CA1330081C - Bicyclic heterocyclyl containing n-(bicyclic heterocyclyl)-4-piperidinamines - Google Patents

Abstract

ABSTRACT

BICYCLIC HETEROCYCLYL CONTAINING N-(BICYCLIC HETEROCYCLYL)-4-PIPERIDINAMINES.

Bicyclic heterocyclyl containing N-(bicyclic heterocyclyl)-4-piperidinamines having antihistaminic and serotonin-antagonistic properties which compounds are useful agents in the treatment of allergic diseases.

Description

- 1 3300~1 -BICYCLIC HETEROCYCLYL CONTAINING ~-~BICYCLIC ~ETEROCYCLYL)-4-PIPERIDINAMINES.

BacXground of the lnvention:
In U.S. Patent No. 4,219,559 there are described a number of N-heterocyclyl-4-piperldinamines having the formula r rl2 l-N ~ I ~NI ~ V~ ~ n which compounds are useful as ant.ihistaminic.agents.
The compounds of the present invention differ from the prior art compounds essentially by the nature of the l-piperidinyl substituent and by the fact that the compounds of the present invention are not only potent histamine-antagonists but also potent serotonin-antagonists.

1 3300~ ~

Descriptlon of the preferred embodiments:
This inventio~ is concerned with novel N-heterocyclyl-4-piperidinamines which may struct~rally be represented by the formula 3~

the pharmaceutically acceptable acid addition salts and the possible stereochemically isomeric forms thereof, wherein:
A =A -A =A is a bivalent radical having the formula -CH=CH-CH=CH- (a), -N=CH-CH=CH- . (b), -CH8N--CH=CH- ( c ), -CH=CH-N=CH- . (d), or -CH=CH-CH=N- (e), wherein one or two hydrogen atoms in said radicals (a) - (e) may, each independently from each other, be replaced by halo, lower alkyl, lower alkyloxy, trifluoromethyl or hydroxy;
R is a member selected from the group consisting of hydrogen and lower alkyl~
R is a member selected from the group conSisting of hydrogen, alkyl, cycloalXyl, Ar and lower alkyl substltuted with one or two Ar radicals;
R is a member selected from the group consisting of hydrogen, lower alkyl, cycloalkyl, (lower alkyl)-CO-, lower alkyl-O-(CO)- and Ar -lower alkyl~
L is a membsr selected from the group consisting of a radical of formula Het-CsH2s~N ~ (f);
( 2)n a radical of formula Het CsH28 (g); and a radical of formula ~ 3300~ ~

Het-CsH2s-Z-C-Y-Alk- (h~, wherein n is 0 or the integer 1 or 2;
s is 0 or an integer from 1 to 6 inclusive;
Alk is lower alkanediyls Y is O, S, NR or a direct bond;
X is O, S, CH-NO2 or NR 1 Z is O, s, ~R5 or a direct bond; and Het is an opti.onally substituted five- or six-membered heterocyclic ring containins at least one nitrogen atom and being condensed with an optionally substituted five- or six-membered ring, provided that:
i) when Het is connected to C H2 on a carbon atom then said five- or six-membered ring is not condensed with an optionally substituted benzene ring;
ii) when L is a radical either of formula tf), or of formula tg) wherein Y is other than a direct bond, or of formula ~h) wherein Z is other than a direct bond, wherein in said radicals tf), tg) or (h) Het i8 connected to C H2 on a nitrogen atom then.s is not Ot iii) when AlsA2-A3-A4 is a radical of formula ta) or tb) and L is a radical of formula ~g) wherein s is 0 and Y is a direct bond then Het i8 other than a 2,3-dihydro-2-oxo-lH-benzimidazol-l-yl or a 2,3-dihydro-3-oxo-benzoxazln-4-yl radical;
said R3 being hydrogen, lower alkyl, (Ar2)1Ower alkyl, 2-lower alkyloxy-1,2-dLoxoethyl or a radical of formula -Ct~X)-R , R
being hydrogen, lower alkyl, Ar , Ar -lower alky~, lower alkyloxy, Ar2-lower alkyloxy, mono- or di(lower alkyl)amino, Ar -amino, Ar -lower alkylamino or Ar -lower alkyltlower alkyl)amino;
said R4 being hydrogen, lower alkyl, cyano, nltro, Ar -sulfonyl, lower alkylsulfonyl, lower alkylcarbonyl or Ar2-carbonyl~ and said R being hydrogen or lower alkyl~
wherein Ar is a member selected from the group consisting of phenyl, being optionally substituted with up to three substituents each 1 3300~ 1 independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alh~l, lower alkyloxy, lower alkylthio, mercapto, amino, mono- and di(lower alkyl)amino, carboxyl, lower alkyloxycarbonyl and lower alkyl-CO-; thienyl;
halothienyl; furanyl; lower alkyl substituted furanyl; pyridinyl;
pyra~inyl; thia~olyl and imidazolyl optionally substituted by lower alkyl; and wherein Ar is a member selected from the group consisting of phenyl being optionally substituted with up to three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, mercapto, amino, mono- and di(lower alkyl)amino, oarboxyl, lower alkyloxycarbonyl and (lower alkyl)~CO.
As used in the foregoing definitions the term halo is generic to fluoro, chloro, bromo and iodo; the term "lower alkyl" is meant to include straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, l-methylethyl, l,l-dimethylethyl, propyl, 2-methylpropyl, butyl, pentyl, hexyl and the likeJ "alkyl" is meant to include lower alkyl radicals, as deflned herelnabove, and the higher homologs thereof havlng from 7 to 10 carbon atoms; the term "cycloalkyl" is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclohexylJ and "lower alkanediyl" is meant to lnclude bivalent stralght or branch chalned alkanediyl radlcals having from 1 to 6 carbon atoms.
It is evident that in the compounds of formula (I) the bicycllc condensed ring system may be unsaturated or partly or completely saturated.
The compounds of formula (I) wherein Het ls a heterocycle which is substituted wlth a hydroxy, mercapto or amino radical may contain in their structure a keto-enol tautomeric system or a vinylog system thereof and conse~uently these compounds may be present in their keto form as well as their enol form.

Preferred co~pounds within the invention are those whereln Het ls a member of the group consisting of ~ ~1-l), ~ ~ (1-2), ~ ~ (1-3), ~ ~ l3 (1-4), B ~ ~ lS (1-5), 3 ~ (1-5), lS ~ Rl ~ (1-8~, ~nd ~ o(1~9 wherein each Xl is Lndependently O or S;
R , R , R , R and R are each independently hydrogen, lower alkyl, Ar2-lower alkyl, hydroxylower alXyl or lower alkyloxycarbonyl~
R9 Rll Rl2 Rl3 Rl4 Rl5 Rl6 and Rl8 are each lndependently hydrogen, lower alkyl, hydroxy, mercapto, ~ower alkyloxy, lower alkylthlo, halo and (lower alkyloxycarbonyl)lower alXyl;
25 Bl i9 -CHeCH-CH=cH-, -S-cH-CH- or -N=CH-NH-~B is -CH-CH-CH-CH-, -S-(CH2)2, -S-(CH2)3 , or -(CH2)4;
B ls -CH~CH-CH-CH-, -CH~N-CH=CH-, -CH2-NH-(CH2)2-, -S-CH=CH- or -N=CH-CH=CH-;
B is -CH2-NH-(CH2)2-, -N=CH-CH=CH- or -N=CH-N=CH-;
B is -N=CH-CH=CH-, -CH=CH-N=CH- or -CH=N-CH=N-;
B is -CH-CH-CH~CH- ox -CH-N-CH=N-; 2 3 4 wherein one or two hydrogen atoms in said radicals Bl, B , B , B , B or B or in the benzene part of the radicals of formula (1-2), (i-3) or (i-9) may be replaced by lo~er alkyl, lower alkylthlo, lower ~, 1 3300~ 1 alkyloxy or halo where said hydro~en atom is bonded on a carbon atom~
or by lower alkyl, lower alkyloxycarbonyl, Ar2-lower alkyl, where said hydrogen is bonded on a nitrogen atom.
It is clear tha~ R , R , R12, R13 R14 R15 R16 R17 18 where the radical of formula (i-l), respectively (i-4), (i-5), (i-6) and (i-7) is connected to C H2 on the atom bearing R , R , R , R
R , R , R , R or R
Particularly preferred compou~ nl-c those wherein L is a radical (g) or (h) wherein Het i8 as descrihed hereinabove for the preferred compounds.
The most preferred compounds are selected from the group consisting of 3-L2-L4~ L3-(2-furanylmethyl)-3H-imidazoL4~5-b~pyridin-2-yl~amino-1-piperidinyl~ethyl3-2-methyl-4H-pyrido~l~2-a~pyrimidin-4-one and the pharmaceutically acceptable acid addition salts thereof.
In order to simplify the structural representation of the compounds of formula (I) and of certain prec~llsors and intermediates thereof the R ~l -N ~ N ~ ~ ~ ~ 3 -radlcal wlll hereafter be represented by the symbol D.
The compounds of formula (I) can generally be prepared by reactlng an lntermediate of formula ~II) with a plperldlne of formula (III) followlng art-known alkylatlng procedures.

Het_Ql + Q2-D alkylatlon > (I) reaction (II) IIII~
In III) and IIII) Ql and Q are selected 90 that ln comblnatlon wlth Het a blvalent radical of formula (f), (g) or Ih) ls formed durlng the alkylatlon reactlon, said (f), Ig) and Ih) havlng the previously descrlbed meaning.
For example, the compounds of formula (I) can generally be prepared by N-alkylating a plperldlne of formula (III) whereln Q ls hydrogen, sald plperldlne belng repre~ented by the formula IIII-a), wlth a reagent of formula (II) havlng the general for~ula L W, (II-a).

~, .,, i 1 3300~1 ~-W + HD N-alkylation (I) reactlon (II-a) (III-a) In (II-a) W represents an appropriate reactive leaving group such as, for example, halo, e.g., chloro, bromo or iodo, or a sulfonyloxy group, e.g. ~ethylsulfonyloxy or 4-~ethylphenylsulfonyloxy.
Additionally, the compounds of formula (I) wherein L is a radical of formula (f), a radical of formula (g) wherein Y is other than a direct bond, Y, or a radical of formula (h) wherein ~ is other than a direct bond, Z , said compounds being represented by the formulae (I-a-l), respectively (I-a-2) and (I-a-3), Can be prepared by alkylating an intermedlate of formula (III-b) wlth a reag~nt of formula (II-b).

Het-C H2 -W + Q -D~ 8 2s ~ Z n (II-b) (III-b) 20 Het-C H2 ~Y -Alk-DHet-C H2 ~Z -C-Y-Alk-D
(I-a-2) (I-a-3) In (III-b) Q2a ls a radical of formùla HN ~ , respectlvely a X (CH2) radical of formula HY -Alk- or HZ -C-Y-Alk-. In (II-b) W has the previously deflned meanlng of W and, where s ls 0, lt may also represent a lower alkyloxy, lower alkylthio or lower alkylsulfonyl group.
The compounds of formula (I-a-2) may also be prepared by alkylatlng a piperidine of formula (III) wherein Q2 ls a radlcal of formula -Alk-W, sald plperidlne being represented by the formula (III-c), wlth a reagent of formula (II) wherein Ql is a radlcal of formula -C H2 ~YlH, sald reagent being represented by the formula (II-c).

Het-CsH2s-YlH + W-Alk D r~Z~ ~ (I-a-2) (II-c) ~ c) The compounds of formula (I) wherein L is a radical of formula Het-C H2 -Z-C(=X)-Yl-Alk, said compounds being represented by the formula (I-a-4), may also be prepare~ by N-alkylating a piperidine of formula (III-c) with a reagent of formula (II) wherein Q is a radical of formula -C H2 -Z-C(=x)-~ H, said reagent being represented by the formula (II-d).
X X
Het-C H -Z-~-YlH + (III-c) alkylatio~ Het-C H2s-z-C-Y -Alk D
s 2s reaction (II-d) (I-a-4) The alkylation reactions are con~eniently conducted in an inert organicsolvent such as, for example, an aromatic hydrocarbon, e.g., benzene, methylbenzene, dimethylbenzene, and the like; a lower alkanol, e.g., methanol, ethanol, l-butanol and the like; a ketone, e.g., 2-propanone, 4-methyl-2-pentanone and the like; an ether, e.g., 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran and the like; N,N-dimethylformamide (DMF); N,N-dimethylacetamide (DMA); nitrobenzene; l-methyl-2-pyrroli-dinone; and the like. The addition of an appropriate base such as, for example, an alkali metal carbonate or hydrogen carbonate, sodium hydride or an organic base such as, for example, N,N-dtethylethanamine or N-(l-methylethyl)-2-propanamine may be utillzed to pick up the a~id which is liberated during the course of the reactlon. In some circumstances the addltion of an iodide salt, preferably an alkali metal iodide, is appropriate. Somewhat elevated temperatures may enhance the rate of the reaction.
The compounds of formula (I) can also be prepared by the cyclo-desulfurization reaction of an appropriate thiourea derivative of the formula Ri ~-N~}N-IC-NH~A2 12 4= ~3 (IV) 1 3300~1 _9_ Said cyclodesulfurization reaction may be carried out by the reaction of (IV) with an appropriate alkyl halide, preferably iodomethane in an appropriate reaction-inert organic solvent, e.g., a lower alkanol such as methanol, ethanol, 2-propanol and the like.
Otherwise, the cyclodesulfurization reaction may be carried out by the reaction of ~IV) with an appropriate metal oxide or salt in an appropriate solvent according to art-known procedures.For example, the compounds of formula (I) can easily be prepared by the reaction of (IV) with an appropriate Hq(II) or Pb(II) oxide or salt, such as, for example HgO, HgC12, Hg(OAc)2, PbO or Pb(OAc)2. In certain instances it may be appropriate to suFplement the r~action mixture with a small amount of sulfur. Even so methanediimines, especially N,N'-methane-tetraylbis[cyclohexanamine] may be used as cyclodesulfurizing agents.
The compounds of formula (I) wherein L is a radical of formula (h) wherein Z is Z , Y is NH and X is O or S, said X being represented by Xl and said co~pounds by the formula (I-b-l), can generally be prepared by reacting an isocyanate or isothiocyanate of formula (V) with a reagent of formula (VI).
xl Het-C H2 ~Z H + Xl-C'N-Alk-D > Het-C H2 ~Z -C-NH-Alk-D
(V) (VI) (I-b-1) The compounds of formula (I) wherein L is a radical of formula (h) wherein Z is NH, Y is yl and X is X , said compounds bein~
represented by the formula (I-b-2), can be prepared by reacting an isocyanate or isothiocyanate of fonmula (VII) with a piperidine of formula (VIII).
Xl s 2s HY-Alk-D __~ Het-C H2 -NH-C-Yl-Alk-D
(VII) (VIII) (I-b-2) The reaction of (V) with (VI) and (VII) with (VIII) is generally con-ducted in a suitable reaction-inert solvent such as, for example,an -lO- 1 3300~ 1 ether, e.g. tetrahydrofuran and the like. Elevated temperatures may be sultable to enhance the rate of the reaction.
The compounds of formula (I) wherein L is a radical of formula (h) wherein Z is a direct bond and X is Xl, said compounds belng represented by the formula (I-c), may be prepared by reacting a piperidine of formula (VIII) with a reagen~ of formula (IX~.

xl xl 1O Het-C H2 -~-OH + (VIII) ~ Het-C H2 -C-Y -Alk-D (I-c) (IX) The reaction of (VIII) with (IX) may generally be conducted following art-known esterification- or amidation reaction procedures. For example, the carboxylic acld may be converted lnto a reactive derivative, e.g. an anhydride or a carboxylic acid halide, which subsequently, is reacted with (VIII); or by reacting (VIII) and (IX) with a suitable reagent capable of forming amides or esters, e.g.
dicyclohexylcarbodiimide, 2-chloro-1-methylpyridinium iodide and the like. Said reactions are most conveniently conducted in a sultable solvent such as, for example, an ether, e.g. tetrahydrofuran, a halogenated hydrocarbon, e.g. dichloromethane, trlchloromethane or a polar aprotic solvent, e.g. N,N-dimethylformamlde. ~he addition of a base, e.g. N,N-diethylethanamine may be approprlate.
The compounds of formula (I) wherein L is a radlcal of fo mula (g) whereln Y is a direct bond and s is O, sald compounds being represented by the formula (I-d), may also be prepared by reacting an appropriate alkenylene of formula (X) with a plperidlne of formula (III-a) by stlrrlng and, if desired, heating the reactants together.
Het-lower alkenediyl-H t (III-a) ~ Het-Alk-D (I-d) (X) ~ he compounds of formula (I) wherein L i8 a radical of formula (g), wherein Het ls a radical of formula (i-5) wherein R15 ls hydrogen, s is 0, Y is a dlrect bond and -Alk- is -CH2-, sald compounds being 1 33~0~ 1 represented by the formula (I-e) may conveniently be prepared by reacting an intermediate of for~ula H-3 (III-a) with a reagent of formula (XI) in the presence of formaldehyde or a polymeric form thereof.

3 ~ ~ ~ CH 0 or polymeric + (III-a) > ~ ~ ~ R14 B 2 form thereof N CH2-D
(XI) (I-e) Said reaction may conveniently ~e conducted in a suitable solvent, e.~.water, acetic acid, propanoic acid or mixtures of such solvents.
Elevated temperatures may be appropriate ~o enhance the reaction rate.
The compounds of formula (I) may also be prepared followlng procedures for preparing condensed bicycllc r~ngsystems whlch are lS known in the art or analogous procedures thereof. A number of 5uch cyclization procedures will be described hereinafter.
The bivalent radical R used in the description of these cyclizatlon reactions has the followlng meaning:
s 2s ~ ~ (j~
(C~2)n -C H2 -Y-Alk- (j-2); or X
-C H -Z-~-Y-Alk- (j-3).
For example, where Het is a radical of formula (1-1) belng connected to R by the nitrogen atom bearing R8, said Het may be formed by condensing an lntermediate (XII) with a ~C-Xl generating agent, e.g.
urea, thlourea, l,l'-carbonylbis[lH-imidazole], lower alkyl carbono-halidate, phosgene, thiophosgene, trichloromethyl carbonohalidate and the li~e.
R
1 ~ NH-R ~C Xl B ~ ~
C-NH-X-D ~ ~ ,N-K-D
l generat~ng r X agent ~
(XII) ~I-i-l) 1 3~00~ 1 ~he compounds of formula (I-f-l) wherein R is hydrogen (I-f-l-a) may additionally be prepared by cyclizing an intermediate of formula xl ~H~c-NH-K-D
(XIII), which may in situ be generated by ~-W
Xl reacting a reagent (XIV) with an amine (XV).

N-C=X
B ~ C-W2 + H2N-~-D ~ ~XIII).

Xl (XV) (XIV) w2 a~ used throughout the description of the final compounds and lntermedia~es 18 an appropriate reactive leaving group, such as, for example, halo, e.g., chloro, bromo or iodo, a sulfonyloxy group, e.g.
methylsulfonyloxy or 4-methylphenylsulfonyloxy, a lower alkyloxy, lower alkylthlo, Ar -oxy or Ar -thio group.
~he reaction of ~XII) with the ,C=Xl generatlng agent and the cyclization of ~XIII) may conveniently be conducted ln a sultable solvent such aY, for example, an ether, e.g. l,l-oxybisethane, tetrahydrofuran, an halogenated hydrocarbon, e.g. dichloromethane, trlchloromethane, a hydrocarbon, e.g. benzene, methylbenzene, an alcohol, e.g. methanol, ethanol, a ~etone, e.g. 2-propanone, 4-methyl-2-pentanone, N,N-dimethylformamide, ~,N-dlmethylacetamide, or mixtures of euch solvents, optionally ln the presence of an appropriate b~e surh as, for example, N,N-diethylethanamine, an alkall or earth alkallne metal carbonate or hydrogen carbonate. In order to enhance the reaction rate, it may be sultable to heat the reaction mlxturç.

-13- `- 1 3300~ 1 Further, where Het is a radical of formula (i-2), said Het may be generated by cycli~ins an intermediate (XVI) with an acid (XVII) or a suitable functional derivative thereof, thus giving a compound of formula (I-f-2). Alternatively an intermediate (XVIII) may be condensed with an aromatic amino acid or -thloacid of formula (XIX), giving also a compound (I-f-2).

H2 + R9CoOH >

lxl (XVII) ~ N ~ R
~XVI) ~ N-K-D

~ ~ NH2 + R9--C-NH-K-D ~ (I-f-2) ~ IllxlH
X (XIX) (XVIII) The reaction of (XVI) with (XVII) and of (XVIII) with (XIX) may be conducted in a suitable reaction-inert solve~t, such as, for example, a hydrocarbon, e.g. benzene, methylbenzene, an alcohol, water, In some instances it may be appropriate to use higher temperatures ln order to reduce the reaction time.
Where Het is a radical of formula (i-3), said Het may be formed by reacting the previously described intermediate (XVI) with an appropriate acetylene derlvative (XX), thus giving a compound of formula (I-f-3).

(X~ + C~_C~ ;o (I-f-3) - `~ 3300~3 1 -lfi-wherein R -CH2- ls a suitable substituent on raid radlcal (1-3).
~he reactlon of (XX) wlth (XVI) may be conducted in a suitable solvent such as, for example, an alcohol, e.g. methanol, ethanol. Elevated temperatures may also be appropriate to shorten the reactlon tlme.
Addltionally, where Het is a radical (i-5), said Het may be created by condenslng a reagent (XXI) with an intermediate (XXII), thus glvlng a compound (I-f-4).

B ~ l15 3 ~ ~ K-D

(XXI) (XXII) (I-f-4) Further, where Het is a radlcal of formula (1-6), wherein Het is connected to K by the thlazole ring, said Het may be formed during the cyclization of a reagent (XXIII) with an intermediate (XXIV), thus giving a co~pound (I-f-5).

B~W + H2N-C-K D ~ ~ K--D

(XXIII) (XXIV) (I-f-5) Where Het ls a radlcal (i-6) being connected to K by the B
containing rlng and bearing a 2-mercaptosubstltuent, sald Het may be formed during the cycllzatlon of an intermedlate (XXV) wlth CS2, thus glvlng a compound (I-f-6~.

B4 ~ W + CS2 ~ 4 ~ S ~ SH
30 ~ NH2 ~ N
K-D K-D
(XXV~ (I-f-6) `- I 3300~ 1 Where Het is a radical of formula (i-7) being connected to R either by the B5 containing ring or by the imidazole ring, said Het is formed during the condensation reaction of a reagent (XXVI) with an intermediate (XXVII) respectively by the cyclodesulfuri~ation reaction of an intermediate (XXVIII), thus giving a compound (I-f-7) respectively (I-f-8).
~17 w ~ ; ~BS ~BS

(XXVI) ~XXVII) (I-f-7) 15 B ~ NH_R17 cyclodesulfurizationj 5~ ~ ~ -D
NH-IC-X-D reaction (I-f-8) (XXVIII) The reactions of (XXI ) with (XXII), of (XXIII) with (XXIV), of (XXV) with CS2 and (XXVI) with ~XXVII) may conveniently conducted in a sultable reaction-inert solvent, such as for example one of the solvents glven hereinabove for the preparation of (I-f-l) optionally in the presence of an appropriate base, e.g. one of the ba3es also de3cribed for the preparation of (I-f-l); higher temperatures may be used to enhance the reactlon rate.
The cyclodesulfuri~ation of (XXVIII) may be aonducted following the ~ame reactlon circumstances as described herelnabove for the preparation of (I) starting from (IV).
Where Het is a radical (i-8), said Het may be formed furing the condensation of an intermediate (XXIX) with a ~C=Xl generating agent, following the same procedures as previou~ly de~crlbed for the preparation of ~I-f-l) starting from (XII), Rl9 NH-Rl9 ~ Xl B6 ~ + CC~X ~ B ~ ~-K-D

(XXIX) (I-f-9) -' 1 3~3.0a~l The compounds of formula (I) wherein L is a radical of formula (g), said compounds being represented by the formula ~I-g), may alRo be generated by reducing an lntermediate (XXX) with an approprlate complex metal hydride, e.g. lithium alumlnium hydride, in a suitable solvent such as, for example, an ether, e.g. tetrahydrofuran, 1,1'-oxybisethane and the like.
O
Het~C H -Y-Alk'-C-D reduction > Het-C H2 -Y-Alk~-CH2-D~
(XXX) (I-g) Alk' having the previously defined meaning of Alk, provided that one methylene function i8 mlssing.
The compounds of formula (I) can also be converted into each other following art-known procedures of functional grouptrans-formation. Some examples will be cited hereinafter.
The compounds of formula (I) having a nitro substituent can be converted into thelr corresponding amines by stirring and, if desired, heatlng the starting nitro-compounds ln a hydrogen-containlng medlum ln the presence of a suitable amount of anappropriate catalyst auch as, for example, platlnum-on-charcoal, palladium-on-charcoal, Raney-nickel and the like catalysts.
Sultable solvents are, for example, alcohols, e.g. methanol, ethanol and the llke.
Halo atoms substituted on aryl groups may be replaced by hydrogen following art-known hydrogenolysis procedures, i.e. by stirring and, if deslred, heating the starting compounds in a suitable solvent under hydrogen atmosphere ln the presence of an approprlate catalyst, e.g.
palladlum-on-charcoal and the like catalysts. Said halo atoms may also be replaced by a lower alkyloxy or a lower alkylthio substituent by reacting the starting halo-compound with an appropriate alcohol or thloalcohol or, prefer~bly, an alkali- or earth alkaline metal salt or an appropriate alcohol or thloalcohol in a suitable solvent.
The compounds of formula (I) wherein L is a radical ~g) wherein Y
is NH can be converted into a compound of formula (I) wherein L is a 1 3300~

radical (g~ wherein Y is N-CO(lower alkyl~ or N-CO(Ar ~ by reacting the starting amine with an appropriate carboxylic acid or a derivative thereof such as, for example, an acid halide, an acid anhydride and the like.
The compounds of formula (I~ wherein L is a radical (g) wherein Y
is NB can be converted into a compound of formula (I) wherein L is a radical (g~ wherein Y is N-CO(lower alkylamino), N-C0-N~-Ar , N-CS(lower alXylamino) or N-CS-NH-Ar by reacting the starting amine with an appropriate ~socyanate or isothiocyanate in a suitable solvent.
The compounds of formula (I) having an Het substituted with a thio (=S) radical may be converted into the corresponding oxo (=0) analogs by reacting the former compounds with a peroxide, e.g. hydrogen peroxide, in a suitable solvent.
Compounds of formula (I) containing an ~et which is unsaturated may be converted into the corresponding compounds wherein Het is saturated or partly saturated following art-known reducing procedures.
In all of the foregoing and in the following preparations, the reaction products may be isolated from the reaction mixture and, if necessary, further purified according to methodologies generally known in the art.
The compounds of formula (I) have basic properties and, consequently, they may be converted to their therapeutically active non-toxic acid addition salt forms by treatment with approprlate acids, such as, for example, inorganic acids, such A8 hydrohalic acid, e.g. hydrochlorlc, hydrobromic and the like, and sulfuric acid, nitric acid, phosphoric acid and the liket or organic acids, such as, for example, acetic, propanoic, hydroxyaceti~, 2-hydroxy-propanoic, ethanedioic, 2-oxopropanoic, propanedioic, butanedioic, (Z)-2-butenedioic, (E)-2-butenedioic, 2-hydroxybutanedioic, 2,3-dihydroxybutanedioic, 2-hydroxy-1,2,3-propanetricarboxylic, methanesulfonic, ethanesulfonic, benzenesulfonic, 4-methylbenzene-sulfonic, cyclohexanesulfamic, 2 hydroxybenzoic, 4-amino-2-hydroxy-benzoic and the like acids. Conversely the salt form can be converted by treatment wlth alkali into the free ~ase form.

1 ~-300~ 1 Some intermedlates and starting materials in the foregoing preparations are known compounds which may be prepared according to art-known methodologies of preparing said or simllar compounds and others are new. A number of such preparation methods will be described hereinafter in more detail.
The intermediates of formula (III-a) can conveniently be prepared starting from a thiourea derivative of formula P-N ~ 12 ~2~

whereln P is an appropriate protective group such as, for example, lower alkyloxycarbonyl, Ar -CH2-O-CO-, Ar -CH2- and the llke, by a cyclodesulfuri~atlon reaction following the same procedure as described herelnabove for the preparation of (I) starting from (IV) and, subsequently eliminating the protective group P in the thus obtained intermediate of formula R Rl P- ~ N ~ A3 The eliminatlon of the protective group P in (XXXII) may generally be carried out following art-known procedures such as, for example, by hydrolysls in alkallne or acidic aqueous medium.
The intermediates of formula (III-b) and (III-c) may be derived from the corresponding intermediates of formula (III-a) by reacting the latter wlth a sultable reagent following art-known N-alkylating procedures.
For example, intermedlates of formula (III-b) wherein Q represents a radical of formula H2N-CH2-~lk'-, (III-b-l)~ can also be prepared by reacting an lntermediate of formula ~III-a) wlth a nltrlle of formula (XXXIII) followlng art-known N-alkylating procedures and subsequently converting the thus obtained nltrile (XXXIV) into the corresponding amine (III-b-l) following art-known nltrile to amine - 1 3300~ 1 reducing procedures, e.g., by catalytically hydrogenating procedures and the liXe.
NC-Alk'-W + HDN-alkylation NC-Alk'-D
(XXXIII) (III-a) reaction (XXXIV) nitrile to amine 2 2 (III-b-l) reduction reaction In (XXXIII), (XXXIV) and ~III-b-l) AlX' has the same meaning as Alk provided that one methylene function is missing.
~ he intermediates of formula (III-b-l) may alternatively be prepared by reacting a reagent (XXXv) with (III-a) following art-known ~-alkylating procedures and subsequently converting the thus formed intermediate (XXXVI) into the free amine following art-known depro-tection procedures.

P-NH-Alk-W + H-D N-alkylatio~ P-NH-Alk-D deprotectio~ H2N-Alk-D
~XXXV) (III-a) (XXXVI) ~ b-l) The intermedlates of formula (III-b) wherein Q2a represents a radical of formula HYl-C82-CH2-, (III-b-2), may also be prepared by the reaction of (III-a) with a reagent of formula (XXXV) by stirrlng and, lf desired, heating the reactants together in a suitable ~olvent.

CH2; -CH2 + (III-a) > 2 2 (III-b-2) ( XXXV ) ~he intermediates of formula (III-b) wherein Q 18 a rad~cal of for~ula HYl-Alk-, (III-d), may be converted lnto an intermedlate of formula (III-c) by convertlng the function ~ H ~nto an approprlate leaving group, e.g., where yl is O, by convertlng a hydroxy functlon into a chloro atom, wlth thionyl chloride, phosphoryl chlorlde and the llke.

1 3300~ 1 The intermediates of form~la (III-b-l) may also be derived from an appropriate corresponding carbonyl-oxidated form by reactlng said carbonyl-oxidated form wlth hydroxylamine and reducing the thus obtained oxime following art-known methods, e.g., catalytic hydrogenation and the like reducing methods.
During one of the reactions the intermediates wherein R and/or R and/or R and/or R is hydrogen may be converted into the corres-ponding intermediates wherein R and/or R and/or R and/or R ls other than hydrogen following art-known N-alkylating, N-acylating or reductive N-alXylating procedures.
The intermediates of formula (XXXI) and the intermediates of formula (XXXI~, wherein R is hydrogen, said intermediates being represented by the formula (XXXI-a), may be prepared by reactlng a piperidlne of formula (XXXVI-a) or (XXXVI-b) with an aromatlc reagent of formula (XXXVII-a) or (XXXVII-b).

P-N ~ NIH +~ A3 A2~ ~ (XXXI-a) (XXXVI-a) (XXXVII-a) ~5 ~ ~A3 A2~A ~R H ~ A3 A~ A R

(xxxvI-b) (XXXVII-b) (XXXI-a) The intermediates of formula (XII) can convenlently be prepared by reacting an intermediate (XV) with a reagent of formula (XXXVIII) ~ v~N~y~X
Bl ll Xl + (XV) > (XII) .
(XXXVI~I) T-3300~ 1 The intermediates of formula (XV) may be prepared by N-alkylating an intermediate (III-a) with a sultable N-protected reagent, followed by an appropriate deprotectlon reaction The intermediates of formula (XIX) may be prepared by N-alkylatlng (III-a) with a reagent R -CO-NH-~-W .
The inter~ediates of formula (XXII) whereln W i9 halo, sald lntermediates being represented by the formula (XXII-a), can be prepared by halogenating an lntermediate (XXXIX), which can be prepared by N-alkylatlng (III-a) with a reagent of formula 10 R-CH2-CO-IC-W.
O halo R15-CH -C-~-D halogenatlon Rl5-cH-c-K-D

(XXXIX) (XXII-a) The lntermedlates of formula (XXIV) wherein R is -NH-Alk-, said lntermedlates belng represented by the formula (XXIV-a), may be prepared by reacting an intermediate of formula (VI), wherein X is S, (VI-a), with ammonia or an ammonium salt, e.g. ammonlum chloride, ln the presence of a sultable solvent such as, for example, a lower alcohol, e.g. methanol.
S=N-C-Alk-D ammonla or ammonlum sal~ H2N-CS-NH-Alk-D
(VI-a) (XXIV-a) The lntermediates of formula (XXV) and (XXVII) may be prepared by reacting an intermedlate (III) with an appropriate reagent of formula (XL), respectlvely (XLI) following the same procedures as described herelnabove for the preparatlon of (I) starting from (II).
W

Q ~ 2 (III) ~ (XXV) ~ (XLI) + (III) _~ (XXVII) -22- 1 3300~ 1 The intermediates of form~la (XXVIII) wherein K is -NH-Alk-, said intermediates being represented by the formula (XXVlII-a), may be prepared by reacting an intermediate (VI-a) with a reagent (XLII), optionally in the presence of a suitable solvent.
NH-R17 ~ NH-R7 ~5 ¦1 + (VI-a) B5 il NH2 ~_~`NH-~-NH-Alk-D
(XLII) (XXVIII-a) The intermediates of formula (XXIX) can conveniently be prepared by N-alkylating an intermediate (XLIII). Said intermediate (XLIII) may be prepared by reducing an intermediate (XLIV) followlng art-known nitro to amine reducing procedures.

~6 ~ No2 reduction B6 ~ NH2 N-alkylation ~XXIX) NH-X-D > NH-K-D
(XLIV) (XLIII) The intermediates of formula (XLIV) may be prepared by alkylating an intermediate of formula (XV) with an appropriste N-alkylatlng reagent.
The intermediates of formula (XXX) can be prepared by N-acylating an intermedlate ~ a) wlth an appropriate reagent of formula Het-C H2 -Y-Alk'-CO-W2.
The lntermediates of formula (II) can conveniently be prepar~d following art-known procedures as described in, for example, U.S.
Patent Number 4,335,127, U.S. Patent Number 4,342,870 and European Patent Publication Number 0,070,053.
From formula (I) it is evident that the compounds of this invention may have several asymmetric carbon atoms in their structure. Each of these chiral centers may be present n a R- and a S-configuration, this R- and S-notation being in correspondence with the rules described by R.S. Cahn, C. Ingold and v. Prelog ln Angew. Chem., Int.
Ed. Engl., 5, 385, 511 (1966).
Pure stereochemically isomeric forms of the compounds of formula (I) may be obtained by the application of art-known procedurss.

1~30~ 1 Diastereoisomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g., counter current distribution, and enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids.
Pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically.
It is evldent that the cis and trans diastereomeric racemates may be further resolved lnto their optical isomers, cis(+), cis(-), trans(+) and trans(-) by the application of methodologies known to those skilled in the art.
Stereochemically isomeric forms of the compounds of formula (I) are naturally intended to be embraced within the scope of the lnvention.
The following examples are intended to illustrate and not to limit the scope of the present invention. Unless otherwise stated all parts therein are by weight.

-24- 1 ~3008 1 EXPERIMENTAL PART
-A. Preparation of Intermediates Example 1 A mixture of 90 parts of 4-chloro-3-nitropyridine, 71 parts of 4-fluorobenzenemethanamine, 63 parts of sodium carbonate and 900 parts of N,N-dimethylacetamide was stirred for 1 hour at 50C. Water was added and the product was extracted with 4-methyl-2-pentanone.
The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and 10 dried, yielding 106 parts t75~) of N-[(4-fluorophenyl)methyl~-3-nitro-4-pyridinamine; mp. 136.8C (intermediate 1).
In a similar manner there were also prepared:

R -CH2-HN A~ A2 ~ A~

l o. R -- R" ~p.
in C
_ _ _ 2 2-furanyl CH-CH-CH=CHN02 85.6 3 4-F-C H CH~CH-CH-N 2 4 4-F-C H CH-N~O)-CH=CH 2 25 5 2-pyridinyl NsCH-CH=CHNo2 113.6 6 2-thienyl CH-CH-CH=CHN02 7 4-F-C6H4 CH-C(OCH3)-CH=CH N2 ~
8 4-F-C H CHsCH-C(OCH3)=CH N2 9 4-F-C H CH-CH-C~CH3)=CH No2 99 9 30 10 2-thienyl N~CH-CH=CHN02 11 3-furanyl N~CH-CH=CHN02 -12 5-méthyl-2-furanyl N-CH-CH-CH 2 1 3300~ 1 ~xample 2 To a stirred and cooled ~0C) solution of 8.7 parts of N-[(4-fluorophenyl)methyl]-4-nitro-3-pyridinamine, l-oxide and 150 parts of trichloromethane was added dropwise a solution of 10.2 parts of phosphor trichloride in 75 parts of trichloromethane. Upon completion, the mixture was all~wed to reach room temperature and stirring was continued for one hour at reflux temperature. The reaction m~xture was cooled and the solvent was evaporated. The residue was stirred in trichloromethane. The product was filtered 10 off and dried, yielding 9 parts of N-[~4-fluorophenyl)Methyl]-4-nitro-3-pyridinamine monohydrochloride tintermedlate 13).
Example 3 A mixture of 56 parts of N-t3-nitro-2-pyridinyl)-2-pyridine-methanamine, 2 parts of a solution of thiophene in ethanone 4~ and 15 400 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room temperature with 4 parts of platlnum-on-charcoal catalyst 5~. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 20 43.5 parts of N2-t2-pyridinylmethyl)-2,3-pyridlnediamlne;
mp. 134.9C (intermediate 14).
In a similar manner there were also prepared:

R -CH2-HN ~ A.~ A2 H2N A4~

No. Rl Al-A2 A3=A4 base or mp.
salt in C

15 2-furanyl CH-CH-CH=CH base -16 4-F-C6H4 CH~CH-N=CH base 163.7 17 4-F-C6H4 CH~N-CH=CH HCl 208.9 35 18 2-thienyl CH~CH-CH=CH base -________________________________________________________ 1 3300~ 1 I________________________________________________________ ~o. R Al=A2_A3=~4 base or mp.
salt in C

5 19 2-furanyl N=CH-CH=CH base 20 4-F-C H CH=C(OCH3)-CH=CH base 21 4-F-C6H4 CH=CH-C(OCH3)=CH base -22 4-F-C ~ CH=CH-C(CH3)=CH base -23 2-thienyl N=CH-CH=cH base 10 24 3-furanyl N=CH-CH=CH base -25 5-methyl-2-furanyl N=CH-CH=CHbase . .
Example 4 To a stirred and cooled mixture of 4 parts o sodium hydroxlde ln 60 parts of wate~ were added ~uccessively 7.9 parts of carbon disulfide and 17.2 parts of ethyl 4-amino-1-plperidinecarboxylate at a temperature below 10C. Stirrin~ was continued for 30 mlnutes at thls temperature. Then there were added dropwise 10.9 parts of ethyl 20 carbonochlorldate (exothermic reaction: temp. rlse~ to about 35C).
Upon completion, stlrrlng was continued for 2 hours at 60C. The reactlon mixture was cooled and the product was extracted wlth methylbenzene, ~he extract was drled, flltered and evaporated, yieldlng 22 parts (100~) of ethyl 4-isothiocyanato-1-piperidlne-25 carboxylate as a residue ~intermediate 26).Example 5 A mixture of 54 parts of ethyl 4-isothiocyanato-1-plperi-dinecarboxyl~te, 48 parts of N2-(2-furanylmethyl)-2,3-pyridine-diamine and 450 parts of tetrahydrofuran was st~rred and refluxed 30 overnight. The reaction mixture was evaporated and the residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane.
~he product was filtered off and dried, yielding 76 parts ~75~) of ethyl 4-~2-[~2-furanylmethyl)amlno]-3-pyridlnyl~amlnothioxo-methyl]amlno]-l-piperidinecarboxylate; mp. 132.7C ~intermediate 27).

~ 3300~ ~

In a similar manner there were also prepared:

Rl-HN ~A2 CH -CH -O-C-N 3 N-C~ 4 A base ~ ~ Al=A2_A3=A4 mp.
in C
28 2-furanylmethyl CH=CH-CH=CH

6 4 2 CH=CH-CH=N
6 4 2 CH=CH-~=CH 166.0 31 4-F-C6H4CH2 CH-N-CH=CH
15 32 2-pyrldlnylmethyl N-CH-CH=CH -33 H CH~CF-CF=CH
34 2-thienyl~ethyl CH=CH-CH=CH
35 4-F-C6H4-CH2 CH=CH-C(OCH3)=CH
36 4-F-C6H4~H2 CH~C(OCH3)-CH=CH
20 37 4-F-C6H4-CH2 CH-CH-C(CH3)=CH
38 cyclohexyl CH-CH-CH~CH
39 2-thienylmethyl N~CH-CH=CH -40 3-furanylmethyl N-CH-CH=CH
41 5-methyl-2-furanyl N~CH-CH=CH
-methyl 2xample 6 A mixture of 42.5 parts of ethyl 4-~(phenylmethyl)-amino]-1-30 piperidinecarboxylate, 30 parts of 1-isothiocyanato-2-nitrobenzene and 270 parts of tetrahydrofuran was stirred for 3 hours at room temperature. 2,2'-Oxybispropane was added and stirring was continued overnight. The preclpltated product was filtered off and dried, yielding 48.5 parts (68.5~) of ethyl 4-l[[(2-nitroPhenYl)amino)-1 3300~ 1 amino]thioxomethyl](phenylmethyl)amino]-l-piperidinecarboxylate; mp.
140C (intermediate 42).
A mixture o 48.5 parts of ethyl 4-[[[(2-nitrophenyl)-amino)-amlno]thioxomethyl](phenylmethyl)amino]-l-piperidinecarboxylate and 600 parts of methanol, saturated with ammonia, was hydrogenated at normal pressure and at 30C with 15 parts of palladium-on-charcoal catalyst 10~. Aftex the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyfld~and the flltrate was evaporated, yielding 47 parts (100%) of ethyl 4-~[[(2-aminophenyl)-10 amino)amino]thioxomethyl]~phenylmethyl)amino]-l-piperidinecarboxylate as a residue (intermediate 43).
Example 7 A mixture of 74 parts of ethyl 4- [ [ [2-[(2-fUranY1methY1)aminO]-3-pyridinyl]aminothioxomethyl]aminoj-l-piperidinecarboxylate, 96 parts 15 of mercury(II)oxide, 0.1 parts of sulfur and 800 parts of ethanol was stirred and r~fluxed for 3 hours. The reaction mixture was filtered over Hyflo and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 52.5 parts (79~) of ethyl 4-~3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-20 piperidinecarboxylate~ mp. 149.2C (intermediate 44).
In a simllar manner there were also prepared:
CH3 CH2 ~ N/~ U R1 A1 1lA3 base R N A4~

No. R R2 Al=A2~A3=A4 mp.
in C
_ _ 45 2-furanylmethyl HCH=CH-CH~CH 135.8 46 4-F-C6H4~H2 H CH=CH-CH-N212.5 47~ 4-F-C6H4-CH2 H CH=CH-N-CH
48~ 4-F-C6H4-CH2 HCH=N-CH=CH 168.6 3 5 ------_ _ _ _ _ _ * Trademark - 1 3300~ i --No R R2 Al=A2_A3=A4 mp.
in ~C

49 2-thienylmethyl HCH=CH-CH=CH 142.7 50 2-pyridinylmethyl HN=CH-C~=CH 141.3 51 H H. CH=CF-CF=CH 234.9 6 4 2 H CH=CH-C(OCH3)=CH -53 4-F-C6H4~H2 H CH=C(OCH3)-CH5C~ -10 54 H C6H5CH2 CH=CH-CH=CH

55 4-F-c6~4~H2 H CH=CH-C(CH3 )=CH 202.0 56 cyclohexyl H CH=CH-CH=CH -57 2-thienylmethyl H ~=CH-CH=CH
58 3-furanylmethyl H N=CH-CH=CH
15 59 5-methyl-2-iuranyl-H N=CH-CH=CH -methyl _ _ ~ : dihydrochloride monohydrate.

20 Example a A mixture of 57.5 parts of ethyl 4-(lH-benzimidazol-2-ylamino)-1-piperidinecarboxylate, 33 parts of 2-(chloromethyl)pyridine hydrochloride, 43 parts of sodi~m carbonate, 0.1 parts of potassium $odide and 630 parts of N,N-dimethylformamide was stirred and heated 25 overnight at 70C. The reaction mixture was cooled and poured onto water. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol ~96:4 by volume) as eluent. The pure 30 fractions were collected and the eluent was evaporated. The residue was crystallized from 4-methyl-2-pentanone, yielding 30 parts (40~) of ethyl 4~ (2-pyrldinyl)methyl]-1~-benzimidazo~-2-yl]amino]-1-piperidinecarboxylate; mp. 161.5C (intermedlate 60).

1 3300~ 1 -3b-In a similar manner there were also prepared:
C 3 2 ~ 1-No. R R Al=A2-A3 A4 - -ln C
' 10 61 3-pyridinyl H CH=CH-CH-CH 191.4 62 2-pyrazinyl H CH=CH-CH=CH 178.5-179.3 63 4-F-C H H CH=CF-CF=CH lR2.3 64 4-thiazolyl H CH=CH-CH=CH 156.2 15 65 4-F-C H CH3 CH=CH-CH=CH
6 3 6 4 H CH=CH-CH=CH -67 4-F-C H C6H5 CH=CH-CH=CH

Example 9 A mixture of 50 parts of ethyl A-~;3-(2-furanylmethyl)-3H-lmidazo[4,5-b~pyridin-2-yl]amino]-1-piperidinecarboxylate, 50 parts of potassium hydroxlde, 400 parts of 2-propanol and 20 drops of water was stlrred and refluxed fo~ about 5 hours. The reaction mixture was evaporated and water was added to the resldue. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were dried, flltered and evaporated. The solid residue was stirred in l,l'-oxybisethane. The product was flltered off and dried, yielding 34 parts (85~) of 3-(2-furanylmethyl)-N-(4-plperidlnyl)-3H-imidazo[4,5-b~pyridin-2-amine; mp. 159.0C
(intermedl~te 68).

In a similar manner there were also prepared:

~ R A1 HN ~ ~ A~ base No. R R2 - Al=A2_A3=A4 mp.
in ~C

211.0 70 2-thienylmethyl H CH=CH-CH=CH -71 4 C6 4 2 H CH=CH-C(OCH3)=CH
72~ 4-F-C6H4-CH2 CH3 CH=CH-CH-CH 222.
6 4 2 H CH=C(OCH3)-CH-CH
6 4 2 H CH=CH-C(CH3)=CH -6 4 2 C6H5- CH=CH-CH=CH -76 cyclohexyl H CH=CH-CH-CH 180.0 20 77 2-thlenylmethyl H N=CH-CH=CH
78 3-uranylmethyl H N=CH-CH~CH -79 5-methyl-2-uranyl-H N=CH-CH=CH
methyl 25 ~ ~ dlhydrochlorlde monohydrate.

Example 10 A mixture of 30 parts o ethyl 4-[~1-[(2-pyr~dlnyl)methyl]-lH-benzimidazol-2-yl]amlno]-1-piperidinecarboxylate and 300 parts o a 30 hydrobromlc acid solution 48~ in water was stlrred and heated for 3 hours at 80C. The reactlon mixture was evaporated and the resldue was crystallized rom methanol, yielding 41 parts (93.2~) o N-(4-piperidinyl)-1-[(2-pyridinyl)methyl]-lH-benzimidazol-2-amine tri-hydrobromide; mp. 295.9C (lntermediate 80).

In a similar manner there were also prepared:

~ N C3 Al-a N A4~

No. R Al=A2_A3=A4 base or mp.
salt form ln _ ' 81 3-pyridinyl CH=CH-CH=CH 3HBr >260 82 2-pyrazinyl CH-CH-CH=CH 3HBr 83 4-P-C H CH~CH-CH=N 2E~r ~300.6 84 4-F-C H CH=CHN=CH 2~3r 279.4 2~pyridinyl N=CH-CH=CH 3H~3r 265.5 86 4-F-C6H4 CH-N-CH=CH 2HBr.~2O 291.6 87 4-F-C H CH~CF-CF=CH 2H~r 210.6 88 4-thiazolyl CH-CH-CH=CH 2H~3r.H2O 223.5 89 3-CH3C6H4 CH~CH-CH=CH 2HBr -Example 11 50 Parts of 1-[(4-fluorophenyl)methyl]-N-(4-plperldinyl)-lH-benzimidazol-2-amine dlhydrobromide were taken up in water. The free base was liberated wlth a sodium hydroxide solutlon 50~ and extracted with dlchloromethane. The extract was dried, filtered and evaporated. The resldue was boiied in 2-propanone. The product was filtered off and dried, yielding 17 parts (87.5~) o 1-[(4-fluoro-phenyl)methyl~-N-(4-plperidlnyl~-lH-benzimidazol-2-amlne; mp.
30 215.5C ~intermediate 90).
Example 12 A mixture o 2.1 parts of 3-buten-2-one, 9.7 parts of 1-~4-fluorophenyl)methyl~-N-(4-piperidinyl)-lH-benzimidazol-2-Amine and 120 parts of ethanol was stirred for 3 hours at reflux temperature.
The reaction mixture was evaporated. The residue was purifled by column-chromatography over silica gel using a mixture of trichloro-methane and methanol (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2-propanone and 2,2'-oxybispropane, yielding 5 parts (42~) of 4-[4-[[1-~(4-fluorophenyl)methyl]-1~-benzimidazol-2-yl]amlno]-1-piperidinyl]-2-butanone; mp. 131.3C
(intermediate 91).
~ stirred solution of 47.5 parts of 4-[4-[[1-[(4-fluorophenyl)-methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]-2-butanone and 10 500 parts of acetic acid was acidified with a hydrobromic acid solution in glacial acetic acid. Then there were added dropwise 11.8 parts of bromine dissolved in acetic acid. Upon completion, stirring was continued overnight at room temperature. The precipitated product was filtered off and suspended in 2-propanone. The product 15 was filtered off and dried, yielding 23 parts (48.3~) of l-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-l-piperidinyl]-2-butanone dlhydrobromide (intermedlate 92).
Example 13 A mixture of 9 parts of oxirane, 3.24 parts of 1-(4-fluorophenyl-20 methyl)-N-(4-piperidinyl)-lH-benzlmidazol-2-amine and 400 parts of methanol was stlrred ~irst overnight at room temperature and further for 4 hours at 50C. The reaction mixture was evaporated. The resldue was purifled by column-chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, 25 (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystalllzed from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 15 parts of 4-[1-(4-fluorophenylmethyl)-lH-benzimidazol-2-ylamino] 1-piperidineethanol; mp. 138.7C (intermediate 93).
30 Example 14 A mixture of 11.5 parts of 4-chlorobutanenitrile, 48.5 p3rts of 1-(4-fluorophenylmethyl)-N-~4-piperidinyl)-lH-benzimidazol-2-amine dihydrobromide, 30 parts of sodium carbonate and 270 parts of N,N-dimethylfor~amide was stirred and heated overnlght at 70C. The 35 reaction mixture was poured onto water and the product was extracted with trichloromethane. The extract was dried, ~iltered and evaporated. The residue was crystallized twice from a mixture of 4-methyl-2-pentanone and 2,2'-oxybispropane, yielding 2.2 parts (80~ of 4-[[1-[t4-fluorophenyl)methyl]-lH-benzlmidazol-2-yl]-amino]-l-piperldinebutanenitrile; mp. 130.5C (lntermediate 94).
In a similar manner there were also prepared:

~C_C32_~3 ~Al~ A2 No. Rl 'AlZA2~A3~A4- mOpc.
95 4-F-C6HiCH2 -N-CH-CH=CH-183,7 96 ~2-pyridinyl)methyl -CH-CH-CH=CH- 152.6 97~ 4-F-C6H4-CH2 -CH~CH-CH=N- 173.9 9~ ~2-furanyl)methyl -CH-CH-CH=CH- 194.4 99 (2-pyrldinyl)methyl -NsCH-CH=CH- 170.0 100 ~2-furanyl)methyl -N~CH-CH=CH- 157.0 20 101 ~2-thlenyl)methyl -CH-CH-CH~CH- 191.7 102 C6H5-CH2 -CH-CH-CH~CH- 180,4 103 4-F-C6H4-CH2 -CH~CH-C(OcH3)=CH 174-8 104 4-F-C6H4-CH2 -CH-C(OCH3)-CH=CH 222-0 105 pheny 1 -CH~CH-CH=CH- -25 106 3-CH3C6H4-CH2 -CHGCH-C~=CH- -: hemihydrate In a slmilar manner there was also prepared:
4-~[1-~2-furanylmethyl)-lH-benzimidazol-2-yl]amino]-1-piperidine-30 butanenitrile ~intermedlate 107).
Example 15 To a st~rret mlxture of 2.5 parts of llthlum alumlnum hydrlde and 225 parts of tetrahydrofuran was added dropwlse a solutlon of 13 parts of 4-~[1-~2-thienylmethyl~-lH-benzlmidazol-2-yl]~mlno~-1-35 piperldlneacetonltrlle ln tetrahydrofuran under nltrogen atmosphere.

~ .

: ' , , Upon completion, stirring was continued for 3 hours at reflux. Thereaction mixture was cooled in an ice bath and decomposed by the successive additions of 2.5 parts of water, 7.5 parts of a sodium hydroxide solution 15~ and 7.5 parts of water. ~he whole was ~ilter~d over Hyflo*and the filtrate was evaporated. The residue was crystallized from acetonitrile, yielding 9.5 parts (72~) of N-[1-(2 aminoethyl)-4-plperidinyl~-1-(2-thienylmethyl)~lH~benz~
-imidazol-2-amlne; mp. 137.1~C (intermediate 108).
Example 16 10 A mixture of 12 parts of 4-[~1-[(4-fluorophenyl)methyl~-lH-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidineacetonitrile and 200 parts of methanol saturated with ammonia was hydrogenated at normal pressure and at room t~mperature with 2 parts of Raney-nickel ratalyst. After the calculated amount of hydrogen was taken up, the 15 catalyst was filtered off and the filtrate was evaporated. The residue was crystalli~ed from acetonitrile, yielding 10 parts ~78~) of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[(4-fluorophenyl)methyl]-lH-imida~o[4,5-b]pyridin-2-amine monohydrate~ mp. 116.9C
(intermediate 109).
Following the same procedure and using equivalent amounts of the appropriate starting ~aterlals, there were al~o prepared:

Rl .
H2N ( 2)n 3 ~ ~ ba~e _ No. n Rl _Al=A~_A38A4_ mp in l _ 110 4 4-F-c6H4-cH2 -CH=CH-CH=CH- -111 2 4-F-c6H4~cH2 -N=CH-CH=CH- 174.5 112 2 (2-pyridinyl)methyl -CH=CH-CHsCH- 145.1 113 2 (2-furanyl)methyl -CH=CH-CH=CH- 163.0 114 2 (2-pyridlnyl)methyl -N=CH-CH=CH- 151.1 1157 2 (2-furanyl)methyl -N=CH-CH=CH- 182.0 35 116 6 5 2 -CH=CH-CH=CH- 131.6 117 2 4-F-c6H4-cH2 -CH=CH-C(OCH3)=CH-____________________________~__________________________ * Trademark 1 3300~ 1 _____________________________________________________1 o. n Rl ~Al=A2~A3=A4~ C
L18 2 4-F-C H -CH2 -CH=C(OCH3)-CH=CH-119 2 C6H5 -CH=CH-CH=CH-5 120 2 3 6 4 2 -CH=CH-CH=CH- -121 4 (2-furanyl)methyl -CH=CH-CH=CH-~ : (E)-2-butenedioate ~1:3) monohydrate salt.

10 Exa le 17 mp A mixture of 12 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-~(4-fluorophenyl)methyl)-5-methoxy-lH-benzlmidazol-2-amine and 150 parts of a hydrobromic acid solution 48~ in water was stirred and heated for 48 hours at 80C. The reaction mixture was evaporated and 15 the residue was suspended in 2-propanol. The product was filtered off and dried, yielding l8.5 parts (95.7~) of 2-[[1-(2-aminoethyl)-4-piperidlnyl]amino]-1-[(4-fluorophenyl)methyl~-lH-benzimldazol-S-ol trihydrobromlde monohydrate mp. ~250C ~intermediate 122).
~xample 18 To a stirred and cooled (-10C) mlxture of 12.6 parts of carbon disulfide, 5.2 parts of N,N'-methanetetraylbis[cyclohexanamlne~ and 45 parts oi tetrahydrofuran was added dropwlse a solution of 8.5 parts of N-[1-~2-amlnoethyl)-4-piperidinyl~ 2-furanylmethyl)-lH-benzimidazol-2-Amine in 45 parts of tetrahydrofuran. ~pon completion, 25 stirring was continued overnight at room temperature. The reaction mixture was evaporated and the residue was purlfied by column chromatography over silica gel using trichloromethane as eluent. The pure fractions were collected and the eluent was evaporated. The residue was cryQtalllzed from acetonitrlle, yleldlng 6.7 parts of 30 1-(2-furanylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-piperidinyl]-lH-benzlmldazol-2-amlne ~intermedlate 123).

In a similar manner there were also prepared:

xl SCN- ( CE~2 ) m~N ~ A3 base No. m Rl ~Al=A2~A3=A4~
_ _ .
124 2 6 4 2 -CH=CH-CH=N-10 125 2 (2-pyridinyl)methyl -N=C~-CH=CH-126 2 4-F-C H ~H -N=CH-CY=CH-127 2 (2-pyridinyl)methyl -CH=CH-CH=CH-128 2 C6H5 -CH=CH-CH=CH-129 2 (2-thlenyl)methyl -CH=CH-CH=CH-15 130 2 4-F-C H-CH -CH=CH-CH=CH-131 3 4-F-C H ~H -CH=CH-CH=CH-132 2 (2-furanyl)methyl -N=CH-CH=CH-Example 19 A mixture of 5.4 parts of 3,4-pyridinediamlne, 16 parts of 1-(2-furanylmethyl)-N-[1-~2-lsothiocyanatoethyl)-4-piperldinyl~
benzlmldazol-2-amine and 135 parts of tetrahydrofuran was stlrred and refluxed overnight. The reaction mixture was evaporated in vacuo. The resldue was purified by column chromatography over sillca gel using a mixture of trichloromethane and methanol, saturated wlth ammonia, (95:5 by volume) as eluent.The pure fractlons were collected and the eluent was evaporated, yleldlng 18 parts (87~) of N-(4-amlno-3-pyrldlnyl)-N'-[2-[4-[[l-(2-furanylmethyl)-lH-benzimi dazol-2-yl]amino~-1-piperidinyl]ethyl]thiourea (intermediate 133).
Following the same procedure and uslng equlvalent amounts of the approprlate startlng materials, there were also prepared:

1 330~

Rl L -N-ll-HN-(CH ) -N ~ ~ ~ A~ 3 base R N ' A~f No, L' n R2 Rl -Al'A2-A3=A4- C
134 4-amino-3-pyridlnyl 2 H 6 4 2 -CH=CH-CH-CH- -13.5 3-amino-2-pyridinyl 2 H 6 4 2 -CH=CH-CH-CH- -136 4-amino-3-pyridinyl 2 % 4-F-C6H4CH2 -CH=CH-CH=N-10 1374-amino-3-pyridinyl 2 H 2-pyridinylmethyl -N=CH-CH-CH- -138 4-amino-3-pyridlnyl 2 H 6 4 2 -N CH-CHsCH- -139 4-amino-3-pyridinyl 2 H 2-pyridinylmethyl -CH=CH-CHzCH- -140 4-amino-3-pyridinyl 2 H C6H5 -CH=CH-CH~CH- -141 4-amino-3-pyridinyl 2 H 2-thienylmethyl -CH=CH-CB=CH- -15 142 5-amino-4-pyrimi- 2 H 4 6 4 2 -CH=CH-CH=CH- -dinyl 143 4-amino-3-pyridinyl 4 H 4-F-C6H4CH2 -CH~CH-CH=CH- -144 4-amino-3-pyrldinyl 3 H 4-F-C6H4CH2 -CH=CH-CH=CH- -145 4-amino-3-pyridlnyl 2 H 2-furanylmethyl -N=CH-CH~CH-20 146 4-(methylamino)- 2 H 4-F-C6H4CH2 -CH-CH-CH~CH- -3-pyrldinyl 147 (4-F-C6H4CH2) 2 H 4-F-C6H4CH2 -CHDCH-CH~CH- -amino-3-pyridinyl 25 148~ 4-amino-3-pyridinyl 2 CH3 4-F-C6H4CH2 -CH~CH-CH=CH- 128.1 ~ : monohydrate Example 20 A mixture of 120 part# of methanol saturated with ammonia and 4.1 parts of 1-(4-fluorophenylmethyl)-N-[1-(2-isothiocyanatoethyl)-4-plperidinyll-lH-benzimidazol-2 amine was stirred overnight at room temperature. The rea~tlon mixture was evaporated and the residue was ---1 3300~ 1 purlfied by column chromatography over silica gel using a mixture of trlchloromethane and methanol (95:5 by volume), ~aturated with ammonia, as eluent. The pure fractions were collected and the eluent was evaporated. The resldue was suspended in l,l -oxybisethane. The product was filtered of~ and crystallized from acetonitrile, yielding 1.1 parts (26~) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidi~yl]ethyl]thiourea; mp.
186.1C (intermediate 149).
Example 21 A mixture of 3.4 parts of 6-chloro-3-nitro-2-pyridinamlne, 7.4 parts of N-[1-(2-aminoethyl)-4-piperidinyl]-1-[~4-fluorophenyl)-methyl]-lH benzimidazol-2-amine and 10 parts of 1-methyl-2-pyrrolidinone was stirred and heated for 2 hours at 150C. ~he reaction mixture was cooled and ta~en up in methanol saturated wlth 15 ammonia. The whole was evapora~ed and water was added to the residue. The product was extracted three times wlth 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated in vacuo. The resldue was purified by column chromatography over slllca gel uslng a mixture of trichloromethane and methanol (95:5 by 20 volume) as eluent. The pure fractions were collected and the eluent was evaporated. The resldue was crystallized from 4-methyl-2-pentanone, yielding 5 parts (50~) of N -~2-[4-[[1-[(4-fluoro-phenyl)methyl]-lH-benzimidazol-2-yl]-amino~-1-piperidinyl]ethyl]-3-nitro-2,6-pyridinedlamine; mp. 205.7C (intermedlate 150~.
Followlng the same procedure and using egulvalent amounts of the appropriate ~tarting materials, there were also prepared:
1-[(4-~luorophenyl)methyl]-N-[1-[2-[(2-nitrophenyl)amino~ethyl]-4-piperldinyl~-lH-benzimldazol-2-amine; mp. 190.2C
~lntermediate 151)J and 6-chloro-N4-~2-[4-[[1-[~4-fluorophenyl)methyl]-lH-benzlmldazol-2-yl]amlno]-1-plperldlnyl]ethyl]-4,5-pyrlmidinediamines mp. 216.7C
~intermediate 152).

~3300~ 1 Example 22 To a stirred mixture of 9.16 parts of 2-amino-5-(methylthio)-benzoic acid and 100 parts of 1,4-dioxane were added dropwise slowly 9.8 parts of trichloromethyl carbonochloridate. Upon completlon, stirring was continued for 2 hours. The reaction mixture was evaporated. The residue was crystallized f~om acetonitrile. The product was filtered off and dried, yielding 8 parts (76~) of 6-(methylthio)-2H-3,1-benzoxazine-2,4(1H)-dionet mp. 219.4C
(intermediate 153).
10 Example 23 A mixture of 10 parts of N -[2-[4-[[1-[(4-fluorophenyl)-methyl]-lH-benzimidazol-2-yl]amino]-1-piperidlnyl]ethyl]-3-nitro-2,6-pyridlnediamine, 3 parts of a solution of thiophene in methanol 4~ and 400 parts of methanoll saturated with ammonia~was 15 hydrogenated at normal pressure and at room temperature with 4 parts of palladium-on-charcoal catalyst 10~. After the calculated amount of hydrogen was ta~en up, the catalyst was filtered off and the filtrate was evaporated, yielding 9 parts (94~) of N -[2-[4-[[1-~(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino~-1-plperidinyl~-20 ethyl]-2,3,6-pyridinetriamine as a resldue (intermediate 154).
In a similar manner there was also prepared:
N-[2-~4-[~ (4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl~ethyl]-1,2-benzenediamine (intermediate 155).
Example 24 A mixture of 4.4 parts of N-(5-bromo-1,3,4-thiadiazol-2-yl)-acetamide, 7.3 parts of N-[1-(2-aminoethyl)-4-piperidinyl~ (4-fluorophenyi)methyl]-lH-benzimidazol-2-amine, 3.18 parts of sodium carbonate and 135 parts of N,N-dimethylformamide was gtlrred overnight at 80-90C. The reaction mixture was evaporated. The 30 residue was purified by column chromatography over silica gel using a mixture o~ trichloromethane and methanol ~90:10 by volume) as eluent. ~he pure fractions were collected and the eluent was evaporated. The re~idue was crystallized from a mixture of acetonitrile and 2,2 -oxybispropane, yieldlng 1.7 parts of 35 N-~2-~4-~ (4-fluorophenyl~methyl]-lH-benzimidazol-2-yl~amlno]-1-1 3300~31 piperidinyl]ethyl]formamide; mp. 153.2C (intermediate 156).
Example 2S
~ o a stirred and hot (50C) mixture of 4.1 parts of 2H-3,1-benzoxazine-2,4(1H)-dione and 31.5 parts of N,N-dlmethylformamide was added dropwise a solution of 9.4 parts of N-~1-(2-aminoethyl)-4-piperidinyl]-l-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-amine ln 31.5 parts of N,N-dimethylformamide at SQC. Upon completion, stirrinq was continued for 3 hours at 50C. Water was added and the product was extracted with 4-methyl-2-pentanone. The extract was 10 dried, filtered and evaporated. The resldue was cry~tallized from acetonitrile, yielding 9.B parts (80~) of 2-amlno-N-[2-[4-~[1-[(4-fluorophenyl)-methyl]-lH-benzimidazol-2-yi~am~no]-1-piperidinyl]-ethyl~ben~amide~ ~p. 171.7C (intermediate 157).
In a similar manner there were also prepared:
15 2-(ethylamino)-N-[2-[4-[[1-[4-(fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzenamide5 mp. 139.8C
(intermediate 158);
N-[2-[4-[[1-[~4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-l-plperidlnyl~ethyl]-2-(methylamino)benzamide monohydrate~
20 mp. 147.8C (intermediate 159);
2-amino-N-[2-[4-[[1-~2-furanylmethyl)-lH-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]benzamide; mp. 167.3C (intermediate 160)~
N-[2-[4-[[1-(2-furanylmethyl)-iH-benzimidazol-2-yl]amino]-1-piperi-dinyl]ethyl]-2-(methylamino)benzamide monohydrate~ mp. 133.0C
25 (intermediate 161)~
2-amino-N-[4-[4-[[1-(2-furanylmethyl)-lH-benzimidazol-2-yl]amino]-1-piperidinyl]butyl]benzamide; mp. 151.0C (intermediate 162)~
2-amino-N-[4-[4-[[1-1(4-fluorophenyl)methyl]-lH-benzlmidazol-2-yl]-amino]-l-piperidinyl]butyl]benzamide~ mp. 186.7C (lntermediate 30 163)~ and 2-amino-N-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]-amino]-l-plperidinyl]ethyl]-5-(methylthio)benzamide~ mp. 184.6C
(intermediate 164~.

1 3300~ 1 Example 26 A mixture of 1.5 parts of 6-chloro-N -[2-[4-[[1-[(4-fluoro-phenyl)methyl]-lH-ben~imida~ol-2-yl]amino]-1-piperldinyl]ethyl]-4,5-pyrimidinediamine, 3 parts of a solution of thiophene in ethanol 4~, 1 part of potassium acetate and 120 parts of methanol was hydrogenated at normal pressure and at room temperature with 1 part of palladium-on-charcoal catalyst 10~. After the calculated amount of hydrogen was taken up, the catalyst was filtered off and the filtrate was evaporated. The solid residue was ta~en up ln water.
10 The solution was treated with ammonla. The product was extracted with trichloromethane. The organic layer was separated, dried, filtered and evaporated. The residue was crystallized from a mixture of 4-methyl-2-pentanone, yielding 1 part (72.4~) of N -[2-[4-[[1-[(4-fluorophenyl)methyl~-lH-benzimidazol-2-yl~amino~-1-15 piperidinyl]ethyl~-4,5-pyrimidinediamine; mp. 207.7C tintermediate 165) Example 27 A mixture of 30 part~ of 4-hydroxy-2-mercapto-6-methyl-5-pyrimidineethanol, 25 parts of potassium carbonate, 270 parts of 20 N,N-dimethylacetamide and 75 parts of water was stirred at room temperature and 36 parts of 1,3-dibromopropane were added at once:
temperature rises to 50C. The whole was stirred overnight at room temperature. The reactlon mixture was evaporated and water was added to the residue. The solld product was washed with water and dried in 25 vacuo at 100C, yielding 21 parts (58~) of 3,4-d~hydro-7-(2-hydroxy-ethyl)-8-methyl-2H~6H-pyrimido[2~l-b][l~3~thiazin-6-one1 mp. 155C
(intermsdiate 166).
In a slmllar manner there was also prspared:
2,3-dihydro-6-(2-hydroxyethyl)-7-methyl-5H-thlazolo[3,2-a]pyrimldin-30 5-one~ mp. 148.7C (lntermediate 167).
Example 28 A mixture of 20 parts of 3,4-dihydro-7-(2-hydroxyethyl)-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thia~in-6-one, 50 parts of acetic acld and 180 pArts of a hydrobromlc acid solutlon 67~ in acstlc acid was 35 stirrsd and heated to reflux. Stirring was contlnued overnlght at 3'~OS l reflux temperature. The reaction mixture was evaporated and the solid residue was triturated ln 2-propanone. The product was filtered off and dried, yielding 24 parts (100~ of 7-~2-bromo-ethyl)-3,4-dihydro-8-methyl-2H,6H-pyrimido[2,1-b][1,3]thiazin-6-one monohydrobromlde; mp. 215C (intermediate 168).
In a similar manner there was also prepared:
6-(2-bromoethyl)-2,3-dihydro-7-methyl-5H-thiazolo[3,2-a]pyrimidin-5-one monohydrobromide~ mp. 237 2c (intermediate 169).
Example 29 A mixture of 27 parts of ethyl 2-[(ethoxycarbonyl)methylamino]-benzoate, 16 parts of 2-aminoethanol and 90 parts of dimethylbenzene was stirred and refluxed overnight. The reaction mlxture was cooled.
The precipitated proauct was filtered off and crystallized from 2-propanol, yielding 4.5 parts (20~) of 3-~2-hydroxyethyl)-1-methyl-15 2,4(lH,3H)-qu-tnazollnedlone (intermediate 170).
A mixture of 4.5 parts of 3-(2-hydroxyethyl)-1-methyl-2,4(1H,3H)-quinazollnedlone r 8 parts of thionyl chlorlde and 75 parts of trlchloromethane was stirred and refluxed i'or 5 hours. ~he reactlon mixture was evaporated, yielding 4.5 parts ~95~D) of 3-~2-chloro-20 ethyl)-1-methyl-2,4~1H,3H)-quinazolinedione as A resldue ~intermediat~ 171).
Example 30 A mixture of 50 parts of 2-thiazolamine, 76 parts of 3-acetyl-4,5-dlhydro-2(3H)-furanone, 1.2 parts of concentrated hydrochloric 25 acid and 270 parts of methylbenzene was stirred and rsfluxed for 2 hours using a water-separator. The reaction mlxture i5 cooled and 340 parts of phosphoryl chloride were added at a temperature between 20 and 30C. The whole was heated slowly to 100-llODC and stirring was continued for 2 hours at this temperature. The reaction mixture 30 was evaporated and the residue was poured onto a mixture of crushed lce and ammonlum hydroxlde. The product was extracted wlth trichloromethane. The extract was dried, filtered and evaporated.
The residue was purified by column chromatography over sillca gel using ~ mixture of trichloromethane and methanol ~95:5 by volume) as 35 eluent. The pure fractlons were collected and the eluent was 1 ~300~ 1 evaporated. ~he residue was crystallized from a mixture of 2-propanol and l,l'-oxyblsethane, yielding 36 parts of 6-~2-chloro-ethyl)-7-methyl-SH-thia~olo[3,2-a]pyrlmidin-5-one (lntermediate 172).
Example 31 A mixture of 4.76 parts of 6-chloro-N -methyl-4,5-pyridine-diamine, 26.6 parts of 1,1,1-triethoxyethane and 30 parts of acetic acid anhydride was stirred and refluxed for 3 hours. The reaction mlxture was evaporated. The residue was crystalli~ed f~om a mixture of hexane and methylbenzene. The product was filtered off and drled, 10 yielding 5.3 parts (96.3~) of 6-chloro-8,9-dimethyl-9H-purine (intermediate 173).
Example_32 A mixture of 4.76 parts of 6-chloro-N methyl-4,5-pyrimidine-diamine and 7.2 parts of urea was stirred and heated for 1 hour at 15 180~C. After coollng, the residue was suspended in water. The product was filtered off and dried, yielding 3.3 parts ~60~) of 6-chloro-9-methyl 9H-purin-8-ol (intermediate 174).
Example 33 A mixture of 9.5 parts of 3-(2-chloroethyl)-2,6-dimethyl-4H-20 pyrido[l,2-a]-pyrlmidin-4-one, 160 parts of methanol and 40 parts of 2-propanol saturated with hydrogen chlorlde was hydrogenated at normal pressure and at room temperature with 2 parts of palladium-on-charcoal catalyst 10~. After the calculated amount of hydrogen was taken up, the catalyst was filtered off over Hyflo*and the 25 filtrate was evaporated, yielding 9.5 parts (86~) of 3-(2-chloro-ethyl)-6,7,8,9-tetrahydro-2,6-dimethyl-4H-pyrldo[1,2-a~pyrimidin-4-one monohydrochloride (lntermediate 175).
In a slmllar manner there were also prepared:
3-(2-chloroethyl)-6,7,8,9-tetrahydro-2,6,8-tr ~ethyl-4H-pyrido[1,2-a]~
30 pyrimidin-4-one monohydrochloride (intermedlate 176)s 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2,7-dimethyl-4H-pyrido~1,2-a]pyrl~
midin-4-one monohydrochloride (intermedlate 177).

* Trademark 1 3300~1 B. Preparatlon of Flnal compounds.
E~ample_34 A ml~ture of 5.52 parts of 6-(2-bromoethyl)-3,7-tlmethyl-SH-thlazolo[3,2-a]pyrimidin-5-one monohydrobromide, 7.3 psrts of 1-[(4-fluorophenyl)methyl]-N-(4-plperldinyl)-lH-benzlmidazol-2-am~ne dih~drobromlde, 6.4 parts of sodlum carbonate and 135 parts of N,N-dlmethylforma~1de was stirred a~d heated over~lght at 70C. The reaction mixture was poured onto water. The product was extracted wlth trlchloromethane. The e~tract was drlet, flltered ant e~aporated. The 10 residue was purlfied by colum~ chromatography o~er slllca gél uslng`a ml~ture of trlchloromethane aDd methanol (94:6 by volume), saturated wlth ammonla, as eluent. The pure fractlo~s were collectet snt the eluent was e~sporatet. The resldue was crystallizet from acetonltrlle, ylelding 5 parts (62.ô%) of 6-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzlmidazol-2-yl]amino]-1-piperldlnyl]ethyl]-3,7-timethyl-5a-thiazolo[3,2-a]pyrlmitln-5-one; mp. 141.0C (co~pou~d 1).
Following the same proeedure and u81ug equivalent amounts of the appropriste startlng materlals, there ~ere also preparet:

Ca2_Ca2_N~N~ ~A3 _ Comp. Het Rl Al~A2~A3~A4 ~a8let for~ PC

. ~_ _ l 2 ~ ~N- 4-F-C6a4-CH2- -ca-ca-ca-ca- a2o 222.6 C1~3 3 ~ C ~ ~ ~ 4-F-C6~4-CH2- -CH-CH-CH~CH- b~se 190.7 _______ __ _________ ____ _ ____________ _______________ ______ - 1 330~1 No. Het Rl AlCA2_A3_A4 base or mpC-_ _ 4 ~N ~ 4-F-C6H4-Ca2- -C~-CH-C~-C~- 2~ 0 237.3 ~ ~ 2-furanyl- -cH~cH-cH-ca- base 108~1 lS ~N ~ methyl- -N~C~-CH-CH- base 202.4 7 a CL~ 4-F-C6H4-CH2- -N-C~-CH-C~- base 99 7 IC~3 ~ 4-F-C6H4-CH2- -CH-C~-C~-CH- base 222.7 30 9 ~ cL~ 2-furanyl- -C~-Ca-C~-CH- H20 129.1 H C ~ N~ ~ 2-furanyl- -N-CH-C~-CH- base 127.4 35 --- -___~_ __ ~ ____ _________________ ~_ _ __ ~_~__ __ 1 33aa~ l -~7-CNomP Het Rl ~a;t form C
ClH3 'Q~ 2-furanyl- -CH=CH-CH=CH_ base 258.0 ~ 4-F-C H -CH2- -N=CH-CH'CH- H O 196.1 13 C ~ ~ 2-furanyl- -CH~CH-CH~CH- base 107.4 14 ~r~ 2-furanyl- -N~CN-CH-CH- base 161.2 ~r~ 4-F-c6H4-cH2- -CH'cH-cH-cH- 2H O 229.1 16 ~r~ 4-F-C H -CH - -N-CH-CH'CH- 3HC1 239.3 17 ~Nr~ 4-F-C6H4-CH2- -CH-CH-CH-CH- base 241.1 ______~______________________________w______________________________ -- 1 3~0081 ____________________________________________________________________.
N~P-Het Rl A A A salt form C
. _ 18 ~ methyl -CH=CH-CH~CH- b~se 224.5 19~ ~ 4-thiazolyl- -CH-CH-CH~CH- base 167.1 N ~ methyl 1~ O ~ ~ 2-fu gnyl~CH-CY-CH- ~aHe 221-0 21 Cl ~ 2-fura~yl--N~CH-CH~CH- ba~e 219.7 1 3300~, ~

Example 35 A mlxture of 3.34 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrido-[1,2-a]pyrimidin-4-one, 6 parts of 3-(4-~luorophenylmethyl)-N-~4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amlne dihydrochloride, 4.8 5 parts of sodiuo carbonate, 0.1 parts of potassium lodlde and 135 parts of N,N-dimethylformamide was stirred and heated overnight at 70C. The reaction mixture was poured onto w3ter. The product was extracted with trichloromethane. The extract was dried, ~iltered and evaporated. The resldue was purifled by col~mn-chromatography over 10 silica gel using a mixture of trichloromethane and methanol, saturated wlth ammonia, ~96:4 by volume) a8 eluent. The pure frac'ions were collected and the eluent was evaporated. The residue was crystallized from acetonitrile, yielding 4 parts ~60~) of 3-[2-[4-[13-[(4-fluorophenyl)methyl]-3H-imidazo[4,5-b]-pyr$din-2-yl~amlno]-15 1-piperidinyl~ethyl]-2-methyl-4H-pyrido[1,2-a~pyrimidin-4~one dihydrochloride1 mp. 195.7C (compound 22).
In a slmilar manner there were also prepared:

Rl L _~ 3 NH ~ ~ A3 _ .
25 No. Rl Al~A2_A3~A4 balt form Pc O
23 ~ CH2)2 4~F~C6H4~cH2~ -CH-CH~CH~CH- ~ O 226.9 H

L ~ N~CH2)2 furanyl -CN~CH-CH-CH- base 23~3 4 ____________________________________________________________________ ~3003 1 omOp. L Rl A =A2-A3-A4 b se or ~p.

H
2 ~ 8(CH2)2 F C6d4 ~H2 -N CH-CH-CH- u2o 251.6 26 ~H ~ 2-furanyl- -N-CH-CH~CH- base 231.7 15 ~ 2 ~ ~ ~ CH ~ 4-F-c6H4-CH2- -CH-CH-CH-CH- b~2e 115.1 2 N ~ CH2)2 fhra D 1--N-CH-CH-CH- base 186 4 20 ~ ~ ~ CH2)3 4 F C6H4-CH2- -cH~cH-cH~cH- b~ 245 3 ~ ~ CH2)3 2 furanyl -CH'CH-CH~CH-base 250.7 31 C ~ ~ (CH ) 2-fur~nyl- -CH~CH-CH~CH- base 103.6 32 ~ ~ 2-furanyl- -N-CH CH~CH- base 234.0 ---______ 1 3300~ 1 CNOp.......... L R Al~A2_A33A4 base or mp.

5 ~ 31 ~ ~ CH ) 4_F-C5H4-CH2- -CH'CH-CH'CN- H 2D7. ¦

~ ~ CH2)2 methyl-CHsCH-CH-CH- base 217.4 CH 3 , , ~ ~ H2)2 2 furanylN=CH-CHeCH- base 195.0 N ~ O

36 ~ N(CH2)2 4 F C6HiCH2- -N-CH-CH~CH- 2HC1 291.2 H

N(CH2)3 4 F C6H4CH2 -N~CH-CH~CH- H2O 236.1 38 L ~ ~ 4-F-C6H4-CH2- -N=CH-CH~CH- 2HC1 259.6 30 3 H3C-N ~ (CH ) methyl -CH-CH-CH-CH- base 192,0 35 40 ~ ~N ~ 4-F-C~H4-CH2--CH~CH-CH-CH- base 234.8 ____________________________________________________________________ I
fNmOp. L R Al A2 A3 A4 base or mp.

5 41 ~N ~ 4-F-C6H4-CH2- -CH=CH-CH=CH- base 196.6 42 H C ~ ~ 1(CH2~2 methyl -N=CH-CH=CH- base 195.3¦

H3C ~ ~ NICH ) 4 ~ C6H4~CH2~ -N=cH-cH=cH- HHHr 246.6 ~ N ~ CH2)2 2 furanyl- -cH=cH-cH=cH- 3H O 211.2 ~ ) 4 F-C6H4-CH2- -CH~CH-CH~CH- 2H o 223.2 25 I N~fCH3 ¦ 46 ~ CH2)2 6H4 CH2- -N=CH-CH=CH- base 204.8 0 47 ~N ~ CH ) 2-furanyl- -N3CH-CH~CH- base 177.8 48 ~ N~ ~ H ) 2-furanyl- -N=CH-CH=CH- base 153.8 _____________________________________________________________________ - 1 3300~1 _omp. L Rl Al=A2-A3=A4 base or mp.
No. salt form C
_ _ ~ ~ ~ 2 4-F-c6~4-cH2- -CH=CH-CH=cH- base 187.1 0l ~d ~ Cd2)2 4 F C6N4-CH2- -CH=Cd-C CH- baN 168.7 ~ N ~ CH2)2 3-pyr d nyl- -cH=cH-cH=cH- base 205.1 52 ~ CH ) 2-th enyl- -CH=CH-CH=CH- base 219.4 CN2)2 4 F C6H4 Cd2 -CH - CH-3=CH- bo=~ 222.3 54 ~ CH ) 2-furanyl- -N~CH-CH~CH- base 175.6 ~ ~ Cd2) 2 py dinyl- -N=CH-CH=CH- b 207.3 35 ~ ~ ~ (CH2)2 2 pyridinyl- -CH~CH-CH=CH- base 193.3 _____________________________________________________________________ 1 33~0~1 ____________________________________________________________________ CNoP. L Rl Al=A2 A3 A4 base or mp.
. ~' .
~ N ~ CH2) 2 pyridinyl- -CH=CH-CH=CH- base 193.8 , ~ Z-f r ~yl- -2~C:-CH~C~- b~be 20:.4 ~ 2 2 methyl -CH=CH-CH=CH- base 214.0 ~ N ~ CH2)2 4 F C6H4-CH2- -CH=C~-N=CH- b 230.5 ~ N ~ CH2)2 2-PYridy1m~thy1 -N3CH-CH=CH- baae 166.0 62 ~ C~2)2 4 thiazolyl -CH-CH-CH-CH- base 158.8 30 63 ~ ~ 2-furanyl -N=CH-CH=CH- base 86.2 Y ~ (CH2)2 methYl _____________________________________________________________________ ~NmoP.- L R Al=A2_A3=A lt form C
I _ 5 64 ~ CH2)2 thLazolyl -CH=C~-CH=CH- base 239.5 10 ~ 6 ~ ~ CHz)2 3 pyrLdinyl- -CH=CH-CH=CH- base 235 l~

lS ~ 6 ~ C~2)2 PhrldinYl -C3=CH-CH=CH- base 238.B~

~ ~ ~ C~2)2 pyrl~inyl -N-C~-CH-CH- bdse 240,2 _ Example 36 A mlxture of 3.15 parts of 3-(2-chloroethyl)-2-methyl-4H-pyrldo~l,2-a]pyrlmldln-4-one, 8.26 parts of N-~4-plperldinyl)-1-(2-pyrazinylmethyl)-lH-benzimidazol-2-amlne trlhydrobromide, 6.4 parts of sodlum carbonate, 0.1 parts of potasslum iodide and 90 parts of N,N-dlmethylacetamide was stlrred and heated overnlght at 80C. The reactlon mixture was poured into water. The product was extracted wlth trlchloromethane. The extract was drled, filtered and evaporated. The residue was purified by column chromatography over silica gal using a mixture of trichloromethane and methanol, saturated wlth ammonla, (96:4 by volume) ag eluent. The pure fractlons were collected and the eluent was evaporated. The resldue was cry~talllzed from acetonitrile. The product was flltered off and dried, yl~ldlng 5 parts (67.4~) of 2-methyl-3-~2-[4-[[1-~2-pyrazinyl-1 3300~1 methyl)-lH-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-4H-pyrido-[1,2-a]pyrimidin-4-one; mp. 204.4C (compound 68).
In a similar manner there were also prepared:

L _ ~ NH ~ ~ ~ 3 ;Comp. L R Al_A2_A3=A4 lt form C
_. _ 69 ~ ~ (CH2)2 4-Cl-C6H~-CH2- -CH=CH-CH=CH- base 208.0 15¦ ~ ~N ~ H3 1 70 N ~ (CH2)2 4-F-C6H4-CH2- -CH=CF-CF=CH- base 132.3 20 ~ 71 ~ ~ (CH2)2 CH3-C~2- -CH3CH-CH'CH- 1/2H O 225.9 72 ~ ~ CH2)2 ~ -CH=CH-CH3CH- base 238.5 73 ~ ~ ~CH2)2 cyclohexyl -CH=CH-CH=CH- base 156.2 74 ~ -N3CH-CH=CH- H2O 153.3 ~ CH ) 2-furanyl- -N=CH-CH=CH- base 175.8 ____________________________ _____ ________________________ ________J

- 1 3300~31 Comp. L Rl Al_A2 A3-A4 base or mp.
No. salt form C

6 ~ ~ ~C 2)2 fhrlnyl -N=CH-CH=CH- H2O 218.3 77 ~ ~CH2)2 2-furanyl- -N=CH-CH=CH- H2O 140.6 78 ~ ~ ( 2)2 4 F C6H4 CH2- -CH=CH-C=CH- base 192.8 15 79 ~ ~ 2)2 4 F C6H4-CH2- -cH=N-cH=cH 3 HCl 251.6 ~ N CH ) 2-th enyl- -CH=CH-CH=CH- base 243.4 Bl ~ ~ ( 2)2 methyl -N-CH-CH~CH- base 82 ~ ~ CH2)2 th 1 Y -NYCH-CH=CH- base ~

a 3 ~ ~ (CH2)2 2-furanyl- -N-CH-CHDCH- base -methyl 34 ~ ~ (CN2)2 th 1 Y N-CH-CN~CN- b~3e -- ` t ~300~ 1 _______________________________________________________________ Comp. L R Al A2 A3 A4 base or mp.

5 ¦ aS C ~ (CH2)2 m th 1 Y -N=CH-CHsCH- base 86 ~ CH2)2 2-furanyl- -N=CH-CH=CH- base methyl 87 ~ ~ 2-thienyL- -N=CH-CH=CH- base 15 88 ~ ~ (CH2)2 methyl Y -N=CH-CH=CH- base H

~ N~CH2)2 2-furanyl- -N=CH-CH=CH- base methyl In a simllar manner there were also prepared:
3-~2-[4-[[1-[~4-fluorophenyl)methyll-lH-benzlmldazol-2-yl~phenyl-methyl)amino]-l-piperidinyllethyl]-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[l~2-a]pyrimldin-4-one (E)-2-butenedioate(l:l)t mp. 186.4C
25 ~compound 90)5 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]methyl-amino~ plperldinyl]ethyl]-2-methyl-4H-pyrido[1,2-a~pyrimidln-4-one trihydrochloride; mp. 244.7C (compound 91)t and cis-3-~2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzlmidazol-2-yl]amino]-30 3-methyl-1-piperidlnyl]ethyl]-2-methyl-4H-pyrido[1,2-a]pyrimidln-4-one~ mp. 160.6C (compound 92).

1 3300~ 1 Example 37 A mixture of 2 parts of 6~chloro-9H-purine-9-ethanol~ 3.7 parts of N-[1-(2-aminoethyl)-4-piperidinyl~-1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-amine, 1.06 parts of sodium carbonate and 45 parts of N;N-dimethylace~amide was stirred and heated for 3 hours at 130~C.
The reaction mixture was poured into water and the product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was crystallized from acetonitrile. The product was filtered off and dried, yielding 208 parts (53~) of 10 6-[[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl~amino]-1-piperidinyl]ethyl]amino]-9H-purine-9-ethanol; mp. 168.7C (compound 93).
In a slmilar manner there were also prepared:

15 Rl ~ R"' ~ NH-CH2-cH2 N 3 ~ ~ A

-,Comp. R' R" R"' Al8A2-A3-A4 mOpc.
!
94 CH3 H 4-fluoro -CH=CH-CH=CH- 188.0 2595 C6H5CH2 H 4-fluoro -CH=CH-CH=CH- 145.5 96 CH3 CH3 4-fluoro -CH=CH-CH=CH- 211.7 97 H H 4-fluoro -CH=CH-CH-CH- 151.4 98 CH3 OH 4-fluoro -CH-CH-CH=CH- 257.1 99 CH3 H 3-CH3 -CH=CH-CH=CH- 188.9 30100 CH3 H H -CH~CH-CH~CH- 207.5 101 CH3 H 4-fluoro -CH=C-CH=CH- 194.5 102 CH3 H 4-fluoro -CH-CH-C=CH- 186.1 OH
_ _ - ` 1 3300~ 1 ~xample 38 A mixture of 2.8 parts of 2-(methylthio)thlazolo[5,4-b]pyridine and 5.5 parts of N~ (2-aminoethyl)-4-piperidinyl~-1-[(4-fluoro-phenyl)methyl]-lH-benzimida~ol-2-amine was stirred for 24 hours at 140~C. The reaction mixture was purified by column chrom4tography over sillca gel u~ing a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume ) as eluent. The pure fractions wer~ collected and the eluent was evaporated. The residue was crystalllzed from zcetonitrile. The product was filtered off and 10 dried, yieldlng 1.9 parts (25~) of N-[2-[4-[[1-~(4-fluorophenyl)-methyl~-lH-benzimidazol-2-yl]amino]-1-plperldlnyl]ethyl]thlazolo-[5,4-b]pyrldin-2-amlnel mp. 203.5C (compound 103).
In a similar manner there was also prepared:
N-~2-~4-~ (4-fluorophenyl)methyl]-lH-benzlmldazol-2-yl]amino]-1-15 plperidinylleth~l]thlazolo[4,5-c]pyridin-2-amlne~ mp. 192.6C
(compound 104).
Example 39 A mixture of 2.5 parts of thiazolo[5,4-b]pyridine-2-thlol, 1 part of a sodium hydride disperslon S0~ and 45 parts of N,N-dimethyl-20 formamide was stirred ~or 1 hour. Then there was added a solution of6.9 parts o~ N-tl-(2-chloroethyl)-4-piperldlnyl]-l-(4-fluorophen methyl)-lH-benzimldazol-2-amlne ln 45 parts of N,N-dlmethylform-amide. The whole was stirred overnight. Water was added dropwlse.
The product was extracted wlth 4-methyl-2-pentanone. The extract was 25 dried, filtered and evaporated. The residue WAg purlfied by column chromatography over silica gel using a mixture of tr$chloromethane and methanol, saturated with ammonia, (95:5 by volume) as eluent.
The pure fractions were collected and the eluent was evaporated. The residue was crystalllzed from acetonitrile. The product was flltered 30 off and dried, yieldlng O.S parts (6.4~) of 1-t(4-fluorophenyl)-methyl]-N-~1-[2-~thlazolo~5,4-blpyridin-2-ylthlo)ethyl]-4-piperi--dinyl]-lH-benzimldazol-2-a~ine; mp. 159.9C ~compound 105).
Example 40 To a stlrrad and cooled (0C) mixture of 3.8 parts of poly~oxy-- 1 3300~ 1 methylene) 37~, 15.5 parts of 1-[(4-fluorophenyl)methyl]-N-(4-piperidlnyl)-lH-benzlmidazol-2-amine and 7 parts of glacial acetic acld were added 6.5 parts of 2-methyllmidazo[1,2-A~pyrldlne under nitrogen atmosphere. The whole was heated slowly to 50C and stirring was continued at SoC for 2 hours. After stlrrlng was contlnued overnight at room temperature, the reaction mixture was poured into water and the whole was made alkaline with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, flltered and evaporated. The residue was purified 10 by column chromatography over silica gel uslng a mlxture or trlchloromethane and methanol, saturated wlth ammonla, (96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystalllzed from acetonltrlle. The product was flltered off and dried, yieldlng 6.7 parts (30~) of 15 1-t(4-fluorophenyl)methyl]-N-[1-1(2-methylimidazo[1,2-a]pyridin-3-yl)methyl]-4-plperldlnyl~-lH-benzimidazol-2-amlne; mp. 198.1C
(compound 106).
Example 41 To a stlrred mlxture of 5.3 par:s of 4-[1-(4-fluorophenylmethyl)-20 lH-benzimidazol-2-ylamino~-1-piperidineethanol dlhydrochlorlde, 2.8 parts of a sodium hydrlde dispersion 50~ and 90 parts of N,N-dl-methylformamide were added 2.55 parts of 2-(methylsulfonyl)thiazolo-[5,4-b]pyrldine. The whole was stirred for 2 hours. The reactlon mixture was poured into water. The product was extracted with 25 4-methyl-2-pentanone. The extract was drled, flltered and evaporated, The resldue was purified by column chromatography over slllca gel using a mixture of trichloromethane, hexane and methanol (45:45:10 by volume) as eluent. The pure fractlons were collected and the eluent was evaporated. The residue was crystalllzed from 30 acetonltrlle The product was filtered off and drled, yleldlng 0.9 parts (15~) of 1-[(4-fluorophenyl~methyl]-N-[1-[2-~(thlazolo[5,4-b]-pyridln-2-yl)oxy~ethyl]-4-piperidinyl~-18-benzimidazol-2-amine~
~p. 151.0C (compound 107).

Example 42 A mixture of 8 parts of N-[2-[4-[[1-[~4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidlnyl]ethyl]-N'-[4-~methyl-amino)-3-pyridinyl]thiourea, 15 parts of mercury(II)oxide, 0.1 parts of sulfur and 120 parts of ethanol was stirred and refluxed for 3 hours. After the addition of another 15 parts of mercury(II)oxide, stirring at reflux was continued for 2 hours. The reaction mlxture was ~iltered over Hyflo*and the filtrate was evaporated. The residue was purified by column chromatography over silica gel using a 10 mixture of trichloromethane and methanol saturated with ammonia (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallizea from acetonitrile. The product was filtered off and dried, yielding 4.4 parts (59%) of N-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-15 2-yl]amino]-1-piperidinyllethyl]-1-methyl-lH-imidazo[4,5-c]pyridin-~-amine monohydrate~ mp. 144.6C (compound 108).
In a similar manner there were also prepared:

Rl Het-NH-cH2-cH2-N ~ NH ~ ~ A

25 FNmOP~- Het - Rl Al A2 A3 A4 base or mp.
H
109 ~ ~ 4-F-C H4-CH2- -CH=CH-CH=CH- bage 250.5¦
N

H
110 ~ ~ 4-F-C6H4-CH2- -CH-CH-CH=CH- base 259.3 H
35 111 ~ ~ 2-furanyl- -CH-CH-CH-CH- bass 229.8 N N methyl _________________________________________________..___________________ * Trademark ~ 33008 1 CNmOp......... Het R A salt form C
_ _ _ . _ 5 112 ~ ~ 4-F-C6H4-CH2- -CH=CH-CH=N- base 276.7 113 ~ ~ 2-pyridinyl -N=CH-CH=CH- base 243.0 methyl 15 114 ~ ~ 4-F-C6H4-CH2- -N-CH-CH=CH-4(COOH)2 238.8 115 ~ 2-pyridinyl - -CH=CH-CH=CH- base 233.0 N methyl H
116 ~ ~ phenyl -CH~CH-CH~CH- base 212.6 25 117 ~ ~ 2-thienyl- -CH=CH-CH=CH- base 232,6 N methyl 30 118 ~ ~ N~ 4-F-C6H -CH2- -CH~CH-CH=CH- base 265.6 119 ~ ~ 2-furanyl- N CH (CH-COOH) methyl ~1:3).H O
_____________________________________________________________________ NmOp....... Het R 1 A2 A3 A4 base or mp.
_ _ 1 2 ~
12Q ~ 4-F-C6H4-CH2- -CH~CH-CH=CH- base 219.' Example 43 A mixture of 18 parts of N-(4-amino-3-pyridinyl)-N'-[4-[4-[[1-10 [(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amlno]-1-piperidinyl]-butyl]thiourea~ 7 parts of mercury(II)oxide, 1 part of sulfur and 180 parts of tetrahydrofuran was stirred and refluxed for 5 hours.
The reactlon mixture was filtered hot over Hyflo and the filtrate was evaporated. The residue was purified by column chromatography 15 over silica gel using a mixture of trichloromethane and methanol saturated with ammonia, (9a:10 by volume) as eluent. The pure fraction8 were collected and the eluent was evaporated. The residue was crystallized from a mixture of tetrahydrofuran and trichloro-methane, yielding 5 parts ~29%) of N-[4-[4-[[1-[(4-fluorophenyl)-20 methyl]-lN-benzimidazol-2-yl]amino]-1-piperidinyl]butyl]-lH-imidazo-[4,5-c]pyridin-2-aminet mp. 228.2C ~compound 121).
In a slmilar manner there were also prepared:
N-[3-~4-[~1-[(4-fluorophenyl)methyl]-lH-benzimldazol-2-yl]amino]-1-piperidlnyl]propyl]-lH-imldazo[4,5-c]pyridln-2-amine ethane-25 dioate~Z:7)~ mp. 220.4C ~compound 122)s and N-t2-~4-[[1-[~4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]-3-methyl-3H-imidazo[4,5-c]pyridln-2-amlne ethane-dioate~l:3) monohydrate~ mp. 242.3C ~compound 123).
Example 4~
To a stlrred mixture of 7.7 parts of 2-~ethylamino)-N-[2-[4-[[1-[~4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]-ethyl]benzamlde~ 2 parts of N,N-diethylethanamlne and 90 parts of tetrahydrofuran were added dropwise 1.6 parts of ethyl carbono-~ ;S300S I

chloridate. Upon completion, 6tirring was contlnued for 1 hour at room temperature. The reactlon mixture was evaporated and 4-methyl-2-pentanone was added to the residue. The organic phase was washed wlth water, dried, filtered and evaporated. ~he resldue was purlfled by column chromatography over silica gel uslng a mixture of trichloromethane and ~ethanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The resldue was further purified by HPLC using a mixture of methylbenzene and ethanol (90:10 by volume) as eluent. The pure fraction was collected 10 and the eluent was evaporated. The resldue was crystalllzed from acetonitrlle, yleldlng 2.2 parts (25~) of ethyl [1-[2-[1-ethyl-1,4-dlhydro-2,4-dloxo-3(2H)-quinazolinyl~ethyl]-4-piperidlnyl]-[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]carbamate~ mp. 160.3C
(compound 124).
15 Example 45 To a stirred mlxture of 4 parts of 2-(ethylamlno)-N-[2-[4-[[1-[(4-fluorophenyl~methyl]-lH-benzimidazol-2-yl]amino]-1-piperldlnyl]-ethyl]benzamide, 1.06 parts of sodium carbonate and 65 part~ of dlchloromethane was added dropwise a solutlon of 2 parts of methyl 20 carbonochloridate in dichloromethane. Upon completion, stirring was contlnued overnight at reflux temperature. Water was added and the product was extracted with dichloromethane. ~he extract was dried, flltered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trlchloromethane 25 and methanol (90:10 by volume) as eluent. The pure fract'ons were collected and the eluent was evaporated. The resldue was converted lnto the hydrochloride salt in acetonltrlle and 2-propanol. The salt was filtered off and dried, yieldlng 1.8 part of 1-ethyl-3-[2-[4-[1-[(4-fluorophenyl)methyl]-lH-benzlmldazol-2-yl~amino~-1-plperi-30 dlnyl~ethyl~-2,4(1H,3H)-quinazolinedlone dihydrochloride) mp. +260C
(compound 125).
Example 46 A mlxture of 6 parts of 2-amlno-N-[2-[4-[[1-[(4-fluorophenyl)~
methyl~-lH-benzlmidazol-2-yl]amino~-1-plporialnyl~ethyl~-5-(mothyl-3S thlo)benzamide, 1.78 parts of l,l -carbo~ylbis[lH-lmiaazole] and 90 parts of tetrahydrofuran was stirred and refluxed overnight. The reaction mlxture was evaporated. The residue was crystallized from acetonitrlle. The product was filtered off and dried, yleldlng 5.2 parts (85~) of 3-[2-[4-[[1-[t4-fluorophenyl)methyl]-lH-benzlmidazol-2wyl]a~ino]-1-piperidlnyl]ethyl]-6-(methylthlo)-2,4(1H,3H)-quina-zollnedione; mp. 238C (compound 126).
In a slmllar ~anner there were also prepared:
3-f4-[4-~[1-[(4-fluorophenyl)methyl]-lH-benzlmldazol-2-yl~amino]-1-plperidinyl]butyl]-2,4(1H,3H)-quinazolinedlone$ mp. 212.6C
(compound 127); and 3-[4-[4-[[1-(2-furanylmethyl)-lH-benzimldazol-2-yl]amino]-1-piperidinyl]-butyl]-2,4(1H,3H)-qulnazollnedionet mp. 194.3C
(compound 128).
Example 47 To a stlrred mixture of 4,7 parts of N-[2-[4-[11-(2-furanyl-methyl)-lH-benzimidazol-2-yl]amino]-1-plperidlnyl]ethyl~-2-(methylamino)-benzamide, 2.02 parts of N,N-diethylethanamine and 195 p~rts of dichloromethane was added dropwise a solution of l.i4 parts of carbonoth$oic dichloride in dlchloromethane. Upon completion, stirring was continued overnight at room temperature. The reaction mlxture was poured into water. The layers were separated. $he organic layer wa dried, filtered and evaporatod. The ~esidue was purlfled by column chromatography over sillca gel uslng a mlxture of trlchloromethane and methanol, saturated with ammonia, ~96s4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The resldue was crystallized from acetonltrlle, yieldlng 1.4 parts ~27.5~) of 3-[2-~4-ffl-t2-furanylmethyl)-lH-benzimldazol-2-yl]a~ino]-1-piperidinyl]ethyl]-2,3-dihydro-1-methyl-2-thloxo-i(lH)-quinazolinone; mp. 188.4C ~compound 129).
~n a simllar manner there was also prepareds 3-~2-[4-~[l-i~4- luorophenyl)methyl]-lH-benzl~ldazol-2-yl]amlno]-1-plperidinyl]ethyl]-2,3-dihydro-i-methyl-2-thioxo-4tlH)-guinazollnones mp. 215.8C (compound 130).

Example 48 To a stlrred ~olution of 10.9 parts of N 11-(2-amlnoethYl)-4-piperidlnyl]-1-~4-fluorophenylmethyl)-lH-benzi~ldazol-2-amlne in 150 parts of tetrahydrofuran was added dropwise a solutlon of 6 parts of methyl 2-isothiocyanatobenzoate in 30 parts of tetrahydrofuran at room temperature: sllghtly exothermic reactlon, the temperature rose to 30C. Upon completion, stirring at room temperature was contlnued for one hour. The reactlon mixture was evaporated. The resldue was stlrred ln trichloromethane. The formed preclpltate was flltered off and crystalllzed from 2-propanone. The product was flltered off and dried, yleldlng 5.2 parts of 3-[2-[4-[1-~4-fluorophenylmethyl)-lH-benzimidazol-2-ylamlno]-1-piperidinyl~ethyl~-1,2-dlhydro-2-thloxo-4(3H)-qu~nazollnone~ mp. 198.5C (compound 131) In a simllar manner there were also prepared:
15 3-[2-[4-[[1-(2-furanylmethyl~-lH-benzlmldazol-2-yl]amlno~-1-plperidinyl]ethyl]-2,3-dihydro-2-thioxo-4(1H)-gulnazolinone~ mp.
146.0C (compound 132);
3-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzlmidazol-2-yl]amino]-1-plperidlnyl~ethyl]-2,3-dihydro-6-methyl-2-thloxothleno[2,3-d~-20 pyrimidln-4(1H)-one~ mp. 236.4C (compound 133)~ and 3-[2-[4-~[1-(2-furanylmethyl)-lH-bQnzlmidazol-2-yl]amino]-1-piperl-dinyl]ethyl~-2,3-dlhydro-6-methyl-2-thloxothleno[2,3-d]pyrlmldln-4(1H)-one monohydrateJ mp. 214.5C (compound 134).
Example 49 To a stirred mlxture of 4.1 parts of 3-[2-[4-[[1-[(4-fluoro-phenyl)methyl]-lH-benzlmldazol-2-yl]amino]-1-plperldlnyl]ethyl]-2,3-dlhydro-6-methyl-2-thloxothieno[2,3-d]pyrlmldin-4(1H)-one, 5.6 parts of potasslum hydroxlde, 81 parts o~ ethanol and 8 parts of water were added dropwlse 60 parts of a hydrogen peroxide solutlon 33. The whole was stlrred overnlght. The reaction m~xture was evaporated.
$he resldue was purlfied by column chromatography over slllca gel uslng a ~ixture of trlchloromethane and methanol (9OslO by volume) a~ eluent. $he pur~ fractlons were collected and the eluent was evaporated. The re~due was crystalllzed rom 2-propanone. $he product wa~ fllt-red off and d~led, yleldlng 2.2 parts (55~) of 1 ~300~ 1 3-~2-[4-[[1-[(4-fluorophenyl~methyl]-lH-benzlmidazol-2-yl~amlnol-1-piperidinyl]ethyl]-6-methylthleno[2,3-d]pyrimidine-2,4(1H,3H)-dione~
mp, 187.6C (compound 135).
ln a slmilar manner there was al~o prepared:
5 3-[2-[4-[[l-(2-furanylmethy~ benzimidazol-2-yl~amlnol-l-piperi dinyl]ethyl~-6-methylthieno[2,3-d]pyrimidine-2,4(1H,3H)-dlone; mp.
151.7C (compound 136).
Example 50 A mixture of 4.86 parts of 2-amino-N-[2-t4-[[1-[(4-fluorophenyl)-methyl~-18-benzimidazol-2-yl]amino]-1-piperldlnyl]ethyl~benzamide, 1.4 parts of formic acld and 45 parts of methylbenzene was stirred and refluxed overnight. The reaction mixture was evaporated and the residue was taken up in trichloromethane, water and am~onium hydroxide. The organic phase was separated, dried, filtered and evaporated. The residue was crystalllzed from acetonitrile, yielding 3.6 parts (73~) of 3-[2-[4-[[1-[(4-fluorophenyl~methyl~-lH-benz-imidazol-2-yl~amino]-1-piperidinyl]ethyl]-4(3H)-quinazolinone~ mp.
190.6C ~compound 137).
Example 51 A mixture of 3.7 parts of 2-amino-5-(methylthio)benzolc acid and 8,9 parts of N-~2-[4-[[1-[(4-fluorophenyl)methyl~-18-benzimidazol-2-yl]amlno]-1-piperidlnyl~ethyl~formamide was sSirred for 5 hour~ at 150-160C. The whole was purifled by column chromatography over silica gel uaing a mlxture of trichloromethane and methanol, saturated wlth ammonla, (95:5 by volume) as eluent. ~he pure ~ractions were collscted and the eluent was evaporated. The residue wa~ cry~tallized from a mixture of l,l -oxybisethane and aceto-nitrile. The product was flltered off and drled, yielding 4.5 parts (41.5~) of 3-[2-[4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl~amino]-1-piperidlnyl]ethyl]-6-(methylthioi-4(38)-quinazolinone~
m~. 101.4C (compound 138).
~xample 52 A mlxture o~ 3 part~ of 2-amino-N-[2-[4-[[1-[4-fluorophenyl)-methyl]-lH-benzim~dazol-2-yl]amlno]-1-piperidinyl~ethyl~benzenamlde, 20 parts of acetic acid anhydrlde and 40 parts o~ water was ~tirred 1 ~300~ 1 overnight at 120C. The reaction mixture was cooled and ammonium hydroxide was added. The product was extracted with 4-methyl-2-pentanone. The extract was dried, filtered and evaporated. The residue was puri~ied by column chromatography over sllica gel uslng a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent wa~
evaporated. The residue was crystallized from acetonitrile, yieldlng 2 parts (67~) of 3-~2-[4-[[1-[(4-fluorophenyl)-methyl]-lH-benz-imidazol-2-yl]amino]-1-piperidinyl]ethyl]-2-methyl-4(3H)-quinazoli-10 none; mp. 185.5C (compound 139).
In a s~mllar manner there was also prepared:3-~2-t4-[[1-(2-furanylmethyl)-lH-benzlmidazol-2-yl]amino]-1-piperldi-nyl]ethyl]-2-methyl-4t3H)-quinazolinone; mp. 155.7C; (compound 140).
Example 53 A mixture of 8.85 parts of 2-amino-N-[2-~4-[~ 4-fluorophenyl)-methyl]-lH-benzlmidazol-2-yl~amino]-1-piperidlnyl~ethyllbenzenamide, 1.9 part~ of ethyl 2-propynoate and 40 parts of ethanol wa~ stlrred and refluxed for 24 hours. The reaction mixture was evaporated. The re~idue was purifled by column chromatography over sllica gel u~lng 20 a mixture of trlchloromethane and methanol, saturated with ammonia, ~95~5 by volume) aR eluent. The pure fractlon~ wero collected and the eluent wa~ evaporated. The residue wa~ converted into the ~E)-2-butensdioate salt ln ethanol. The salt wa~ flltered o~f and drled, yleltlng 5.1 part~ of ethyl 3-~2-[4-t[1-~(4-fluorophenyl)-25 methyl~-lH-benzlmldazol-2-yl]amino]-1-piperldlnyl~ethyl~-1,2,3,4-tetrahydro-4-oxo-2-qulnazolineacetate ~E~-2-butenedloate ~1:2)s mp. 195.6C tcom~ound 141).
Example 54 ~ mixture of 3.2 parts of N-[2-~4-ttl-t4-fluorophenyl)methyl]-lH-30 benzlmidazol-2-yl]amlno]-1-piperidinyl]ethyl]-1,2-benzenedlamlne, 1.25 part~ of l,l -bi~lH-imidazol-l-yl]methanethione and 45 parts of tetrahydrofuran was ~tirred overnlght at room temperature. The reactlon mixture was evaporated and the resldue wan taken up in 4-~ethyl-2-pentanone. The organic phase was washed twice wlth water, 35 drled, flltered and evaporated. The re~idue wa~ purlfled by column ~ o chromatography over sili~a gel using a mixture of trichloromethane and methanol (90:10 ~y volume) as eluent. The pure fractlons were collected and the eluent was evaporated. The residue was crystal-ll~ed from acetonitrlle, yielding 1.9 parts of 1-[2-[4-[[1-~(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl~-1,3-dihydro-2H-benzimidazole-2-thione; ~p. 235.3CC (co~pound 142).
Example 55 To a stlrred mixture of 4.6 parts of N -~2-~4-~ (4-fluoro-phenyl)methyl]-18-benzimldazol-2-yl]amino]-1-plperidinyl]ethyl]-4,5-10 pyrimidinediamine, 2.25 parts of N,N-diethylethanamine and l9S parts of dichloromethane were added dropwlse 1.75 parts of carbonothiolc dichloride. Upon completion, stirrLng was continued for 3 hours at reflux temperature. The reaction mixture wa~ evaporated. The residue was purifled by column chromatography over sillca gel using a 15 mlxture of trichloromethane and methanol, saturated with ammonla, (95:5 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The resldue was converted into the hydrochloride salt in ethanol and 2-propanol. The salt was filtered off and dried, yleldlng 1 part (15.4~) of 9-[2-[4-[[1-1~4-fluoro-20 phenyl)methyl]-lH-benzimldazol-2-yl]amlno]-1-plperldlnyl]ethyll-7,9-dihydro-8H~purlne-8-thlone trihydrochlorlde .dihydrate; mp. 244.7C
(compound 143).
Example 56 7.5 Part~ o~ 6-chloro-N -[2-l4-~ 4-fluorophenyl)methyll-lH-25 benzimida~ol-2-yl]amino]-l-piperidinyl]ethyl]-4~5-pyrlmldlnediamine and 3.6 parts of urea were heated together till about 220C durlng 10 minutes. The resul~lng melt was cooled and suspended in water.
- The ~olld was flltsred off, washed wlth water and ethanol and recrystalllzed from a mixture of N,N-dlmethylacetamlde, ethanol and 30 water, yleldlng 3.9 parts ~49.9~) of 6-chloro-9-[2-[4-[11-[~4-fluorophenyl)methyl~-lH-benzimidazol-2-yl]amino]-1-piperldinyl]ethyl]-7,9-dihydro-88-purln-8-one; mp. 266.2C lcompound 144).

In a similar manner there was also p.epared:

9-t2-[4-~ t4-fluorophenyl)methyl]-lH-benzi~nidazol-2-yl]amln piperidinylJethyl~-7,9-dihydro-8H-purin-8-one; mp. 260.5C;
~compound 145).
Example 57 A mixture of 5 parts of ethyl ethanimidate hydrochloride, 9 parts of N -[2-[4-[[1-[(4-fluorophenyl)methyl~-lH-benzimidazol-2-yl]-amino]-l-piperidlnyl]ethyl]-2,3,6-pyridinetrla~ine and 100 parts of acetic acid was stirred overnight at room temperature. The reaction 10 mixture was evaporated. The residue was dissolved in trichloro-methane. Water was added and sodium hydrogen carbonate was added till foaming had ceased. The layers were separated. The organic layer was dried, filtered and evaporated. The resldue was purifled by column-chromatography over silica gel using a mixture of 15 trichloromethane and methanol, saturated with ammonla, (95:5 by volume~ as eluent. The pure fractlons were collected and the eluent was evaporated. ~he resldue was crystallized from 2-propanone. The product was filtered off and dried, yieldlng 4.8 parts (48.5~) of N-~2-[4-[[1-[(4-~luorophenyl)methyl]-lH-benzimidazol-2-yl]aminol-1-20 piperidlnyl]ethyl]-2-methyl-lH-imidazo[4~5-b]pyridln-5-amines mp.
202.0C (compound 146).
Example 50 A mlxture of 6.5 parts of ethyl 3-bromo-4-oxo-1-plperidlne-carboxylate, 8.6 parts of N-[2-[4-[[1-[(4-fluorophenyl)methyl~-25 lH-benzlmidazol-2-yl~-amlno]-1-piperidinyl~ethyllthlourea and 80 parts of absolute ethanol was stirred and refluxed overnlght. The reaction mixture was evaporated and water was added to the resldue.
~he f ree ba~e was llberated with a sodium hydroxlde solution and extracted wlth 4-methyl-2-pentanone. The extract was dried, filtered 30 and evaporatsd. The olly residue was converted lnto the (E)-2-butene-dioate salt ln 2-propanone and ethanol. The salt was f lltered off and drlsd, yielding 6.66 parts of ethyl 2-~[2-[4-[[1-[4-fluoro-phenyl)methyl]-lH-benzlmidazol-2-yl]amlno]-1-plperldlnyl~ethyll-amino]-4,5-dlhydro-thlazolo[4,5-d]pyridlne-6(7H)-carboxylate 35 (E)-2-butenedioate (1:2) monohydrate; mp. 183.4C (co~pound 147).

1 3300~ 1 Example 59 A mlxture of 7 part Qf 6-~hloro-N -[2-[4-[[1-[(4-fluoro-phenyl)methyl]-lH-benzlmidazol-2-yl]amino~-1-plperidlnyl]-ethyl~-4,5-pyrlmidinedla~ine, 2.1 parts of carbon d~sulflde and 90 parts of N,N-dlmethylfor~amide was stirred overnight at 70C. ~he reactlon mixture was poured into water. The product was extracted with trichloromethane. ~he extract was dried, filtered and evaporated. ~he residue was crystallized from ethanol. The product was filtered off and dried in vacuo overnight at 120C, yielding 2.3 10 parts ~29~) of 7-[[2-[4-~[1-[(4-fluorophenyl)methyl]-lH-benz-imidazol-2-yl]amino~ piperidinyl]ethyl]amlno]-thiazolo[5,4-d]-pyrimidine-2-thiol monohydrochloride; mp. 226.5C tcompound 148).
Ex~le 60 A mixture of 2 parts of 2-thiazolamlne, 12.7 parts of 1-bromo-4-15 [4-[[1-[(4-fluorophenyl)methyl]-lH-benzimidazol-2-yl]amlno]-1-piperidi-nyl]-2-butanone, 6.4 parts of sodium carbonate and 135 parts of methylbenzene was stirred and refluxed for 3 hours using a water separator. The whole was filtered and the filtrate was evaporated.
The residue was purified twice by col~mn chromatography over silica 20 gel using a mixture of trichloromethane and methanol, saturated with ammonia, ~96:4 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was cry~tal-lized from acetonitrlle, yielding 0.5 parts t5.3~) of 1-[~4-fluoro-phenyl)methyl]-N-[1-[2-~imidazo[2,1-b]thiazol-6-yl)ethyl]-4-piperi-25 dinyl]-lH-~enzlmidazol-2-amine; mp. 222.7C ~compound 149).
In a ~imilar manner there were also prep~red:
1-[~4-fluorophenyl)methyl]-N-[1-[2-~imidazo[1,2-a]pyridin-2-yl)ethyl~-4-piperidinyl~-lH-ben~imidazol-2-amine; mp. 208.0C~ ~omp. lS0)7 and 1-[~4-fluorophenyl)methyl]-N-[1-[2-(imidazo[3,2-a]pyrimidin-2-yl)-30 ethyl]-4-plper1dlnyl]-lH-benzlmidazol-2-am~neJ mp. 263.8CJ
~compound lSl).
Exa~ple 61 A mixture of 4 parts of 1-~(4-fluorophenyl)methyl]-N-[l-[~lmidazo[l~2~a]pyrazln-2-yl)methyl]-4-plperldlnyl]-lH-35 benzimldazol-2-amine, 50 parts of ?cetlc acld and B0 parts of 1 ~-300~'1 methanol was hydrogenated at normal pressure and at 20C wlth 2 parts of platinum-on-charcoal catalyst 5~. After the calculated amount of hydrogen was taXen up, the catalyst was filtered off and the flltrate was evaporated. The resldue was purified by column chro~atography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (96:4 by volume) as eluent. The pure fractlon~ were collected and the eluent was evaporated. The residue was converted into the hydrochloride salt in ~thanol. The salt was filtered off and dried, yielding 1.5 parts (32~) of 1-[(4-fluorophenyl)methyl~-N-[l-10 ~(5,6,7,8-tetrahydroimldazo[1,2-a]pyrazln-2-yl)methyl]-4-piperidinyl]-lH-benzimidazol-2-amine trihydrochloride; mp. 279.7C ~compound 152).

The useful antihistaminic properties of tXe compounds of formula (I) are demonstrated in the following test procedure.

Protection of rats from comDound 48/80-induced lethality.

Compound 48/80, a mixture of oligomers obtained by condensation o~
4-methoxy-N-methylbenzeneethanamine and formaldehyde has been 20 descrlbed as a potent histamine releasing agent (Int. Arch. Allerqy, 13, 336 ~1958)). The protection from compound 48/80-lnduced lethal circulAtory collapse app~ears to be a simple way of evaluating quantitativaly the antihistaminic activity of test compounds. Male rats of an inbred Wistar strain, weighing 240-260 q wese used ln the 25 sxperlment. After overnlght starvation the rats were transferred to conditloned laboratorles (temp. = 21 + 1C, relatlve humldity ~ 65 +
5~).
The rats were treated subcutaneously or orally wlth a test compound or wlth the solvent (NaCl solution, 0.9~,. One hour after treatment there 30 was ln~ected lntraver.ously compound 48/80, freshly dissolved in water, at a dose of 0.5 mg/kg (0.2 ml/100 g of body welght). In control nxperiments, whereln 250 solvent-treated animals were ln~ected wlth the standard dose of compound 4a/80, not more than 2.8~ of the animals survlved after 4 hours. Survival after 4 hours ls there~ore consldered 35 to ~e a safe crlterlon of a protective effect of drug admini~tration.

1 3~00~ 1 The ~D50-values of the compou~ds of formula (I) are listed in the first colu~n of table 1. Said ED50-values are the values in mg/kg body weight at whlch the tested compounas protect 50~ of the tested anlmals against compound 48/80-lnduced lethallty.
The compounds of formula (I) and the phar~aceutically acceptable acid addition salts thereof are also potent serotonin-antagonists.
The potency of the subject compounds as serotonin-antagonlsts is clearly evldenced by the results obtalned ln the followlng tests wherein the antagonlstic actlvity of the subject compounds on the 10 effect of serotonin is examined.

Antagonlstic actlvity on the effects of serotonln ln the gastric leslon test.
__ _ _ .

A. Lesions induced by compound 48/80:
Compound 4a/80 ~a mlxture of oligomers obtalned by condensatlon o 4-methoxy-N-methylbenzeneethanamine and formaldehyde) is a potent releaser of vasoactive amlnes from endogenous storss such as, for 20 example, hlstamine and serotonln. Rats in~ected wlth compound 48/80 exhlblt conslstent changes of blood flow ln dlfferent vascular beds:
cyanosls of the ears and the extremltles are promlnent wlthin flve mlnutes after in~ectlon of the compoundt the rats dle ~rom shock wlthln 30 minutes. The shock, followed by dead, can be avoided if the 25 rats ars pretreated with a classlcal H 1 antagonist.
However the stlmulatory effects on gastrlc secretlon are not suppressed so that rats treated wlth compound 48/80 and protected from shoc~ by an H 1 antagonlst may exhiblt all signs of intenslve gastrlc gland actlvity: gross autopsy shows dlstended stomachs wlth 30 abnormal contents and rough brlght red patches all over the mucosa, corresponding to areas of dlslntegrated glands. A number of known serotonin-~ntagonlsts such as, for example, methysergide, cypro-heptadlne~ clnanserln, mlanserln, plpa~perone, splperone, plzotlSen and metergol~ne, prevent completely the cyanosls of ears and 35 extremltle3 as well as the leslons ln the glandular area of the `- 1 3300~ 1 stomach and the abnormal gastric distension.
Method:
~ ale rats of a Wistar inbred strain, weighlng 220-250 g, were starved overnight, water being available ad libitum. The test compounds were administered orally as a solution or as a suspension ln aqueous medlum. A control rat and a "blan~ rat received the test compound. One hour later 5-[4-(diphenylmethyl)-1-pipera~lnyl-methyl~-l-methyl-lH-benzimidazole-2-methanol was administered subcutaneously to all rats at the dose of 2.5 mg/kg. Two hours after 10 the oral or subcutaneous admlnistration of the test compound, the compound 48/80 (freshly solved in water at a concentration of 0.25 mg/ml) was lnjected l~travenously into all rats ~dose: 1 mg/kg) except the "blank" rats.
Four hours after the lntravenous injection of compound 48/80, the rats 15 were decapltated and the stomachs were removed. Subsequently the stomachs were inspected for distension and contents tblood, fluid, food) and thoroughly rinsed. The macroscopic lesions were scored from 0 to *~1, 0 correspondlng to complete absence of vislble leslons and the highest score corresponding to reddish rough patches coverlng more 20 than half the glandular area.
The second column of Table 1 shows for ~ numker of compounds of formula ~I) the doses (in mg/kg body welght) at which the distenslon of the stomach as well as the lesions ln the glandular area of the stomach are completely abGent in 50~ of the test rats (ED50-value).
The compounds listed ln Table 1 are not glven for the purpose of limitlng the lnventlon thereto but only to exempllfy the useful pharmacologlcal activ~ties of all the compounds wlthin the scope of formula (I~.

Table 1 _ _ . Column 1 Column 2 Co~pound 48/80 gastric le8ion Comp. lethality test in test No. rats-ED50 in mg/Xg EDso in ~g/kg . body weight body weight 42 - ~ 0.16 0.63 4 0.16 0.31 109 0.04 0.04 147 0.31 0.63 110 0.16 0.31 111 0.02 0.08 112 0.02 0~16 113 0.04 114 0.02 0.63 24 0.08 0.63 0.16 0.16 0.04 22 0.16 -26 0.08 6 O.OB 0.63 7 0.04 0.31 1 0.31 0.63 8 0.16 0.63 9 0.08 0.16 0 0.08 0.16 115 0.02 0.16 27 0.08 11 0.08 0.04 12 0.16 0.31 28 0.04 0.16 0.16 31 0.04 0.02 _ _ 1 3300~' 1 Table 1 ~cont'd) _ . Column 1 Colu~n 2 .
Compound 48/80 gastrlc leslon Co~p. lethality test in te~t No. rats-EDsO in mg/kg EDso ln mg/kg body weight body weight 32 0.04 117 0.02 0.31 146 0-04 0.08 121 0.02 Q.02 122 0.02 0.63 119 0.04 . 0.63 108 0.04 0.16 34 0.08 0.16 0.02 ~

13 0.02 0.08 14 0.02 -36 0.16 . 15 0.16 0.31 37 0.16 16 0.16 38 0.04 39 0.16 0.63 0.16 0.16 41 0.16 0.63 42 0.16 43 0.16 44 0.16 ~
0.08 132 0.16 _ 150 0.08 0.63 17 0.31 0.63 18 0.08 0.16 129 0.08 0.31 . 35 48 0. oa Table 1 (cont'd) _ _ ~
Column 1 Colu~n 2 Compound 48~80 gastric lesion Comp. lethallty test in test S No. rats-EDsO in mg/kg EDso in mg/kg body ~eight body welght 149 ~ 1 0.08- ~ - 0.08-128 0.08 ~
151 0.08 49 0.16 0.63 152 1 0.08 0.63 94 1 0.31 0.63 1 0.16 0.63 96 1 0.16 -93 1 0.08 0.16 144 ! 0.08 97 ' 0.08 0.04 143 1 0.31 0.63 107 1 0.16 19 I 0.08 0.01 69 1 0.16 100 0.16 103 0.16 0.63 0.31 0.63 102 0.08 ~
68 0.08 -104 0.16 0.31 74 0.04 0.16 0 04 0.63 , o 01 ~
76 0.08 ~
77 0.16 0.31 21 0.04 0.63 79 0.16 52 0.31 1.25 1 33~08 1 Table 1 (cont'd) Colwmn 1Column 2 Compound 48/80 g2strlc leslon Comp. lethality test in test No. rats-ED50 in mg/kg ED50 ln mg/kq body weightbody weight 54 0.31 0.08 0.16 57 0.16 58 0.04 0.63 59 0.08 0.31 61 0.04 0.31 62 0~04 0.63 63 0.08 0.63 lS 80 0.16 0.63 64 0.08 0.31 66 0.16 0.63 .

20 In view of their antihistaminic and serotonln-antagonistlc properties, the compounds of formula (I) and thelr acid-addltion salts are very useful ln the treatment of allergic dlseases such as, for ex~mple, allergic rhinitls, allergic con~unctlvlties, chronlc urticarla, allergic a~tma and the like.
ln vlew o their useful pharmacological propertles the sub~ect compound~ may be formulated lnto various pharmaceutlcal forms for administration purposes. To prepare the pharmaceutlcal composltlons of this lnventlon, a ph~r~aceutically effectlve amount of the particular compound, in base or acld-addition salt form, as the active ingredient 30 ls combined ln intimate admixture with a pharmaceutlcally acceptable c~rrier, whlch carrler may take a wide varlety of forms dependlng on the form o preparatlon desired for adminlstration. These pharma-ceutical composltions are desirable in unltary dosage ~orm sultable, preferably, for admlnlstratlon orally, rectally or by parenteral 3S ln~ectlon. For exa~ple, in preparing the composltlons ln oral dosage form, any of the usual pharmaceuti_al medla may be employed, such as, 1 3300~3 1 for example, water, glyeols, olls, alcohols a~d the like in the ease of oral liquid preparations such as suspenslons, syrups, elixirs and solutions; or solid carriers such as starehes, sugars, kaolin, lubrieants, binders, disintegrating agents ana the like ~n the ease of powders, pills, capsules and tablets. seeauSe of their ease ln adminlstration, tablets and capsules represent the most advantageous oral dosage unlt form, ln which case solld pharmaeeutical carrlers are obviously employed.
For parenteral eompositions, the carrier will u~ually eomprise sterile 10 water, at least ln large part, though other ingredlents, for example, to ald solublllty, may be lncluded. Injectable solutlons, for example, may be prepared ln whleh the carrier comprises sallne solution, glucose solution or a mixture of sallne and glucose solutlon. Injeetable suspenslon6 may also be prepared in whieh case appropriate llquld 15 carriers, suspending agents and the like may be employed. Aeld addltion salts of (I), due to thelr lnereased water solubllity over the corresponding base form, are obviously more sultable in the preparatlon of aqueous composltions.
It ls espeelally advantageous to formulate the aforementloned 20 phar~aceutlcal composltlons ln dosage unlt form for ease of adminls-tration and uniformlty of dosage. Dosage unit form as used ln the specification and claims hereln refers to physically discrete units sultable a8 unitary dosages, each unlt eontalnlng a predetermined quantlty of actlve lngredlent ca~culated to produee the deslred thera-25 peutic effeet ln assoeiation with the requlrud pharmaceutieal earrier.Examples of such dosage unit forms are tablets ~lncluding seored or eoated tablets), capsulee, pllls, powder paekets, wafers, lnjeetable solutions or suspensions, teaspoonfuls, tablespoonfuls and the ltke, and segregated multlples thereof.
~he following for~ulations exemplify typleal pharmaeeutlcal eompositlons ln dosage unit form sultable for systemlc admlnlstratlon to anlmal and human ~ubjeets ln accordance wlth the present lnventlon.
These exa~plos are glven to illustrate and not to llmit the scope of the present inventlon.

~ 33008 1 i tn (A I.) as used thrUg d of f ormula ( I ), a po harmaceutiCallY acceptab thereof.
Sxam ~ 2 : O~AL DROPS
A I was dissolved ln 0.5 propanoic acid and 1.5 liters of the pOlyethylene glyCl at 60-80 C-o 40C these ~ere added 35 i ture wag stirred well-Df 90dium saccharin 1 ing there were added 2-1 q s to a Volume of 5 OmpriSing 10 millisrams gOlution waS fllled in 15 Exa~ple 63 : ORALth 1 4-hydroxybenzoate an were digsolved in 4 lit f thiS golutin were dl95 diOic acid and thereafte cO~bined with the remai 1 2 3-propanetriol and d d thereto. 40 Grams of gO
g of water and 2 millil b ry egsenCe were added-h fOr~er, water was adde oral solution compriSing r teaspoonful (5 millili was filled in gUitable sxample 64 : CAPSULE
A I 6 grams sodium l~ury t se 0 B grams colloldal tearate were vigorou31y ub5equentlY ~llea lnt cap~ules, comprising, 35 lngredient~

i~ .

1 3300~ 1 Ex le 65 : FILM-CPATED TABLETS
amp Preparatlon of tablet core A mlxture of 100 grams of the A.I., 570 grams lactose and 200 grams starch was mixed well and thereafter humidlf~ed with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 milllllters of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystal-line cellulose and 15 grams hydrogenated vegetable oil. The whole was mlxed well and compressed into tablets, giving 10.000 tablets, each 10 containing 10 milligrams of the active ingredient.
Coating To a solution of 10 grams methyl cellulose ln 75 mlllll1ters of denaturated ethanol there was added a solution of 5 gramq of ethyl cellulose in 150 mllllllters of dichloromethane. Then there were added 15 75 mllllliters of dlchloromethane and 2.5 milliliters 1,2,3-propane-trlol. 10 Grams of polyethylene glycol was molten and dissolved in 75 mllllliters of dichloromethane. The latter solution was added to the former and then there were added 2.5 grams of magneslum octadecanoate, 5 grams of polyvinylpyrrolidone and 30 miliiliters of concentrated 20 colour suspenslon (Opaspray X-1-2109~;and the whole was homogenated.
The tablet coreq were coated wlth the thus obtalned ~ixture in a coatlng apparatus.
Exa le 66 : INJECTABLE SOLUTION
_ mp 1.8 Grams methyl 4-hydroxybenzoate and 0.2 grams propyl 4-hydroxy-25 benzoate were dlssolved ln about 0.5 llters of bolllng water forlnjection. After coollng to about 50C there were added whlle stlrrlng 4 grams lactic acid, 0.05 propylene glycol and 4 grams of the A.I..
The solution was cooled to room temperature and supplemented with water for lnjectlon q.s. ad 1 liter volume, glvlng a solution of 4 30 mllligrams A.I. per mllllliters. The solutlon was qterllized by filtratlon ~U.S.P. XVII p. 811) and fllled ln sterlle containers.
Exam le 67 : SUPPOSITORlES
P
3 Grams A.I. was dissolved in a solution of 3 grams 2,3-dihyd~oxy-butanediolc acld ln 25 ~llllliter~ polyethylene glycol 400. 12 Gram3 35 surfactant and trlglycerldes q.s. ad 300 grams were molten together.
* Trademark ~3300~ 1 The latter mixture was ~lxed well with the former solution. The thus obtalned ~ixture was poured onto moulds at a tempsrature of 37-38~C to form 100 suppositories each containlng 30 mllligrams of the active ingredient.

The present invention i3 al50 related with a meShod of treating allergic diseases in warm-blooded animals suffering from said allergic diseases by ad~inistering an effective anti-allergic amount of a compound of formula (I~ or a pharmaceutically acceptable acld addition 10 salt thereof.
Suitable dose~ administered daily to qubjects are varying from 0.1 to 100 mg, more preferably from l to 50 mg.

.

Claims (12)

1. A process for preparing a chemical compound having the formula (III-a) a pharmaceutically acceptable acid addition salt or a possible stereo-chemically isomeric form thereof, wherein:
R is hydrogen or a lower alkyl;
R1 is lower alkyl substituted with Ar1, said Ar1 being lower alkyl substituted furanyl;
R2 is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxy-carbonyl or Ar2-lower alkyl wherein Ar2 is a member selected from the group consisting of phenyl being optionally substituted with up to three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, mercapto, amino, mono-and di(lower alkyl)amino, carboxyl, lower alkyloxycarbonyl and (lower alkyl)-CO; and A1=A2-A3=A4 is a bivalent radical having -C=CH-CH=CH- (a), -N=CH-CH=CH- (b), -CH=N-CH=CH- (c), -CH=CH-N=CH- (d), or -CH=CH-CH=N- (e), wherein one or two hydrogen atoms in said radicals (a)-(e) may, each independently from each other, be replaced by halo, C1-C6-alkyl, C1-C6-alkyloxy, trifluoromethyl or hydroxy characterized by the cyclodesulfurization of a compound of formula (XXXI) wherein R, R1, R2 and A1=A2-A3=A4 are as given above and P is an appropriate protective group by a) reacting the compound of formula XXXI with an appropriate alkyl halide in an appropriate reaction-inert organic solvent or b) reacting the compound of formula XXXI with an appropriate metal oxide or salt in an appropriate solvent.

2. The process of claim 1 wherein the alkyl halide is iodomethane.

3. The process of claim 1 or 2 wherein the reaction-inert organic solvent is a lower alkanol.

4. The process of claim 1 or 2 wherein the reaction-inert organic solvent is methanol, ethanol, or 2-propanol.

5. The process of claim 1 weherein the metal oxide or salt thereof is an Hg(II) or Pb(II) oxide or salt.

6. The process of claim 5 wherein the metal oxide or salt thereof is selected from HgO, HgCl2, Hg(OAc)2, PbO or Pb(OAc)2.

7. The process of claim 1 wherein the cyclodesulfurization process includes the presence of sulfur.

8. The process of claim 1 wherein a methanediimine is used as a cyclodesulfurizing agent.

9. The process of claim 8 wherein said methanediimine compound is N,N'-methane-tetraylbis[cyclohexanamine].

10. A chemical compound having the formula (III-a) wherein R is hydrogen or lower alkyl;
R1 is lower alkyl substituted with Ar1, said Ar1 being lower alkyl substituted furanyl;
R2 is hydrogen, lower alkyl, lower alkylcarbonyl, lower alkyloxycarbonyl or Ar2-lower alkyl wherein Ar2 is a member selected from the group consisting of phenyl being optionally substituted with up to three substituents each independently selected from the group consisting of halo, hydroxy, nitro, cyano, trifluoromethyl, lower alkyl, lower alkyloxy, lower alkylthio, mercapto, amino, mono-and di(lower alkyl)amino, carboxyl, lower alkyloxycarbonyl and (lower alkyl)-CO; and A1=A2-A3=A4 is a bivalent radical having the formula -CH=CH-CH=CH- (a), -N=CH-CH=CH- (b), -CH=N-CH=CH- (c), -CH=CH-N=CH- (d), or -CH=CH-CH=N- (e), wherein one or two hydrogen atoms in said radicals (a)-(e) may, each independently from each other, be replaced by halo, C1-C6-alkyl, C1-C6-alkyloxy, trifluoromethyl or hydroxy.

11. The compound, N-[2-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]amino]-1-piperidinyl]ethyl]thiazolo[4,5-c]-pyridin-2-amine.

12. The compound, 3-[(5-methyl-2-furanyl)methyl]-N-(4-piperidinyl)-3H-imidazo[4,5-b]-pyridin-2-amine.