CA2189652C - Novel hydroximic acid derivatives, pharmaceutical compositions containing them and process for preparing same - Google Patents

Abstract

The invention relates to novel compounds of formula (I), wherein X means halogen; Z stands for an aromatic group, pyridinyl group or the like; and R represents an alkyl or phenylalkyl group or an -A-N(R1)R2 group, and in the latter R1 and R2 stand, independently from each other, for hydrogen or alkyl group; or R1 and R2, together with the adjacent nitrogen atom, form a 5- to 7- membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said heterocyclic group optionally being substituted by at least one alkyl group; and A stands for a straight or branched chain alkylene group, as well as the pharmaceutically acceptable ac id addition salts thereof; furthermore, to processes for the preparation of the above novel compounds, and pharmaceutical compositions containing these compounds or their pharmaceutically acceptable acid addition salts as active ingredients. Further, the invention relates to certain novel intermediates o f formula (II). The compounds of formula (I) possess anti-ischaemic effect and therefore, they are useful for treating ischaemic states and diseases, e.g. myocardial ischaemia (induced e.g. by occlusion of the coronary arteries).</ SDOAB>

Description

,~ w0 95/30649 PGT/HU95100014 218~~52 NOVEL HYDROXIMIC ACID DERIVATIVES, s PHfARMACEUTICAL COMPOSITIONS CONTAINING THEM AND
PROCESS FOR PREPARING SAME
The invention relates to novel, biologically active hydmximic acid deriva-~o tives of the formula X
Z - C (I), ~~'' N - OR
wherein ~s X means halogen;
Z stands for an aromatic group, pyridinyl group or the like; and R represents an alkyl or phenylalkyl group or an -A-N(R 1 )R2 group, and in the latter R 1 and RZ stand, independently from each other, for hydrogen or alkyl 2o group; or R1 and R2, together with the adjacent nitrogen atom, form a 5- to 7-membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said het-erocyclic group optionally being substituted by at least one alkyl group; and 2s A stands for a straight or branched chain alkylene group, as well as their pharmaceutically acceptable acid addition salts and pharmaceuti-cal compositions containing these compounds. Furthermore, the invention relates to a process for the preparation of the above compounds and to a method for the treatment of ischaemic states or diseases in mammals, including men.

X as halogen means fluorine, chlorine, bromine or iodine; compounds con-taming chlorine as X are preferred.
Z as an aromatic group is preferably a phenyl, phenylalkyl, substituted phenyl, substituted phenylalkyl group or naphthyl group. The phenyl group of the s above substituted groups may be substituted by 1 to 3 identical or different group(s), which is {are) suitably halogen, haloaIkyl, alkyl, hydmxy, alkoxy, nitm, amino, mono- or dialkylamino groups.
The term "Z stands for a pyridinyl group or the Iike" means a pyridinyl group or its homologues, e.g. picolyl or lutidyl group. Pyridinyl group is particu-io larly preferable; whereas 3-pyridinyI group proved to be most advantageous.
Above and in the forthcoming, alkyl or alkoxy groups as R, RI and RZ or as substituents contain preferably 1 to 8, suitably 1 to b, most preferably 1 to 4 carbon atoms unless stated otherwise. Methyl, ethyl or n_-propyl groups are most greferred.
1s Thus, phenylatkyl group is in most cases benryl or pheaethyl group;
whereas the mono- and dialkylamino groups are preferably monoCl,.4allcyl or diCl.~alkyl.groups, respectively.
The haloalkyi group may contain one or more above-mentioned hslogen(s}
or it may be a perfluoroalkyl group. Preferred are e.g. the chloromethyl, 2-w chloroethyl ar tr iffuoromethyl groups.
The heterocyclic group farmed by R1, R~ and the adjacent nitrogen to-gether is preferably pipeadino, piperazino or moxpholino group. These groups may optionally be substituted by at least one alkyl group defined above. Thus, these groups may be e.g. a 4-methylpiperazinyl or 2,2-dimethylpiperidi~l group.
2s The alkylene group A may contain a straight or branched chain, and suit-ably it contains 1 to 8, preferably 1 to 5 carbon atoms. The 1,2-ethylene, 1,3-pro-PYI~~ ~d 1,4-butylene groups are especially advantageous.

2a According to one aspect of the present invention, there is provided a compound of the formula Z- C
N-(JR
wherein X means halogen; Z stands for unsubstituted phenyl;
benzyl; phenylethyl; phenyl, benzyl or phenylethyl substituted with one to three identical or different groups selected from halo, halo-C1_8 alkyl, C1-a alkyl, hydroxy, C1_4 alkoxy, nitro, amino, mono- or di-C1_4 alkylamino; C1_$
alkylphenyl; naphthyl; unsubstituted pyridinyl; or pyridinyl substituted with one or more methyl; and R represents a C1-$
alkyl or phenyl-C1-$ alkyl group or an -A-N (R1) RZ group, and in the latter; R1 and R2 stand, independently from each other, for hydrogen or C1-$ alkyl group; or R1 and Rz, together with the adjacent nitrogen atom, form a 5- to 7-membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said heterocyclic group optionally being substituted by at least one Ci-s alkyl group; and A stands for a straight or branched chain C1_$ alkylene group or a pharmaceutically acceptable acid addition salt thereof; with the proviso that: (i) when X is Cl and R is methyl, Z is not phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-t-butylphenyl, or 4-nitrophenyl; (ii) when X is Cl and R is ethyl, Z is not naphthyl; (iii) when X is C1 and R is n-propyl, Z is not phenyl or 4-methylphenyl; (iv) when X is C1 and R is i-propyl, Z is not phenyl; (v) when X is Br and R is methyl, Z
is not phenyl; and (vi) when R is an alkyl, Z is not phenyl singly substituted with fluoro-C3_$ alkyl.

2b Compounds and salts of the present invention may be used to treat an ischaemic state or disease in a mammal.
All compounds of the formula (I) are novel. A
part of the starting materials for their preparation is known whereas others are new. The methods of prepara--3.,-tion of the new starring materials are described in the corresponding examples.
Insecticides being structurally sinular to the compounds of the formula (I) are disclosed in the Japanese patent application published under No.
60.0008253 (Kokai) as well as ~3-blocking agents being structurally similar to the compounds of the formula (I) are claimed in the European patent specification No, EP 0 417 210.
Structurally, the compounds disclosed in the latter document differ from the compounds of formula (17 in that a -CH2-CH(OH)-CH2-(2-hydroxy-propylene) moiety is present between the terminal -NR1R2 group and the remaining part of the molecule instead of the unsubstituted straight or branched alkylene group symbolized by A in the compounds of the formula (I). The compounds described in the European patent specification 0,417,210 are diabetes selective (3-antago-nists and can be used especially in the therapy of diabetic angiopathy.
Beltrao, T. M. et al describe the preparative and spectroscopic investigation of O-methylbenzamidoximes of the formula p-Rl-C6H4-C(N~i~-NOR (R~Me, R1 = H, Me, Cl, Br, NO~ in their article "Preparation and spectral study of 0-methylbenzamid-oximes" [An. Acad. Bras. Cienc.1978, (50}2,159-64]. The synthetic route described is traditional, starting with addition of hydroxylarnine to a substi;tutcd benzonitrile, fol-lowed by O-methylation with Me2S04. Beside the investigation of the tautomerism of the products in solution by IR spectroscopy it is also described that some of the 0-methylbenzamidoximes was found to be active against Tnpanosorna cruzi.
The~struchuaily closest analogues of compounds of formula (I} from the prior art are the classical ii-adrenergic receptor antagonists, more specifically the family of the (3-blocker asyloxygropanoIamine derivatives. These compounds always possess a secon-dazy hydroxyl group is their alkyfene moieties binding the terminal -NR1R2 goup to the molecule, and the 5AR studies have clearly demonstrated that this substructure is essential for their biological activity (see in this respect e.g.
Comprehensive Medicinal Chemistry (ed. C. Hansch), Vol. 3. "Membranes and Receptors" (ed. J. C.
Emmett), Pergamon Press, 1990, pp. 199,200 and 206].~It has to be noted that the presence of this hydroxyl group introduces chirality to the structure of these compounds.

'CA 02189652 1996-11-05 w':v;,.'=:::.,~,j~~.3:-.=' .

4.,;,.:.
.., '' ~ ::'':~ ... ,._~w w w ~ w w vv vv ~ v ~ v v v v ~ v v v v ~ v v ~ ~ v v v v ~w v v v v wv v w v - 3a,-However, it is always desirable that compounds for medicinal use have the sim-plest possible structure that makes their preparation and biological investigation easy.
Recently researchers have been seeking particularly for molecules without chirality in order to avoid the laborious and expensive~~nvestigation of the stereoisomeric forms and their mixtures, required more and more by the registration authorities in the last few years. However, based of the similarities between both the chemical structures and the biological effect of the above mentioned Q-Mockers and the compounds described in the cited BP 0,417,210 patent specification, it could be expected that omitting the hydroxyl group from latter derivatives should result in loss of their biological activity as well.
Surprisingly, we have found that compounds of formula (I) i.e. hydroximic acid derivatives having an aminoalkyl portion that contains no hydroxyl functionality, pos-sess therapeutically valuable biological activity, consequently, they are useful as active ingredients in medicaments. Based on this recognition the invention provides biologi-cally active chemical substances that can be prepared and biologically assessed without the difficulties typically arising at the closely related optically active compounds.
The compounds of the formula (I) can be prepared by using several known proc-esses from which the following ones will be described without intending any*
limita-tion as to the scope claimed.
a) A compound of the formula ~NH2 Z - C (II), -OR
wherein Z and R are as defined form formula (I), or an acid addition salt thereof is treated with a diazotizing agent known per se in the presence of a hydrogen halide.
Alkali metal nitrites (e. g. sodium or potassium nitrite) or an alkyl nitrite (e.g.
isoamyl nitrite or tart-butyl nitrite) are useful diazotizing agents in the presence of a hy-drogen halide (e.g. hydrochloric acid, hydrogen bromide or the like). After carrying out the reaction at a temperature between -5°C and 15°C, the mixture is stirred until de-composition of the transitorily formed diazonium salt, preferably for 10 to 60 minutes.
b) A compound of the formula ~ X
Z - C (III), \N-OH
wherein X and Z are as defined for the formula (I), is reacted with a compound of the ~1MENCf D SHEEN w ~"'' ., ,,~ 1 ~~~~~
formula R - Y (IV), wherein R is as defined above and Y means a leaving group. This reaction is carried out at room temperature in the presence of an acid binding agent.
c) A compound of formula s Z- C~O V
NH-OR
or formula Z - CH = NOR (VI), respectively, wherein Z and R are as defined above, is treated with a suitable io halogenating agent.
For halogenation of the compounds of the formula (V) e.g. thionyl chloride, phosphorus pentahalides, phosphorus oxyhalides, phosgene, carbon tetrachlor-ide/triphenylphosphine, hydrogen fluoride/pyridine, diethylamino-sulfur-trifluor-ide and the like are useful. The reaction is earned out at an elevated temperature, is suitably at the boiling point of the reaction mixture.
For halogenation of the compounds of the formula (VI) elemental halogens (e.g. chlorine or bromine) hypohalogenites (e.g. sodium hypohalogenite, tert-butyl hypohalogenite) or N-chlorosuccinimide, N-bromosuccinime and the like are useful. The reaction is carried out in the presence of an organic solvent, e.g.
2o chloroform or benzene, suitably at room temperature.
d) Alternatively, if it is desired to prepare a compound containing an -A-N(R1)R2 group as R, belonging therefore to a narrower group of the com-pounds of the formula (I), an amine of the formula HN(R 1 )R2, wherein R 1 and R2 are as defined for the formula (I), is reacted with a compound of formula 25 ~ X
Z - C .~ (VII), ~N-O-A-Y
wherein Z, X, Y and A are as defined above. This reaction is performed in an or-ganic solvent.
AN;~IvD~D StiE~T

WO 95/30649 - ~' v ~~ ~~ ~ PCT/HU95/00014 If desired, the compounds of the formula (I) prepared by using any of the processes a), b), c) or d), respectively, can be converted to pharmaceutically ac-ceptable acid addition salts in a manner known per se.
During our investigations on the compounds prepared it has been found that s they possess anti-ischaemic effect.
The reperfusion-induced arrhythmia [ventricular tachycardia (VI) and ven-tricular fibrillation (VF)] was studied on anaesthetized rats. The myocardial is-chaemia was elicited by compressing the left-sided descending coronary artery for 5 minutes and after the ceasing thereof, by a 10-minute reperfusion of the to heart. ECG was continuously monitored and the change of the mean duration of VT and VF under effect of the test compounds as well as the survival were measured in the first 3 minutes of reperfusion. The test compounds were adminis-tered in an intravenous (i.v.) dose of 1 mg/kg by 5 minutes before compressing the left-sided descending coronary artery. The survival of experimental animals is was found to be 100% by using e.g. the compounds of Examples 2 and 7.
The vasorelaxant effect of the compounds was investigated in vitro on the thoracal aorta isolated from rabbit [Am. J. Physiol. 257, 1327-1333 (1989)].
(Jur results are summarized in Table 1.
Table 1 Compound No. 2 4 5 6 7 8 9 Ref ECSp (x 10-5 2.7 8.2 2.4 1.3 0.6 1.5 7.6 8.3 M) 2o Reference drug: Bepridil ~Eur. J. Pharm. 166, Z41-24y (191iy)J.
The number of compounds is given as number of the corresponding Example in the present patent application.
Furthermore, the effect of compounds of the invention in the treatment of complications associated with the diabetic angiopathy was studied. The in vivo 2s action was measured on rats, by the change of rate of the impulse conduction in an STZ-induced diabetic state as follows.
The rate of motor and sensory impulse conduction (MCR or SCR, respect-t) ~~~I:,;~

ively) of the sciatic and tibial nerve, respectively, as mixed type nerves was de-termined by using the method of E. F. Stenley [Experimental Neurology 71, 497-506 (1981) as modified by P. De Koning and W. H. Gispen: Peptides 8, 415-412 ( 1987)]. The electrophysiological measurements were carried out on anaesthe-s tined male Cr:Wistar rats at the end of a one-month period of treatment with mg/kg administered orally (p.o.). The sciatic or tibial nerve, respectively, was excited by needle electrodes stitched near the nerve on the lower extremity and the electromyographic (EMG) responses of the plantar muscle were registered.
Five EMG-s each were averaged and the results were stored in a computer. The to latency periods of the motor and sensory components were measured. The rates of impulse conduction were calculated from the ratio of the distance between two sites of excitation to the differences of latency.
The reduced impulse conduction of the diabetic animals was restored by the compounds investigated in the following percentage values:
Compound No. MCR correction (%) SCR correction (%) Reference drug*40 45 * 50 mg/kg of aminoguanidine The active compounds of the invention can be administered mainly by oral or parenteral route, e.g. in a daily dose of 1-10 mg/kg body weight to an adult 2o human.
For the preparation of oral compositions e.g. lactose or starch may be used as filling material. Gelatine, (carboxymethyl)cellulose sodium, methyl cellulose, polyvinylpyrrolidine or starch gum are useful binding or granulating agents.
Po-tato starch or microcrystalline cellulose are mainly added as disintegrating agents though ultraamylopectin, formaldehyde-casein and the like are also suitable.
Use-Afvl~t'~D~D S~E?

_7-ful anti-adhesive and sliding materials are talc, colloidal silicic acid, stearin, ca1_ cium or magnesium stearate or the Like.
Tablets can be prepared e.g. by wet granulation and subsequent compres-sion. After mixing the active components and excipients as well as optionally a s part of the disintegrating additive they are granulated together with the aqueous, alcoholic or aqueous-alcoholic solution of the binding agent in a suitable equip-ment, then the granular substance is dried. Thereafter, the other disintegrating, sliding and antiadhesive auxiliaries are mixed to the dried and the mixture is compressed to tablets. Optionally the tablet is provided with a groove to for facilitating the administration- Tablets caa directly be prepared also by com-pression fmm a mixture of the active ingredient and suitable auxiliaries. If de-sired, the tablets may be converted to drag~es by using additives commonly em-ployed for the preparation of medicaments such as stabiliriag, savouring agents and dyes, e.g. sugar, cellulose derivatives [methyl- or ethylcellulose, {carb-1s oxymethylxellulose sodium and the like), polyvinylpyrrolidone, calcium phos-phate, calcium carbonate, food dyes, food dye lacquers, aromatizing agents, iron oxide pigments and the like.
For the preparation of capsules, a mixture containing the active ingredi-ents) and auxiliaries is filled into capsules.
zo For parenteral administration the composition is formulated to an injectable solution. For preparing such a solution the active ingredients are dissolved in distilled water andlor various organic solvents, e.g. glycol ethers, optionally in the presence of solubilizing agents such as polyoxyethylene sorbitan monolau TM TM TM
rate, monooleate or monostearate (Tween 20, Tween 60 or Tween 80, respec ts lively). In addition, the injectable solution may contain various auxiliaries, e.g.
preserving agents such as benzyl alcohol, methyl or propyl p-hydroxybenzoate, benzalkonium chloride or phenyl mercury borate and the like; as well as antioxi dants, e.g. ascorbic acid, tocopherol, sodium pyrosulfate and optionally complex fonming substances such as ethylenedismine betraacetate for binding metal traces;
3o furthermore pH-adjusting agents and buffers as well.as optionally, a Local anaes-thetic such as lidocairue. Before filling the in ectable solut ion containing the composit ion of the imrent ion into the ampoule, the solution is filtered and after filling in, it is sterilized.
The invention also relates to a method for the treatment of ischaemic states or diseases. This method comprises administering a therapeutically effective amount of an active compound of formula (I) or a pharmaceutically acceptable acid addit ion salt thereof tc:~ the pat lent .
A further aspect of the invention comprises commercial packages eac°h c.ompr isinc~ a pharmaceutically acceptable amount of a compound of formula (Ii together with inst ruct ions for use tY~ereof' in t neat inq an ischaemic state or disease in a mammal.
The invention relates also to certain novel intermediates of formula ~:IT), from which the following ones are preferred:
N-(3-piperidino-7.-propoxyi-3-pYridinecarboxamidine, N-methoxY-3-pyridinecarboxarnidine, 2Q N-(3-morpholinopropoxy)-3--pYridinecarboxamidine, N-t2-piperidinoethoxy3-3-pyradinecarboxamidine, N- [ 3- ( 1--piperidinyl ) -propcvxy ~ -3 ' - f t r if luoromet:hyl ) benzamidine, N-[3-(4-methylpiperazin-1-y1)1-propoxy]-3-pyridine-carboxami.dine, N-(2,2-dimethyl-3-piperidinapropoxy)-3-pyridinecarboxamidine and acid addit ion salts of these compoxtnds .

The irzventican is illustr-~~tec in more detail by the f of lowin4 non-- 1 unit ::lr~c~ Exarnpies .
Exan~:Le- 1-Pr-e~~acat ion c:ofi W--berrxyl.cmy-- r- pyr~idinecarboxinridovl cYrloride hydror:k~rlori.de A 1 ~~ sa:~>_rt :~ can K~c,~r.rt:.t-rin~lrrc~ r~ . :3~5 cx ( a~ . :~
rnmc,l~~~s ~ c:,f N-~ben2yloxy-;3--~7yridine~:.~a .rboxamidinrra h~~~ir ochloride in the mixtura of ~7,~~ rn~ c>f c~on~.entrateca tryc~rc~cfl-a:lorac arad and '73 ml of water a t~c~c:, lNd to '>'~C' ~~cud a . ~~a c:t i :3 3 . ;? mmales I of sc,dilm~
nitrite dissolved in 1 ~ ml of waterw are dropwise added. The mixture ;st irwred cat this i:prrrperat:r.rr.~~> far: addit Tonal :~0 minutes. Aft:c~r~ layc~r~frrcx 50 ml of c~hl<::>rofc~rm to the mixture, it ~Ls alkalirri2:ec~i to ~a~i ~ tc~ ~ by ~rdd:~.n~ ss~lid sodium carbonate. After separ:at:v.on c:~f: ttwe ctrlorafor:rnic phase, the aqueous phase js ac~airwr extr,act:ed tw:~cr with 50 ml of cZn7_c?rcaf~,rm eac~rr,~ then t: he combined c:hloroformic '' 3:1f)5.. ~ ~~ca solution is washed with 10 ml of saturated saline solution, dried over anhydrous sodium sulfate and evaporated.
The residue obtained (5.49 g, 79%) is dissolved in 55 ml of isopropanol and rot of a 2.l molar solution of hydrogen chloride in isopropanol are added to s obtain the hydrochloride salt of the product in a yield of 3.88 g (5l%), m.p.: 146-151.5 °C (recrystallized from methanol/ether).
1H-NMR (DMSO); 9.1-8.8 (broad, LEA, NI~i+), 9.07 (d, 1H), 8.90 (dd, 1H), 8.56 (m, 1H), 7.9 (dd, 1H pyridine 2-6-4-5), 7.5-7.3 (m, SH Ph), 5:38 (s, 2H
CH2) PPm io 13C-NMR (DMSO):146.4, 142.3, 139.2, 129.8, 125.8 (pyridine.2-6-4-3-5), 133.0 [C(CI)=NO], 135.9, 128.5, 128.3, 128.2 (Ph), 77.3 (CH2) ppm.
Elementary analysis for C13H11NOCI.HCI:
calculaied: C 55.1; H 4.3; N 9.9; C125.0%;
found: C 55.0; H 4.2; N 10.1; Cl 25.2%.
'i B) 2,38 g (10 mmoles) of N-(benryloxy)nicotinamide (Beilstein Handbook of Organic Chemistry Fifth Supplementary Series (Springer Verlag, Berlin, 1986-1996) 22 , page 120) are boiled under reflex in 20 ml of thionyl chloride for 2 hours. After distiil-ing off the excess of thionyl chloride, the residue is crystallized from isopropanoi to give 1.75 (62%) of the desired product, the physical characteristics of which are identical to those of the product prepared by method A).
zo Example 2 Preparation of N-(3-piperldinopropoxy~3-pyridinecarboaimidoyl chloride dihydrochloride A) After cooling to 0°C a mixture of 10 ml of distilled water and 4.36 ml of concentrated hydrochloric acid, Z g (7.62 mmoles) of N-(3-piperidino-1-prop-zs oxy)-3-pyridinecarboxamidine are added under stirring. To the yellow solution 2.7 g (3.81 mmoles) of sodium nitrite dissolved in 10 ml of water are added dropwise at -5°C during 30 minutes. After stirring the greenish solution at -5°C
far I .5 hours, the pH of the solution is adjusted to 10 by adding 1 N aqueous so-dium hydroxide solution under cooling, then the solution is extracted 3 times with 40 ml of chloroform. The organic phase is washed with Z0 ml of wateF, dried over sodium sulfate and evaporated. The residue is purified by column chromatography (Merck Kieselgel 60; eluent: chloroformlmethanol I:I) to obtain 1.7 g (79.2%} of the base corresponding to the title compound s The title hydrochloride is prepared from the base obtained by adding au etbanolic solution of hydrogan chloride, m.p_: 165-167°C.
IR (KBr) y cm-1: 3015, 2945, 26I?, 2515, 2088, 1982, 1600, 1570, 143?, 1402, 1200, 1060, 988, 912, 808.
1H-NMR (DMSO-d~: 9.0 (dd, 1H, Ar-H), 8.8 (dd, IH; Ar-H), 8.3 (dd, IH, Ar-1o H), 7.7 (ddd, IH, Ar-H~ 4.4I (t, 2H, -0CH2), 3.41-137 (m, 12H), 1.8 (quintet, 2H, -OCH2 CFi2CI~ PFm.
13C-NMR (DMSO-d6}: 1485 (d, Ar), 144.7 (d, Ar), 136.4 (d, Ar), 133.5 (s, C-Cl), 128.6 (s, Ar), 124.2 (d, Ar), 72.5 (t, OCH~, 52.4 (t, CH2-1~, 51.4 (t, N-CH2-CH2-CH2-CH2-CH2), 22.6 (t, 0-CH2-CH2-CH2), 21.6 (t, N-CH2_ Zs CH2-CH2-CHI, 20.8 (t, N-CH2-CH2-CH2..CH2-CH2) PPm.
The above starting material can be prepared as follows:
After dissolving 2.86 g (51.06 avnoles) of potassium hydroxide in 20 ml of abs. ethanol, 6.45 g (47.0 mmoles) of 3 pyridinecarboxamide oxime are por-tionwise added while stirring. After dissolution, 7.7 g (47.66 nimoles} of 1-(3-20 chloropmpyl)piperidine dissolved in 5 ml of ethanol are drogwise added After 9-hour reaction, the precipitated potassium chloride is filtered ofd the ethanolic solution is clarified by activated carbon and evaporated. Afar taping up ia-mI of chloroform, the evaporation residue is washed 3 times with I00 ml of 1 N
sodium hydroxide solution each, then with 50 ml of water. After separation, the is . organic phase is dried over sodium sulfate, filtered and evaporated. The oily rtsi-due becomes crystalline on cooling. The crystals arc triturated with about ZO
mI
of ether, filtered and dried to give a beige product in a yield of 4.8 g (38.9%).
IR KBr Y cm-I: 3422, 3107, 2937, 2870, 28I9, 1640, 1479, 1391, 1309, 1194, -il-1123, IOS9,1042, 982, 916.
IH-NMR (DMSO-d6): 8.ss (du, IH, J1~I,8 HZ, 320.8 Hz, Ar (2) 1~, s.ss (an, 1H, Ar(6)H), 8.01 (dt, 1H, Ar(4~, 7.40 (ddd, 1H, Ar(5)H), 6.16 (broad, ZH, NHS, 4.00 (t, 2H, ~=6.6 Hz, OCH~, 2.43 (m, 2H, overlapped, s OCH2CH2I~, 2.33 (m, 4H, N-CH2CH2CH2CH2CH2), 1.77 (quintet, 2H, OCH2CH2CH~, 1.48 {m, 4H, N-CHZCH2CH2CH~, 1.40 (m, 2Fi, N-CH2CH2CH2CH2CH~ ppm.
13C ~ HMSO-d6): I49.9 (d, Ar), 149.0 (s, C-l~IH~,146.6 {d, Ar), I33.1 (d, Ar), 128.3 (s, Ar), 123.1 (d, Ar), 49.9 (t, OCH2), 553 (t, OCH2CH2CH2), 53.9 (t, OCH2CH2CH2-N-CHZ), 26.1 (t, OCH2CH2), 25.4 (t, N-CH2_ CH2CH2CH2CH2), 24.0 (t, N-CH2CH2CH2CH~ ppm.
B) 5.49 g (0.04 moles) of nicotinic acid amidoxime (Beilstein Handbook of Organic Chemistry Fifth Supplementary Series (Springer Verlag, Berlin, 1986-1996) E
III/IV 22, page 439) are added under stinting to a solution containing 2.24 g (0.04 males of potassium hydroxide is 30 ml of ethanol while stirring and, after complete disso-1s lution, 3.93 al (6.3 g, 0.04 moles) of I-chloro-3-bromopmpane are dropwise added during 15 minutes. After boiling the reaction mixture under reflex for 6 hours and then cooling down, the inorganic salt precipitated is filtered off and the solution is evaporated under reduced pressure. The residue is dissolved in 100 ml of chloroform, washed with s0 ml of 2 N sodium hydroxide solution, then SO ml zo of water, dried over sodium sulfate and evaporated.
The oily residue is dissolved at -s°C in a. mixture of 80 ml of distilled water and Z3 ml of 37% hydrochloric acid. To this salutian I3.79 g (0.2 moles) of sa-diem nitrite dissolved in 60 ml of water are dmpwise added at the same temper$-ture, then the reaction mixture is stirred at -s°C for additional 2 hours. Subse-ts quently, 150 ml of chloroform and 200 ml of sodium hydroxide solution are added and it is extracted. The organic phase is washed with s0 ml of water, dried over sodium sulfate and evaporated.
The obtained compound of formula (VII) [wherein Z = 3-pyridinyl, Y=X~I sad A~(CFi2}3] is dissolved in 100 ml of benzene, cooled to -10°C and 7.g 1 ml (6.81 g, 0.08 moles) of piperidine are dropwise added under stirring.
.After boiling the mixture under reflex for 8 hours, then cooling down, the solid piperidine hydrochloride precipitate is filtered off and thoroughly washed with s benzene, The filtrate is twice extracted with 200 mI of 3 N aqueous hydrochloric acid solution each. The combined aqueous phase is made alkaline upto pFi 10 by adding 4 N sodium hydroxide solution, then extracted twice with 150 ml of chlo-roform each. The combiaed chloroformic phase is dried over sodium sulfate, fil-feted and evaporated.
1a The brown oily n-sidue is purified by column chromatography (Merck Kie-seigel 60, eluent: chloroformlmethanol l : l ) to obtain 4.81 g (42.7°/) of base which is converted to the dihydrachloride salt as described in Example 3A.
Example 3 Preparation of N-methory~3-pyridinecarbo:clmldoyl c8>oride hydro-1s chloride A) A solution containing 2.5 g (13.3 mmoIes} of N-methoxy-3-pyridineear-boxamidine hydrochloride in the mixture of 3.7 ml of concentrated hydrochloric acid and 36 ml of water is cooled to S°C, then a solution of 1.14 g (16. 4 mmoles} of sodium nitrite in 6.5 ml of water is dropwise added and stirred at the xo same temperature for additional 30 minutes.
After layering 30 ml of chloroform to the mixture and then adjusting the pH-value to 8-9 by adding solid sodium carbonate, the chloroformic phase is separated, the aqueous layer is again extracted with 30 ml of chloroforms, then the combined chloroformic solution is washed with ~IO ml of saturated saline sole.
2s flop, dried over sodium sulfate and evaporated The obtained residue weighing 1.9 g is dissolved is 10 ml of isopropanol and 5.2 ml of 2.1 molar solution of hydrogen chloride in isopmpanol are added to obtain the hydrochloride salt in title in a yield of 1.06 g (36%), m.p.: 13b-I39°C.
3H-NMR (DMSO}: I 1.5 (broad, IH, NFi'~'), 9.06 (d, 1H), 8.9I (dd, Ice, 8.59 (m, .,~... wo 9sr~o6a9 ~ 1 ~ H f~ 5 2 rcrn~r9sroooia 1H), 7.93 (dd, 1H pyridine 2-6-4-5), 4.1 (s, 3H, CH3) ppm.
13C-~g {DMSO): 145.7, 142.1, 139,7, 129.8, 12b.0 (pyridine 2-6-4-3-5), 132.2 [C(CI~NO], 63.5 (CH3) ppm.
The above starting material is prepared as follows:
s The mixture containing 6.85 g (0.05 mmoles) of 3-pyridinecarboxamid-oxime, 3,37 g (0.06 moles) of potassium hydroxide, 3.15 ml (7.18 g, 0,051 moles) of methyl iodide and 100 ml of ethanol is stirred at mom temperature for 3 hours. After evaporation, the residue is dissolved in 100 ml of water, extracted 3 times with 100 ml of ethyl acetate each, the combined organic phase is washed 1o with 100 ml of 1 N sodium hydroxide solution, then twice with SO ml of satu-rated saline solution each, dried over sodium sulfate and evaporated.
The obtained residue (3.5 g) is dissolved in 50 ml of ether, clarified with activated carbon and again evaporated to obtain 3.14 g (42%) of solid product, m.p.: 49-56°C.
~s After dissolving the crude product in 30 ml of isopropanol, 9.8 ml of 2.1 molar solution of hydrogen chloride in isopropanol are added to obtain the hy-drochloride, which is then crystallized to give 3.38 g (36%) of the aimed hydro-chloride, m.p.: 158-164°C (recrystallized from methanoUether).
B) Gaseous chlorine is introduced in a slow flow for 30 minutes to the so-20 lution of 2.72 g (20 mmoles) of 0-methyl-nicotinealdoxime dissolved in 30 ml of chloroform. After evaporating the mixture to dryness, the residue is recrystallized from isopropanol to give the title hydrochloride in a yield of 2.4 g (58%), the physical characteristics of which are identical to those prepared by method A).
Example 4 2s Preparation of 0-(3-diethylaml~vpropyl)-3-pyridlnehydroiimoyl c6lo-ride hydrochloride 9.5 g (37.9 mmoles) of N-(3-diethylaminopropoxyr3-pyridinecarbox-amidine are added under stinxng to the mixture of 65 ml of distilled water and 21.7 ml of concentrated hydrochloric acid, cooled to 0°C. To the yellow solution 13.08 g (189.5 mmoles) of sodium nitrite dissolved in 54 ml of distilled water are dmpwise added at -5°C during 50 minutes, then the reaction mixture is stirred at a temperature of -5°C for 2 hours. Subsequently, the pH of the solution is ad-justed to I I by adding 2 N sodium hydroxide solution and the mixture is ex-s traded 3 times with 70 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate aad evaporated. The residue is purified TM
by column chromatography (adsorbent: Merck Kieselgel 60; eluent: chloro-formlmethanol 1:I~ The base obtained in a yield of 5.17 g (50,6°f°) is trans-formed by adding methanolic solution of hydrogen chloride to obtain the title lo hydrochloride, m.p.: i52-153°C.
IR (KBr) y cm I: 3044, 2937, 2752, 2533, 2658, 2492, 1587, 1477, 1416, I055, 1022, 976, i39?, 816, 704.
1H-NMR (DMSO-d6): I I.I {broad, 1H), 9.0 (dd, 1H, Ar-H), 8.7 (dd, IH, Ar-H
JI=5.3 Hz, J2=l.SHz), 8.I8 (dt, 1H, Ar-H, J=8.7 Hz,, J2~J3~1.5 Hz), 7~3 1s (dd, 1H, Ar I~, 4.45 (t, 2H, J=6.2 Hz, OCH~, 3.I (m, 2H, CH2CH2 I~, 3_1 (m, ZH, CH2CH3), 2.2 (m, 2H, OCH2-C~ ), 1.23 (t, 3H, J--72 Hz, ~3) PPm-I3C ~ ~~0~): 151.4 {d, Ar), 147.1 {d, Ar), I34_6 (s, C-Cl), I34.4 (d, A,r), I27.2 (s, Ar), 123.6 (d, Ar), 72.2 (t, OC_H~, 46.7 {t, _CH2N), 45.8 (t, zo N-CH2-CH3), 22.5 {t, CH2-CH2-CH2), 8.1 (q, CH3) ppm.
Example 5 Prep$ration of 0-{3-morpholinopropyl) 3-pyrIcii~nehydro=imoyl clalo-ride dlhydrochlorlde 2.5 g (9.45 mmoles) of N-(3-morpholinopropoxy)-3 pyridinecarboxamidine 2s are added to the mixture of I S ml of distilled water and 5.4I ml of concentrated hydrochloric acid cooled to O°C under stirring. To the yellow solution 326 g (47.25 mmoles) of sodium nitrite dissolved in 15 ml of water are dropwise added at a temperature of -5°C during 30 minutes. The reaction mixture is stirred at -IS--5°C for 2 hours. Then, the pH of the solution is adjusted to. l l by adding 2 N
sodium hydroxide solution and it is attracted 3 times with 5 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate and evaporated. An ethereal solution of hydrogen chloride is added to the evapo-s ration residue until reaching pH=2 value to obtain 2.42 g (71.8%) of the title di-hydrochloridc, mp.: 196-200°C.
IR {KBr) y cm' I : 3017, 2483, 2095, 1630, 1574, 1551, 1480, 1350, I28I, I l I
l, 1083, 980, 808, 7I4, 675.
IH-NMR {DMSO-d6): l L4 (broad, 1H), l L I5 (broad, IH), 9.i2 (d, 1H, J=1.5 to Hz), 8.92 (dd, IH, Jl=5.3 Hz, J2a5.3 Hz) 8.60 (dt, IH, J=8.7 Hz, J2=J3=1,5 Hz). 7.91 (dd. IH, 3I=8.7 Hz, 32=5.3 Hz), 4.44 (t, 2H, OC -~.2I ), 3.9 (m, 4H, N-CH2-CHZ-0), 3.44 (d, 2H, J=12.2 Hz, N-C~-CH2-0, equ), 3.3-3.0 (m, 2H, N-C -I~"2-CH2-0, ax.), 3.3-3.0 (m, 2H, CH2-CHZ-N), 2.3 (m, ~ ~2-~~-~?a pPm-Fs 13G-NMR (DMSp-d6): 146.6 (d, Ar), I43.0 (d, Ar), 139.3 (d, Ar), I33.3 (C-Cl), 129.7 (s, Ar), 125.7 (d, Ar), 72.8 (t, OC_H2), 62.9 {t, N-CH2-t~I2-0), 52.6 (t, CH2-CH2-N), 50.7 (t, N-_CH2-CH2-0), 22.6 (t, 0-CH2-C_H2-CH2 N) ppm.
Elementary analysis for C~3H18N30z.2HCl:
2o calculated: C 43.8; H 5.65; N 11.78%;
found: C 44.4; H 5.7; N I 1.9%.
The above starting substance is prepared as follows:
To the solution of 5.72 g (0.102 moles) of potassium hydroxide in 40 ml of ethanol 12.89 g (0.094 moles) of 3-pyridineaidoxime are added under stirring, 25 then, after dissolution, 15.6 g (0.0953 moles) of 1-(3-chloropropyl)morpholine dissolved in 10 ml of ethanol are dropwise added to the reaction mixture, which is boiled under reflux for 9 hours. The precipitated potassium chloride is filtered o~ the filtrate is clarif ed by using activated carbon and evaporated. After disso-lotion of the residue in 200 ml of ehlomform, the solution is washed 3 times with 100 mI of 1 N sodium hydroxide solution each, then 3 times with 100 ml of wa-ter each. After drying the orgaaic phase over sodium sulfate and filtering, the fil-trate is evaporated. The residue is purified by column chromatography s (adsorbent: Merck Kicselgel 60; eluent: chloroformlnzethanol 5:I). The purified base is crystallized from ether to obtain a yield of 3.6 g (14.49°~0), m.p.: 61-63°C.
1H NMR (DMSO-d6): 8.85 (d, IH, r 1.5 Hz, Ar), 8.62 (dd, 1H, Jz~.3 Hz, J2~1.5 Hz, Ar), 7.94 {dt, IH, Ja8.7 Hz, J2=J3=1.5 Hz, Ar), 7.31 (dd, 1H, 31.7 Hz, J2=5.3 Fiz, Ar), 4.96 (bmad s, 2H, N~, 4.16 {t, 2H, J$6.5 Hz, =N-O-CH,~, 3.70 {t, 4H, N-CH2-CH,~-O), 2.48 (t, 2H, Jg6.5 Hz, over-Lapped, N-0-CH2-CH2-CHI I~; 2.47 (m, 4H, N C~-GH2-O), L92 (m, 2H, O-CH2-C,~_CH~ N) ppm.
13C-NMR (DMSO-d6): 150.7 (d, Ark 14935 (s, _C-NHS, 147.0 (d, Ark i33.4 (d, Ar), I28.5 (s, Ar), 123.3 (d, Ar), 72.0 (t, =N-O-Cue, 66.9) t, N-CH2_ ~s C -I~-O), 55.8 (t, -O-CHZ-CH"~ I~, 53.7 (t, N-CH2-C~~-O), 26~ (t, N-O_ ~2-c~2) ppm-m le 6 _.
Preparation of 4-(Z-ptperidinoethy~ 3-pyridinehydrozimoyl chloride hydrochloride 2.6 g (10.47 mmoles) of N-(Z-piperidino~thoxy)-3-pyridinecarboxamidine are added under stirring to the mixuu~e of I7 ml of distilled water sad 6 ml of concentrated hydrochloric acid, cooled to 0°C. Then, 3.62 g (52.45 nzmoles) of sodium nitrite dissolved in 15 ml of distilled water are dropwise added at -5°C
during 30 rninutes_ After adjusting the pH value to 1 I by adding 2 N sodium hy-2s droxide solution, the mixture is extracted 3 times with 50 ml of chlomform each.
The organic phase is washed with 30 ml of water, dried aver sodium sulfate and evaporated. The evaporation residue weighing 138 g (49.23%) is transformed to the tide hydrochloride salt, m.p.: 149-150°C (crystallized from ether) by adding methanolic hydrogen chloride solutioa IR (KBr) Y cm-I: 3433, 2945, 2633, 2540, 1587, 1450, 1414, 1271, 1459,1038, 1007, 954, 920, 822, 706.
1H-NMR (DMSO-db): 11.12 (broad s, 1H), 9.03 (d, 1H, J--1.5 Hz, Ar), 8.72 (dd, s 1H, J1~5.3 Hz, J2~1.5 Hz), 8.20 (tit, J=8.7 Hz, J2 J3~1.5 Hz, Ar}, 7.52 (dd, 1H, J1~8.7 Hz, J2~53 Hz, .Ark 4.38 (t, J=5.0 Hz, OC I~, 3.48 (t, 3--5.0 Hx, overlapped CH2-CHI I~, 3.5-3.0 (m, 4H, N-CH."~-CH2CH2), 2.0-1.6 (m, 4H, N-CH2-CH2CH2), 1.20 (m, ax., H, N-CH2CH2CH~ PPS
I3C..~ (D~p-~); I51.6 (d, Ar), 147.3 (d, Ar), 135.8 (s, C-Cl}, 134.S (d, to Ar),12?.6 (s, Ark 123.6 (d, Ar), 69.7 (t, OCH~, 53.9 (t, CH2-C_Fi2l~, 52.2 (t, N-CH2-CH2CH~, 22.0 (t, N-CH2-C_H2CH~, 20.9 (t, N-CH2-CH2CH2) PPm-Elementary analysis for C13H18N30CLHCI:
calculated: C S 1.33; H 6.30; N I3,8I %;
~s found: C 51.4; H 6.3; N I3.8%.
The above starting substance is prepared as follows:
After dissolving 6.45 g (4?.0 mmoles) of 3-pyridinecarboxamidine in 120.4 ml of 0.83 N potassium hydroxide solution in ethanol under stirring, 8.6s g (47.0 mmoles) of 1-(2-chloroethyl)piperidine hydmohloride are added under stzrring, 2o then tile reaction mixture is boiled under reflux for 4 hours. The precipitated po-tassium chloride is filtered off, the filtrate is clarified by activated.-carbon and evaporated. The residue is dissolved in 100 ml of chlamform and the organic solution is washed 3 times with 100 ml of 1 N sodium hydroxide solution each, then with 50 ml of water. The organic phase is dried over sodium sulfate and 25 evaporated. The residue is purified by column chromatography (adsorbent:
TM
Merck Kieselgel 60; eluent: chlomform/methanol 3:1). The purified pmduct is recrystallized from ether to give 2.69 g (Z3.S%) of the aimed product, m. p.:

83°C. (from ether).

1H-NMR (DMSO-d~): 8.86 (d, 1H, J=1.5 Hz, Ar), 8.60 (dd, 1H, J1=5.3 Hz,-32=1.5 Hz, Ar), 7.93 {dt, 1H, J=8.7 Hz, J2=J3=1.5 Hz, At), ?.28 (dd, IH, Jl=8.7 Hz, J2=5.3 Hz, Ar), 5.16 (broad s, 2H, NIA, 4.23 (t, 2H, J=5.9 Hz, =N-0-CHI, 2.70 (t, 2H, J=5.9 Hz, O-CH2-C i~-N), 2.48 (m, 4H, N-C i~"2-s CHZ-CHI, 1.57 (m, 4H, N-CH2-CH2-CH2), 1.43 (m, 2H, N-CH2-CH2_ ppm I3C-~ (DMSO-ds): 150.6 (d, Ar), 149.8 (s, C_-NHS, 147.1 (d, Ar), I33,4 (d, Ar), 128.6 {s, Ar), 123.2 (d, Ar), 71.3 (t, =N-0-CIA, 54.9 (t, -0-CH2--CH2-N-~H~, 25.8 (t, -N-CH2-~Hx-O), 24.1 S (t, -N-CH2-CH?-'CHI
io ppm.
Example 7 Prepar$tion of o-(3-~piperidinaprQpyi)-3-nitro-benz6ydrozimoyl cl~lor-ide hydrochloride 3.2Z g (10.5 mmoles) of N-(3-piperidinopmpoxy)-3-nitrobenzamidine are 1s added under stirring to a mixture of 15 ml of distilled water and 15 ml of concen-trated hydrochloric acid, cooled to 0°C. Then, 3.62 g (52.05 mmoles) of sodium nitrite dissolved in 10 ml of water are dropwise added to the reactioa mixture at -5°C during 30 minutes. 'The pH value of the solution is adjusted to 10 by adding 2 N sodium hydroxide solution, then it is extracted 3 times with 50 ml of ehloro-20 . form tech. The organic phase is washed with 30 ml of water, dried over sodium sulfate and evaporated. The evaporation residue is purified by column chroma-tography (adsorbent: Merck Kieselgel 60; eluent: chloroform/methanol 1:I). The obtained base weighing 1.7 g (49.7%) is transformed to the title hydrochloride by adding as ethereal solution of hydrogen chloride, m.p.:173-175°C.
2s IR (KBr) y cm-1: 3424, 2926, 2953, 2649, 2546, 1614, 1591, IS33, 1452, 1354, 1295,1252,1049, 994, 733.
1H-NMR (DMSO-d5): 10.75 {broad s), 8.5I (t, J1=.i2=1.9 Hz, Ar), 8.40, 8.25 21 ~~~b52 ~~- WO 95/30b49 PCT/HU95/00014 (dd, 2H, J1=8.1 Hz, J2=1.9 Hz), 7.81 (t, J1=J2=8.1 Hz), 4.44 (t, J=6.2 Hz), 3.45 (m, 2H, CH2NCH2), 3.15 (m, 2H, CH2NCH2), 2.85 (m, 2H, CH2-NCH2), 2.25 (m, 2H, OCH2GH,2CH2N), 2.0-1.6 (m, 5H), 1.4 (m, 1H, N-CH2CH2CH2CH2CH2) ppm.
s 13C_~ (DMSO-db): 147.1 (s, Ar), 134.9, 132.9 (s, C-Cl), 134.9 (s, Ar), 132.7, 130.5 (d, Ar), 125.3 (d, Ar), 121.0 (d, Ar), 72.7 (t, OCH2), 52.6 (t, CH2-N), 51.6 (t, N-C_H2CH2CH2CH2GH2), 22.9, 21.2 (t, OC_H2CH2), 22.9, 21.2 (t, N-CH2CH~H2CH2CH2 and OCH2-CH2 ), 22.0 (t, N--CH2CH2CH2CH2CH2) PPm.
to Example 8 Preparation of N-[3-(1-piperidinyt)propoay] 3'-(triftuoromet6yl)benz-imidoyl chloride hydrochloride To a solution containing 4 g (11.0 mmoles) of N-[3-(1-piperidi nyl)propoxy]-3'-(trifluoromethyl)benzamidine hydrochloride in the mixture of is ml of distilled water and 10 ml of concentrated hydrochloric acid 2.07 ml of 40%
aqueous sodium nitrite solution are dropwise added at a temperature of -5°C un-der stirring. The reaction mixture is stirred at -5°C and then 3 times an additional amount 1 ml of the above sodium nitrite solution each is added every 2 hours.
After additional stirring for 4 hours, the excess of the reagent is decomposed with 2o urea, then the solution is diluted with 35 ml of water and extracted twice with 35 ml of ether each. The aqueous phase is alkalinized by adding 4 N sodium hydrox-ide solution and extracted 3 times with 40 ml of ethyl acetate each. The organic phase is washed 3 times with 20 m! of water each, 4 times with 30 ml of buffer solution (pH=5) each, then washed with 20 ml of saturated saline solution, dried 2s over sodium sulfate and evaporated. The residue is transformed by adding a methanolic solution of hydrogen chloride to obtain the title compound in a yield of 2.56 g (60%), m.p.: 124-129°C (from ethyl acetate).
IR (KBr) y cm-1: 3425 (broad), 2941, 2648, 2548, 1333, 1244, 1165, 1123, 1072, 995, 984, 802, ?09, 698.
1H-NMR (DMSO-d~: 11.4 (1H, broad, NH), 8.I3 (1H, d, 3=8.0 Hz), 8.05 (IH, s}, 7.92 (d, IH, 3=8 Hz), 7,76 (t, 1H, 3=8 Hz), Ar), 4.40 (t, 2H, J=6 Hz), OCH~, 3.50-3.35 {m, 2H), 3.2-3.0 (m, 2H}, 2.95-2.75 (m, 2H, 3xNCH~, s 2.35-2,15 (m, 2H, CH2), 2.0-1.6 (m, SH), 1.5-I25 {m, IH, 3xCH2lpipe-ridine) PPm.
13GNMR (DMSO-d6): 135.4 [C(C1~N0], 132.5, 130.7, 130.1, 129.4 (q, 3=32 Hz), 127.4 {q, J=3.5 Hz), 122.8 {q, 3--3,8 Hz, Ar), 123.5 (q, J=270,8 Hz, CF3), ?2.6 (OCH2), 52.7, SLb (?acNCH~, 22.9, 22.0, 21.2 (3xCH~ ppm.
ro Elementary analysis for Ci6HzoNz~F3Cl.HCI:
calculated: C 49.88; H 5.49; N 7.27%;
found: C 49.8; H 5.6; N 7.6'0.
The above starting substance can be prepared as follows:
A solution containing 8.0 g (40 mmoles) of 3-(trifluoromethyl)benzamid-rs oxime, 4.68 g (29.0 mmoies) of N-(3-chloropropyt)piperidine and L68 g (29.8 mmoles} of potassium hydroxide in 100 ml of ethanol is boiled under reflex for 2.5 hours. After filteri.~g off the potassium chloride precipitated, the filtrate is evaporated to dryness under reduced :presswe. The residue is recrystaliized from water, filtered, washed with water and dried The crude base obtained in a yield 20 of I L 1 g (86%), m.p.: 53-62°C, is dissolved in 22 ml of ethyl acetate and acidi-fied with ?.8 ml of 4.3 molar methanolic hydrogen chloride solution. After evaporation, the pmduct is reciystallized from pure ethyl acetate to give 6.1 g (42.5°/) of the aimed pmduct.
(IR KBr) y cm 1: 3412, 3082 {broad), 2949, 1655, 1325, 1171, 1121, 1072, 986, zs 920, 905, 808, 700.
lI~-NMR (DMSO.-d6): 8.00 (s, lI~, 7.98 (d, IH, J=8.0 Hz), 7,75 (d, 1H, J=8.4 Hz), 7.62 (t, 1H, J=8.0 Hz, Ar), 6.23 (s,~2H, NHS, 3.98 (t, 2H, J=6 Hz, OCH2), 2.45-2.25 (m, 6H, 3xNCH2}, I.79 (quintet, 2H, 3=7 Hz, CH2), l.fi-1.3 (m, 6H, 3xCH2lpiperidine) PPS
13GNMg (DMSO-d6): 149.6 [C{NH~NO], 133.4, 129.5, 129.1, 128.8 {q, 3=32 ~), 125.5 (q, J-3.5 Hz) and 121.9 (q, J=3.8 Hz, Ar), 123.9 (q, J--270.8 Hz, CF3), 70.8 (OCII~, 55.1, 53.8 (2xnCH2), 26.0, 25.3, 23.9 s (3xCH~ pptn.
Elementary analysis for C16Hz2N30F3.HCl:
calculated: C 52.53; H 6.34; N 11.49%;
found: C 52.I; H 63; N 11.2%.
E~aglple 9 to Preparation of N-[3-(4..methylpiperaz~-1 yl)..1-propory]-3 pyridlne-carboxlmldoyl chloride trlhydroc6loride L5 g (5.4 mmoles) of N-j3-(4-methylpiperazin-1-yI)-1-propoxy]-3-pyri-dinecarboxamidine are added under stirring to a mixture containing IO ml of distilled water and 14 ml of concentrated hydrochloric acid, cooled to 0°C. To is the yellow solution 1.86 g (0.027 moles) of sodium nitrite dissolved in 5 ml of distilled water are dmpwise added at -5°C temperature during 30 minutes. After stirring the reaction mixture at -5°C for 1.5 hours, the pH value of the solution is ad3usted to 10 by adding 2 N sodium hydroxide solution and extracted 3 limes with 50 ml of chloroform each. The organic phase is washed with 30 ml of water, 2o dried over sodium sulfate and evaporated. After dissolving the residue in ethyl acetate, the title compound is precipitated by adding ethereal hydrogen chloride solution until pH 2. The precipitate is filtered, washed with ether and recrystal-Iized from 80 ml of ethanol after clarifying with activated carbon to obtain the title trihydmchloride in a yield of 1.0 (45.7%).
as 1H NMR (DMSO-d6): 9.06 (d, 1H, J=1.6 Hz, Ar), 8.80 (d, 1H, J---4.9 Hz, Ar), 8.36 (dt, 1H, Jl=8.2 Hz, J~J3=1.6 Hz, Ar), 7.72 (dd, IH, Jl=8.2 Hz, J2=4.9 Hz, Ar), 4.43 (t, 2H, 7=6.3 Hz, OCH2), 3.65 (broad, 8H, NCH2CH2), 3.3 {t, 2H, J=7.8 Hz, CH2CH2CH2N), 2.84 (s, 3H, CH3), 2.30 {m, ZH, CH2CH2CHl) PPS
13C ~ (DSO-~): 149.0 {d, Ar}, 145.01 (d, Ar), I36.9 (d, Ar}, 133.9 (s, C=N}, 128.7 (s, Ar) 124.7 (d, Ar), 72.4 (t, OCH2}, 52.4 (t, CH2 I~, 49.2, 47.8 (t N-CHZ-_CH2N), 4L7 (q, N-CH3), 22_9 (t, CH2CH2CH~ Ppm.
s The above starting substance can be prepared as follows:
2.74 g (0.02 moles) of 3-pyridinealdoxime me added to the solution of 1.24 g (0.022 moles) of potassium hydroxide in 30 ml of ethanol. After dissolution, 3.15 g (0.02 moles) of N-methyl-N-(3-chioropropyl)piperazine dissolved in IO
ml of ethanol are dropwise added to the reaction mixture during about 10 min-io ores. The mixture is boiled under reflex for 11.5 hours while stirring. The pre' cipitated potassium chloride is filtered off, the filtrate is clarified by the means of activated carbon and Celite~ filtering aid and then evaporated in a mtavapor equipment. The residue is dissolved in 100 ml of chloroform, washed twice wifh 30 mi of 2 N sodium hydroxide solution each, then with 30 mI of water, the or-1s ganic phase is dried over sodium sulfate and evaporated. The residue is purified TM
by column chromatography (adsorbent: Merck Kieselgel 60; eluent~ a mixture of chloroform, methanol and concentrated ammonium hydroxide in a ratio of 30:5:0.2) to obtain 1.72 g (31.0%) of product.
1R (ICBr) Y cm-1: 3387, 2947, 2802, 1730, 1639, 1450, 1389, 1283, 1242, 1194, zo 1150, 1083, 814, 710.
1H-NMR (DMSO-d6): 8.85 (d, 1H, 3=2.0 Hz, Ar), 8.b1 (dd, IH, J1~4.9 Hz, 32=2.0 Hz, Ar), 7.95 (dt, 1H, 3I=7.7 Hz, J2=J3=2.0 Hz, Ar), 7.29 (dd, 1H, J1~7.7 Hz, J2=4.9 Hz, Ar), 5.1 (bs, 2H, NH2), 4.13 (t, 2H, J~,4 Hz, OC -Ice), 2.5 (m, l OH, J~5.9 Hz, -OCH2-CH2CH2, 2xNCH~-CSI N), 2.27 2s (s, 3H, (CH3~ 1.95 (m, 2H, -CH2_CH2CH2) PPm.
13C-NMR (DMSO-d~): 150.5 (d, Ar), 149.3 (s, C--N), 146.9 (d, Ar), 133.3 (d, Ar}, 128.5.{s, Ar), 123_1 (d, Ar), 72.0 (t, OC_H~ 55.2 (t, OCH2CH~CH~, 2~ ~'~b52 -. wo 95r3o649 54.9 (t, 2xNf H2CH2N), 53.0 {t, 2xNCH~H2N), 45.9 {q, N-~H3), 26.5 {t, -OCH2-CH2CH2) PPm.
E~le 10 Preparation of 0-(2,2-dimet6yl-3-piperidinopropyl~.3-pyridinecarbo-s hydrozimoyl chloride To a solution containing 2.23 g (7 63 mmoles) of N-(2,2-dimathyl-3 piperi-dinopropoxy)-3-pyridinecarboxamidine in 30 ml of a 1:1 mixture of concentrated hydrochloric acid and water 2.63 g (38.2 mmoles) of sodium nitrite dissolved in ml of water are dropwise added at 0°C. The reaction mixture is stirred at the io same temperature for additional 2 hours, then the pH value is adjusted to 12 by adding 2N sodium hydroxide solution and the mixture is extracted twice with 30 ml of chloroform each. The organic phase is washed with 30 ml of water, dried over sodium sulfate, filtered and evaporated. The oily residue (1.83 g) is purified by column chromatography to give the title compound as a pale yellow oil in a ~s yield of 1.62 g (68.5%).
IR (KBr) Y cm-1: 3433, 2934, 2783, 1583, 1475, 1416, 1271, 1157, 1113, 1055, 1034, 1003, 914, 860, 806, 704.
1 H-NMR (CDC13): 9.06 ( 1 H, dd, J 1=2.4 Hz, J2=1.0 Hz, pyridine 2-H), 8.61 ( 1 H, dd, J 1=4.8 Hz), J2=1.7 Hz, pyridine 6H), 8.08 ( 1 H, ddd, J 1=8.1 Hz, 2o J2=2.4 Hz, J3=1.7 Hz, Pyridine 4-H), 7.30 (1H, ddd, J1=8.1 Hz, J2=4.8 Hz, J3=1.0 Hz, pyridine SH), 4.14 {2H, s, OCH2), 2.46 (4H, t, J=4.9 Hz, piperidine), 2.18 {2H, s, CH2N), 1.55 (4H, m, piperidine), 1.37 (2H, m, piperidine), 0.94 {6H, s, CH3) ppm.
The above starting material is prepared as follows:
2s 2.74 g (0.02 moles) of pyridine-3-amidoxime are added under stirring to a solution of 2.46 g (0.044 moles) of potassium hydroxide in 40 ml of abs.
ethanol under stirring. After dissolution, 4.52 g (0.02 moles) of (1-(2,2-dimethyl-3-chloropropyl)-piperidine hydrochloride are pordonwise added, then additional ~~ ~~~'J6~J2 wo 9sr~osa9 rcTn~ua ml of ethanol are added. After boiling the heterogeneous mixture under reflux for 11 hours, the solid precipitate is filtered off, washed with ethanol and the solu-tion is evaporated. After adding I00 ml of chloroform to the residue, the solution is washed twice with 100 ml of 2 N sodium hydroxide solution each, then 50 ml s of water. The organic phase is dried over sodium sulfate, filtered and the solution obtained is evaporated. The oily brown residue is purified by column chromatog-raphy to give the pale yellow oily product in a yield of 2.23 g (38.4%).
IR (KBr) Y cm-1: 3323, 2935, 2866, 2785, 1637, 1477, 1393, 1157, 111, 1057, 995, 943, 8I4, 708.
~0 1H-NMR (CDC13): 8.87 (1H, dd, J1=2.2 Hz, J2~.7 Hz, Pyridine-2H), 8.60 (1H, dd, J1=4.8 Hz, J2=1.7 Hz, Pyridine-6-H), 7.93 (1H, ddd, Jl=8.1 Hz, J2=2.2 Hz, J3=1. 7 Hz, Pyridine-4-H), 7.30 ( 1 H, ddd, J 1=8.1 Hz, JZ=4.8 Hz, J3=0.7 Hz, pyridine-5-H), 4.89 (2H, bs, NH2), 391 (2H, s, OCH2), 2.48 (4H, t, J~.8 Hz, piperidine), 2.17 (2H, s, CCH2N), 1.55 (4H, m, piperidine), 1.44 is (2H, m, piperidine), 0.95 (6H, s, CH3), ppm.

Claims (28)

CLAIMS;

1. A compound of the formula wherein X means halogen;

Z stands for unsubstituted phenyl; benzyl;
phenylethyl; phenyl, benzyl or phenylethyl substituted with one to three identical or different groups selected from halo, halo-C1-8 alkyl, C1-8 alkyl, hydroxy, C1-4 alkoxy, nitro, amino, mono- or di-C1-4 alkylamino; C1-8 alkylphenyl;
naphthyl; unsubstituted pyridinyl; or pyridinyl substituted with one or more methyl; and R represents a C1-8 alkyl or phenyl-C1-8 alkyl group or an -A-N (R1) R2 group, and in the latter;

R1 and R2 stand, independently from each other, for hydrogen or C1-8 alkyl group; or R1 and R2, together with the adjacent nitrogen atom, form a 5- to 7-membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said heterocyclic group optionally being substituted by at least one C1-8 alkyl group; and A stands for a straight or branched chain C1-8 alkylene group or a pharmaceutically acceptable acid addition salt thereof;

with the proviso that:

(i) when X is C1 and R is methyl, Z is not phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-t-butylphenyl, or 4-nitrophenyl;

(ii) when X is C1 and R is ethyl, Z is not naphthyl;

(iii) when X is C1 and R is n-propyl, Z is not phenyl or 4-methylphenyl;

(iv) when X is C1 and R is i-propyl, Z is not phenyl;

(v) when X is Br and R is methyl, Z is not phenyl;
and (vi) when R is an alkyl, Z is not phenyl singly substituted with fluoro-C3-8 alkyl.

2. A compound or salt of formula (I) according to claim 1, wherein Z stands for pyridinyl or pyridinyl substituted with one or more methyl.

3. A compound or salt of formula (I) according to claim 2, wherein Z stands for a 3-pyridinyl.

4. A compound or salt of formula (I) according to any one of claims 1 to 3, wherein R represents an -A-N(R1)R2 group, where R1 and R2 together with the adjacent nitrogen form a piperidino, piperazino or morpholino group.

5. A compound or salt of formula (I) according to any one of claims 1 to 4, wherein A means a C1-5 alkylene group.

6. N-benzyloxy-pyridinecarboximidoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

7. N-(3-piperidinopropoxy)-3-pyridinecarboximidoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

8. N-methoxy-3-pyridinecarboximidoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

9. O-(3,3-dimethylaminopropyl)-3-pyridinehydroximoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

10. O-(3-morpholinopropyl)-3-pyridinehydroximoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

11. O-(2-piperidinoethyl)-3-pyridinehydroximoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

12. O-(3-piperidinopropyl)-3-nitro-benzhydroximoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

13. N-[3-(1-piperidinyl)propoxy]-3'-(trifluoromethyl)-benzimidoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

14. N-[3-(4-methylpiperazin-1-yl)-1-propoxyl]-3-pyridine-carboximidoy1 chloride or a pharmaceutically acceptable acid addition salt thereof.

15. O-(2,2-dimethyl-3-piperidinepropyl)-3-pyridine-carbohydroximoyl chloride or a pharmaceutically acceptable acid addition salt thereof.

16. A pharmaceutical composition, which comprises as active ingredient a compound or salt of any one of claims 1 to 15, together with a pharmaceutically acceptable carrier or additive.

17. A pharmaceutical composition according to claim 16 for the treatment of an ischaemic state or disease in a mammal.

18. A process for the preparation of a compound of formula wherein X means halogen;

Z stands for unsubstituted phenyl; benzyl;
phenylethyl; phenyl, benzyl or phenylethyl substituted with one to three identical or different groups selected from halo, halo-C1-8 alkyl, C1-8 alkyl, hydroxy, C1-4 alkoxy, nitro, amino, mono- or di-C1-4 alkylamino; C1-8 alkylphenyl;
naphthyl; unsubstituted pyridinyl; or pyridinyl substituted with one or more methyl; and R represents a C1-8 alkyl or phenyl-C1-8 alkyl group or an -A-N (R1) R2 group, and in the latter;

R1 and R2 stand, independently from each other, for hydrogen or C1-8 alkyl group; or R1 and R2, together with the adjacent nitrogen atom, form a 5- to 7-membered, saturated heterocyclic group optionally containing an additional nitrogen, oxygen or sulfur atom, said heterocyclic group optionally being substituted by at least one C1-8 alkyl group; and A stands for a straight or branched chain C1-8 alkylene group, or a pharmaceutically acceptable acid addition salt thereof, which process comprises:

a) treating a compound of formula wherein Z and R are as defined above, or an acid addition salt thereof, with a diazotizing agent in the presence of a hydrogen halide or b) reacting a compound of the formula wherein X and Z are as defined above, with a compound of the formula R - Y

wherein R is as defined above and Y means a leaving group, in the presence of an acid binding agent; or c) treating a compound of the formula or a compound of formula Z-CH=NOR (VI) , wherein Z and R are as defined above, with a halogenating agent; or d) reacting a compound of formula wherein Z, X, Y and A are as defined above, with an amine of formula NH (R1) R2, where R1 and R2 are as defined above, to obtain a compound of formula (I), wherein R means an -A-N (R1) R2 group;

with the proviso that:

(i) when X is Cl and R is methyl, Z is not phenyl, 4-methoxyphenyl, 4-methylphenyl, 4-chlorophenyl, 4-t-butylphenyl, or 4-nitrophenyl;

(ii) when X is Cl and R is ethyl, Z is not naphthyl;

(iii) when X is Cl and R is n-propyl, Z is not phenyl or 4-methylphenyl;

(iv) when X is Cl and R is i-propyl, Z is not phenyl;

(v) when X is Br and R is methyl, Z is not phenyl;
and (vi) when R is an alkyl, Z is not a phenyl singly substituted with fluoro-C3-8 alkyl, and, if required, converting the obtained product prepared according to any of the above processes a), b), c) or d), respectively, to a pharmaceutically acceptable acid addition salt.

19. Use of a therapeutically effective amount of a compound or salt according to any one of claims 1 to 15 for treating an ischaemic state or disease in a mammal.

20. Use of a therapeutically effective amount of a compound or salt according to any one of claims 1 to 15 in manufacture of a medicament for treating an ischaemic state or disease in a mammal.

21. A commercial package comprising a pharmaceutically effective amount of a compound or salt according to any one of claims 1 to 15 together with instructions for use thereof for treating an ischaemic state or disease in a mammal.

22. N-(3-piperidino-1-propoxy)-3-pyridinecarboxamidine, or an acid addition salt thereof.

23. N-methoxy-3-pyridinecarboxamidine, or an acid addition salt thereof.

24. N-(3-morpholinopropoxy)-3-pyridinecarboxamidine, or an acid addition salt thereof.

25. N-(2-piperidinoethoxy)-3-pyridinecarboxamidine, or an acid addition salt thereof.

26. N-[3-(1-piperidinyl)-propoxy]-3'-(trifluoromethyl)benzamidine, or an acid addition salt thereof.

27. N-[3-(4-methylpiperazin-1-yl)-1-propoxy]-3-pyridinecarboxamidine, or an acid addition salt thereof.

28. N-(2,2-dimethyl-3-piperidinopropoxy)-3-pyridinecarboxamidine, or an acid addition salt thereof.