CA2211889C - Vasoconstrictive substituted 2,3-dihydro-1,4-dioxinopyridines - Google Patents

Abstract

The present invention is concerned with compounds of formula (I), the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein =a1-a2=a3-a4=
is a bivalent radical of formula (a):
=N-CH=CH-CH=, (b): =CH-NCH-CH=, (c):
=CH-CH=N-CH=, (d): =CH-CH=CH-N=, wherein one or two hydrogen atoms can be substituted by halo hydroxy, C1-6 alkyl or C1-6 alkyloxy; R1 is hydrogen or C1-6 alkyl; R2 is hydrogen or C1-6 alkyl; R3 is hydrogen or C1-6 alkyl; Alk1 is C1-5 alkanediyl; Alk2 is C2-15 alkanediyl; Q is a five- or six-membered heterocyclic ring containing at least one nitrogen atom or a radical of formula -C(NR5R6)=C-R4 wherein R4 is hydrogen, cyano aminocarbonyl or C1-6 alkyl; R5 is hydrogen C1-6 alkyl, C3-6 alkenyl or C3-6 alkynyl; R6 is hydrogen or C1-6 alkyl; or R5 and R6 taken together may form a bivalent radical of formula -(CH2)4- or -(CH2)5-. Pharmaceutical compositions, preparations and use as a medicine are described.

Description

WO 96!24596 PCT/EP96/00396 VASOCONSTRICTPdE SUBSTITUTED 2,3-DIHYDRO-1,4-DIOXINOPYRIDINES
The present invention relates to novel substituted 2,3-dihydro-1,4-dioxinopyridines, processes for their prep,~arations, pharmaceutical compositions containing them and their use as a medicine, in particular for the prevention or treatment of disorders characterized by excessive vasodilatation, especially migraine.
Migraine is a non-lethal disease suffered by one in ten individuals. The main symptom is headache; other symptoms include vomiting and photophobia. For many years the most widely used treatment for migraine involved the administration of ergotalkaloids, which show however several adverse side effects. Recently a iryptamine derivative, i.e.
sumalriptan, was introduced as a novel antimigraine drug. We have now surprisingly found that the present novel substituted 2,3-dihydro-1,4-dioxinopyridines show 5-HTi-like agonistic activity anal can thus be used in the treatment of disorders characterized by excessive vasodilatation, especially migraine.
EP-A-0,559,285, published on September 8, 1993, discloses 1,4-dioxino[2,3-b]pyridine derivatives as strong ser~tonine ligands with preference for the 5-HT1A
receptor useful as antidepressants or as anti-anxiety agents.
The present invention is concerned with compounds of formula a a2 i\ ~I-N-~2-N-'Q (I)~
a t. ~ R2 Ri a4 the N oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein =ai-a2=a3-a4= is a bivalent radical of formula =N-CH=CH-CH= (a), =CH-N=CH-CH= (b ) =CH-CH=N-CH=
=CH-CH=CH-N= (d), wherein one or two hydrogen atoms can be substituted by halo, hydroxy, Ci.~alkyl or Ci..~alkyloxy;

O
O
Ri, R2 and R3 each independently are hydrogen or Ci_6alkyl;
Alki is Ci_Salkanediyl;

Alk2 is C2_lsalkanediyl;
Q is a radical of formula ~~ -R4 N-. R17 N-R5 (~)> ~ ~\R18 Rs N=~ R7 N-N
~~/~~R 19 R2o' N
N
R9 (~)' ~N
N ~ ~R22 ( I
Rio Rll ~N~-. i2 Rz3 ~ ~R (~?> ~N~~
/N~(CH~q R24~~' N (1J)>

N=N R25 (~) 26 W / y ' .--R

~ R

N-- ~ ( (CH2)r N

~N (f~> --~~S J R27 ( ~ )>

wherein R4 is hydrogen, cyano, aminocarbonyl or C1_6alkyl;
R5 is hydrogen, C1_6alkyl, C3~alkenyl or C3_6alkynyl;
R6 is hydrogen or Cl_6alkyl; or , RS and R6 taken together may form a bivalent radical of formula -(CH2)4- or -(CH2)5- ;
R~ and Rg each independently are hydrogen, hydroxy, halo, Cl_6alkyl, Cl_6alkyloxy, aryloxy, CI_6allcylthio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloalkyl)amino, aminocarbonyl, Cl_6alkyloxycarbonylamino, C1_6alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;

WO 96/24596 PCTlEP96/00396 R9 is hydrogen, hydro;{y, halo, C1-6alkyl, Cl_6alkyloxy, aryloxy, Cl_6alkylthio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloalkyl)amino, amino-carbonyl, Cl.~alkyloxycarbonylamino, Ci_6alkylaminocarbonylamino, piperidinyl, PY~lidinYl;
Ri~ is hydrogen, C1_6allcyl, Cl_6alkylcarbonyl, or arylCl_6alkyl;
Rl l and R12 are hydrogen or taken together with the carbon atom to which they are connected form C(~~);
qis 1 or2;
R13 is hydrogen, C1_6aLkyl, Cl.~allcylcarbonyl, or_arylCl_6alkyl;
R14 is hydrogen, hydroxy, halo, Cl_6alkyl, Cl_6a.lkyloxy, aryloxy, Cl_6alkylthio, cyano, amino, mono- or di(Cl~alkyl)amino, mono- or di(C3~cycloalkyl)amino, aminocarbonyl, Ci~alkyloxycarbonylamino, Cl_6alkylaminocarbonylamino, piperidinyl, pyrrolidinyl;
Rls and R16 each independently are hydrogen, hydroxy; halo, Cl_6alkyl, C1_6alkyloxy, aryloxy, Cl_6a.lkylvthio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloallcyl)atnino, aminocarbonyl, Cl_6alkyloxycarbonylamino, Cl_6alkyl-aminocarbonylami:no, piperidinyl, pyrrolidinyl;
Rl~ and Rig each independently are hydrogen, hydroxy, halo, Cl_6alkyl, C1_6alkyloxy, aryloxy, Cl_6allcylthio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloalkyl)~unino, aminocarbonyl, Cl_6alkyloxycarbonylamino, Cl_6alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
R19 and R2a each independently are hydrogen, hydroxy, halo, C1_6alkyl, C1_6alkyloxy, aryloxy, Cl_6aikylthio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloalkyl)~unino, aminocarbonyl, Cl_6alkyloxycarbonylamino, Cl_6alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
R21 and R22 each independently are hydrogen, hydroxy, halo, C1_6alkyl, C1_6alkyloxy, aryloxy, Cl_6alkyli:hio, cyano, amino, mono- or di(C1_6alkyl)amino, mono- or di(C3_6cycloalkyl)amino, aminocarbonyl, C1_~alkyloxycarbonylamino, Cl_6alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
R23 and R24 each independently are hydrogen, hydroxy, halo, C1_6alkyl, Cg_6alkyloxy, aryloxy, Ci-6alkylt.hio, cyano, amino, mono- or di(Cl_6alkyl)amino, mono- or di(C3_6cycloalkyl)a.mino, aminocarhonyl, Cl_6alkyloxycarbonylamino, C1_6alkyl-aminocarbonylamino, piperidinyl, pyrrolidinyl;
r is 1 or 2;
R25 and R26 are hydrogen or taken together with the carbon atom to which they are connected form a C(O);
R2~ is hydrogen, halo or C1_6alkyl, and aryl is phenyl optionally substituted with halo, hydroxy, Cl.~atkyl or C1_6alkyloxy.
Some of the compounds of formula (n may also exist in their tautomeric forms.
Such forms although not explicitly indicated in the above formula are intended to be included within the scope of the present invention.
As used in the foregoing definitions halo defines fluoro, chloro, bromo and iodo;
Cl~alkyl defines straight and branch chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl and the like; C3~alkenyl defines straight and branch chained hydrocarbon radicals containing one double bond and having from 3 to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl and the like;
and the carbon atom of said C3~alkenyl being connected to a nitrogen atom preferably is saturated, C3_6alkynyl defines straight and branch chained hydrocarbon radicals containing one triple bond and having from 3 to 6 carbon atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl, 3-hexynyl, and the like; and the carbon atom of said C3_6alkynylradical being connected to a nitrogen atom preferably is saturated; C3~cycloalkyl is generic to cyclopropyl, cyclobutyl, cyclopentyl and cyclo-hexyl; Ci_Salkanediyl defines bivalent straight and branch chained saturated hydrocarbon radicals having form 1 to 5 carbon atoms, such as, for example, methylene, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl and the branched isomers thereof; C2_15~~~y1 defines bivalent straight and branch chained saturated hydrocarbon radicals having from 2 to 15 carbon atoms such as, for example, 1,2-ethanediyl, 1,3-propanediyl, 1,4-butanediyl, 1,5-pentanediyl, 1,6-hexanediyl, 1,7-heptanediyl, 1,8-octanediyl, 1,9-nonanediyl, 1,10-decanediyl, 1,11-undecanediyl, 1,12-dodecanediyl, 1,13-tridecanediyl, 1,14-tetradecanediyl, 1,15-pentadecanediyl and the branched isomers thereof. The term "C(0)" refers to a carbonyl group.
The pharmaceutically acceptable acid addition salts as mentioned hereinabove are meant.
to comprise the acid addition salt forms which can conveniently be obtained by treating the base form of the compounds of formula (I) with appropriate acids such as inorganic acids, for example, hydrohalic acid, e.g. hydrochloric or hydrobromic, sulfuric, nitric, phosphoric and the like acids; or organic acids, such as, for example, acetic, hydroxy-acetic, propanoic, lactic, pyruvic, oxalic, malonic, succinic, malefic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic, p-aminosalicylic, pamoic and the like acids. Conversely, said acid addition salt forms can be converted in the free base forms by treatment with an appropriate base.

WO 96/24596 PCTlEP96/00396 The term addition salt ~~lso comprises the hydrates and solvent addition forrn.s which the compounds of formula (~ are able to form. Examples of such forms are e.g.
hydrates, alcoholates and the like.
The term "stereochemically isomeric forms" as used hereinbefore defines all the possible isomeric forms which the compounds of formula (I) may possess. Unless otherwise mentioned or indicated" the chemical designation of compounds denotes the mixture of all possible stereochem:ically isomeric forms, said mixtures containing all diastereomers and enantiomers of the basic molecular structure. More in particular, stereogenic centers may have the R- or S-configuration; and C3_6-alkenyl radicals may have the E-or Z-configuration. Stereochemically isomeric forms of the compounds of formula (I) are intended to be embraced within the scope of this invention.
The radical "=al-a2=a3-~a4" is suitably a radical of formula (a) or (d);
Rl is suitably methyl or hydrogen, preferably Rl is hydrogen;
R2 is suitably methyl or hydrogen, preferably R2 is hydrogen;
R3 is suitably methyl or hydrogen, preferably R3 is hydrogen;
Alkl is suitably Ci_3alkanediyl, preferably Alkl is methylene;
Alk2 is suitably C2~alkanediyl, preferably Alk2 is 1,3-propanediyl;
Q is preferably a radical of formula (bb) or (hh);
R~ and Rg each independently are suitably hydrogen, hydroxy, halo or methyl, preferably both R~ and R8 are hydrogen;
R19 and R2~ each independently suitably are hydrogen, hydroxy, halo or methyl, preferably R19 is hydrogen and R2o is chloro.
Interesting compounds ,are those compounds of formula (I), wherein R1 and R2 both are hydrogen.
Also interesting compounds are those compounds of formula (I), wherein =al-a2=a3-a~= is a bivalent radical of formula (a).
Another goup of interesting compounds are those compounds of formula (I), wherein =al-a2=a3-a4= is a bivalent radical of formula (d).
Particular compounds a~-e those interesting compounds of formula (I), wherein Q is a radical of formula (bb) or (hh), especially (bb).
Particularly interesting compounds are those interesting compounds, wherein Q
is a radical of formula (bb), R~ and Rg are both hydrogen.

WO 96!24596 PCT/EP96/00396 Preferred compounds are N [(2,3-dihydro-1,4-dioxino[2,3-b)pyridin-3-yl)methyl)-N-2-pyrimidinyl-1,3-propanediamine;
N [(2,3-dihydro-1,4-dioxino[2,3-b)pyridin-2-yl)methyl)-N-2-pyrimidinyl-1,3-propanediamine;
N (6-chloro-3-pyridazinyl)-N-[(2,3-dihydro-1,4-dioxino[2,3-b)pyridin-2-yl)methyl)-1,3-propanediamine; the pharmaceutically acceptable acid addition salts or the stereochemically isomeric forms thereof.
The compounds of formula (I) can generally be prepared by N alkylating an amine of formula (!l) with an intermediate of formula (III), wherein W2 is a reactive leaving group such as, for example, a halogen, methanesulfonyloxy or toluenesulfonyloxy, optionally in appropriate solvents such as, e.g. 2-butanone, tetrahydrofuran, toluene or N,N dimethylformamide.

a2~a ~ O Alk1_W2 + H-N-AIk2_N-Q ---~ (I) a3~. ~ R2 Rl O
Stirring and heating may enhance the reaction rate. Optionally a suitable base may be added to pick up the acid that is formed. during the course of the reaction such as, for example, sodium or potassium carbonate, sodium or potassium hydrogen carbonate, N,N diethylethanamine or pyridine.
The compounds of formula (I) may also be prepared. by reacting a diamine of formula (IV) with a reagent of formula (~. In the formulas (IV), (V) and all the following formulas the variabels "=al-a2=a3-aq.-", Rl, R2, R3, Alkl, Alk2 , and Q are as defined under formula (I). In formula (V) Wl is a reactive leaving group such as, for example,.a halogen, methoxy, ethoxy, phenoxy, methylthio, ethylthio or benzenethio.

a a2 l O p~l---N-,~2-N-H + W1-Q ----~ (I) a3 i R R1 O
Said reaction can be performed by stirring the diamine of formula (IV) with the reagent of formula (~ optionally in an appropriate solvent such as, for example, ethanol, dichloromethane, tetrahydrofuran, toluene or mixtures thereof. Optionally a base, such WO 96/24596 ~ ) O PCTlEP96/00396 as, for example, sodium or potassium carbonate, sodium or potassium hydrogen carbonate, N,N diethylethanamine or pyridine, can be added to pick up the acid that may be formed during the course of the reaction. Preferably the reaction is performed at the reflux temperature of the reaction mixture.
5.
The compounds of formula (1) may also be prepared by reductive N-alkylation of an aminoderivative of formula (VIII] with an appropriate aldehyde of formula (VII), wherein Alk3 is a direct bond or Cl.4alkanediyl.

R3 O jai O Alk3-C-H
pat O a w a2 w AIk3-C-Y
a3~a4 O
O ~ (~
H N-Allcz N Q a O R3 R2 Rt a2i y Allot-N-Alkz_N-Q
a3~ r R2 R1 ~ as O ~I) Said reaction is performed by stirring the reactants in an appropriate solvent such as, for example, ethanol, tetrahydrofuran, toluene or mixtures thereof. Optionally a water separator can be used to remove the water that is formed during the course of the reaction.
The resulting imine can then be induced by reactive hydride reagents such as, for example, sodium borohydride, or by catalytic hydrogenation on an appropriate catalyst, such as, for example palladium on charcoal, platinum on charcoal, Raney nickel and the like in a suitable solvent such as, for example, methanol, tetrahydrofuran, ethyl acetate, or acetic acid. Optionally the reaction may be performed at elevated temperatures and/or pressures.
The intermediate aldehyde of formula (VII) can be prepared by reducing an acyl derivative of formula (VI) wherein Alk3 is defined as above and Y is halo. The acyl halide can be prepared by reacting the acid of formula (VI) wherein Y is OH, with a halogenating reagent such as thionylchloride, phosphorus trichloride, phosphorus tribromide, oxalylchloride and the like. The latter reaction may be performed in an excess of the halogenating reagent or in appropriate solvents such as, for example, dichloromethane, toluene, tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide.
Stirring and elevated temperatures may be appropriate to enhance the rate of the reaction.
Said reduction of the acylhalide of formula (VI) can for instance be perfoitned by *Trademark _g_ catalytic hydrogenation with a catalyst such as palladium on charcoal, palladium on bariumsulfate, platinum on charcoal and the like in appropriate solvents such as, for example, tetrahydrofuran; preferably in admixture with a dipolar aprotic solvent, such as, for example N,N dimethylformamide. Optionally a catalyst poison can be added, such as thiophene, quinoline / sulfur and the like.
The reaction sequence starting from the intermediate of formula (VI) and yielding compounds of formula (I) may be performed as a one-pot procedure.
The compounds of formula (I), can also be converted into each other by functional group transformations. For instance the compounds of formula (I), wherein Q
represents a pyrimidinyl moiety, said compounds being represented by formula (IX), can be converted into the tetrahydroanalogs of formula (X) following art-known catalytic hydrogenation procedures.

jai O
a2 w Alkl-N-AIk2-N--C --12 Ii ~ ~ 3 H
a3~ i R R N R N
as O ai au O Alkl-N-Alkz,N~
12 I1 ~
a3~ i R R N
as O
Furthermore, compounds of formula (I) bearing a C3_6alkynylgroup or C3~alkenyl-group can be converted into the corresponding compounds bearing Cl_6alkylgroup following art-known hydrogenation techniques.
Compounds of formula (I) bearing a cyanogroup can be converted into the corresponding compounds bearing an aminomethyl substituent following art-known hydrogenation techniques.
Compounds bearing an alkyloxy substituent can be converted into compounds bearing a hydroxy group by treating the alkyloxy compound with an appropriate acidic reagent such as for example, hydrohalic acid, e.g. hydrobromic acid or borontribromide and the like.
Compounds bearing an amino substituent can be N-acylated or N alkylated following art-known N-acylation or N alkylation procedures.
The N oxide forms of the compounds formula (I) may also be prepared following art-known methods.
Intermediates of formula (III), wherein "=al-a2=a3-a4" is a bivalent radical of formula (a) have been described in EP-A-0,559,285.

WO 96!24596 PCT/LP96/00396 Intermediates of formula (11I), wherein "=at-a2=a3-a4 " is a bivalent radical of formula (b) wherein one or two hydrogen atoms of the pyridine moiety can be substituted by halo, hydroxy, Cl_6alkyl or Cl_6alkyloxy, said intermediates being represented by formula (III-b), are deemed novel.

N ~ ~ y_Wz O
(III-b) Intermediates of formula (III), wherein "=al-a2=a3-a4 " is a bivalent radical of formula (c) wherein one or two !hydrogen atoms of the pyridine moiety can be substituted by halo, hydroxy, Cl_6alkyl or Cl_6alkyloxy, said intermediates being represented by formula (III-c), are deemed novel.

y_W2 N /
O
(~-c) Intermediates of formula (III), wherein "=al-a2=a3-aq." is a bivalent radical of formula (d) have been described) in Heterocycles, 36 (10), 2327 (1993).
Pure stereochemically i~~~omeric forms of the compounds of this invention may be obtained by the application of art-known procedures. I~iastereoisomers may be separated by physical separation methods such as selective crystallization and chromatographic techniques, e.g. liquid chromatography. Enantiomers may be separated from each other by the selective crystalli;iation of their diastereomeric salts with optically active acids.
Said pure stereochemically isomeric forms may also be derived from the corresponding pure stere;ochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereaospecifically. Preferably if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation.
These methods will advantageously employ enantiomerically pure starting materials.
Stereochemically isomeric fortes of the compounds of formula (I) are obviously intended to be included within the: scope of the invention.
The compounds of formula (I), the pharmaceutically acceptable acid addition salts and stereochemically isomeric forms thereof have interesting pharmacological properties in that they show SHTI-likf; agonistic activity. The compounds of the present invention have a remarkable vasoconstrictor activity. They are useful to prevent and treat conditions which are related to vasodilatation. For instance, they are useful in the treatment of conditions characterized by or associated with cephalic pain, e.g. cluster headache and headache associated with vascular disorders, especially migraine.
These compounds are also useful in the treatment of venous insufficiency and in the treatment of conditions associated with hypotension. ' The vasoconstrictor activity of the compounds of formula (I~ can be determined using an in vitro-test as is described in "Instantaneous changes of alpha-adrenoreceptor affinity caused by moderate cooling in canine cutaneous veins" in the American Journal of Physiology 234(4), H330-H337, 1978; or in the test described in the pharmacological example, wherein the serotonin-like response of the compounds of the present invention was tested on the basilar arteries of pigs.
In view of their useful pharmacological properties, the subject compounds may be formulated into various pharmaceutical forms for administration purposes.
To prepare the pharmaceutical compositions of this invention, an effective amount of a particular compound, in base form or acid addition salt form, as the active ingredient is combined in intimate admixture with a pharmaceutically acceptable carrier, which carrier may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are desirably in unitary dosage form suitable, preferably, for administration orally, rectally, percutaneously, or by parenteral injection. For example, in preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols and the like in the case of oral liquid preparations such as suspensions, syrups, elixirs and solutions: or solid carriers such as starches, sugars, kaolin, lubricants, binders, disintegrating agents and the like in the case of powders, pills, capsules and tablets. Because of their ease in administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier will usually comprise sterile water, at least in large part, though other ingredients, to aid solubility for example, may be included. Injectable solutions, for example, may be prepared in which the carrier comprises saline solution, glucose solution or a mixture of saline and glucose solution. , Injectable suspensions may also be prepared in which case appropriate liquid carriers, suspending agents and the like may be employed. In the compositions suitable for , percutaneous administration, the Garner optionally comprises a penetration enhancing agent and/or a suitable wetting agent, optionally combined with suitable additives of any nature in minor proportions, which additives do not cause a significant deleterious effect to the skin. Said additives may facilitate the administration to the skin and/or may be WO 96/24596 PCTlEP96100396 helpful for preparing tlhe desired compositions. These compositions may be administered in various ways, e.g. a.s a transdermal patch, as a spot-on, as an ointment.
It is especially advantageous to formulate the aforementioned pharmaceutical compositions in dosage unit form for erase of administration and uniformity of dosage. Dosage unit form as used in the specificaition and claims herein refers to physically discrete units suitable as unitary dosages, each unit containing a predetermined quantity of active ingredient calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspooni:uls, tablespoonfuls and the like, and segregated multiples thereof.
The compounds of the present invention therefore may be used as medicines in conditions related to vasodilatation, more in particular hypotension, venous insufficiency and especially cephalic pain among which migraine. The compounds of the present invention also provide a method of treating warm-blooded animals suffering from conditions related to vasodilatation, such as, hypotension, venous insufficiency and especially cephalic pant among which migraine by administering an effective amount of a compound of formula (1), a pharmaceutically acceptable acid addition salt or a stereoisomeric form thereof. Those skilled in the art could easily determine the effective amount from the test results presented hereinafter. In general it is contemplated that an effective daily amount would be from 1 wg/kg to 1 mg/kg body weight, and in particular from 2 ~,g/kg to 200 ~,g/kg body weight. It may be appropriate to administer the required dose as two, three, four or more sub-doses at appropriate intervals throughout the day.
Said sub-doses may be formulated as unit dosage forms, for example, containing 0.005 to 20 mg, and in particular 0.1 mg to 10 mg of active ingredient per unit dosage form.
The following examples are intended to illustrate and not to limit the scope of the present invention in all its aspects.
Experimental part Al Preparation of the intermediates Example 1 2-chloro-pyrimidine (24.3 g) was added portionwise to a mixture of 1,3-propanediamine (85 g) in toluene (240 mL) while stirring at reflux temperature. The reaction mixture was stirred and refluxed for 3 hours. The reaction mixture was cooled, the precipitate was filtered off and the filtraae was evaporated. The residue was distilled in vacuo, yielding 53 g (65.7%) of N-2-pyrimidinyl-1,3-propanediamine (intermediate 1).

WO 96!24596 PCT/EP96/00396 x 1 2 A mixture of 3,6-dichloropyridazine (25 g), 1,3-propanediamine (62 g) and sodium carbonate (18 g) in ethanol (500 mL) was stirred and refluxed overnight. The reaction mixture was filtered over dicalite and the filtrate was evaporated. The residue was crystallized from acetonitrile. The crystals were filtered off and dried, yielding 20.7 g of N (6-chloro-3-pyridazinyl)-1,3-propanediamine; mp. 124.9°C
(intermediate 2).
Methanesulfonyl chloride (1.7 mL) in dichloromethane (10 mL) was added dropwise to a mixture, cooled on an ice bath, of (~)-2-(hydroxymethyl)-2,3-dihydro-1,4-dioxino-[2,3-b]-pyridine (2.4 g), prepared as described in Heterocycles, ,~ (10), 2327 (1993), and N,N diethylethaneamine (4 mL) in dichloromethane (45 mL) and the mixture was stirred at 5 °C for 1 hour. The precipitate was filtered off and the filtrate was extracted with water. The organic layer was dried over Na2S04, filtered and evaporated, yielding 3.54 g of (~)-2,3-dihydro-1,4-dioxino[2,3-b]pyridine-2-methanol methanesulfonate(ester) (intermediate 3).
In a similar way was prepared (~)-2,3-dihydro-1,4-dioxino[2,3-b]pyridine-3-methanol methanesulfonate(ester) (intermediate 4).
B~ Preparation of the final compounds xam !e 4 Intermediate 3 (3.68 g) and intermediate 2 (6.22 g) were stirred at 100 °C for 1 hour.
The mixture was purified first by an open column chromatography over silica gel (eluent:
CH2C12/(CH30H/NH3) 96/4) and then by HPLC (eluent : hexane/CH2C12/
(CH30H/NH3) 10/9/1). The pure fractions were collected, evaporated and the residue was recrystallized from CH3CN, yielding 0.77 g (12%) of (~)-N (6-chloro-3-pyridazinyl)-N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-2-yl)methyl]-1,3-propane-diamine (mp. 100.8 °C; compound 1). .
Exam 1 Intermediate 4 (1.98 g) and intermediate 1 (2.46 g) were stirred at 100 °C for 1 hour.
The mixture was purified first by flash chromatography over silica gel (eluent : CH2C12/
CH30H 96/4, 94/6 and 90/10) and then by an other flash chromatography (eluent CH2C12/(CH30H/NH3) 96/4). The pure fractions were collected, evaporated and the residue was converted into the ethanedioic acid salt (1:1) in ethanol, yielding 1.26 g (40%) of (~)-N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine ethanedioate(1:1) (mp. 193.6 °C;
compound 2).

WO 96/24596 PCTlEP96100396 In a similar way was p»epared (~)-N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-2-yl)methyl)-N-2-pyrimidinyl-1,3-propanediamine etha~ledioate(l:l) (mp. 181.2 °C; compound 3).
Pharmacolp~ical examt~l~
Exam lie C
Segments of basilar artE;ries taken from pigs (anaesthetised with sodium pentobarbital) were mounted for recording of isometric tension in organ baths. The preparations were bathed in Krebs - Hensc~leit solution. The solution was kept at 37 °C
and gassed with a mixture of 95% 02 - 5°'o C02. The preparations were stretched until a stable basal tension of 2 grams was obtained.
The preparations were made to constrict with serotonin (3x10'7 M). The response to the addition of serotonin was measured and subsequently the serotonin was washed away.
This procedure was repeated until stable responses were obtained. Subsequently the test compound was administered to the organ bath and the constriction of the preparation was measured. This constrictive response was expressed as a percentage of the response to serotonin as measured previously. The lowest active concentration was defined as the concentration at which 50 % of the response to serotonin is obtained.
Table 1 presents the lowest active concentrations of the compounds of formula (1].
Table 1 Co. No. lowest active concentration (M) 1 >1x10-6 1 x 10-~

3 3 x 10-6 E. Composition examples "Active ingredient" (A.L) as used throughout these examples relates to a compound of formula (I), a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.
Example 7 : ORAL DRC>PS
S00 Grams of the A.I. was dissolved in 0.51 of 2-hydroxypropanoic acid and 1.51 of the polyethylene glycol a1: 6080°C. After cooling to 3040°C
there were added 351 of polyethylene glycol and the mixture was stirred well. Then there was added a solution of 1750 grams of sodium saccharin in 2.51 of purified water and while stirring there were added 2.51 of cocoa flavor and polyethylene glycol q.s. to a volume of 501, providing an oral drop solution comprising 10 mg/ml of A.L. The resulting solution was filled into suitable containers.
Example 8 : ORAL SOLUTION
9 Grams of methyl 4-hydroxybenzoate and 1 gram of propyl 4-hydroxybenzoate were dissolved in 41 of boiling purified water. In 31 of this solution were dissolved first 10 grams of 2,3-dihydroxybutanedioic acid and thereafter 20 grams of the A.I. The latter solution was combined with the remaining part of the former solution and 121 1,2,3-propanetriol and 31 of sorbitol 70% solution were added thereto. 40 Grams of sodium saccharin were dissolved in 0.51 of water and 2 ml of raspberry and 2 ml of gooseberry essence were added. The latter solution was combined with the former, water was added q.s. to a volume of 201 providing an oral solution comprising 5 mg of the active ingredient per teaspoonful (5 ml). The resulting solution was filled in suitable containers.
Example 9 ' CAPSULES
20 Grams of the A.L, 6 grams sodium lauryl sulfate, 56 grams starch, 56 grams lactose, 0.8 grams colloidal silicon dioxide, and 1.2 grams magnesium stearate were vigorously stirred together. The resulting mixture was subsequently filled into 1000 suitable hardened gelatin capsules, comprising each 20 mg of the active ingredient.
Example 10 ' FILM-COATED TABLETS
~xe.~x~o~.Q~.t~hl~t.~oze A mixture of 100 grams of the A.L, 570 grams lactose and 200 grams starch was mixed well and thereafter humidified with a solution of 5 grams sodium dodecyl sulfate and 10 grams polyvinylpyrrolidone in about 200 ml of water. The wet powder mixture was sieved, dried and sieved again. Then there was added 100 grams microcrystalline cellulose and 15 grams hydrogenated vegetable oil. The whole was mixed well and compressed into tablets, giving 10.000 tablets, each containing 10 mg of the active ingredient.
C~uati~g To a solution of 10 grams methyl cellulose in 75 ml of denaturated ethanol there was added a solution of 5 grams of ethyl cellulose in 150 ml of dichloromethane.
Then there were added 75 ml of dichloromethane and 2.5 ml 1,2,3-propanetriol. 10 Grams of polyethylene glycol was molten and dissolved in 75 ml of dichloromethane. The latter solution was added to the former and then there were added 2.5 grams of magnesium octadecanoate, 5 grams of polyvinylpyrrolidone and 30 ml of concentrated colour suspension and the whole was homogenated. The tablet cores were coated with the thus obtained mixture in a coating apparatus.

Ex~mnle 11 ~ INJE ABLE SOLUTION
1.8 Grams methyl 4-hyiroxybenzoate and 0.2 grams propyl 4-hydroxybenzoate were dissolved in about 0.51 of boiling water for injection. After cooling to about 50°C there were added while stirring 4 grams lactic acid, 0.05 grams propylene glycol and 4 grams of the A.L. The solution was cooled to room temperature and supplemented with water for injection q.s. ad 11, giving a solution comprising 4 mg/ml of A.L. The solution was sterilized by filtration (IJ.S.P. XVII p. 811) and filled in sterile containers.

Claims (11)

Claims

1. A compound having the formula a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein =a1-a2=a3-a4= is a bivalent radical of formula:
=N-CH=CH-CH= (a), =CH-N=CH-CH= (b), =CH-CH=N-CH= (c), or =CH-CH=CH-N= (d), wherein one or two hydrogen atoms are optionally substituted by halo, hydroxy,:
C1-6alkyl or C1-6alkyloxy;
R1, R2 and R3 each independently are hydrogen or C1-6alkyl;
Alk1 is C1-5alkanediyl;
Alk2 is C2-15alkanediyl;
Q is a radical of formula wherein R4 is hydrogen, cyano, aminocarbonyl or C1-6alkyl;
R5 is hydrogen, C1-6alkyl, C3-6alkenyl or C3-6alkynyl;
R6 is hydrogen or C1-6alkyl; or R5 and R6 taken together may form a bivalent radical of formula -(CH2)4- or -(CH2)5-;
R7 and R8 each independently are hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R9 is hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyloxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono- or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R10 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, or arylC1-6alkyl;
R11 and R12 are hydrogen or taken together with the carbon atom to which they are connected form C(O);
q is 1 or 2;
R13 is hydrogen, C1-6alkyl, C1-6alkylcarbonyl, or arylC1-6alkyl;
R14 is hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyloxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono- or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R15 and R16 each independently are hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R17 and R18 each independently are hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R19 and R20 each independently are hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R21 and R22 each independently are hydrogen, hydroxy, halo, C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl, C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
R23 and R24 each independently are hydrogen, hydroxy, halo; C1-6alkyl, C1-6alkyl-oxy, aryloxy, C1-6alkylthio, cyano, amino, mono- or di(C1-6alkyl)amino, mono-or di(C3-6cycloalkyl)amino, aminocarbonyl; C1-6alkyloxycarbonylamino, C1-6alkylaminocarbonylamino, piperidinyl, or pyrrolidinyl;
r is 1 or 2;
R25 and R26 are hydrogen or taken together with the carbon atom to which they are connected form a C(O);
R27 is hydrogen, halo or C1-6alkyl, and aryl is phenyl optionally substituted with hale, hydroxy, C1-6alkyl or C1-6alkyloxy.

2. A compound as claimed in claim 1, wherein R1 and R2 both are hydrogen and Alk2 is 1,3-propanediyl.

3. A compound as claimed in claim 2, wherein "=a1-a2=a3-a4=" is a bivalent radical of formula (a) or (d).

4. A compound as claimed in any one of claims 1 to 3, wherein Q is a radical of formula (bb) or (hh).

5. A compound according to claim 1 wherein the compound is N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-3-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;
N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-2-yl)methyl]-N'-2-pyrimidinyl-1,3-propanediamine;

N-(6-chloro-3-pyridazinyl)-N-[(2,3-dihydro-1,4-dioxino[2,3-b]pyridin-2-yl)methyl]-1,3-propanediamine; a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof.

6. A pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a compound according to any one of claims 1 to 5.

7. A process of preparing a pharmaceutical composition as defined in claim 6, characterized in that a compound as defined in any one of claims 1 to 5 is intimately mixed with a pharmaceutically acceptable carrier.

8. A compound as defined in any one of claims 1 to 5 for use in conditions related to vasodilation,

9. An intermediate of formula wherein one or two hydrogen atoms of the pyridine moiety are optionally substituted by halo, hydroxy, C1-6alkyl or C1-6alkyloxy; R3 and Alk1 are defined as in claim 1, and W2 is a reactive leaving group, an acid addition salt thereof or a stereochemically isomeric form thereof.

10. An intermediate of formula wherein one or two hydrogen atoms of the pyridine moiety are optionally substituted by halo, hydroxy, C1-6alkyl or C1-6alkyloxy; R3 and Alk1 are defined as in claim 1, and W2 is a reactive leaving group, an acid addition salt thereof or a stereochemically isomeric form thereof.

11. A process for preparing a compound as claimed in claim 1, characterized by a) reacting an intermediate of formula (III), wherein "=a1-a2=a3-a4=", R3 and Alk1 are as defined in claim 1 and W2 is a reactive leaving group, with an intermediate of formula (11), wherein R1, R2, Alk2 and Q are as defined in claim 1;

b) reacting an interemediate of formula (IV), wherein =a1-a2=a3-a4=, R1, R2, R3, Alk1 and Alk2 are as defined in claim 1,with an intermediate of formula (V), wherein Q is as defined in claim 1 and W1 is a reactive leaving group;

c) reductively N-alkylating an intermediate of formula (VIII), wherein R1, R2, Alk2 and Q are as defined in claim 1, with an aldehyde of formula (VII) wherein "=a1-a2=a3-a4=" and R3 are as defined in claim 1, Alk3 is a direct bond or C1-4alkanediyl;