2.96 (m, 2H), 3.50 (br,1 H), 4.84 (d, 2H), 6.43 (d, J = 5.5,1 H), 6.9-7.4 (m,10 H), 7.72 (d, J = 9,1 H), 7.96 (d, J = 2,1 H), 8.52 (d, J
= 5.4,1 H)-Example 99 trans-NI-(7-Chloro-quinolin-4-yl)-N4-[2-(3,4-dichloro-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride 20 Analogously to Example 88 using 3,4-dichlorophenethylamine.
Yield: 20% of white crystals (from methanol/diethyl ether), m.p.
~250~C.

ISP mass spectrum: peaks at 450.2 ((M+H)+,10%), 276.3 (23%), 25 225.9 (100%); 1 H NMR of the free base in DMS0-d6 ~ (ppm): 1.63 (br, 4H), 2.00 (br, 2H), 2.20 (br, 2H), 3.0-3.4 (m, 5H), 3.8 (br,1 H), 7.06 (d, J = 7 Hz,1 H), 7.28 (dd, J = 2 and 8 Hz,1 H), 7.61 (m, 2H), 7.76 (dd, J = 2 and 10 Hz,1 H), 8.08(d, J = 2 Hz,1 H), 8.54 (d, J = 7 Hz,1 H), 8.76 (d J = 10 Hz,1 H), 9.08 (d, J = 8 Hz, 1 H), 9.34 (br, 2H), 30 14.4 (br,1 H) .
~xample 1 00 trans N1-(7-Chloro-quinolin-4-yl)-N4-(4-methoxy-benzyl)-35 cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 4-methoxybenzylamine. Yield:
20% of beige crystals (from methanol/ether). M.p. >250~C.

CA 02237997 1998-0~,-1~, WO 97/18193 PCT~EP96/04866 ISP mass spectrum: peaks at 396 ((MtH)+, 85 %), 276 (100%); 1H-NMR in DMS0-d6, ~ (ppm): 1.50 (br, 4H), 2.20 (br, 4H), 3.10 (br,1 H), 3.60 (br,1 H), 3.77 (s, 3H), 4.10 (br, 2H), 6.62 (d, J = 7.5 Hz,1 H), 5 7.00 (d, J = 10 Hz, 2H), 7.15 (d,1 H), 7.46 (dd, J = 2 and 12 Hz,1 H), 7.51 (d, J = 10 Hz, 2H), 7.60 (d, J = 2 Hz, lH), 8.37 (d, J = 12 Hz, 1 H), 8.40 (d, J = 7.5 Hz,1 H).

Example 10 1 o trans-N1 -(7-Chloro-quinolin-4-yl)-N4-[2-(2,6-dichloro-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2,6-dichlorophenethylamine. Yield:
38% of white crystals (from methanol-ether). m.p. >250~C.

ISP mass spectrum: peaks at 448 (M+, 35%),276 (35%), 225 (100%); 1 H-NMR of the free base in DMS0-d6, o (ppm): 1.46 (br, 4H), 2.11 (br, 4H), Z.99 (m, 3H),3.21 (br,4H), 3.55 (br, lH), 6.58 20 (d, J = 5.5 Hz,1 H), 7.02 (d,1 H), 7.33 (t, J = 8.5, Hz,1 H), 7.44 (dd, J
= 2 and 9 Hz,1 H), 7.50 (d, J = 8.5 Hz, 2H), 7.77 (d, J = 2 Hz,1 H), 8.35 (d, J = 9 Hz,1 H),8.39 (d, J = 5.5 Hz,1 H).

Fxample 1 02 trans N,-(7-Chloro-quinolin-4-y,)-N4-(3,4-dichloro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 3,4-dichlorobenzylamine. Yield:
30 50% of white crystals (from methanol/ether). M.p.>250~C.

ISP mass spectrum: peaks at 434 (M+, 35%), 276 (100%); 1 H-NMR
of the free base in DMS0-d6, o (ppm): 1.32 (br, 4H),1.98 (br, 4H), 3.40 (br,1 H), 3.80 (s, 2H), 6.53 (d, J = 5.5 Hz,1 H), 6.90 (d,1 H), 35 7.38 (dd, J = 2 and 9.5 Hz, lH),7.41 (dd, J = 2 and 8 Hz, lH),7.58 (d, J = 8 Hz,1 H), 7.66 (d, J = 2 Hz,1 H), 7.76 (d, J = 2 Hz,1 H),8.32 (d, J = 9.5 Hz,1 H), 8.37 (d, J = 5.5 Hz,1 H).

~q Fxample 1 03 trans-N1 -Benzo[1,3 Jdioxol-5-ylmethyl-N4-(7-chloro-quinolin-4-yl)-cyclohexane- 1,4-diamine dihydrochloride Analogously to Example 88 using piperonylamine. Yield: 41~o of white crystals (from methanol/ether). M.p. >250~C.

ISP mass spectrlJm: peaks at 410 ((M+H)+, 35%), 278 (55%), 276 0 (100%); 1 H-NMR of the free base in CDCI3 ~ (ppm): 1.34 (br, 4H), 2.08 (br, 4H), 2.60 (br,1 H), 3.55 (br,1 H), 3,77 (s, 2H), 4.80 (d, 1 H), 5.95 (s, 2H), 6.43 (d, J = 5.5 Hz,1 H), 6.81 (br, 4H), 7.35 (dd, J
= 2 and 9 Hz,1 H), 7.61 (d, J = 9 Hz,1 H), 7.94 (d, J = 2 Hz,1 H), 8.52 (d, J = 5.5 Hz,1 H).

Fxample ? 04 trans-4-{ 2-[4-(7-Chloro-quinolin-4-ylamino)-cyclohexylamino]-ethyl }-2-methoxy-phenol dihydrochloride Analo~ously to Example 88 using 4-hydroxy-3-methoxyphenethyl-amine. Yield: 14% of beige crystals (from methanol/ether). M.p.:
209~C.

25 ISP mass spectrum: peaks at 426 (M+, 100%), 428 (M~2H+, 35%);
1 H-NMR of the free base in DMS0-d6, ~ (ppm): 1.50-2.00 (m, 8H), 2.65 (br, 2H), 2.70-3.00 (m, 3H), 3.60 (br,1 H), 3.74 (s, 3H), 6.50 (d, J = 5.5 Hz, lH), 6.61 (dd, J = 2 and 8 Hz,1H), 6.68 (d, J = 8 Hz, 1 H), 6.78 (d, J - 2 Hz,1 H), 6.85 (d, î H), 7.42 (dd, J = 2 and 9 Hz, 30 IH), 7.76 (d, J = 2 Hz, lH), 8.37 (d, J = 5.5 Hz,1H), 8.40 (d, J = 9 Hz,1 H), 8.72 (s,1 H).

CO~

WO 97/18193 PCT/Er9~ G~
Examp/e 1 05 trans-N1 -(7-Chioro-quinolin-4-yl)-N4-~2-(2,3-dimethoxy-phenyl)-ethyl]-cyclohexane-1,4-diamine dihydrochioride Analogously to Example 88 using 2,3-dimethoxyphenethylamine.
Yield: 25% of beige crystals (from methanol/ether). M~p: 284~C.

ISP mass spectrum: peaks at 440 (M+,100%), 442 (M+2H+, 35%);
0 1 H-NMR of the free base in CDCI3 ~ (ppm): 1.85 (br, 4H), 2.10 (br, 2H), 2.30 (br, 2H), 2,65 (br,1 H), 2.96 (br, 4H),3.49 (br,1 H),3.85 (s, 3H), 3.87 (s, 3H), 4.80 (d,1 H), 6.44 (d, J = 6 Hz,1 H), 6.85 (m, 2H), 7.02 (m,1 H), 7.35 (dd, J = 2 and 10 Hz,1 H), 7.62 (d, J = 10 Hz, lH), 7.95 (d, J = 2 Hz,1H), 8.53 (d, J = 6 Hz, lH).
Example 7 06 trans-N~ -(7-Chloro-quinolin-4-yl)-N4-(3,5-dimethoxy-benzyl)-cyclohexane-1,4-diamine Analogously to Example 88 using 3,5-dimethoxybenzylamine.
Yield: 50% of white crystals (from methylene chloride/ether).
M.p:150~C.

2s ISP mass spectrum: peaks at 426(M+,100%),4Z8 (M+2H+, 55%); 1 H-NMR of the free base in CDCI3, ~ (ppm): 1.33 (br, 4H), 1.99 (br, 4H), 3.45 (br,1 H),3.73 (s, 6H), 3.73 (s, 2H), 6.36 (m,1 H), 6.53 (d, J =
5Hz,1 H), 6.55 (d, 2H), 6.89 (d,1 H), 7.41 (dd, J = 2 and 9 Hz,1 H), 7.76 (d, J = 2 Hz),1 H), 8.31 (d, J = 9 Hz,1 H),8.39 (d, J = 5 Hz,1 H).
Example 1 07 trans-N1 -(3-Chloro-benzyl)-N4-(7-chloro-quinolin-4-yl)-cyclohexane-1,4-diamine dlhydrochloride Analogously to Example 88 using 3-chlorobenzylamine. Yield: 50%
of white crystals (from methanol/ether). M.p. > 280~C.

~1 WO 97/18193 PCT/EP~G;II 1~66 ISP mass spectrum: peaks at 400 (M+, 100%), 40Z (M+2H+, 90%);
1 H-NMR of the free base in CDCI3, ~ (ppm): 1.25 (m, 4H), 2.08 (br, 2H), 2.23 (br, 2H), 2.60 (br,1 H), 3.49 (br,1 H), 3.83 (s, 2H), 4.90 (d, lH), 6.44 (d, J = 5.5 Hz, lH), 7.25 (m, 3H), 7.35 (m, lH), 7.35 (dd, J
s = 2 and 9 Hz, lH), 7.62 (d, J = 9 Hz, lH), 7.95 (d, J = Z Hz, lH), 8.51 (d, J = 5.5 Hz,1 H) .

Fxample 1 08 10 trans Nl-(7-Chloro-quinolin-4-yl)-N4-(2,4,6-trimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2,4,6-trimethoxybenzylamine.
Yield: 26% of white crystals (from methanol/ether). M.p. 271~C.
ISP mass spectrum: peaks at 456 ~M+,100%), 458 (M+2H+, 35%);
1 H-NMR of the free base in CDCI3, ~ (ppm): 1.32 (br, 4H), 2.08 (br, 2H), 2.Z5 (br, 2H~, 2.48 (br,1 H), 3.48 (br,1 H), 3.81 (s, 9H), 3.81 (s, 2H), 4.78 (d,1 H), 6.13 (m, 3H), 6.44 (d, J - 5.5 Hz,1 H), 7.34 (dd, J
20 = 2~rid 9 #z,11~3, 7.60 (d, J' = 9 Hz, lH), 7.94~d, i - 2~1z, lH), 8.51 (d, J = 5.5 Hz,1 H).
ExampJe 1 09 trans-Nl -(7-Chloro-quinolin-4-yl)-N4-(2,4-dichloro-benzyl)-25 cyclohexane- 1,4-diamine dihydrochloride Analogously to Example 88 using 2,4-dichlorobenzylamine. Yield 53% of white crystals (from methanol/ether). M.p. 232~C.

30 ISP mass spectrum: peaks at 434 (M+, 100%), 436 ((M+2H)+, 85%);
1 H-NMR of the free base in DMS0-d6, ~ (ppm): 1.23-1.50 (m, 41{), 1.98 (br, 4H), 2.48 (br, 2H), 3.50 (br, 1 H), 3.60 (s, 2H), 6.52 (d, J
= 5.5 Hz,1 H), 6.85 (d,1 H), 7.41 (d, J = 6.5 Hz,1 H), 7.42 (dd, J = 2 and 8.5 Hz,1 H), 7.57 (d, J = 2 Hz,1 H), 7.61 (d, J = 6.5 Hz,1 H), 7.75 35 (d, J = 2 Hz,1 H), 8.33 (d, J = 8.5 Hz,1 H), 8.36 (d, J = 5.5 Hz,1 H).

~2 CA 02237997 1998-0~

~xample 1 70 trans-N, -(7-Chloro-quinolin-4-yl)-N4-(3,4-dimethoxy-benzyl)-cyclohexane-1 ,4-diamine dihydrochloride Analogously to Example 88 using veratrylamine. Yield 22% of white crystals (from methanol/ether). M.p. > 270~C.

ISP mass spectrum: peaks at 426 ((M+H)+, 100%); 1 H-NMR o~ the ~o free base in CDCI3, â (ppm): 1.25-1.50 (m, 4H), 2.10 (br, 2H), 2.28 (br, 2H), Z.60 (br,lH), 3.49 (l~r,lH), 3.80 (s, 2H), 3.87 (s, 3H), 3.90 (s,3H), 4.80 (d,1 H), 6.44 (d, J = 5.5 Hz, 1 H), 6.84 (m, 2H), 6.91 (d, J
= 2 Hz, 1 H), 7.35 (dd, J = 2 and 9 Hz, 1 H), 7.61 (d, J = 9 Hz, lH), 7.95 (d, J = 2 Hz, 1 H), 8.52 (d, J = 5.5 Hz, 1 H).

Fxamp/e 11 1 trans-N1 -(7-Chloro-quinolin-4-yl)-N4-(2,4-dimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2,4-dimethoxybenzylamine. Yield 20% of white crystals (from methanol/ether). M.p. > 270~C.

El mass spectrum: peaks at 426 (M+, 2%), 274 (100%), 151 (90%);
2s 1 H-NMR of the free base in DMSO-d6, ~ (ppm): 1.40 (m, 4H), 2.00 (br, 4H), 2.50 (br, 1 H), 3.48 (br, 1 H), 3.73 (s, 2H), 3.75 (s, 3H), 3.79 (s, 3H), 6.50 (m, 3H), 6.91 (d, lH), 7.24 (d, J = 8 ~z, lH), 7.42 (dd, J = 2 and 9.5 Hz, 1 It), 7.76 (d, J = 2 Hz, 1 H), 8.32 (d, J = 9.5 Hz, 1 H), 8.37 ~d, J = 5 Hz, 1 H).
3~
Examp~e 1 ~ 2 trans-N, -(7-Chloro-quinolin-4-yl)-N4-(3,4,5-trimethoxy-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 3,4,5-trimethoxybenzylamine.
Yield 36% of white crystals(~rom methanol/ether). M.p. >250~C.

~3 iSP mass spectrum: peaks at 456 ((M+H)+, 100%); 1H-NMR of the free base in CDCI3, ~ (ppm): 1.37 (br, 4H), 2.15 (br, 2H), 2.30 (br, 2H), 2.70 (br,1 H), 3.50 (br, 1 H), 3.80 (s, 2H),3.83 (s, 3H), 3.88 (s, 6H), 4.80 (d,1 H), 6.44 (d, J = 5.5 Hz,1 H), 6.58 (s, 2H), 7.35 (dd, J =
5 2 and 10 Hz, lH), 7.62 (d, J = 10 Hz, lH), 7.95 (d, J = 2 Hz, lH), 8.52 (d, J = 5.5 Hz,1 H).

~xample 7 13 0 trans-N1-(7-Chloro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane-1,4-diamine trihydrochloride ~nalogously to Example 88 using 4-dimethylamino-benzylamine.
Yield Z0% of beige crystals (from methanol/ether). Dec. from 240~C.

ISP mass spectrum: peaks at 409 ((M+H)+, 75%), 276 (75%); 1 H-NMR of the free- base in CDCI3, ~ (ppm): 1.25-150 (m, 4H), 2.20 (br, 4H), 2.60 (br,1H), 2.93 (s, 6H), 3.50 (br,1 H), 3.76 (s, 2H), 4.80 (d, 20 1 H), 6.43 (d, J = 5.5 Hz,1 H), 6.72 ( d, J = 9 Hz, 2H), 7.22 (d, J = 9 Hz, 2H), 7.35 (dd, J = 2 and 9 Hz,1 H), 7.61 (d, J = 9 Hz,1 H), 7.95 (d, J = 2 Hz,1 H), 8.52 (d, J = 5.5 Hz,1 H).

Example 1 14 trans-NI-(7-Chloro-quinolin-4-yl)-N4-(2,6-difluoro-benzyl)-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using 2,6-difluorobenzylamine. Yield 30 42% of white crystals (from methanol/ether). M.p. 262~C.

ISP mass spectrum: peaks at 402 ((M+H)+,100%), 276 (95%), 202 ('/2(M+2H)2~; 95%); 1 H-NMR of the free base in CDCI3, ~ (ppm): 1.35 (m, 4H),1.75 (br,1H), 2.10 (br, 2H), 2.25 (br, 2H), 2.55 (br, lH), 35 3.49 (br, 1 H),3.95 (s, 2H), 4.84 (d,br, 1 H), 6.44 (d, J = 5.5 Hz,1 H), 6!70 (m, 2H), 7.25 (m,1 H), 7.35 (dd, J = 2 and 9 Hz,1 H), 7.61 (d, J
= 9 Hz, lH),7.95 (d, J = 2 Hz, 1H), 8.51 (d, J = 5.5 Hz, lH).

CA 02237997 1998 - 0 . - 1 .

WO 97/18193 PCT/Er961~ GC
Fxample 1 1~

trans-N1 -(7-Chloro-quinolin-4-yl)-N4-(2-pyridin-2-yl-ethyl)-cyclohexane-1,4-diamine trihydrochloride Analogously to Example 88 using 2-(2-aminoethyl)-pyridine. Yield 26% of white crystals (from methanol/ether). M.p. 225~C.

El mass spectrum: peaks at 380 (M+, 20%), 288 (20%), 259 (35%), 179 (85%), 93 (100%); 1 H-NMR of the free base in CDCI3, ~ (ppm):
1.21-1.43 (m, 4H), 2.09 (br, 2H), 2.22 (br, 2H), 2.60 (br, lH), 3.04 (AB system, 4H), 3.50 (br, 1 H), 4.81 (d, br, 1 H), 6.43 (d, J = 5.5 Hz, 1 H), 6.92 ( d, J = 9 Hz, 2H), 7.21 (m, 2H), 7.35 (dd, J = 2 and 9 Hz, 1 H), 7.60 (m, lH), 7.95 (d, J = 2 Hz, 111), 8.52 (d, J = 9 Hz, 1 H), 8.55 15 (d, J = 5.5 Hz, lH).

Fxamp/e 1 16 trans-N1-(1 H-Benzimidazol-2-ylmethyl)-N4-(7-chloro-quinolin-20 4-yl)-cyclohexane-1,4-diamine trihydrochloride Analogously to Example 88 using (2-aminoethyl)-benzimidazole.
Yield 22% of white crystals (from methanol/ether). M.p. >250~C.

25 ISP mass spectrum: peaks at 406 ((M+H)+, 55%), 276 (50%), 224 (35%), 204 ('/2(M+2H)Z~; 100%); 1 H-NMR of the free base in d6-i~MS0, ~ (ppm): 1.18-1.50 (m, 4H), 2.01 (d, br, 4H), 3.64 (br, 1 H), 4.01 (s, 2H), 6.53 (d, J = 5.5 Hz, 1 H), 6.92 ( d, J = 9 Hz, 2H), 7.13 (m, 2H), 7.42 (dd, J = 2 and 9 Hz, 1 H), 7.50 (br, 1 H), 7.75 (d, J = 2 30 Hz, 1H), 8.31 (d, J = 9 Hz, 1H), 8.37 (d, J = 5.5 Hz, 1H), 12.2 (br, 1H).
Example 1 1 7 3 ~ trans-N 1-( 7-Chl oro-quinoiin-4-yl) -N4- [ 2-(1 H-indol-3 -yl )-ethyl ~-cyclohexane-1,4-diamine dihydrochloride Analogously to Example 88 using tryptamine. Yield 19% of white crystals (from methanol/ether~. M.p. >250~C.
~5 CA 02237997 1998-0~

ISP mass spectrum: peaks at 41 9 ((M+H)+, 40%), Z76 ( 1 00%); 1 H-NMR of the free base in d6-DMS0, ~ (ppm): 1.12-1.50 (m, 4H), 1.99 (br, 4H), 3.08-3.64 (m, 4H), 4.42 (m, 2H), 6.51 (d, J = 5.5 Hz, 1 H), 5 6.88-7.12 (m, 3H), 6.72 ( d, J = 9 Hz, 2H), 7.17 (d, J = 2 Hz, 1 H), 7.33 (d, J = 8 Hz, 1 H), 7.42 (dd, J = 2 and 9 Hz, 1 H), 7.52 (d, J - 7.5 Hz, 1 H), 7.76 (d, J = 2 Hz, 1 H), 8.31 (s, 1 H), 8.36 (d, J = 5.5 Hz, 1 H), 1 0.80 (s, br, 1 H).

The intermediates used in the foregoing Examples are in part accessible according to known and described procedures or can be prepared in the following manner:

ExamPle 7 18 1 s (2R)-N 1 -(7-Chloro-quinolin-4-yl)- 1, 2-propane-diamine (starting material for Example 1 ) 2.9 g of (S)-2-amino-1-chloro-N-(7-chloro-quinolin-4-yl)-20 propane are held at 1 1 0~C/40 bar in 30 ml of methanol and 30 ml of liquid ammonia in a bomb tube for 20 hrs. After cooling the ammonia is carefully allowed to evaporate and the residue is then poured into 100 ml of saturated sodium chloride solution and extracted twice with 100 ml of dichloromethane. The organic 25 phase is dried over sodium sulphate and evaporated. The crude product is chromatographed on neutral aluminium oxide in dichloromethane/methanol 1 0:1 and then crystallized from dichloromethane/toluene. 1.9 g (80%) of (2R)-N1-(7-chloro-chinolin-~-yl)-1 ,2-propane-diamine are obtained as white 30 crystals; m.p. 145~C

Example 1 1 g (S)-N2-(7-Chloro-quinolin-4-yl)-1 ,2-propane-diaminedihydro-3 5 chloride (starting material for Example 2) CO~
-CA 02237997 1998-0~

Step ~

Z3 g of L-alaninol and 57.4 g of 4,7-dichloroquinoline are held at 150~C in 100 ml of 1-methyl-2-pyrrolidone for 6 hrs.
s After cooling the reaction mixture is poured into 500 ml of cold 2N HCI and extracted three times with 200 ml of dichloro-methane. The acidic-aqueous phase is made basic with 28% NaOH, ~ with the product separating. After stirring in an ice bath for 30 min. the product is filtered off and then recrystallized from 0 300 ml of 2-propanol/150 ml of ethanol. There are obtained 51.2 g (74%) of (S)-2-amino-N-(7-chloro-quinolin-4-yl)-1 -propanol; white crystals, m.p. 225~C, [a~D = +35~ (c = 1.0, MeOH).

1 H-NMR (250MHz) in d6-DMSOI signals at ~ (ppm): 1.24 (d, J = 6.4 Hz, 311), 3.45 (m,1 H),3.58 (m, ~ H), 3.73 (m,1 H), 4.87 (t, J = 5.6 Hz,1 H), 6.53 (d, J = 7 Hz,1 H), 6.84 (d, J = 7.7 Hz,1 H), 7.44 (dd, J = 2 and 9 Hz,1 H), 7.78 (d, J = 2 Hz,1 H), 8.35 (d, J = 7 Hz,1 H), 8.39 (d, J = 9 Hz,1 H).

20 Step 2 Z7.3 g of (S)-2-amino-N-(7-chloro-quinolin-4-yl)-1-propanol are suspended in 270 ml of chloroform. Then, a solution of 72 ml of thionyl chloride in 70 ml of chloroform is added 25 dropwise thereto while cooling with ice over 30 min., during which the temperature should not exceed 25~C. Subsequently, the mixture is stirred at room temperature for a further 30 min. and at 70~C for 90 min. The reaction mixture is cooled and evaporated, then treated with toluene and again evapora~ed. The 30 resulting foam is dissolved in 500 ml of ethanol while warming, filtered and concentrated to about 300 ml, whereupon crystal-lization occurs. There are obtained 31.6 g (94%) of (S)-2-amino-1 -chloro-N-(7-chloro-quinolin-4-yl)-propanehydrochloride;
m.p. 210~C, ~a]D = ~90~ (c = 1.0, MeOH).
3s 1 H-NMR (250MHz~ in d6-DMSO, signals at ~ (ppm): 1.41 (d, J = 6.5 Hz, 3H), 3.88-4.06 (m, 2H), 4.48 (m,1 H), 7.03 (d, J =
7.3 Hz, 1 H), 7.79 (dd, J = 2 Hz and 9 Hz,1 H),8.15 (d, J = 2 Hz,1 H), ~7 CA 02237997 1998-0~
WO 97/18193 PCT/EP96/'~ 186G
8.59 (d, J = 7.3 Hz,1 H~,8.89 (d, J = 9 Hz 1 H), 9.44 (d, J = 8.41~z, 1 H),14.66 ~s,1 H).

Step 3:
7.1 g of (S)-2-amino-N-(7-chloro-quinolin-4-yl)-1 -propanol are suspended in 70 ml of dichloromethane ander argon, treated with 6.Z ml of triethylamine and then cooled in ice.
3.2 ml of methanesulphonyl chloride are added dropwise thereto 0 at 5~C over 10 min. and the mixture is left to warm for 1 h., diluted with 70 ml of dichloromethane and extracted twice with 100 ml of water. After drying and evaporation the crude product is dissolved in 70 ml of N,N-dimethylformamide and stirred at 70~C with 2 g of sodium azide for 3 h. After cooling the mixture is extracted twice with 200 ml of ethyl acetate and twice with 200 ml of water. The crude product is chromatographed on silica gel in ethyl acetate and crystallized from 15 ml of hot ethyl acetate and 30 ml of hexane. There are obtained 4.3 g (55%) of (S)-2-amino-1-azido-N-(7-chloro-quinolin-4-yl)-propane; white 20 crystals, m.p.137~C, [a]D = ~1300 (c = 1.0, MeOH).

1 H-NMR (Z50MHz) in d6-CDC13, signals at ~ (ppm): 1.41 (d, J = 6.5 Hz, 3H), 3.49-3.65 (m 2H), 3.96 (m,1 H), 5.00 (d, J =
10 Hz,1 H), 6.44 (d, J = 7.3 Hz,1 H), 7.38 (dd, J = 2 Hz and 9 Hz, 25 1 H), 7.68 (d, J = 9 Hz,1 H), 7.97 (d, J = 2 Hz,1 H), 8.56 (d, J =
7.3 Hz,1 H).

Step 4:

2 g of (S)-2-amino-1-azido-N-(7-chloro-quinolin-4-yl)-propane are dissolved in 38 ml of methanol, then 5.3 ml of triethylamine and 3.8 ml of propane-1,3-dithiol are added and the mixture is stirred at room temperature for 72 hrs. The reaction mixture is evaporated and dried in a high vacuum for a 3 5 further 4 h. For crystallization, the resulting oil is triturated -with 15 ml of toluene. 0.98 g (54%) of white crystals, m.p.
113~C, is obtained. For the preparation of the hydrochloride, 0.5 g of free base is dissolved in 10 ml of acetone and then CA 02237997 1998-0~

treated with 2.3 ml of 2N HCI. There is obtained 0.63 g (96%) (S)-N2-(7-chloro-quinolin-4-yl)-1 ,2-propanediamine-dihydro-chloride; white crystals; m.p. 21 0~C, [a3O = + 1 04~ (c = 1 .0, MeOH).

1 H-NMR (250MHz) in d6-DMSO, signals at ~ (ppm): 1.38 (d, J = 6.5 Hz, 3H), 3.16 (m, 1H), 3.36 (m, 1H), 4.51 (m, 1H), 7.01 (d, J - 7 Hz, 1 H), 7.76 (dd, J = 2 Hz and 9 Hz, 1 H), 8.52 (m, 3H), 8.61 (d, J = 7 Hz, 1 H), 8.97 (d, J = 9 Hz, 1 H), 9.47 (d, J = 9 Hz, 1 H), 14.7 (br. s, lH).
0 Example ~ 20 N1 -(7-Chloro-quinolin-4-yl)-2-methyl-propane-1 ,2-diamine (starting material for Examples 3-59).

t 5 198 g of 4,7-dichloroquinoline, 97 g of 1 ,2-diamino-2-methylpropane and 101 g of triethylamine are stirred in 1 1 of N-methyl-2-pyrrolidone at 1 50~C ander argon for 5 hours. Then, the solvent is evaporated in a vacuum and the residue is taken up in 1 1 of water. The pH is adjusted to 1 using 220 ml of Z5%
hydrochloric acid and the mixture is diluted with 6 1 of water and extracted four times with 0.5 1 of ethyl acetate each time.
Then, the clear aqueous solution is treated with about 900 g of KOH, whereby the pH rises to 14 and the product separates in crystalline form. This is filtered off ander suction, rinsed with 2 s about 3 1 of water and, for further purification, recrystallized from 4 1 of acetonitrile. There are obtained 126.7 9 (73%) of Nl-(7-chloro-c uinolin-4-yl)-2-methyl-propane-1,2-diamine, m.p. 182-1 84~C.

lH-NMR in CDCI3, ~ (ppm): 1.25 (m, 2H), 1.28 (s, 6H), 3.08 (d, J = 5 Hz, 1 H), 6.37 (d, J = 6 Hz, 1 H), 7.37 (dd, J = 2 Hz and 8 Hz, H), 7.76 (d, J = 8 Hz, 1 H), 7.95 (d, J = 2 Hz, 1 H), 8.51 (d, J = 6 Hz, 1 H).

~q CA 02237997 1998-0~
WO 97/18193 PCT/Er9(i/~86b Fxample 12 1 ( 1 S,2S)-N 1 -(7-Chloro-quinolin-4-yl~-cyclohexane-1 ,2-diamine (starting material for Examples 60-67) 13.6 g of (1S,2S)-(+)-1,2-diaminocyclohexane, 23.6 g of 4,7-dichioroquinoline and 16.6 ml of triethylamine are held at 1 50~C in 150 ml of 1-methyl-2-pyrrolidone ander argon for 16 hrs. Then, the solvent is largely distilled off at 0.1 Torr/
10 80~C and the residue is triturated with 300 ml of 1.5N HCI. The resulting aqueous suspension is extracted three times with 300 ml of dichloromethane and then made basic with concen-trated ammonia, with gum-like clumps separating. The super-natant solution is decanted off and extracted twice with 400 ml 15 of dichloromethane. The crude product obtained from these extracts is purified by two-fold flash chromatography on neutral aluminium oxide (Brockmann activity ll) with dichloromethane and dichloromethane/ethanol 30:1. Crystallization is effected from 40 ml of dichloromethane and 60 ml of ethyl acetate by 20 distillation of the former. Yield: 4 g (12%) of (lS,2S)-N-(7-chloro-quinolin-4-yl)-cyclohexane-1,2-diamine; m.p. 1 60~C, r.a]D = +129.30 (MeOH, c = 1.0).

Fxamp/e 1 ~2 cis-N1 -(7-Chloro-quinolin-4-yl)-cyclopentane-1 ,3-diamine (starting material ~or Example 68) 2g.5 g of cyclopentane-1,3-diamine dihydrobromide 30 [prepared according to 0. Diels, J.H. Blom and W. Knoll, Liebigs Ann. 443, 242 (t 925)3 are held for 6 hours in a heating bath at 1 80~C together with 19.8 g of 4,7-dichloroquinoline and 27.8 ml of triethylamine in 100 ml of 1-methyl-2-pyrrolidone. The cooled reaction mixture is poured into 1 1 of water and the pH of 35 the mixture is adjusted to 7 using 10% aqueous KOH. The mixture is extracted firstly with 5 0.5 I portions of ethyl acetate, the pH
is increased to 12 using KOH and the mixture is again extracted with 3 0.5 I portions of ethyl acetate. The latter extract gives, , CA 02237997 1998-0~
WO 97/18193 PCT/Er96/0~866 after evaporation of the solvent, 29.9 g of a crude product which, for further purification, is chromatographed on 500 g of silica gel with a dichloromethane-methanol mixture in the ratio by voiume 97:3. After a fore-run of 2.5 ll which consists of a 5 mixture of the product with byproducts, there is obtained in the subsequent 3.75 1 of eluate, an almost pure product which, after evaporation of the solvent, is obtained as a yellow oil and which, as such, can be used for the further reactions. Yield: 5.1 g of cis-N-(7-chloro-quinolin-4-yl)-cyclopentane-1,3-diamine lH-NMR in DMS0-d6, ~ (ppm): 1.44 (m, 2H),1.71- 2.13 (m, 5H), 2.22 (quint., J = 6.9 Hz,1 H), 3.34 (m,1 H), 3.97 (m,1 H), 6.46 (d, J = 6 Hz,11~),7.30 (d, J= 7.5 Hz), 7.44 (dd, J = 2 Hz and 9 Hz, H),7.77 (d, J = 2 ~Iz,1 H), 8.26 (d, J = 9 Hz,1 H), 8.39 (d, 15 J = 6 Hz, lH3.
Fxamp/e 1 23 cis-N1 -(7-Chloro-quinolin-4-yl)-cyclohexane-1,4-diamine 20 (starting material for Examples 69-87) Step 1:

trans-N-(7-Chloro-quinolin-4-yl)-4-aminocyclohexanol 414.2 g of 4,7-dichloroquinoline, 380 g of trans-4-amino-cyclohexanol hydrochloride and 255 g of triethylamine are heated to reflux overnight in 1.0~ 1 of 1-methyl-2-pyrrolidone ander an argon atmosphere. After cooling the reaction mixture 3.8 1 of 30 water and 380 ml of 28% sodium hydroxide solution are added thereto while stirring and cooling. The separated reaction product is filtered off ander suction, washed with water until the wash water is neutral and dried at 100~C/12 mbar. Yield 491 g (84.9%) of trans-N-(7-chloro-quinolin-4-yl)-4-aminocyclo-35 hexanol.

CA 02237997 1998-0~

Step 2:

trans-N-(7-Chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclo-hexylamine 447 ml of methanesulphonyl chloride are added portionwise within 20 minutes while cooling with an ice bath to a mixture of 1 157 g of trans-N-(7-chloro-quinoiin-4-yl)-4-aminocyclohexanol and 868 ml of triethylamine in 6.1 1 of dichloromethane. After a 0 clear solution has formed transiently the product begins to separate. After 2 hours the mixture is filtered and the filtrate is evaporated to dryness. Filter residue and evaporation residue are combined and triturated in 8 1 of water. The mixture is again filtered, washed with a further 8 1 of water and thereafter with 5 4 1 of isopropanol and the product obtained is dried at 50~C/
12 mbar. Yield: 2028 g (90%) of trans-N-(7-chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclohexylamine, m.p.: 154-1 59~C.

Step 3:
cis-N-(7-Chloro-quinolin-4-yl)-cyclohexyl-1 ,4-diamine 433 g of trans-N-(7-chloro-quinolin-4-yl)-4-methane-sulphonyloxy-cyclohexylamine are reacted at 80~C for 10 hours 25 with 80.7 g of sodium azide in 2.16 1 of N,N-dimethylformamide.
After cooling to room temperature 2.36 1 of ethyl acetate and 2 1 of water are added thereto in succession, the pH is adjusted to 9 by the addition of 28% sodium hydroxide solution and the phases are left to separate. The aqueous phase is back-extracted a 30 further seven times with 0.5 1 of ethyl acetate each time. The pooled ethyl acetate extracts are combined and evaporated. The evaporation residue crystallizes after the addition of 0.5 1 of n-hexane. It is filtered off ander suction and dried at 40~C/
12 mbar. The thus-obtained crude product (256 g) consists to 35 78% of trans-N-(7-chloro-quinolin-4-yl)-4-azido-cyclohexyl-amine (corresponding to 192 g, 53%) in addition to 18% of an elimination product and 7% of unreacted trans-N-(7-chloro-quinolin-4-yl)-4-methanesulphonyloxy-cyclohexylamine.

7~

CA 02237997 1998-0~

WO 97/lX193 PCT/EP96/04866 220 g of this crude product are suspended in 2.5 1 of isopropanol. 203 ml of triethylamine, 7.24 ml of 1,3-propane-dithiol and 54.8 g of sodium borohydride are added thereto in s succession and the mixture is warmed to 40~C while stirring.
After 16 hours a further 54.5 g of sodium borohydride are added thereto. After a total reaction period of 40 hours the mixture is cooled using an ice bath and excess hydride is decomposed by the slow addition of 180 ml of ~lacial acetic acid. After the 0 hydrogen evolution has died away the reaction mixture is evaporated on a rotary evaporator. Then, 0.3 1 of methanol is added thereto and the mixture is again evaporated. Addition of methanol and evaporation are repeated a total of 5 times with 0.3 I portions each time. Thereafter, the residue is taken up in 3 1 of 3N sodium hydroxide solution and extracted three times with 1 1 of dichloromethane each time. The combined dichloro-methane phases are then extracted with 1.5 1 of water, with the aqueous phase being adjusted to pH 7 by the addition of about 2 1 of 1 N hydrochloric acid. The extraction is repeated twice with 20 2 1 of water/dil. hydrochloric acid while maintaining this pH.
After combining the aqueous extracts the pH is adjusted to 12-13 using 28% sodium hydroxide solution and the product is extracted with 3 1 I portions of ethyl acetate. After evaporation of the solvent pure, crystalline cis-N-(7-chloro-quinolin-4-yl)-cyclo-25 hexyl-1,4-diamine remains behind in a yield of 128 g and can be used without further purification. It can be recrystallized from methanol-diethyl ether (20.6 g from 32 g of crude product in 50 ml of methanol and 400 ml of diethyl ether); m.p. 139-140~C.

30 'H-NMR in DMS~-d6, ~ (ppm): 1.65 (m, 6H), 1.89 (m, 2H), 3.05 (m, ~H), 3.6Q ~m, 1#), 3.75 (~" ~ H), 6~50 ~d, J = 5.~ Hz, 11~, 6.84 (d, J = 7 Hz1 1 H), 7.44 (dd, J = 2 Hz and 8.5 Hz, 1 H), 7.78 (d, J =
2 Hz, 1 H), 8.38 (d, J = 6.5 Hz, 1 H), 8.42 (d, J = 8.5 Hz, 1 H).

CA 02237997 1998-0~

Fxamp/e 1 24 4-(7-Chloro-quinolin-4-ylamino)-cyclohexanone 5 Starting material for Examples 88-117 and analogues.

13.6 g of trans-4-(7-chloro-quinolin-4-ylamino)-cyclohexanol (Example 123, step 1) are dissolved in 100 ml of dimethyl sulphoxide and 68 ml of triethylamine and cooled to 0 +10~C under argon. A solution of 25.5 g of sulphur trioxide-pyridine complex in 100 ml of dimethyl sulphoxide is added dropwise in such a manner that the internal temperature does not exceed +1 5~C. After stirring for an additional 90 minutes 800 ml of water are rapidly added dropwise. The emulsion obtained becomes a filterable suspension after vigourous stirring at +10~C. The filter material is recrystallized from ethanol-ether. Yield: 10.1 g (75%) of beige crystals; dec. 195~C.

Ei mass spectrum: peaks at 274 ~M', 65%), 217 (100%). lH-NMR in 20 DMS0-d6 ~ ~ppm): 1.85 (m, 2H), 2.25 (m, 4H), 2.60 (m, 2H), 4.06 (m, 1 H), 6.68 (d, J = 7.5 Hz,1 H), 7.05 (d, J = 9Hz,1 I l), 7.46 (dd, J = 2 andl 0 Hz, 1 H), 7.79 (d, J = 2 Hz, 1 H), 8.36 (d, J = 10 Hz, 1 H), 8.44 (d, J = 9 tlz, 1 H).
Any of the compounds described in the foregoing can be formulated as the active ingredient according to methods known per se to give pharmaceutical preparations of the following composition:

1. 500 mg tablets Active ingredient 500 mg Lactose powd. 1 49 mg Polyvinylpyrrolidone 1 5 mg 3 5 Dioctyl sodiumsulphosuccinate1 mg Na carboxymethylstarch 30 mg Magnesium stearate 5 mg 700 mg 7~

CA 02237997 1998-0~

2. 50 mg tablets Active ingredient 50 mg s Lactose powd. S0 mg Microcrystalline cellulose82 mg Na carboxymethylstarch 15 mg 200 mg 0 3. 100 mg capsules Active ingredient 100.0 mg Lactose powd. 104.7 mg Corn starch 70.0 mg Hydroxypropylmethylcellulose 10.0 mg Dioctyl sodiumsulphosuccinate 0.3 mg Talc 12.0 mg Magnesiumstearate 3.0 mg 300.0 mg 4. 500 mg suppositories Active ingredient 500 mg Suppository mass ad 2000 mg 2s 5. 100 mg soft gelatine capsules Active ingredient 100 mg Medium chain triglyceride300 mg 3 o 400 mg

Claims (9)

Claims

1. N1-Aralkyl-N2-quinolin-4-yl-diamine derivatives of the general formula wherein R1 signifies halogen or trifluoromethyl;
R2 signifies hydrogen, halogen or trifluoromethyl;
A signifies or (C5-C6)-cycloalkylene;

n signifies 1-4;
R3 and R4 each independently signify hydrogen or methyl;
p signifies 0 1-3 and B signifies pyridyl, furyl, naphthyl, benzo[1,3]dioxolyl, phenyl or substituted phenyl, with the number of substituents being 1-3 and the substituents being selected from a group consisting of halogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, trifluoromethyl, cyano, di-C1-C4-alkyl-amino or their N-oxides, phenyloxy, phenyl, methylsulphanyl or as well as pharmaceutically acceptable salts of basic compounds of general formula I.

2. Compounds according to claim 1, wherein R1 signifies chlorine, R2 signifies hydrogen, p signifies 1 or 2, A signifies -CH2C(CH3)2- and B signifies a benzene ring which is mono-, di- or tri-substituted.

3. The compounds N1-(7-Chloro-quinolin-4-yl)-N2-(3-chloro-benzyl)-2-methyl-propane-1,2-diamine, N1-(7-chloro-quinolin-4-yl)-N2-(benzyl)-2-methyl-propane-1,2-diamine, N1-(7-chloro-quinolin-4-yl)-N2-(2-hydroxy-3-methoxy-benzyl)-2-methyl-propane-1,2-diamine, N1-(7-chloro-quinolin-4-yl)-N2-(2-hydroxy-5-methoxy-benzyl)-2-methyl-propane-1,2-diamine, N1-(7-chloro-quinolin-4-yl)-N2-(4-hydroxy-3-methoxy-benzyl)-2-methyl-propane-1,2-diamine, trans-N1-(7-chloro-quinolin-4-yl)-N4-[2-(3,5-dimethoxy-phenyl)-ethyl]-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(4-methoxy-benzyl)-cyclohexane-1,4-diamine, trans-N1-(7-chloro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane-1,4-diamine and trans-N1-(7-chloro-quinolin-4-yl)-N4-(2,6-difluoro-benzyl)-cyclohexane-1,4-diamine in accordance with claims 1 and 2.

4 Compounds according to claim 1 , wherein R1 signifies chlorine, R2 signifies hydrogen, p signifies 1, A signifies cyclohexane-1,2-diyl or cyclohexane-1,4-diyl and B

signifies a benzene ring which is unsubstituted or mono- or di-substituted.

5. The compounds (1S,2S)-N1-(7-Chloro-quinolin-4-yl)-N2-(benzyl)-cyclohexane-1,2-diamine, (1S,2S)-N1-(7-chloro-quinolin-4-yl)-N2-(4-chloro-benzyl)-cyclohexane-1,2-diamine, (1S,2S)-N1-(7-chloro-quinolin-4-yl)-N2-(4-dimethylamino-benzyl)-cyclohexane-1, 2-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(4-dimethylamino-benzyl)-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(benzyl)-cyclohexan-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(3-chloro-benzyl)-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(2-hydroxy-4-methoxy-benzyl)-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(3,5-dimethoxy-benzyl)-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(4-methylsulphanyl-benzyl)-cyclohexane-1,4-diamine, cis-N1-(7-chloro-quinolin-4-yl)-N4-(4-diethylamino-benzyl)-cyclohexane-1,4-diamine and cis-N1-(7-chloro-quinolin-4-yl)-N4-(biphenyl-4-ylmethyl)-cyclohexane-1,4-diamine in accordance with claims 1 and 4.

6. A medicament, for the treatment or prevention of malaria, containing one or more compounds according to any one of claims 1- 5 and a therapeutically inert excipient.

7. A process for the manufacture of compounds according to any one of claims 1- 5 , which process comprises a) reducing a Schiff's base of the general formula wherein the substituents have the significance described in claim 1, or b) reacting an amine of the formula with a compound of the formula X~(CH2)p-B IV

wherein X signifies a leaving group and the other substituents have the significance described in claim 1, or c) reacting a compound of the formula with an amine of the formula H2N~(CH2)p-B VI

wherein all substituents have the significance described in claim 1, or d) reacting a ketone or an aldehyde of the formula wherein Y signifies or oxo-(C5-C6)-cycloalkyl and R1 and R2 have the significance set forth in claim 1, with an amine of formula Vl and a reducing agent, and e) if desired, converting the compound obtained into a pharmaceutically acceptable acid addition salt.

8. Compounds according to any one of claims 1-5 for use as therapeutically active substances, against malaria.

9. The use of compounds according to any one of claims 1- 5 for the production of corresponding medicaments.