IE39066B1 - Imidazo (4,5-b) pyridines - Google Patents

Imidazo (4,5-b) pyridines

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IE39066B1
IE39066B1 IE195/74A IE19574A IE39066B1 IE 39066 B1 IE39066 B1 IE 39066B1 IE 195/74 A IE195/74 A IE 195/74A IE 19574 A IE19574 A IE 19574A IE 39066 B1 IE39066 B1 IE 39066B1
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phenyl
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compound
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Thomae Gmbh Dr K
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Priority claimed from DE2305339A external-priority patent/DE2305339C3/en
Priority claimed from DE2361757A external-priority patent/DE2361757A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Publication of IE39066L publication Critical patent/IE39066L/en
Publication of IE39066B1 publication Critical patent/IE39066B1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/194—Radicals derived from thio- or thiono carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/06—Five-membered rings having the hetero atoms in positions 1 and 3, e.g. cyclic dithiocarbonates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

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Abstract

1445824 lmidazo[4,5-6]pyridines DR KARL THOMAE GmbH 1 Feb 1974 [3 Feb 1973 12 Dec 1973] 04808/74 Heading C2C The invention comprises compounds of formulµ and their N-oxides and acid addition salts, [wherein R 1 , R 2 and R 3 , which may be the same or different, each represents a hydrogen or halogen atom; a hydroxy, alkyl, allyloxy, benzyloxy, alkylthio, alkylsulphinyl or alkylsulphonyl group; an amino group optionally substituted by one or two alkyl groups; a morpholino or a piperazino group optionally substituted in the 4-position by a phenyl group or an alkyl group containing from 1 to 3 carbon atoms; or an alkoxy group containing from 1 to 4 carbon atoms, optionally substituted by a halogen atom or by a hydroxy, alkoxy, alkylthio, alkylsulphinyl, alkylsulphonyl, alkylamino, dialkylamino, piperidino, morpholino, thiomorpholino, thiomorpholino-S-oxide, thiomorpholino - S,S - dioxide, 4 - alkylpiperazino, 4 - phenylpiperazino, 4 - dimethoxyphenylpiperazino, 4 - phenylethylpiperazino, phenylethylamino, N - methyl - phenylethylamino or N - methyl - dimethoxyphenylethylamino group, provided that when two of R 1 , R 2 , R 3 are H, the other group is other than H, halogen, Me or NH 2 ; or two of the groups R 1 to R 3 together represent a methylenedioxy group and the remaining R 1 , R 2 or R 3 group is as hereinbefore defined; each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms; R 4 represents a hydrogen atom; an alkyl group optionally substituted by a hydroxy, dialkylamino, phenyl dimethoxyphenyl, piperidino, morpholino, 4 - methylpiperazino or 4- phenylpiperazino group, each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more halogen atoms or methoxy groups; provided that where R 4 represents a hydrogen atom at least one of the groups R 1 to R 3 is other than hydrogen; and R 5 represents a hydrogen atom, a halogen atom or an alkyl group of 1 to 3 carbon atoms. In examples, these compounds are prepared by reacting (1) a 2,3-diaminopyridine with (a) an appropriately substituted benzoic acid or an acid- or imido-chloride, ester, anhydride, amide (e.g. N-substituted) or thionomorpholide methiodide thereof, (b) an appropriately substituted 2- phenyl - 1,3 - dithiolan - 2 - ylium iodide, or (c) 4 - (1,3 - dithiolanylidene) - 3 - hydroxy cyclohexadienone; (2) a 3-amino-2-chloropyridine with an appropriately substituted benzamide; (3) converting Ia(R 4 =H) to I(R 4 #H) by reaction with an appropriate organic halide in presence of a base; or (4) interconversion of functional groups present by known methods. In method (1)(a), an intermediate salt or a 2- amino-3-benzamidopyridine or the corresponding amidine, and in method (2) a corresponding N<SP>1</SP>- (2 - chloro - 3 - pyridyl)benzamidine, may be isolated as intermediates. Also isolated are 2-(p-acetamidophenyl)-1H. imidazo[4,5-b]pyridine; and alkylthioalkoxy/ hydroxybenzaldehydes and their methyl ethers. Therapeutic compositions for oral, parenteral or rectal administration comprise compounds of the above formulµ, which are stated to have activity on the blood pressure and heart force, a positive inotropic effect, antiulcus activity, a platelet aggregation inhibiting effect and prolonging activity on the bleeding time. [GB1445824A]

Description

3 f> 0 G 8 thv present invention relates to new imidazole |4,5 - b| pyridines having interesting physiological properties.
According to one feature of the present invention there are provided compound of aeneral fomila (I) 3 and isomers thereof of general formula 3 {ra) {••herein Rj, R£ and R^, which nay be the same or different, each represents a hydrogen or halogen atom; a hy*n>xy, alkyl, allyloxy, benzyloxy, alkyltnio. alkylsulfihyl or alkylsulfonyl group; and amino group optionally substituted by one or two alkyl groups; a morpholino or a piperazino group optionally substituted in the 4-position by a phenyl group or an alkyl group containing from 1 to 3 carbon atoms or an alkoxy nrnup containing from 1 to 4 carbon dtoras. optionally substituted by a halogen atom or by a hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, alkylaraino, dialkylamino, piperidino. morpholino, thiomorpholino, thiomorpholi no - S - oxide, thiomorpholino -S,S - dioxide, 4 - alkylpiperazino, 4 - phenylpiperazino, 4 - dimethoxy-phenylpiperazino, 4 - phenylethylpiperazino, phenylethylamino, N - methyl - phenyl ethyl ami no or N - methyldimethoxy - phenylethylamino group with ttu-proviso that if any two of the groups Rj, *nd R-{ represent hydrogen atoms then the other group is other than a hydrogen or halogen atom, or a methyl or unsubstituted amino group; or two 39066 of the groups to R^ together represent a mathylene-dioxy group and the remaining R^, Rj or Rj group is as hereinbefore defined; each of tha above mentioned alkyl groups containing from 1 to 4 carbon atoms; represents a hydrogen atom; an alkyl group optionally substituted by a hydroxy, dialkylamino, phenyl, diaethoxyphenyl, piperidIno, morpholino, 4-methylplperazino or 4-phenylpiperazlno group, each of the above mentioned alkyl groups containing from J to 4 carbon atoms, or a phenyl group optionally substituted by one or more halogen atoms or methoxy groups with the proviso that where R^ represents a hydrogen atom at least one of the groups R^ to Is other than hydrogen; and R^ represents a hydrogen atom, a halogen atom or an alkyl group containing from I to 4 carbon atoo{3 and the corresponding imidazo {4,5 - 0 pyridine - N - oxides.and isomers thereof and acid addition salts thereof.
In general the compounds of general formula I and isomers thereof of general formula la possess valuable physiological properties, in particular an activity on the blood pressure and heart force, a positive isotropic effect, an antiulcus activity, a platelet aggregation inhibiting effect and a prolonging activity on the bleeding time. 3 9 0 G G -Preferred compounds according to the invention by virtue of their particularly favourable physiologicnl properties are those(wherein R^, R^ and R^ represent hydrogen.atoms and Rj and R^, which may be the same or different, each represents a halogen atom or a methyl, methoxy, ethoxy, alkylthio, alkylsulfinyl, diaIky1amino-alkoxy, morpholinoalkoxy, thiomorpholinoalkoxy, 4-methylpiperazinoalkoxy, 4-phenylpiperazinoalkoxy or alkylsulfinylalkoxy group (wherein each alkyl group contains from 1 to 3 carbon atoms and each alkoxy group contains 2 or 3 carbon atoms)and physiologically compatible acid addition salts thereof. Particularly preferred are the following compounds:- 2-(2,4-Dimethoxy-phenyl)-lH-imidazo! 4,5-b jpyridine and physiologically compatible acid addition salts thereof 2-(2-Methoxy-4-methyimercapto-pheny J)-lH-imidazo-14,5-b] pyridine and physiologically compatible acid addition salts thereof, 2-( 2-Methoxy-4-me thy lsulfl.nyl-phenyl)lH-imidazo [4,5-b] pyridine and physiologically compatible acid addition salts thereof* 2-(2-Methoxy-4-methyl-phenyl)-1H-imidazo[ 4,5-b] pyridine and physiologically compatible acid addition 38060 salts thereof, , 2-(2-Methoxy-5-m«thylmercapto-phenyl)-lH-imidazo [4,5-b] pyridine and physiologically compatible acid 2-(2-Bthoxy-4-methyl-phenyl)-lH-imidazo[ 4,5-b] pyridine and physiologically compatible acid addition salts thereof.
The new compounds of general formula 1 and isomers thereof of general formula la as hereinbefore defined may be prepared by either of the following processes, which processes constitute further features of the invention:- a) Reaction of a compound of fonnula a group of formula R^NH-(wherein R^ is as hereinbefore defined)] with a compound of formula (wherein R^ to R^ are as hereinbefore defined and X represents a carboxyl, thiocarboxyl or dithiocarboxyl addition salts thereof, and (II) [wherein R^ is as hereinbefore defined and Y represents (nr) 39 06 0 group) or a functional derivative thereof, foe example an acid hallde/anhydride, ester or orthoester; and b) '• Reaction of a compound of formula (II) (wherein Rj is as hereinbefore defined and Y represents a halogen atom) with a compound of formula R, (III) jwherein Rj to R^ are as hereinbefore defined and X represents an appropriate. -NR^ containing group (wherein R. is as hereinbefore defined) which is derived from a carboxyl, thicarboxyl or dithiocarboxyl group, for example a nitrile,amide imido ester, imido thioester. imido halide or amidine group].
In each case the reaction is preferably carried out in the presence of a solvent, suitable solvents including for example benzene, pyridine, glycol, toluene, acetone, diethylene glycol and triethylamine. However the reaction may also be performed in the absence of a solvent 39060 The: reaction temperatur#<:W<^;-' it determined by the . -reactivity of the groupX in the compound of formula III uaed but generally th« reaction Is effected at temperatures* from -20 to 2S0*C. If deelred the reaction may be effected in the presence of an acid binding agent, such .as pyridine or triethylnmine, or in the presence of a catalytic quantity of an acid, such as £-toluenesulfonic add, or in the presence of a dehydrating agent,such as phosphorus oxychloride or thionyl chloride.
If for example a compound of formula III wherein X represents a carboxyl or amide group Is used the reaction iis conveniently carried out in the presence of phosphorus oxychloride or thionyl chloride, if desired in the presence of a tertiary organic base such as pyridine or triethyl-amine, preferably at temperatures from -20°C up to the boiling point of the solvent used, e.g. at 120°C.
If for example a compound of formula III wherein X represents a nltrile group is used, the reaction is conveniently performed in the presence of a catalytic quantity of an acid, such as p-toluenesulfonic acid, preferably at temperatures from 120 to 180°C, e.g. at 160°C, optionally in the presence of a solvent. 390U0 It for example a confound of formula III whetrein X represents a thioarai.de group is used, the reaction is conveniently effected in the presence of a solvent, such as glycol, and preferably at temperatures from 100 to 5 150cC. e.g at 130°C.
If a compound of formula II wherein Y represents a halogen atom, e.g. a chlorine atom is used, the reaction is preferably carried out via the corresponding amidine, which is cyclized at elevated temperatures, e.g. at 10 temperatures from 100 to 200°C, optionally without previous isolation.
The compounds of general formula 1 and isomers thereof of general formula la containing a reactive halogen atom obtained according to the p-ocesses of the present invention 15 may, if desired, be subsequently converted into the corresponding amino compounds with amines, and/or compounds of general formula I and isomers thereof of general formula la containing reactive hydrogen atoms, may if desired be subsequently alkylated by means of an alkylating agent In 20 the presence of a base.
In addition a compound of formula 1 or an isomer thereof of formula la may if desired be converted into the 390 6 0 corresponding N-oxide, S-oxide or S,S-oxide compoundby means of an oxidiaing agent. Finally a compoundof formula I or an Isomer thereof of. formula Za may If deelred be converted Into an acid addition salt thereof, preferably into a physiologically compatible acid addition •alt. Suitable acids include for example hydrochloric acid, hydrobromic acid, sulfuric acid, lactic acid, citric acid, tartaric acid, oalelc acid and fumaric acid.
The starting compounds used for the processes according to the invention are known from the literature, or they may be prepared according to known processes (see Examples).
As already mentioned above, the new compounds of general formula I and isomers thereof of general formula la in general show valuable pharmacological properties, those which have been tested showing especially an activity on the blood-pressure, a positive inotropic activity, an antlulcus activity, a platlet aggregation inhibiting effect and a prolonging activity on the bleeding time.
The following compounds have been tested with respect to certain of their biological activities: A - 2— (2,4-Dimethoxy-phenyl)-lH-imidazo[4,5-b]pyridine hydrochloride, 390GG B « -2--I 2-(2-Methylsulfinyl-ethoxy)-4-methoxy-phenyl J- 1H-imidazo-{4,5-b]pyridine hydrochloride, C • 2-(2-Methoxy-4-methylmercapto-phenyl)-lH-imidazo {4,5-b]pyridine hydrochloride 5 D • 2-(2-Methoxy-4-methy1sulf inyl-phenyl)-1H-imidazo (4,5-b]pyridlne hydrochloride, E - 2-(2-Methoxy-5-raethylmercapto-phenyl)-1H-imidazo I4,5-b]pyridine hyrochloride F - 2-(2-Methoxy-4-raethyl-phenyl)-1H-Imidazo[4,5-b] 10 pyridine hydrochloride G - 2-(2-Ethoxy-4-methoxy-phenyl)-lH-imidazo|4,5-b] pyridine hydrochloride, H - 2-(2-Ethoxy-4-methyl-phenyl)-lH-injidazo[ 4,5-b] pyridine hydrochloride, 15 I * 2-(2-Methoxy-4-chloro-phenvl)-lH-imidazo[4,5-bj pyridine hydrochloride and J ~ 2-[2-(2-Methylsulfinyl-ethoxy)-4-methylmercapto-phenyl]-lH-imidazo[4,5-b]pyridine hydrochloride 1. Positive inotropic activity in the isolated auricle of 20 the guinea-pig; Isolated auricles of guinea-pigs were put into an organ bath of 100 ml. The bath has been filled with a tyrode solution - 10 - 3000 G at a temperature of 30°C. The tyrode solution was Infused with carbogen (95X of 02 and 5X of COj). The spontaneous contractions of the auricles were registered isometrically with a Stathatn-Forcs-transducer on a Grass-polygraph. The auricles were charged with 1 g. After sufficient equilibrating time, the substances in question were added to the organ bath. The concentration of the substance in the hath was 1 x 10 * g/ml in each case. 5 auricles were used for each solution.
The following Table gives the results: Table I Substance Increase of the contraction- amplitude in X A 57.0 B 17.5 C 10.3 E 40.9 F 50.2 G 33.9 H 42.9 I 21.4 3D0CG 2. Circulation experiments on the narcotized cut; Cat were narcotized with 30 mg/kg of pentobarbital- sodium i.v. A plastic catheter was Introduced into the arteria femoralis and into the left ventricle of the heart a steel catheter was introduced from the arteria carotis. With Statham-pressure-transducers of the type P23 AA and P23 Dc, the arterial blood-pressure and the pressure in the left ventricle was registered continuously.
From the ventricle-pressure-curve, the contractility parameters dp/dt and V__ were continuously determined max tt by means of an analogous computer. The heart frequency was ascertained from the ventricle-pressure-curve using a tachograph. In addition, the EKG was registered in the II derivation.
All registrations were effected on a Brush-direct-writer. The substances were injected over a vena cannula into the vena femoralis. At least three cats were used for the test on each substance.
The following Table gives the results: - 12 - Table II Subntance Dose Blood-preasure Heart activity ag/kg alteration in an Hg Alteration of the con- Alteration of the heart l.v. traction force In % frequency in % A 0.5 5 20 ♦ 4 1.0 - 5 ♦ 41 ♦ 3 B 0.5 ♦ 10 ♦ 16 «» 2 1,0 ♦ 20 ♦ 29 - 9 C 0.5 ♦ 5 ♦ 22 ♦ 1 1.0 ♦ 10 ♦ 36 ♦ 5 D 0.5 0 ♦ 54 ♦ 5 1.0 - 5 ♦ 39 ♦ 5 £ 0.5 ♦ 10 ♦ 14 0 1.0 ♦ 15 ♦ 25 0 P 0.5 ♦ 10 ♦ 44 3 1.0 ♦ 15 ♦ 53 0 (3 0.5 0 ♦ 7 0 1.0 ♦ 5 ♦ 29 - 5 H 0.5 ♦ 10 * 15 0 1.0 ♦ 15 ♦ 25 0 I 0.5 - 5 ♦ 17 ♦ 2 1.0 - 5 ♦ 19 ♦ 2 J 0.5 ♦ 10 ♦ 14 0 1.0 ♦ 15 ♦ 22 - 15 •J 0 61» None of the compounds showed any toxic side effects using the doses applied.
According to yet a further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of formula I or isomer thereof of formula la or physologi-cally compatible acid addition salt thereof in association with a pharmaceutical carrier or excipient.
The compositions may for example be presented in a form suitable for oral, rectal or parenteral administration. Thus for example compositions for oral administration may be solid or liquid and may take the form of tablets, coated tablets or drops, such compositions comprising carriers or excipients conventionally used in the pharmaceutical art.
For parenteral administration the carrier may be a parenterally acceptable liquid, such as sterile water or a parenterally acceptable oil, e.g. arachis oil, contained in ampoules. For rectal administration compositions may take the form of suppositories, the carrier comprising a suppository base.
Advantageously the compositions may be formulated as dosage units. Each dosage unit preferably contains from 35 to 200 mg, preferably from 50 to 100 mg, of active ingredient.
The following Examples serve Co illustrate the preparation of compounds according to the invention and of pharmaceutical compositions containing the same. 39060 Example 1 2■'(2.4-Dimethoxyphenv 1)-1H-Imidazo[4.5-b1pyrldln< hydrochloride 54.5 g of 2,3-diaminopyridlne and 91.1 g of 2,4-dimethoxybenzoic acid were finely pulverized and added In snail amounts to 1500 ml of phosphorus oxychloride whilst stirring. Afterwards, the mixture was refluxed for 2 hours, and the phosphorus oxychloride was distilled off in vacuo. The residue was triturated with 200 al of 2N hydrochloric acid and the solid product obtained was suction filtered and recrystallized from water.
Yield: 121 g (851 of theory), m.p.: 238*C Example 2 2-(2,4-Diroethpy/pheny1)-1H-imldazo[4,5-bIpyrldine hydrochloride 360 mg of 2,4-dimethoxybenzoic acid were dissolved in 2 m) of pyridine and a solution of 220 mg of 2,3-diaminopyridine in 2 ml of pyridine was added, whereupon the corresponding salt precipitated out. Uhilst 390GG stirring and ice-cooling, 0.38 ml of phosphorus oxychloride were added dropwise and the mixture was stirred for a further hour at 0°C and 1 hour at room temperature. Subsequently the excess of pyridine was 5 removed in vacuo and the residue was dissolved by (i<ldin>; dilute hydrochloric acid. The mixture was neutralized with sodium hydroxide solution and extracted with ethyl acetate. The ethyl acetate layer was evaporated, the residue was treated with a small quantity of 2N hydrochloric Q acid, and the precipitate was suction filtered and recry- stallized from water.
M.p.: 238 to 239°C.
Example 3 2-(2,4-Dimethoxy-phenyl)-iti-lmidazo[4,5-blpyrldlne 5 hydrochloride Prepared analogously to Example 2 from 2,3-diaminopyridine , 2,4-dimethoxybenzoic acid and thionyl chloride.
M.p.: 238 to 239°C. - 16 - 38060 Example 4 2-(2,4»Dimathoxy-phenyl)-lH-ljnldatof4.5-b')pyrldlne hydrochloride 900 mg of 2,4-dlmethoxy-ben»olc acid were converted into the acid chloride by heating in a mixture of 3 ml of benzene and 2 ml of thionyl chloride. Subsequently, the mixture was evaporated in vacuo and the residue obtained was taken up in 5 ml of benzene. This solution was dropped into a solution of 550 mg of 2,3-diamino-pyridine in 5 ml of pyridine whilst stirring. Afterwards, the mixture was heated for a short time at 60*C, then cooled to room temperature, and 0.9 ml of phosphorus oxychloride were added dropwise. After the mixture had been stirred for a further 2 hours at room temperature, 2N hydrochloric acid was added. The mixture was then neutrallized and extracted with ethyl acetate. The ethyl acetate layers were evaporated and a small quantity of 2N hydrochloric acid was added to the residue. The crystals which precipitated were suction filtered and recrystalllzed from water.
M.p.: 217 to 238°C.
Example 5 2-(2,4-Din>ethoxy-phenyl)-lH-laldazo[4.5-b1pyrldlne hydrochloride a) 2-Amlno-3-(2 ,4-dl«ethoxyben»oyl-aiaino)-pyridine hydrochloride 530 mg of 2,4-dimethoxybenzoic acid were converted into the acid chloride analogously to Example 4 and this acid chloride was dissolved in 1 ml of benzene. The solution obtained was added dropwise to a mixture of 440 mg of 2,3-diamino-pyridine, 3 ml of pyridine and 2 mi of trlethylamine. After the whole mixture had been stirred for a further 2 hours at room temperature, water was added, the mixture was neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The ethyl acetate was removed, the residue was treated with dilute hydrochloric acid, the precipitated crystals were suction filtered and recrystallized from ethanol.
M.p.: 172 to 174°C. - 18 - b) 2.4-Dlmethoxv-phenyl)-lH-lmldazof4.5-b]pyrldlne hydrochloride 155 mg of 2-amlno-3-(2,4-dimethoxybenzoyl-amino)-pyridine hydrochloride were dissolved in 2 ml of pyridine. 0.2 ml of phosphorus oxychloride were dropped in whilst stirring at room temperature. After 2 hours Che mixture was poured into water and worked up analogously to Example 4.
M.p.: 237 to 238°C.
Example 6 2-(2.4-Dlmethoxy-phenyl)-lH-lalda>o[4.5-b1py rldlne hydrochlorlde 155 mg of 2-amino-3-(2,4-dimethoxybenzoyl-amino)-pyrldine hydrochloride were heated for 5 minutes at 200 -210°C. The mixture was treated with a small quantity of 2N hydrochloric acid* aM the precipitate was filtered and recrystalllzed from water.
M.p.: 237 to 238°C. - 19 - 9 06 0 Example 7 2~(2,4-Difliethoxy-phehyl)-'lH''linlda»o[4.5-b3pyridlne hydrochloride 155 mg of 2-amino-3-(2,4-dimethoxybenzoyl-amino)-pyridine hydrochloride were refluxed for *30 minutes in 2 ml of glycol. The mixture was then diluted with water, neutralized, extracted with ethyl acetate and processed analogously to Example 4.
M.p.: 238 to 239°C.
Example 8 2-(2 t4-Dimethoxy-phenyl)-lH-lmldazo[4,5-b]pyrldlne hydrochloride 5.45 g of 2,3-diaminopyridine were added in small amounts to 15G ml of phosphorus oxychloride whilst stirring and 9.81 g of methyl 2,4-dimethoxybenzoate were also added dropwise. The mixture was then heated at 120°C. After two hours the excess of phosphorus oxychloride was evaporated in vacuo, the residue was digested with 2N hydrochloric acid and the solid product obtained was suction filtered and recrystallized from water.
M.p.: 238 to 239°C. - 20 - 390 60 Example 9 : i . jf- \ ; . 2-( 2.4-Dlaathoxy-phgny D-1H- tmldaxo f 4.5-b Ipyrldlnc hydrochloride 0*5 ml of morphollne were added whilst stirring to 470 mg of 2,4-dimethoxybenzoyl chloride in 6 ml of toluene. After 20'Minutes the toluene was evaporated, the residue was treated with dilute hydrochloric acid and this mixture was extracted with ethyl acetate. After washing the ethyl acetate layer with sodium bicarbonate solution and evaporating off the solvent, crude 2,4-dimethoxybenzoyl-morpholine was obtained as oil. This oil was dissolved in 5 ml of pyridine, 250 mg of 2,3-diaminopyridine was added and finally 1 ml of phosphorus oxychloride was added dropwlse whilst stirring and ice-cooling. After stirring for 5 hours at 0°C, ice-water was added, the mixture was made alkaline with concentrated ammonia, heated for a short time on the steam bath and extracted with ethyl acetate. The ethyl acetate was removed, and the residue obtained was treated with 2N hydrochloric acid, suction 3 0 0 GO filtered and recrystallized from water. • M.p.: 238°C.
Example 10 2- ( 2,4-Dimethoxypheny l)-lH-lmida»of 4.5->b1pyrldlne hydrochloride 300 mg of 2,4-dlmethoxybenzoyl-(4-chloro-anilide) and 110 mg of 2,3-diaminopyridine were mixed and added in small amounts to 3 ml of phosphorus oxychloride whilst stirring. Afterwards the mixture was refluxed for 8 hous. Then the phosphorus oxychloride was removed in vacuo, the residue was triturated with 2N hydrochloric acid and the solid product obtained vas suction filtered and recrystal-lized from water.
M.p.: 237 to 238°C.
Example 11 2-(2,4-Dimethoxy-phenyl)-lH-imidazo[4«5-b]pyridine hydrochloride 600 mg of 2,4-dime_aoxybenzoyl*(4-chloro-anilide) in a mixture of S ml of benzene and 2 ml of thionyl - 22 - 39060 chloride veri refluxed for 3 hours. After the mixture had been evaporated the exude 2,4- dlaethoxy - N - (4-chlorophenyl)-benzimidic acid chloride vas obtained as an oil. This oil was dissolved In 9 ml of toluene and the solution was added to a solution of 200 mg of 2,3-di-aainopyridlne in 10 ml of lsopiropanol. The mixture was heated for 10 minutes at 70°C. The 2,4-dimethoxy-b«nzolc acid-K-(4-chlorophenyl )-N'-( 2-amino- 3-pyrldy1) -ami dine hydrochloride which formed was not Isolated but was dissolved in 20 ml of glycol after removing the iso-propanol in vacuo. The glycol solution was refluxed for 10 minutee. Subsequently water was added, the mixture was made alkaline with concentrated asmonia, extracted with ethyl aeetcte and worked up as described in Example 4. M.p.: 237 to 238°C.
Example 12 2-(2,4-Dimethoxy-phenyl)-1H-imidazo[4.5-bIpyridine hydrochloride 100 mg of 2,3-diaminopyridine, 200 mg of 2,4-dlmethoxybenzonltrile and 400 mg of p-toluenesulfonic acid 30 0 CO monohydrate were mixed together and heated for 3^ hours at 160°C. The product was' triturated with dilute ammonia and ethyl acetate until the whole product had dissolved. The aqueous layer was extracted with ethyl acejtote. After some time» when the combined ethyl acetate;layers had been extracted with a small quantity of 2N hydrochloric acid, the product crystallized out from the aqueous phase.
M.p.: 237 to 238°C.
Example 13 2-(3,4,5-Trlmethoxyphenyl)-lH-lmldazo[4»5-b3pyrldlne 3.4 gof p-toluene sulfonic acid monohydrate and 15 ml of benzene were heated at 120°C until all the benzene had evaporated. Subsequently 1.1 g of 2,3-diaminopyridine and 2 g of 3,4,5-trimethoxybenzoyl nltrile were added and the mixture was heated for 2 hours at 150°C. After cooling, water was added, the mixture was extracted with ethyl acetate, the ethyl acetate layers were washed with dilute sodium hydroxide solution, evaporated and the residue was recrystallized from isopropanol/petroleum 3 9 0 6 U ether.
M.p. I 226°C.
Example 14 2-(3.4.5-Trlaathoxv-phenyl)-lH-lmldazof4.5-blpyrldine A mixture of 4.2 g of 3,4,5-trimethoxybenzoic acid and 2.2 g of 2,3-diaminopyridine was refluxed for 2 hours in 40 al of phosphorus oxychloride. Subsequently the excess of phosphorus oxychloride was distilled off, vater was added to the residue and the precipitated solid product was suction filtered. The product was dissolved in hot water, made alkaline with concentrated ammonia, and the precipitate was suction filtered and recrystallized from a small quantity of isopropanol.
M.p.: 225 to 226°C.
Example 15 2-(2.5-Dimethoxv-phenyi)-lH-imidazoC4.5-b]pyrldlne a) 2.5-Dimethoxy-thiobenzoyl morpholide A mixture of 10 g of 2,5-dimethoxybenzaldehyde, 10 g of oorpholine and 4 g of sulfur was heated at 130°C for 3^ hours and subsequently dissolved in 300 ml of hot ethanol. The product which precipitated out on cooling, - 25 - 30000 was recrystallized from ethanol.
M.p.: 127°C. b) S-Methyl-2«5-dlmethoxy»thlobenzoyl morpholide iodide 6 g of 2,5-dimethoxy-thiobenzoyl morpholide, 6.5 g 5 of methyl iodide and 30 ml of acetone were refluxed for 8 hours. Subsequently the precipitated solid product was suction filtered and washed with ether. The product obtained was not purified further. c) 2-(2«5-Dimethoxy-phenyl)-lH-imidazof4.5-b1pyrldlne lu 2 g of S-methyl-2,5-dimethoxy-thiobenzoyl morpholide iodide and 1.1 g of 2,3-diaminopyridine were heated in 30 ml of glycol for 40 minutes at 130°C. Subsequently the mixture was poured on ice-water, suction filtered and recrystallized from ethanol/water. 15 M.p.: 235°C.
Example 16 2-(4-Hydroxy-pheny1)-1H-Imidazo f 4,5-b jpyrldlne a) A-Hydroxy-thlobenzoyl morpholide Prepared analogously to Example 15a from 12.2 g of - 2ft - 39060 4-hydroxy-benzaldehyde, 16 g of toorpholine and 3.2 g of sulfur.
M.p205#C b) S-Methvl-4-hydroxy-thlobenryl aorpholide Iodide Prepared analogously to Exasspla 15b from 14.4 g of 4-hydroxy-thiobenzyl morpholide and 2.1 g of methyl iodide in 100 ml of acetone.
M.p.: 181°C. c) 2-(4-Hydroxy-pheny 1)-1H-Imidazof4,5-bIpyridine 1.84 g of S-methyl-4-hydroxy-thiobenzyl morpholide iodide were heate^ for 20 minutes at 130°C with 1.1 g of 2,3-diaminopyridine in 30 ml of glycol. The product precipitated whilst cooling and was dissolved in sodium hydroxide solution and reprecipitated with an acid. Analysis: Calculated: 65.87% C 5.131 H 16.461 N Found: 65.90% C 5.16% H 16.47% N - 27 - 300UO Example-'17' 2 - [4-Methoxy- 2- ( 3.-ch loropropoxy ) -pheny 1 ] - 1H- imidazo [4,5-blpyrldlne hydrochloride a) 4-Methoxy-2-(3»chloro-propoxy)-ben«ov1 aorpho1lde 21.9 g of2-hydroxy-4-tnethoxy-benzoyl morpholide were dissolved In 200 ml of dimethylformamide and 11.2 g of potassium tert.-butoxide were added. After the whole product had dissolved, SO g of l-chloro-3-bromopropane were added and the mixture was heated for 2 hours at 130°C. Subsequently the mixture was evaporated in vacuo, the residue.vas dissolved ir athyl acetate, and the solution was washed with sodium hydroxide solution and water and evaporated. b) 2- [4-Methoxy-2- ( 3-chloropropoxy)-phenyl ]-lH-Imidazo [4.5-b]pyrldlne hydrochloride 20 g of 4-methoxy-2-(3-chloro-propoxy)-benzoyl morpholide, 7 g of 2,3-diamino-pyrldlne and 170 ml of phosphorus oxychloride were refluxed for 2 hours. After - 28 - 3 9 0 6 r. evaporation of the phosphorus oxychloride, the residue was mixed with water, neutralized with sodium hydroxide solution and extracted with ethyl acetate. The hydrochloride was precipitated with ethereal hydrochloric acid.
M.p.: 198°C (decotnp).
Example 18 2-[4-Methoxy-2-(2-chloroethoxy)-phenyl]-lH-imidazo [4,5-blpyridlna hydrochloride a) 4-Methoxy-2-(2-hydroxy-ethoxy)-benzoyl morpholide 23.7 g of 2-hydroxy-4-methoxy-benzoyl morpholide, 33.6 g of potassium tert.-butoxide and 37.4 g of ethylene brooohydrln wer» heated in 100 ml of dlmethylformasiide for 6 hours at 120*C. After evaporation in vacuo, the residue was dissolved la chloroform and the solution was washed with sodium hydroxide solution and water and evaporated, b ) 2- [4-Methoxy- 2 - ( 2 -chloroe thoxy ) -pheny 1 ]-lH-imidazo [4,5-b]pyrldlne hydrochloride 2.8 g of 4-methoxy-2-(2-hydroxy-ethoxy)-benzoyl morpholide, 1.1 g of 2,3-diaminopyridine and 20 ml of phosphorus oxychloride were refluxed for 2 hours. After - 29 - 390G0 evaporation water was added, the mixture was neutralized, extracted with ethyl acetate and the hydrochloride was precipitated with ethereal hydrochloric acid from the organic layer. 5 M.p.: 110*C (decomp.).
Example 19 2-[4-Methoxy-2-(3-chloropropoxy)-pheny1]-1H-imidazo [4 »5-b]pyrldlne hydrochloride a) 4-Methoxy-2-(3-chloropropoxy)-benzoy1 anl1ide 10 2.5 g of 2-hydroxy-4-methoxy-benzoyl anilide, 5 ml of l-chloro-3-brooopropane, 1.12 g of potassium tert.-butoxide and 20 ml of dimethylformamide were heated for 2 hours at 130°C. Subsequently the mixture was evaporated in vacuo, water was added and the mixture was suction is filtered.
M.p.: 87 to 90"C. b) 2-[4-Methoxy-2-(3-chloropropoxy)-pheny1]-1H-imidazo [4»5-b1pyridlne hydrochloride Prepared analogously to Example 17b from 4-methoxy- - 30 - 3 9 0 6 l> 2-(3-chloropropoxy)-benzoyl anillde and 2,3-diamino- pyridine.
M.p.t 198#C.
Example 20 2-[4-Methoxy-2-( 3-«orpholino-propoxy)-phenyl ]-lH- imidazo [4t5-b1-pyrldine 0.5 g of 2-[4-methoxy-2-(3-chloroproxy)-phenyl]-lH-imidazo[4,5-b]-pyridlne hydrochloride were refluxed for 4% hours in 5 ml of morpholine. Water was then added, the precipitate was suction filtered and recrystalli»»d from water.
M.p.: 108 to llu'C.
Example 21 2-[4-Methoxy-2-(2-(4-phenyl-l-piperaziny1)-ethoxy)-phenyl1-lH"imldazo[4,5-blpyridlna Prepared from 1.7 g of 2-[4-raethoxy-2-(2-chloro-ethoxy)-phenyl]-lH-imidazo[4,5-b]pyridine and 3.2 g of 1-phenyIplperazine by boiling for 8 hours in ethanol. M.p.: 164 to 165*C (from isopropanol) - 31 - 390UU Example 22 2-[4-Methoxy-2-(3-diraethylamino-propoxy)-pheny1]-1H- imidazo[4«5-blpyrldine . hydrochloride 1.8 g of 2-[4-methoxy-2-(3-chloropropoxy)-phenyl]-lH-lmldazo[4,5-b]-pyridine hydrochloride and 20 ml of saturated dimethylamine solution In ethanol were heated for 8 hours in a closed vessel at 100°C. Subsequently the mixture was evaporated in vacuo and recrystallized from isopropanol.
M.p.: 209 - 210WC Example 23 2-[4-Methoxy-2-(3-dimethylamino-propoxy)-phenyl]-lH- imidazo-[4.5-b1pyridine dihydrochlorlde 1.64 g of 4-metho.ry-2-(3-dimethylamino-propoxy)-thiobenzoyl morpholide were dissolved in a mixture of 17 nil of glacial acetic acid and 3 ml of acetic anhydride. 1 ml of dimethyl sulfate was added and the mixture was heated on the steam bath for 1 hour. Subsequently, the mixture was evaporated in vacuo. The crude S-methyl-4-methoxy-2-(3-dimethylamino-propoxy)-thiobenzoyl morpholide methyl - 32 - 3 9 0 6 G sultutc otiialned was dissolved In 13 ml of glycol <>.7 g of 2,3-diaminopyridine was added and the mixture was heated for 2 hours at 160°C. Subsequently, the mixture was poured into 50 ml of water, 5 ml of concentrated rj ammonia were added and the mixture was extracted with ethyl acetate. The ethyl acetate layers were evaporated, the residue was dissolved in ethanol, ethereal hydrochloric acid was added and it was again evaporated. The residue crystallized after trituration with toluene and a small lo quantity of ethanol. The product was suction filtered and recrystallized from isopropanol.
M.p.: of the dihydrochloride hydrate: 228 to 2 35°C (decomp.).
Example 24 13 2-(2 ,4-Dimethoxy-pheny1)-3-methyl-3H- Imidazo[4,5-b] pyridine 800 mg of 2 ,4-dimethoxybenzoy I methylami.de we re refluxed for 3 hours with 500 mg of 2-chloro-3-aroinopyridine in 10 ml of phosphorus oxychloride. Subsequently, the - 33 - 3 9 0 G G mixture wa9 poured into water, neutralized with concentrated anvnonia and extracted with ethyl acetate.
After evaporation, the crude N-methyl-N'-(2-chloro-3-pyridyl)-2,4-dimethoxy-benzamidine obtained was dissolved 5 in 10 ml of 10% glycolic sodium hydroxide solution find heated for 4 hours at 180 to 190*C. The mixture was poured into water and extracted with ethyl acetate. The compound obtained was purified by column chromatography (silica gel, eluent CHCl^: MeOH *19 : 1). lu M.p. of the hydrochloride: 196 to 197"C Example 25 2-(2 ,4-Dimethoxy-phenyl)-3-(4-chlorophenyl)-lH-imidazo [4,5-b] pyridine 3 g of 2,4-dimeLl.oxy-benzoyl (4-chloroanilide) and 15 1.3 g of 2-chloro-3-aminopvridine were refluxed for 2 hours in 16 ml of phosphorus oxychloride. Subsequently the mixture was poured into water, neutralized with concentrated ammonia and extracted with ethyl acetate. The ethyl acetate layer was extracted with 3N hydrochloric acid. - 34 - 39066 After neutralization of the aqueous layer, the mixture was again extracted with ethyl acetate. The solid product remaining after evaporation of the organic layer was crystallized fron methanol.
M.p.: 176 to 178°C.
Example 26 2 - (2,4 - Dimethoxy - phenyl) - 1H - imidazo ft,5 - b3 pyridine hydrochloride 2.2 g of 2,3 - diamlnopyridine, 6.8 g of imido chloride of 2,4 - dimethoxy - benzoyl morpholide having the formula cP a och3 and 12 ml of triethylamine were heated for } hour at 120°C in 10 ml of diethyleneglycol dimethyl ether. After cooling, water was added, the reaction mixture was extracted with chloroform and the chloroform layer was extracted with 2N sodium hydroxide solution. The yellow hydrochloride which precipitated from the acidic solution was converted into the base with ammonia, and was purified by column chromatography. The hydrochloride was again precipitated from acetone with ethereal hydrochloric acid.
M.p.: 237 to 238°C. - 35 - 3 0 0 0 0 Example 27 2-(2,4-Dimethoxy-phenvl)-1H-lmlda2o[4,5-b]pyridlne hydrochloride Prepared from 1. 1 g of 2,3-diaminopyridine and 3.5 g of 2,4-dimethoxybenzoyl anhydride by heating for 5 hours at 180°C. The further processing was carried out as in Example 26.
M.p.: 236 to 238°C.
Example 28 2-(2-Methoxyphenyl)-lH-imida2o[4,5-b]pyridine hydrochloride a) 2 - Methoxy - thiobenzoyl morpholide 34 g of 2-methoxyben2aldehyde, 16 g of sulfur and 32.6 g of morpholine were heated for 3 hours at 120°C. The reaction mixture thus obtained was dissolved in ethanol, filtered,cooled at»u the precipitated yellov crystals were suction filtered.
Yield: 54.1 g (91% of theory), m.p.: 80 to 82°C. b) 2-Methoxy- thiobenzovl morDholide methiodide 47.4 g of 2-methoxy-benzoyl thiomorpholide were - 36 - 38060 refluxed for 1 hour in ISO ml of acetone with 25 ml of methyl Iodide and the precipitated yellow crystal* were suction filtered after cooling.
Yields 64.4 g (85% of theory), m.p.t 162 to 164*C c) 2-(2-Methoxyphenyl)-lH-lmlda«o f4.5-bIpyrldlne 19 g of 2-tnethoxy- thiobenzoyl morpholide and 8.7 g of 2,3-diaminopyridine were heated for 3 hours at 120°C in 70 ml of glycol. After cooling, water was added, the mixture was made alkaline with ammonia and extracted with chloroform. The organic layer was washed with water and subsequently 2N hydrochloric acid was added. The precipitated product was suction filtered and the base was Creed with ammonia, dissolved in chloroform and purified by passing it through a silica gel column. The colorless hydrochloride was obtained from acetone by addition of ethereal hydrochloric acid.
M.p.: 233 to 234°C.
Example 29 2-(2-Methoxyphenyl)-3-methyl-3H-imidazo[4»5-b1pyrldlne hydrochloride Prepared analogously to Example 28 from 2-methyl-amino-3-anino-pyrldlne and 2-methoxy- thiobenzoyl morpholide methiodide.
M.p.: 208 - 210°C Example 30 2-f 2-(2-Methoxy-ethoxy)-phenyl'}-lH-lmlda2of4.5-b]pyrldine hydrochloride Prepared analogously to Example 28 fron 2-(2-methoxy-ethoxy)- thiobenzoyl morpholide methiodide and 2,3-diamino-pyridine.
M.p.: 170 to 172°C Example 31 2-(4-Methoxyphenyl)-lH-omidazo[4,5-b]pyrldlne hydrochloride Prepared analogously to Example 28 form 4-methoxy-thiobenzoyl morpholide methiodide (m.p.: 142 to 144°C) and 2 ,3-diamino-pyridine.
M.p.: 243 to 245°C. - 38 - Bxacpla 32 2-{3-Methoxv-4-hydroxy-ph«nvl)-lH-lmlda»or4.5-b1pyrldin« hydrochloride Prepared analogously to Example 28 from 3-methoxy-4-hydroxy thiobenzoyl morpholide methiodide (m.p.: 178 to 180*C) and 2,3-diaminopyridine.
M.p.: 251 to 254*C.
Exacple 33 2.« ( 2,3-Pimethoxy-phenyl) - 1H- imidazo [ 4.5-blpyrldlne hydrochloride Prepared analogously to Example 28 from 2,3-dimfcLhoxy thiobenzoyl morpholide methiodide (m.p.: 138 to 140*C) and 2,3-diaminopyridine M.p.: 270 - 272 Example 34 2- (2-Hydroxy-4-methoxy -pheny 1)- 1H-imidazo 14.5-b ]pyrldlnt hydrochloride Prepared analogously to Example 28 from 2-hydroxy-4-methoxy- thiobenzoyl morpholide methiodide (m.p.: 180 to 181°C) and 2,3-diaminopyridine.
M.p.: 190 to 192°C (decamp.). 39 - 3 9 0 6 G M.p. of the free base: 292 to 293°C Example 35 2-(2 ,4-Dimethoxy-phenyl)-lH- imidazo [4 ,5-b]py rldlne hydrochloride 5 Prepared analogously to Example 26 from 2,4- dimethoxy - thiobenzoyl morpholide methiodide. <m.p.: 138 to 140°C (decomp.)) and 2,3-diaminopyridine.
M.p.: 238°C (from methanol) Example 36 j 2-(2 ,4-Dimethoxy-phenyl)-6-methy1-1H-imidazo[4,5-b] pyridine hydrochloride Prepared analogously to Example 35 from 2,1-diamino-5-methyl-pyridine and 2,4-dimethoxy- thiobenzoyl noroho 1 i <ie methiodide. i M.p.: 260 to 261°C.
Example 37 2-(2 ,4-Dlmethoxy-phenyl)-7-methyl-lH-lmidazo[4 ,5-b] pyridine hydrochloride Prepared analogously to Example 35 from 2,3-diamino- - 40 - 39060 4*tnethyl-pyridine and 2,4-dimethoxy- thiobenzoyl morpholide methiodide.
M.p.i 230 to 231°C.
Example 38 2-(2.4-Dlmathoxy-phenyl)-S-methyl-lH-iinida2of4,5-b] pyridine hydrochloride Prepared analogously to Example 35 froa 2,3-diamino-6-mathyl-pyridine and 2,4-dimethoxy- thiobenzoyl morpholide methiodide.
M.p.: 245 to 246°C.
Example 39 2-(2,4-Dlmathoxv-phfe.i/l)-6-chloro-lH-lmldazo[4,5-b] pyridine hydrochloride Prepared analogously to Exsaple 35 from 2,3-diamino-5-chloro-pyridine and 2,4-dimethoxy- thiobenzoyl morDholide methiodide.
M.p.: 253 to 255°C. - 41 - Example 40 . 2-(2-Ethoxy-4-methoxy-phenyl)-lH-lmida»o[4t5-b]pyridlne hydrochloride Prepared analogously to Example 28 from 2-ethoxy-4-methoxy thiobenzoyl morpholide methiodide (m.p.: 152 to 154°C) and 2f3-di amino-pyridine.
H.p.: 228 to 230*C.
Example 41 2-(2-Hethoxy-4-ethoxy-phenyl)-lH-imlda2o[4,5-b]pyrldlne hydrochloride Prepared analogously to Example 28 from 2-methoxy-4-ethoxy- thiobenzoyl oon'j'o^de. methiodide and 2 ,3-diaminopyridine.
M.p.: 224 to 225°C (from methanol) Example 42 2-(2.4-Diethoxy-phenyl)-lH-imlda2o[4,5-b]pyridlne hydrochloride Prepared analogously to Example 28 from 2,4-diethoxy-thiobenzoyl morpholide methiodide and 2,3-diaminopyridine. M.p.: 224 to 226°C 38060 Example 43 2-[2-(2-Hydroxy-«thoxy)-4-methoxy-phenyl]-lH-lmidazo[4.5-b]-pyrldine hydrochloride Prepared analogously to Example 28 froa 2-(2-hydroxy-ethoxy)-4* »ethoxy-thiobenzoyl morpholide methiodide »nd 2,3-diaminopyridine.
M.p.: 237 to 239*C.
■Example 44 2-[2-(3-Hydroxy-propoxy)-4-methoxy-phenyl]-lH-imidazo [4,5-b] pyridine hydrochloride Prepared analogously to Example 28 from 2-(3-hydroxy-propoxy)-4-methoxy- thiobenzoyl norpholide methiodide and and 2,3-diaminopyridine.
M.p.: 170°C (whilst sintering) Example 45 2-[2-(2 -Methoxy-ethoxy)-4-nathoxy-pheny1]-1H-imidazo [4,5-b]-pyrldlne hydrochloride Prepared analogously to Example 28 from 2- (2-methoxy-ethoxy)-4-methoxy- thiobenzoyl morpholide methiodide and 2,3-diaminopyridine.
M.p.: 191 to 193"C. - 43 - 390 GU . • / • : -Example 46 . 2 - f 2-Methoxy-4- (2-aethylmercapto-ethoxy)-pheny 11-1H-imidazo [4,5-tipyrldlne hydrochloride a) 4- ( 2-Methy lmercapto-ethoxy ) -2-hydroxy-benzaldehyde 5 12 g of 2,4-dihydroxy-benzaldehyde and 9.6 g of potassium tert.- butoxide were dissolved in SO ml of ethylene glycol monomethyl ether, 9.6 g of methylmercapto-ethyl chloride were added and the reaction mixture was stirred for 8 hours at 80°C (bath temperature). After 10 removing the solvent, the residue was dissolved in dilute sodium hydroxide solution, the mixture was extracted twice with chloroform, the aqueous alkaline solution was separated, acidified and extracted with chloroform. The organic phase was dried and evaporated. The residue was purified by column chromatography (silica gel). The oil thus obtained was processed directly. b) 4-(2-Methylmercapto-ethoxy)-2-methoxy-benzaldehyde 9.7 g of 4-(2-methylmercapto-ethoxy)-2-hydroxy-benzaldehyde were dissolved in ethanol together with 6.7 g - 44 - 39060 of potassium tert.-butoxid* 4.3 ml of dimethyl sulfate were added and the mixture was refluxed for 3 hours. A further 1 ml of dimethyl sulfate was then added and the mixture was heated for 1 hour more. After the ethaaol had been distilled off the residue was dissolved In water/ chloroform and 2N sodium hydroxide solution was added. The chloroform layer was separated, washed with water, dried and evaporated.
M.p.: 99 to 100°C (froa cyclohexane) c) 4- (2-Methy lmercapto-ethoxy)-2-methoxv» thiobenzoyl aorpholide Prepared -'nalogously to Example 28a from 4-(2-me thy lmercapto-e thoxy )-2-methoxy-benzaldehy d e.
M.p.: 131 to 132°C (from ethanol) d) 2- [2-Methoxy-4-(2-methylmercapto-ethoxy) -pheny 1 ]- 1H-imidazo [4,5-b]pyrldlne hydrochloride 5.4 g of 4-(2-methylmercapto-ethoxy)-2-methoxy-thiobenzoyl morpholide were refluxed for 1^ hours together with 1.2 ml of methyl Iodide In 50 ml of acetone.
After cooling, the solvent was removed and the syrupy - 45 - 300GU •' methiodide. obtained was heated with 3.6 g of 2,3rdiamino-pyridine in 20 ml of glycol for l*j hours at 120°C. The mixture was diluted with water and extracted with chloroform. Subsequently, 2N hydrochloric acid was added 5 to the organic layer and the yellow precipitate was suction filtered.
M.p.; 197 to 199aC (from methanol) Example 47 2-f 2-Methoxy-4-(2-ethylmercapto-ethoxy)-phenyll-lH-lmldazo- io [4,5-b] pyridine hydrochloride Prepared analogously to Example 46 from 4-(2-cthylmercapto-ethoxy)-k-methoxy- thiobon/oyl mornlio l ld<? .hM 2 ,3-diaminopyrldine. The purification of the final product was effected by chromatography over silica gel and 15 the precipitation of the hydrochloride was effected by dissolving the base in acetone and adding an excess of ethereal hydrochloric acid.
M.p.: 195 to 196°C.
- Ub - SVOtttt .Example 48 2-f2-Methoxy-4- ( 3-mathy lmarcapto-propoxy )-pheny 11- 1H-lml da to [4«3-bTpyrldlna hydrochloride Prepared analogously to Exsople 46 froa 4-(3-nethylmercapto-propoxy)-2-aethoxy«.thiobenzoy1 morphol1de and 2,3-dlanlnopyrldlne.
M.p.i 189 to 191*G (decamp.).
Example 49 2- [ 2-Methoxy-4- ( 3-ethylmercapto-propoxy )-pheny 11- lH-laldazo-[4,5-b]pyrldlna hydrochloride Prepared analogously to Example 46 from 4-(3-ethyl-mercapto-propoxy;-2-methoxy- thiobenzoyl morpholide and 2,3 -dlamlnopyrldlne.
M.p.: 183 to 1S5°C (decomp).
Example 50 2- f 2-(2-Methy lmarcapto-athoxy)-4methoxy-phenyl 1- lH-lmidaxo [4.5-bl pyridine hydrochloride Prepared analogously to Example 46 from 2-(2-methylmercapto-ethoxy)-4-methoxy-'th1obciuoyl Sorphol 1 de and 2,3-dlamlno-pyrldine.
M.p.: 204 to 206°C (decamp.). - 47 - 3 9 0 6 U Example 51 2-f2-(2-Ethylmercapto-ethoxy)-4-tnethoxy-phenyl]-lH- imldato[4,5-b'} pyridine hydrochloride Prepared analogously to Example 46 from 2-(2-ethylmercapto-ethoxy)-4-methoxy».thiobenzoyl moroholide and 2,3-diaminopyridine.
M.p.: 193 to 195®C.
Example 52 2- [ 2 - ( 3-Methy lmercapto-propoxy ) - 4-me thoxy-pheny11 - 1H-lmidazo f4,5-b]pyrldlne hydrochloride Prepared analogously to Example 46 from 2-(3-methylmercapto-propoxy)-4-oethoxy- thiobenzoyl noroholide and 2,3-diaminopyridine.
M.p.: 191 to 193°C.
Example 53 2-[2-(3-Ethylmercapto-propoxy)-4-methoxy-pheriy 1]-1H-lmldazo[4t5-b]pyrldlne hydrochloride Prepared analogously to Example 46 from 2-(3-ethyl-mercapto-propoxy)-4-methoxy-thiobenzoyl morpholide and ?,3 diaminopyridine.
M.p.: 187 to 189°C - 48 - 39060 Example 54 2-(2,3.4-Trim«thoxy-phenYl)-iH-*mlda»or4.5-bl pyridine hydrochloride Prepared analogously to Example 28 from 2,3,4-5 triaethoxy-thiobenzoyl morpholide aethlodlde (m.p.: 147 to 150"C) and 2,3-dlamlnopy rldlne.
M.p.: 231 to 233*C (decoop.).
Example 55 2-(2-Methoxy-3,4-mathylenedloxy-phenyl)-lH-lnil<i*?o 10 [4t5-b1pyrldlne hydrochloride Prepared analogously to Example 28 from 2-oethoxy-3,4-methylenedioxy-thiobenzoyl morpholide methiodide (m.p.: 109 to 1U*C) and 2,3-dlamlnopy rldlne.
M.p.: 266 to 2C3aC. 15 Example 56 2-(2,4-Dlniethoxy-3-hydroxv-pheiryrl)-lH-Imidazo [4.5-bl pyridine hydrochloride Prepared analogously to Example 28 from 2,4-dimethoxy -3-hydroxy-thiobenzoyl raorpJioTide methiodide and 2,3-20 dlamlnopyrldlne.
M.p.: 115 to 118°C. - 49 - 30060 Example 57 2-(2-Methoxy-4-chloro-phenyl)-lH'-imidazo[ 4,5-blpyridlne hydrochloride Prepared analogously to Example 28 from 2-methoxy-4-chloro- thiobenzoyl morpholide methiodide and 2,3-diamlnopyridlne.
M.p.: 302 to 305°C.
Example 58 2-(2-Methoxy-4-methyl-phenyl)-lH-lmldazo[4,5-b]pyridine hydrochloride Prepared analogously to Example 28 from 2-methoxy-4-raethyl-. thiobenzoyl morpholide and 2,3-dlaminopyridine. M.p.: 256°C (decomp.).
Example 59 2-(2-Ethoxy-4~methyl-phenyl)-lH-imidazo[4,5-b]pyrldlne hydrochloride Prepared analogously to Example 28 from 2-ethoxy-4-methy1- thiobenzoyl morpholide methiodide (m.p.: 142 to 144°C) and 2,3-diaminopyridine.
M.p.: 224 to 225°C (decomp.). - 50 - 30086 Example 60 2» ( 2»Mathoxy-4-,methylfflgrcapto-phaiiyl)-lH-lmlda»of4.5«b] pyridine hydrochloride Prepared analogously to Example 25 from 2-methox;'- 4-aethylmerc4pto-benzoyl morpholide (m.p.: 124 to 129°C) and 213-dl amino-pyridine.
M.p.: 232 to 234°C.
Example 61 2- ( 2-Methoxy-5-methy lmercapto-pheny 1) - 1H-imidazo f 4.5»b] pyridine hydrochloride Prepared Analogously to Example 25 from 2-methoxy- 5-inethylmarcapto-benzoyl morpholide (m.p.: 106 to 108°C) and 2,3-diamino-pyrldlne.
M.p.: 247 to 2':8°C.
Example 62 2-(2-Methoxy-4-ethylmercapto-phenyl)-lH-lmlda»of 4,5-b] pyridine hydrochloride Prepared analogously to Example 25 from 2-methoxy-4-ethylmercapto-benzoyl morpholide and 2,3-diamlnopyridine. M.p.: 215 to 217°C. 390UU Example 63 2-(2-Methylmercapto-phenyl)-lH-lmlda»of4,5-blpyrldine hydrochloride Prepared analogously to Example 28 from 2-methyl-mercapto*. thiobenzoyl morpholide methiodide and 2,3-diaminopyridine.
M.p.: 185 to 187ttC.
Example 64 2-(2t4-Blsaethylercapto-phenyl)-lH-»imldazo[4.5-b] pyridine hydrochloride Prepared analogously to Example 28 from 2,4-bismethyl mercapto- thiobenzoyl morpholide methiodide and 2,3-diaminopyridine.
M.p.: 249 to 250°C.
Example 65 2-[2-(2-Methylmercapto-ethoxy)-4-methylmercapto-pheny1]-1H-imidazo [4,5-b]pyrldlne hydrochloride Prepared analogously to Example 28 from 2-(2-methylmercapto-ethoxy)-4-methylmercapto-*h i obenzoy1 morpholide methiodide gnj 2,3-diaminopyridine.
M.p.: 180 to 182°C. - 52 - 390G0 Example 66 2-f2-(2-Dl«thylf»<"*—t-hoxv)-4-«athyl-ph«iyl'l-lH-iittlda»o [4.5«b1 pyridine hydrochloride Prepared analogously to Example 28 from 2-(2- diethylamino-ethoxy)i-4-!Bethyl-th1obenzoy1 norphol ide methiodide hydrochloride and 2,3-diandnopyridine. M.p.: 221 to 223°C.
Example 67 2- ( 2-Ally loxy-4-methoxy-pheny 1) - 1H- imidazo [ 4.5-blpy ridine hydrochloride 16.5 g of 2-allyloxy-4-methoxy-ben*oyl morpholide and 7.1 g of 2,3-diaminopyridine were powdered and Intimately mixed and 30 ml of phosphorus oxychloride were added dropwise whilst stirring. Subsequently, the reaction mixture was refluxed for 3 hours, the excess of phosphorus oxychloride was removed and the residue was decomposed with ice-water. The solution, which had been made alkaline with ammonia, was extracted with chloroform. The organic solution was extracted with 2N hydrochloric acid and the aqueous phase was made alkaline with ammonia and extracted with chloroform. The chloroform solution - 53 - 390GG was dried, treated, with charcoal/tonsil, filtered and evaporated. The residue was dissolved in acetone and the light yellow colored hydrochloride was precipitated with ethereal hydrochloric acid.
M.p.: 189 to 191°C.
Example 68 2- ( 2 .A .5-Trlmethoxy-phertyl)-lH- imidazo [ 4 »5-b Ipy rldlne hydrochloride a) 2-(2,4,5-Trlmethoxy-phenyl)-l ,3-dlthlolanlum-iodine 50 g of 1.2,4-trlmethoxybenzene and ISO g of 2-methylmercapto-l ,3-dithiolanium-methyl sulfate were stirred in 600 ml of glacial acetic acid for 4 hours at 70°C bath temperature. Subsequently, the solvent was removed, the residue was dissolved in a mixture of chloroform and water and fir. excess of potassium iodide solution was added to the aqueous layer, whereby the product precipitated as orange-colored crystals. b) 2-(2,4.5-Trlmethoxy-phenyl)-1H-imidazo[4,5-b1 pyridine hydrochloride 3.8 g of 2-(2,4,5-1rimethoxy-pheny1)-1,3-dithiolanium -iodide and 2 .2 g of 2,3-diaminopyridine were heated for - 54 - 30 0 6 G 10 minutes In 40 ml of glycol at 200*C. After cooling the mixture was extracted vltli ether and then with chloroform. The chloroform layer was extracted with 2N hydrochloric acid and the precipitated yellow hydrochloride was suction filtered and recrystallized from glycol. M.p.j 278 to 280°C Example 69 2-(2'.4.6-Trlaethoxy-phenyl)-lH-lmida2o[4.5-b1pvTldln» hydrochloride a) 2-(2,4.6-Trlmcthoxy-phmy 1) -1,3-dlthlolanlum-iodide 33.6g of phlorogluclnol-trlmethyl ether and 105 g of 2-methylmercapto-l,3-dlthloianlum-aethyl sulfate were held at 75*C for 6 hours In 200 ml of glacial acetic acid and the crystals which precipitated after standing overnight were suction filtered* dissolved in water and the iodide thereof was precipitated with potassium iodide solution.
M.p.: 153 to 154°C. - 55 - 3 0 0 0 <> b) 2-(2,4,6-Trimethoxy-pheny1)-1H-imidaxo[4,5-b] pyridine hydrochloride 4 g of 2-(2 ,4,6-trimethoxy-phenyl)-l,3-dithiolanium-lodide, 2.2 g of 2,3-diaminopyridine and 5 g of )ead acetate-were heated for 10 minutes in 75 ml of glycol. Subsequently the precipitated lead salt was filtered off, the nitrate was diluted with water and the precipitated product was suction filtered. After dissolving in methanolic hydrochloric acid, the product was purified by passage through a silica gel column (eluent: chloroform: methanol ■ 9:1) M.p.: 241 to 244"C (from ethanol) Example 70 2-(2 ,4-Dihydroxy-pheny1)-iri-1mlda zo L 4 ,5-b]pyr tdine hydrochloride Prepared analogously to Example 69 from 3-hydroxy-4-[1' ,3'-dithiacyclopentylidene-(2*)]-cyclohexadiene-(2 ,5)-one-(l) and 2 ,3-diaminopyriaine.
M.p.: 298 to 301°C. - 56 - 39066 Example 71 2«»(4-Diaethvlaaino-ohe:iyl)-lH-ljddagof4.5»bTpyrldlne hydrochloride Prepared analogously to Example 69 froa 2(4-diaethyl amino-phenyl)-1,3-dithiolanlum-iodide and 2,3-diamino-pyridlne in n-propanol.
M.p.: 337 to 339*C.
Example 72 2-( 2-Me thoxy-4-d iae thy lamlno- phenyl )»1H- iml da»o [ 4.5«b ] pyridine hydrochloride a) 2-(2-Methoxy-4-dlmethylaalno-phanyl)-l ,3-dlthiolanlum-iodlde 22.6 g of 3-dimethylamino-anisole, 43.2 g of 2-methylmercapto-l ,3-dithiolanlummethyl sulfate, ISO ml of glacial acetic acid and 22.5 ml of pyridine were refluxed for % hour. After cooling, the mixture was poured into an aqueous potassium iodide solution, the precipitated product was suction filtered and dried.
M.p.: 189 to 195°C (from dimethylformamide) b) 2-(2-Methoxy-A-dlmethyIamlno-phenvl)-lH-Imidazo [4«5-b1pyridine- hydrochloride Prepared analogously to Example 42 from 2-(2-methoxy-4-dlmethylanino-phenyl)-l ,3-dlthlolanium-lodiii and 2,3-diaminopyridine .
M.p.: 258 to 260°C (from methanol) Example 73 2-(2-Methylgulflnyl-phenyl)-lH-imldazo[4«5-b]pyridine hydrochloride 1.35 g of 2-'?-methylm«rcapto-phenyl)-lH-Imidazo [4f5-b]pyridine were dissolved in 20 ml of glacial acetic acid and 0.64 g of 301 hydrogen peroxide dissolved in 5 ml of glacial acetic acid were added dropwise. After standing overnight, the mixture was diluted with water, neutralized with sodium bicarbonate and the precipitated product was suction filtered and dried. By addition of ethereal hydrochloric acid to a methanolic solution of the product the colorless hydrochloride was obtained. M.p.: 205 to 210°C. - 58 - 3906C Example 74 2-(2-Methylsulfonyl-phenyl) - 1H-Imidazo[4.5-blpyridIne hydrochloride 430 mg of 2-(2-methylmercapto-phenyl)-lH-lmidazo S [4,5-b]pyridlne hydrochloride and 370 mg of 301 hydrogen peroxide were heated for 3 hours at 70aC in 20 ml of glacial acetic acid. After evaporation and trituration with petroleum ether, the desired product crystallized. M.p.: 259 to 262°C (from lsopropanol) lo Example 75 2-[2-(2-Methylgulflnyl-ethoxy)-phenyl]-lH-itnldazof 4,5-b] pyridine hydrochloride a) 2-[2-(2-Methylmercapto-ethoxy)-phenyl]-lH-imidazo [4»5-b]pyrldlne hydrochloride IS Prepared analogously to Example 28 from 2-(2- methylmercapto-ethoxy)- thiobenzoyl morpholldeaethiodide and 2,3-dlamlnopyrldlne.
M.P.;: 138 to 140°C. - 59 - b) 2-(2-(2-Methvlsuiflnyl-etJu>xy)»phenylj-lH-imidazo [4,5-blpyrldlne hydrochloride 4.3 g of 2-i2-(2-methylmercapto-ethoxy)-phenyl}-lH-imidazo [4,5-b]pyrldlne hydrochloride and l.S g of 30% hydrogen peroxide were stirred for 2 hours at room temperature in 100 ml of glacial acetic acid. After standing overnight, the mixture was diluted with water, neutralized with bicarbonate and extracted with chlorofoxm. The chloroform layer was evaporated, the residue was dissolved in acetone and the hydrochloride was precipitated with methanolic hydrochloric acid.
M.p.: 163 to 165°C.
Example 76 2-[2-(2-Methylsulf lnyl-etho:r/)-4-methoxy-phenyll-lH-lmldazo[4,5-b]pyrldine hydrochloride Prepared analogously to Example 75b from 2-[2-(2-methylmercapto-ethoxy)-4-methoxy-phenyl]-lH-imidazo[4,5-b] pyridine hydrochloride M.p.: 231 to 232°C. - 60 - 39066 EaaimplV77 ,.A-.. • ■ 2-f2-(2-Ethvl«ulfinyl-athoxy)-4-ttttthoxv-ph«nyl]-lH-'lmidszo [ 4 .S-bl pyridine Prepared analogously to Example 75b from 2-[2-(2-5 ethylmercapto-ethoxy)-4-inethoxy-phenyl]-lH-imldaxo[4,5-b] pyridine hydrochloride.
M.p.: 188 to 189°C.
Example 78 2-[2«(2-MethyIsulfInyl-propoxy)-4-oethoxy-phanyl]-1H-io imlda»o»[4,5-b]pyridlne Prepared analogously to Example 75b from 2-[2-[2-( 3-toe thy lmercapto-prdjpoy)4-fflathoxy-pheny 1]- 1H-imidazo [4,5-b]pyridlne hydrochloride M.p.: 132 to 133#C 15 Example 79 2-f2-(3-Ethylsulfinyl-propoxy)-4-mathoxy-pheny1]-1H-imidazo C 4»5-b]pyrldlne Prepared analogously to Example 75b from 2-[2-(3-e thy lmercapto-propoxy )-4-methoxy-pheny 1 ]-1H- imidazo [ 4»5-b ] 80 pyridine hydrochloride.
M.p.: 126 to 127°C. - 61 - Example 80' 2 - C2-Methoxy-4-methy 1 sulf lnyl-phetry 1)-1H- imidazo T 4«5-b] pyridine hydrochloride• .
V 6.6 g of 2-(2-tn«thoxy-4-methylmercapto-phenyl)-lH-lmldazo(4,5-b]-pyridinewere dissolved in 100 ml of chloroform and a solution of 2.96 g of 3-chloro-perbensoic acid in 600 ml of chloroform was dropped in ac *15 to -20°C during S hours. Subsequently* the mixture was extracted with a dilute sodium carbonate solution and the chloroform layer was dried and evapo.ated. The residue was purified over a silica gel column (eluent: chloroform/methar.o 1 -9:1). By addition of ethereal hydrochloric acid to a methanolic solution of the base the yellow hydrochloride was obtained.
M.p.: 154 to 155"C.
Example 81 2-(2-Methoxy-4-methylsulfony1-pheny1)-1H- imidazo[4,5-b] pyridine hydrochloride Prepared analogously to Example 74 from 2-(2-methoxy -4-methylraercapto-phenyl)-lH-imidazo[4,5-b]pyridine hydrochloride.
M.p.: 240 to 242°C. - 62 - 39 0 6 0 '*> . • ** •" • ' ' I ' 'i • v;" " ' •• • • v ; - • 1- P* •" * . ' * ■: i'i "V • v-r ■' • •' . ^ •' - ';v; i^(2-Heihoxy»4-'ethyl>ulf lnyl-ph<Pvl)-lH-»tfld.dagor4.5-bl pyridine hydrochloride '5/:. Prepared.analogously to fiunpie 80 froa 2-(2- mi«thoxy-4-ethylmercapto-phanyl)-lH-ioida*o£4t5-b]pyridine • '■■ih-r: . ■ - '-■ ' • • t lii to 123»C ' : ; Example 83 2-f2-(2-Methylsulflnyl-ethoxy)-4-ciethylinarcapto-phenyl'l-lH- lmida»of4.3-b7p'yrldina Prepared analogously to Example 80 from 2- [2- methy lmercapto-ethoxy)-4-methylmercapto-phenyl]-lH-imidazo [4>S-b}p3rrldine and an equlmolar quantity of 3-chloro-perbenzolc acid.
M.p.: 191 to 192°C (from acetone) Example 84 2-r2-(2-Me thylsulfliry 1-ethoxy )-4-methyl gulf lny 1-pheny ll-lH-lmldazo f4 » 5-blpyrldlne .
Prepared analogously to Example 80 from 2-[2-(2-methylsulfinyl-ethoxy)-4-methylmercapto-pheny1]-lH- imidazo [4,5-b]pyrldlne and an equlmolar quantity of 3-chloro-perbenzoic acid.
M.p.: 190 to 191#C. - 63 - 3 0 0-6 V» :'T"'V • ■ "-V:. ; ;A ' ; "" - " ■ Example 85 ' :2-l 2-(2-Methylsuiflnyl-ethoxy)-4-tnethyl-phenyll-lH-imidazo [4.5-b] pyridine hydrochloride . i ::;: Prepared analogously to Example 75b from 2-f2-(2-> inethylmercapto-ethoxy)-4-niethyl-phenyl]-lH-imidazo[4,5-b j pyridine hydrochloride.
M.p.: 191 to 192"C (from acetone/ether).
Example 86 2-12-( 2-Methy lsulflnyl-ethoxy)-4-chlorophenyl'l-lH-imidazo [4,5-b] pyridine hydrochloride Prepared analogously to Example 75b from 2-[2-(2-me I; hyme rcapto-ethoxy)-4-chl oro-pheny 1 ]-lH- imidazo j>,5-b] pyridine hydrochloride.
M.p.: 221 to 222°C (from acetone/ether).
Example 87 2-[2-Methoxy-4-(2-methylsulfinvl-ethoxy)-phenyll-lH-Imidazo C 4,5-b]pyridine Prepared analogously to Example 75 b from 2-[2-methoxy-4-(2-methylmercapto-ethoxy)-pheny1]-1H-imidazo [4,5-b]pyridine hydrochloride.
M.p.: 204 to 205°C. - f>4 •• 390 86 Example 88 2-[2»Methoxy-4-(2-othylsulflnyl«ethoxy)-phenyl]-lH-imidazo [A.S^bl pyridine Prepared analogously to Example 75b from 2-[2-taethoxy-4-(2-ethy1 -mercapto-ethoxy)-phenyl]-lH- imidazo [4,5-b}pyridlne hydrochloride.
M.p.: 217 to 219*C Example 89 2"[2-Methoxy-4-(3-aethylsulfInyl-propoxy)-phettyl1-1H-jjalda«o[4.5-b]pyrid<ne Prepared analogously to Example 75b from 2-[2-me thoxy- 4- ( 3-me thy Ime rcapto-propoxy ) -pheny 1 ] - 1H- imidazo [4,5-b)pyridine hydrochloride.
M.p.: 179 to 180°C.
Example 90 2-[2-Methoxy-4-(3-cthylsulflnyl-propoxv)-*phenyl 1-IH-Imidazo [4,5-b] pyridine hydrochloride Prepared analogously to Example 75b from 2-[2-methoxy-4-(3-ethylmercapto-propoxy)-pheny1]-1H- imidazo [4,5-b]pyrldine hydrochloride M.p.: 167 to 168#C. - 65 - Example 91 . v .' ^ ■ 2-(2-Hethoxy-5-methylaulftnyl-phenyl)-lH-ixnldazor4i5-b] pyridine Prepared analogouslytoExample 80 from 2-(2-methoxy-5-methyimercapto-phenyl)-lll-imidaxo[4t5-b]pyrldine hydrochloride.
M.p.: 211 to 212"C. > Example 92 2-(2-Me thoxy-5-methylsulfonyl-phetiyl)-lH-lmldaa;o[4.5-b] pyridine Prepared analogously to Example 74 from 2-(2-methoxy-5-methyimercapto-phenyl)-lH-imidazo[4,5-b]pyridine hydrochloride M.p.: 240 to 241°C.
Example 93 2-(2,4-Dlmethoxy-phenyl-lH-imldazo[4.5-b1pyrldlne-oxide-(4) 1 g of 2-(2,4-dimethoxy-phenyl)-lH-imidazo[4,5-b] pyridine and 1.35 g of 3-chloroperbenzolc acid were stirred for 15 hours at 60°C in 15 ml of glacial acetic acid. Subsequently, the mixture was recrystallized from - 66 - 80068 2Nacaticacidby addition of charcoal. lha further purification .was effacted by boiling with acetone.
M.p.t 266 to 267*C.
Example 94 2-(2,4-Dlaethoxv-phenvl)-3-m«t:hvl-3H-ljalda*of4«5-b1 pyrldlna hydrochloride . : 3*6 g of methyl iodida wara addad dropwise to a solution of 3.5 g of 2 - ( 2 ,4-dlaethoxy-pheny1) - IH- la>l da so [4,5*b]pyridina hydrochlorlda and 27 g of potasslun tert.-butoxide In 40 ml of dimathyIfomaalda. The atixtura was Stirred for 2 hour* at room t«aperature and than evaporated. Tha residue was dissolved in chloroforo/ water, tha organic layer was separated, dried and evaporated. Tha product was purified by colum chrooato graphy and subsequently precipitated froa tha solution in acetone vith ethereal hydrochloric acid.
M.p.: 196 to 197°C. 3 9 0 0 0 Example 95 2-(2-Hydroxy-phenyl)-3-n»ethyl-3H-lmldazQ' f 4,5-blpyridlne hydrochloride Prepared analogously to Example 94 froa 2-(2-hydroxy-phenyl)-lH-lmida2o[4,5-b]pyrldlne and methyl Iodide. M.p.: 215 to 216°C.
Example 96 2-(2-Hydroxy-4-methoxy-pheny1)-3-(3-hydroxypropy1)-3H-laldazof4,5-b]pyrldlne hydrochloride Prepared analogously to Example 94 from 2-(2-hydroxy-4-methoxy-ph«nyl)-lH-imldazo[4,5-b]pyridine and 3-bromo-propano1.
M.p.: 154 to 155°C.
Example 97 2-(2,4-Dimethoxy-phenyl)-3-benzyl-3H-imldazoF4,5-b1pyridlne hydrochloride Prepared analogously to Example 94 from 2-(2,4-dimethoxy-phenyl)-lH-imldazo[4,5-b]pyridlne and benzyl bromide.
M.p.: 148 to 150°C.
Example 98 / 0 _ T\ 4 fsU Ant* 1 \ 1 <} I \ Of* i M _| AtumnOcctiy i/ - jn* iSluqto* r4t5-b]pyrldlne dlhydrochlorlde - 68 - 39060 Prepared analogously to Exaa$le 94 froa 2-( 2-dlme thoxy-pheny1) - lH-lmldazo[4,5-b]pyrldlne and 2-dlethylaodno<rethyl chloride at 80°C.
M.p. t 185*C. ' 5 Example 99 2- ( 214-Dlmetho xy«» phenyl) » 3- ( 3-dime thy laalnopropy 1)-3H-lmldagof4«3-b1pyrldlna dlhydrochlorlde Prepared analogously to Example 94 froa 2-(2,4-dlmethoxy-phenyl)-lH-lmidaxo[4,5-b]pyrldlne and 3-io dimethyiaalnopropyl bromide at 70°C.
M.p.: 190 to 192°C (decomp.)' Example 100 . 2- ( 2-Methoxy- 4-ben ry loxy-pheny 1)-1H-laaldazoT 415-bIpy rid lne Prepared analogously to Example 10 from 2-methoxy-15 4-benzyloxy-benzoy1 morpholide and 2,3-diaraino-pyridine.
M.p. of the hydrochloride: 218 to 219°C (decomp.).
Example 101 2-( 2.4-Dlme thoxy phenyl)-3-butyl-3H- Imidazo f 4.5-b]pyrldlne Prepared analogously to Example 10 from 2,4-dlmethoxy-20 benzoyl morpholide and 3-amino-2-butylamino-pyridlne.
M.p. of the hydrochloride: 218 to 219°C. - 69 - 39 00 0 ."'Example 102 2- ( 2-Methoxy- 4-hydroxy-phenyl)-lH-lmldazof 4, 5-b]pyrldlne Prepared analogously to Example 10 from 2-rnethoxy-4-hydroxy-benzoyl morpholide and 2,3-diamino-pyridine.
M.p.. of the hydrochloride: 230 to 231°C.
Example 103 2-(2-Ethoxy-4-ethylmercapto-phenyl)-1H-Imidazof 4,5-bl-pyrldlne Prepared analogously to Example 10 from 2-ethoxy-4-ethylmercapto-benz"yl morpholide and 2,3-dlamlno-pyridine. M.p. of tha hydrochloride: 198 to 199°C (decomp.).
Example 104 2f 4-Methoxy-2-(3- ( 4-me thyI-1-plperaainy1)-propoxy)-pheny11-lH-loldazor4,5-b]pyrldlne Prepared analogously to Example 21 from 2-[4-methoxy-2-(3-chloro-propoxy)-phenyl]-lH-lmidazo[4,5-b] pyridine and 1-methyIplperazine.
M.p. of the trlhydrochloride: 248°C (decomp.) Example 105 2-T 4-Methoxy-2-(2-thiomorphollne-ethoxy)-phenyl]-lH-Imldazor 4.5-b]pyrldlne Prepared analogously to Example 21 from 2-[4- methoxy-2-(2-chloro-ethoxy)-pheny1]-1H-lmldazo[4,5-b]- - 70 - 380 00 -pyridine and thlomorpholine.
M.p.VlSfl to i60°C> Example 106 - 2»(2«Fliiorb-4«»tBetht>xy-pheny I>- lH-lmldarof 4.3-blpy rldlne Prepared analogously to Example 1 froa 2-fluoro-4-methoxy-benzoic acid and 2,3-diamino-pyridine.
M.p. of the hydrochloride: 237 to 238°C (decomp.).
Example 107 2-(4«Fluor6-2-tftethoxy-phcnyl)-lH-lnida»of 4.5»b1pyrldlne Prepared analogously to Example 1 from 4-fluoro-2-methoxy-benzoic acid and 2,3-diamino-pyridine.
M.p. of the hydrochloride: 235 to 236°C (decomp.)* Example 108 2-(2,4-Dlmethyl-pheny1)-lH-lmida2o[4,5-blpyrldlne Prepared analogously to Example 1 from 2,4-dimethyl-benzolc acid and 2,3-dlamlno-pyridine.
M.p. of the hydrochloride: 185°C.
Example 109 2-(2-Hydroxy-4-methoxy-phenyl)-3-phenyl-3H-lmidazo-r4.5-blpyrldlne 4.9 g of 2-hydroxy-4-methoxy-benzanilide and 2.6 g of 2-chloro-3-amino-pyridlne were refluxed for 1^ hours in 50 ml of phosphorus oxychloride. After distilling off;, the excess of ^phosphorus oxychloride. the residue vas : boiled, for 45 mimites .With 2N hydrochloric acid, neutralized with ammonia and the precipitated .product was[ recrystallized from lsopropanol.
M.p.: 201"C.
Example 110 2-(2-Hydroxy-4-methoxy-pheny1)-3-(2-methoxy-phenyl)-3H-ltnldazof4,5-blpyrldlne Prepared analogously to Example 109 from N-(2-methoxy-phenyl)-2-hydroxy-4-raethoxy-benzamlde and 2-chloro- 3-amino-pyridine.
M.p.: 197°C.
Exnmpt e 111 2- ( 2-Hydroxy- 4-methoxy-phenyl)- 3 - ( 4-methoxy-pheny 1) -3H- imldazor 4.5-blpyrldine Prepared analogously to Example 109 from N-(&-methoxy-phenyl)-2-hydroxy-4-methoxy-benzamide and 2-chloro-3-amino-pyrldine.
M.p.: 175°C.
Example 112 2-(2-Hydroxy-4-methoxy-pheny1)-3-(2-phenylethy1)-3H-itnidazo T 4.5-bl pyridine Prepared analogously to Example 109 from - 72 - N-{2-phenylethyl )-2-hydrdxy-4-me<£hoxy-btnzdiJ»1de and 2-chloro-3-a«ino-pyri'dine.. • M.p.: 155°C* Example 113 ' , 2-(2,4-Pi»ethoxy-phenyl)-3-phenyl-3H-1»idazo &,5-bl pyridine Prepared fros N-phenyl-N'-(2-chloro-3-pyridyl)-2.4-diaethoxy-benzamidine by heating for 5 minutes with sodium hydride in dimethylforaaraide at 120°C.
M.p.: 138°C (from eyelohexane/isopropanol * 9/1}. Lxample 114 2-(2,4-Oimethoxy-phenyl)-3-(2-methoxy-phenyl)-3H- imidazu [4,5-bj pyridine Prepared analogously to Example 113 from N-(2-methoxy-phenyl)-N'-(2-chloro-3-pyridyl)-2,4-dimethoxy-benzamide.
M.p.: 156°C. i D o t; i.
Example 11S 2-(2 t4-Dlmethoxy-phanyl)-3-(4-methoxy-pheny1)-3H- ItnldazoC 4»5-b]pyrldlne Prepared analogously to Example J13 from N-(4-methoxy-phenyl)-N'-(2-chloro-3-pyrldyl)-2,4-dimethoxy-benzamidine.
M.p.: 163°C.
Example ^6 2-(2.4-Dlmethoxy-phenyl)-3-(3,4-dlaethoxy-phenyl)-3H-imldazof4t5-b1py rldlne Prepared analogously to Example 113 from N-(3,4-dimethoxy-pheny1)-N*-(2-chioro-3-pyrldy1)- 2,4-dlmethoxy-benzamldlne.
M.p.: 190°C.
Example 117 2-(3.4-Dlmethoxy-pheny1)-3-(4-methoxy-pheny1)-3H-imldazo-f4,5-blpyridlne Prepared fron N-(4-methoxy-pheny1)-N'-(2-chloro- 3-pyridyl)-2, 4-dime thoxy-benzamidlna analogously to Example 113 or by boiling in chlorobenzene.
M.p.: 181°C.
Example IIS 2-(2,4-Dlme thoxy-pheny1)-3-(3-morpho1Ino-1-propy1)-3H-imidazo[4t5-b]pyrldlne - 74 - 390GG Prepared analogously to Example ^3 from N-(3-oorphoiino-l-propyl)-N,*(2-chloro-3-pyrldyl)-; 2,4-dlmethoxy-benzamidine.
, M.p.j 207®C. 5 . Example 119 2- ( 2.6-Dinethoxyphany1)-1H-imidazoF4.5-blpyrldine hydrochloride 9.1 g of 2,6-diaethoxy-benzoic acid and 5.5 g of 2,3-diaminopyridine were refluxed for 3 hours in 100 ml lc of phosphorus oxychloride. Subsequently the excess of phosphorus oxychloride was distilled off and the residue was carefully decomposed with ice-water. The obtained solution was filtered, neutralized with potassium carbonate and made alkaline with concentrated 15 ammonia. The suspension which formed was extracted three times with chloroform. The chloroform layer was dried over magnesium sulfate, filtered and the solvent was removed. The remaining residue was dissolved in SO ml of methanolic hydrochloric acid, subsequently 20 100 ml of isopropanol were added and the product was kept in the deep freezer overnight. The precipitate was suction filtered and washed with ether.
M.p.: 250 to 254°C. - 75 - 300GG Example ,120. " '• 1 2-(2-Fropox»'»4«-mcthvl-phenvl)-iH-lmidazof 4,5-blpygldtne . ' ' ' hydrochloride Prepared analogously to. Example 119 from 2-propoxy- 4-methy1 - benzoyl morpholide.
M.p.: 221 to 223°C. (decomp.). / Example 121 2- (2-Butoxy»4-methyl-phenyl)-lH-imidazof4.5-b]pyridine hydrochloride 'r; Prepared analogously to Example 119 from 2-butoxy-4-methyl-benzoyl "niorpholMe, M.plt 212 to 213°C (decomp.).
Example 122 2- ( 4-Me thylmercapt o-pheny1)-1H-Imidazo[4,5-blpyridine hydrochloride Prepared analogously to Example 119 from 4-methy1-mercaptobenzoic actd.
M.p.: 230 to 232°C.
Example 123 2-1" 2—C 2-Methy lmercapto- ethoxy) - 5-methy Imercapto-pheny 11 -lH-imidazo[4,5-b]pyrldlne hydrochloride 50 g of S-inethyl=[2=(2=ssthyln!ercapto-ethoxy)-5-methylmercapto]-thiobenzoyl morpholide iodide (obtained by reaction of [2-(2-methylmercapto-ethoxy)-5-methylmercapto]- - 76 - auofttt -thiobenzoyl morpholide with; .methyl iodide in methanol) and 15 g of 2,3-diaminopyridine were heated for 3 hours at 130°C in 150 ml of glycol* After cooling, the mixture was diluted with water and 30 ml of concentrated annonia were added. Subsequently, the mixture was extracted With chloroform, the organic layer was washed with water and 2N hydrochloric acid was added. The precipitate was suction filtered and recrystallized from methanol. M.p.: 190 to 191°C.
Example .124. 2- ( 2-Methoxy- 4-propy laercapto-pheny 1) - 1H- fanldazof 4,5-bl-pyrldine hydrochloric; Prepared analogously to Example 119 from 2-methoxy-4-propylmercapto-benzoyl morpholide.
M.p.: 203 to 204CC (decomp.).
Example 1?5 2-(2-Ethoxy- 4-propy lmercapto-pheny 1) - 1H- imidazo [ 4,5- b 1 -pyridine hydrochloride Prepared analogously to Example '19 from 2-ethoxy-4-propylmercapto-benzoyl morpholide.
M.p.: 182 to 183°C. 0 66 %. ■ V\ / .Example 126 /£,■; ?: V/- >'• £ ;• __ . -■•2-( 2-Methoxy-4" buty lmercapto-pheny 1) - 1H- imldaiof 4,5-b]- • pyridine .hydrochloride ~ Pr^ax^analogcrusly td; Example 119 from ; 2-methoxy-4rbutylii^rcapto-benzoyl morpholide.
M.pii 203 to 204°cr Example i?y 2- ( 2-Ethoxy-4-buty'Iaercapto-pheny 1) -H- Imidazof 4.5-b]-pyridine hydrochloride Prepared analogously to Example 119 from 2-ethoxy-4-butylmercaptobenzoyi morpho1ide.
M.p.: 207 to 208 'C.
Example 128 2- ( 4-Methy lsul f iny I-pheny 1) - 1H- Imidazo [ 4,5-b]pyridine 5.9 g of 2-(4-methy lmercapto-pheny 1)-1H-imidazo-[4,5-blpyridine hydrochloride were dissolved in 100 ml of glacial acetic acid and 2.4 g of 30% hydrogen peroxide were added at 10°C. Subsequently the mixture was stirred for 3 hours, and then left to stand overnight in the refrigerator and for 10 hours at laboratory temperature. The mixture was made alkaline with ammonia and was extracted several times with chloroform. The starting material was separated by column chromatography The residue was suspended in acetone and the crystals - 78 - which formed were suction filtered.
M.PM 2*0 to 242°C.
Exaaole I*9 • 2w(3-gthoxy-5-methylsuiflrryl«» pheny U-lH-lwldasof 4^5-b]» -,t. '(■ Prepared analogously to Exanple 128 from 2-(2-ethoxy-5-methy lme rcapto-ph eny 1)-lH-lmida2o[4,5-b]pyrldlne. M.pit 197 to 198°C.
Exmaplal30 2- f 2- (2-Methy 1 sul f iny 1-ethoxy) ■ 5-aethylmercapto-pheny 11-lH-lmldazof 4,5-blpyrldlne Prepared analogously to Example 12® from 2-[2-(2-me thylmercapto-ethoxy)-5-methylmercapto-phenyI]-IH- r-.' - imidazo [4,5-b]pyridine hydrochloride.
M.p.: 189 to 190°C.
"Example 131 2-(2-Ethoxy-4-ethylsulflnyl-phenyl)-lH-lmida2or 4,5-b]-pyrldlne Prepared analogously to Example 128 from 2-(2-ethoxy-4- propylsulflnyl -phenyl)-lH-imidazo[4,5-b]pyridine hydrochloride.
M.p.: 166 to 167°C. - 79 - 390 GO :v:'- Example*132 - r 1 . .*■' J"' ^ ' .*•; ■ :<£ v#: . • ,/• 2-(2-Methoxv'-4-propvisuif iny 1-pheny i)-lH»lmldaaioF A, S-bl» pyridine' : Prepared/analogously to Example 128 from 2-(2- ' methoxyrA-propylmercapto-pheny1)-IH-imidazo[4,5*bl-pyridine hydrochloride; M.p. : .1.82; to 183°C.
Example 133 2^(2-Ethoxy-4-propy1su1finy1-pheny1) -1H- imida zo r 4,5- b ] -pyridine ., ; ' prepared analogcur1 y to Exasple 128 from 2-(2-ethoxy-4-propy ime;rcapto-phenyl)-lH- imidazo [ 4,5-b]py ridine hydrochloride.
M.p.: 182 to 183°C (decomp.).
Example 334 2-( 2-Ethoxy-4~ butyTsulf iny 1-pheny D-lH-imidazoT 4,5-b]-pyridine Prepared analogously to Example 128 from 2-(2-ethoxy-4-butylmercapto-phenyl)-lH-imidazo[4,5-b]pyrldine hydrochloride.
M.p.: 185,to 186°C. - 80 - Example 135 2- ( 4-Methy 1 sul f ony 1-pheny 1) - IH- Imidazor 4,5- blpyrld tne hydrochloride 6.95 g of 2-(4-methylmercapto-pheny1)-1H-imidazo[4,5-b]pyridine hydrochloride were dissolved in 100.ml. of glacial acetic acid, 8.5 g of 30% hydrogen peroxide were added and.the mixture vas left standing for 4~days at room temperature. After purification by passage through a silica gel column, the residue was dissolved in acetone and the hydrochloride was precipitated with methanolic hydrochloric acid. M.p.: 286°C.
Example 136 2-(2-Ethoxy-4-et-hvlsulf ony 1-pheny l)-lH-lmldazof 4,5-b]-pyrldlne 400 mg of 2-(2-ethoxy-4-ethylmercapto-pheny1)-1H-imidazo[4,5-b] pyridine hydrochloride were dissolved in 30 ml of glacial acetic acid together with 0.5 mi of 30% hydrogen peroxide. The mixture was allowed to stand overnight and was then heated for 1 hour at 90°C.
After cooling, the mixture was diluted with water, neutralized with bicarbonate, extracted with chloroform and the organic layer was evaporated after drying. The residue was purified by column chromatography. M.p.: 207 to 208°C (from acetone). - 81 - 390 GO Example 137 2-( 2-Methoxy-4-propy 1 sul forty 1-pheny 1)-IH-lml dazof 4.5-blpyrld ine ' Prepared analogously to Example 136 from 2-(2-S methoxy-4-propy Ime rcapto-pheny 1) - lH-imidazo[ 4,5-b] - pyridine.
M.p.: 219 to 220°C.
Example 138 2- ( 2-Ethoxy-4-butylsulf ony 1-pheny 1)- IH-ImidazoT 4.5-b] -10 pyridine Prepared analogously to Exasple 136 from 2-(2-e thoxy- 4-buty lmercapto - pheny 1) - IH- Imidazo [ 4,5-b ]py r id ine. M.p.: 156 to 157°C.
Example 139 15 2-f2-Methoxy-4-(2-dimethylamino-e thoxy)-pheny1]-1H- imldazof4,5-b]pyridine dlhydrochlorlde a) 2-T2-Methoxy-4-(2-chloroethoxy)-pheny11-IH-imldazo-f4,5-blpyridlne hydrochloride 14 g of 2-methoxy-4-(2-hydroxyethoxy)-benzoy1 2u morpholide were refluxed for 1^ hours with 7.1 g of 2,3-diaminopyridine in 100 ml of phosphorus oxychloride. Subsequently the mixture was decomposed with ice-water. The gradually crystallizing precipitate was suction - 82 - 990CG filtered and washed with acetone.
M.p.': 266, to 268°C (decomp.). b) 2 g of 2-[2-methoxy-4-(2-chloroethoxy)-phenyl]- 1H-imidazo f 4,5-b] pyridine hydrochloride were heated in a closed vessel for . 12 hours at 120°C with 5 g of dimethylamine in 100 ml of ethanol. After evaporation, the residue was purified by column chromatography. The hydrochloride was precipitated from acetona with methanolic hydrochloric acid and subsequently recrystallized from methanol.
M.p.: y 250°C.
Example 140 2-T 2-Methoxy-4-(3-dlmethylamlno-propoxy)-pheny1]-1H-lmidazo[4,5-b]pyrldlne dlhydrochlorlde Prepared analogously to Example 139 from 2-[2-methoxy-4-(3-chloropropoxy)-pheny1]-IH-imidazo[4,5-b]-pyridine hydrichloride.
M.p.: 238 to 242°C.
Exanp le 141 2-f 2-Methoxy-4-(3-dlethylamlno-propoxy)-pheny11-1H-imldazo[4,5-b] pyridine dlhydrochlorlde - 83 - :«*> o G Prepared analogously to Example 139 from 2-[2-methoxy-4-(3-chloropropoxy)-phany 1 ]-lH-lmidazo[4,5-b]-.pyridine hydrochloride.
M.pv> .222 to 224°C.- V Example . 2*12-Methoxy-'4- ( 3-piperldlno-propoxy)-phenyl]-lH- lmldazo-[A.3-blpyrldlne dlhydrochlorlde Prepared analogously to Example 140 from 2-[2-me thoxy-4-(3-ch1oropropoxy)-pheny1]-IH-loidazo-[4,5-b]pyridine hydrochloride.
M.p.: 225 to 226°C (decomp.).
Example 143 2-f 2-Methoxy-4-(3-(4^pheny1-plperazln-1-y1)-propoxy )-pherry 11 - IH-imidazof 4,5-b]pyrMlne dlhydrochlorlde Prepared analogously to Example 140 from 2-[2-raethoxy-4-(3-chloro-propoxy)-phenyI]-IH-imidazo[4,5-b]-pyrldine hydrochloride.
M.p.: 197 to 200°C.
Example 144 2-T 2-Methoxy-4-(3-(4-(2-methoxyphenyl)-plperzln-l-vl)-propoxy)-phenyl]-lH-l«aldazo[4.5-b]-pyridtne trihydrochlorlde hydrate - 84 - 3 0 0 (Hi ; Prepared oftklogousiy to Example 1*0 from 2-[2-methoxy-4- (3-chlorp-propoxy)-pheny 1]- 1H- lmldazo[ 4,5-b]-pyrldlne hydrochloride.
M.p.: Sintering froa 180°C.
Example 145 2-(2.6-Dichlorophenyl)-lH-lmldazo[4.5-b1pvridine hydrochloride Prepared analogously to Example 119 from 2,6-dlchlorobenzoic acid. Purification by column chromatography.
M.p.: 262 to 264°C (decomp.).
Example 146 2- (2-Methoxy-4-morpho1ino-phenyI)-IH-imidazo[4,5-b]-pyrldine hydrochloride a) 2-(2-Me thoxy-4-morpho1Ino-phenyl)-1.3-dlthlolanlum-iodide 10.5 g of 3-morphollno-anisole and 15.7 g of 2-methylmercapto-1,3-diethiolanium-methyl sulfate were boiled in a mixture of 60 ml of glacial acetic acid and 8.3 ml of pyridine for I hour. After cooling, the mixture was poured into a saturated potassium iodide solution. The red precipitate was suction filtered and washed with water. The product was used without further purification. - 85 - UG b) 22, g' of 2-(2-m'ethbxy-4-morpholino-phenyl)-l,3-dithiol-aniuzn iodide,10.9"g of 2,3-diamlnopyridine and 60 ml of glycol;vere heated for '2. hours at 130°C. After cooling, water was added and the mixture was extracted with chloroform. After evaporation, the residue was purified by column chromatrography and the hydrochloride was precipitated from acetone with ether/hydrochloride acid.
M.p.: 207 to 209°C (decomp.).
Example 147 2-f2-Methoxy-4-(4-methyl-plpera2ln-l-yl)-phenyl')-lH-lmlda»o[4,5-b1 pyridine dlhydrochlorlde Prepared analogously to Example 146 from 3-(4-methyl-piperazin-l-yl)-anisolc.
M.p.: 279 to 282°C.
Example 148 2-f2-Methoxy-4-(4-ethyl-plperazin-l-yl)-phenyll-1H-imidazof4,5-blpyridine dlhydrochlorlde Prepared analogously to Example 147 from 3-(4-ethyl-piperazin-l-«yl)-anl8ole.
M.p.: 218 to 222°C. - 86 - 39 Example 149 2«r2-Methoxy-4-(4»prbpyl-plpTazln-l-yl)-phenyl]-lH-: imidazof 4.5-blpyrldlne dlhydrochlorlde .
Prepared analogously-to Example 146 from y*(4-propyl-plpera*in-1-y1)-anisole.
Hip.r 25f to 258°C.
Example 150 2-f 2-Ethoxy-4-(4-methyl-plpcrazin-1-y1)-pheny1]-1H-lmldazor4»5-b)pyridlne dlhydrochlorlde Prepared analogously to Example 146 from 3-(4-methyl-piperazin-l-yl)-l-ethoxybenzene.
H.p.s 269 to 271°C.
Tuple 151 2-(2-Ethoxy-4-( 4- ethy1-plperazln-1-y1)-pheny1]-1H-lmldazof4.5-b 1-pyridine dlhydrochlorlde Prepared analogously to Example 146 from 3-(4-ethy1-plperazin-1-y1)-1-ethoxybenzene. M.p.: 257 to 259°C.
Example 1S2 2-f2-Methoxy-4-(4-phenyl-piperazln-l-yl)-phenyl'l-lH-imldazof 4. 5-b Ipy rldlne dlhydrochlorlde Prepared analogously to Example 146 from 3-(4-phenyl-plperazin-1-v anisole, M.p.: 217 to 219°C. - 87 - 39060 •' Example l'-il. '.2-f 4-Methoxy-2-( 2-morpho lino-ethoxy )-pheny l]-1H-imldazoC4,5-^blpyrldlne -Prepared from 6.3 g of\2-[4-methoxy-2-(2-chloro-ethoxy)-phenyl]-lHr*lmidazo[4,5-b]pyridine by refluxing for 3 hours.in 60 al of morpholine, distilling off the excess^-of morpholine in vacuo and recrystallizing the residue from isopropanol.
M.p.: 188 to 190°C.
Example 15* 2-f 4-Methoxy-2-( 3-(4-phenyl-piperazln-l-yl)-propoxy) -phenyll-lH-lmidazofA,5-b]pyridlne 10 g of 2-[4-methoxy -2-(3-chloropropoxy)-phenyl] lH-imidazo[4,5-b]pyridine, iG.2 g of 1-pheny1-piperazine and 5 g of potassium carbonate were refluxed for 8 hours in 100 ml of ethanol. After distilling off the ethanol in vacuo, the mixture was recrystallized froa ethanol/water 3:1.
M.p.: 162 to 163°C.
Example 155 2-f A-Methoxy-2-(3-(2-pheny1-ethylamino)-propoxy)-pheny 1]-lH-lmidazof A, 5-b pyridine dlhydrochlorlde - 88 - 39060 • ■■ [ v';v^.v • ' Prepared fey heating 1.77 g of 2-t4-methoxy-2- ( 3-chloropropoxy)-pheny 1 ]- IH- imidazo[4,5-b]py ridine in 10 ml of 2-pheny 1-ethyiamino for lfc hours at 180°C. The free base was converted into the dlhydrochlorlde with methanolie hydrochloric acid. Recrystalllzation from-isopropanol.
M.p.i 238°C.
Example 156 Z-f^-ieathoxy-a^O-tN-inethyl-N-2-pheny lethyl-amlno)-propoxy) -phenyl 1- IH- imidazoT 4. 5-blpyrtdlne dlhydrochlorlde Prepared fr~j 3.2 g of 2-[ 4-methoxy-2-(3-chloropropoxy ) - pheny 1 ] - IH- imidazo [ 4,5-b ]py ridine and 'f . . 2.7 g of N-methy1-2-pheny1-efchylamine by heating for 6 hours in ethanol at 120°C in a closed vessel. The <f{.hydrochloride was precipitated with ethereal hydrochlorLc acid from an ethyl acetate solution of the base, purified by column chromatography and recrystallized from isopropanol. M.p.: 212 to 215°C.
Example 157 2-[4-Methoxy-2-(3-(N-methyl-N-(2-(3.4-dlmethoxyphenvl)-ethyl)-amino)-propoxy)-pheny11-IH-imidazo[4(5-b 3-pyridine dihydrochloride - 89 - 3 a o c c.
• Prepared from 5.0 g of2-[4-methoxy-2-(3-chloro-propoxy)-phenyi]-lH-ioidazo[4,5-b]pyrldi.ne and 8.5 g of N-[2-(3,4-diniethoxy-phenyi)-€thyl]-methy lamlne by refluxJLng for 12 hours in ethylene glycoi monomethyl ether.- Precipitation of the dlhydrochlorlde from ethyl acetate with ethereal hydrochloric acid.
M.p.: ;169°C.
Example 158 2-f4-Methoxy-2-( 3-thlomorpholi.no-propoxy)-pheny ll- 1H-imldazof4.5-blpyridine .• Prepared analogously to Example 157 from 2-[4-methoxy-2-(3-chloropropoxy)-pheny1]-IH-imidazo[4,5-bj-pyridine and thiotnorpholine by heating for 30 hours. Purification was by precipitation of the maleate from ethyl acetate solution. The free base was obtained from the maleate with 2N ammonia.
M.p.: 111°C.
Example 159 2-f 4-Methoxy-2-(2-(4-methy1-piperazin-1-y1)-ethoxy)-phenyll-lH-imldazof 4.5-b") pyridine Prepared from 3.0 g of 2-[4-methoxy-2-(2-chloro-ethoxy)-phenyl]-lH-lmida2o[4j5-b]pyridine and 2.0 g of N-methylpiperazine by refluxing for 40 hours in - 90 - 39 0 6 C ethanol. After purification by coivann chromatography over silica gel, the product was recrystallized from water.
M.p.: 136 to 137°C. "> Example 160 2-f 4-Methoxy-2-( 3-( 4-( 2-pheny lethyp-plperazln-1-y 1)-propoxy>-phany 11 - IH- lmldazof 4,5-blpyrldlne trl-hydrochlori.de Prepared analogously to Exaople 156 from 2-[4-10 roe thoxy-2-(3-chloro-pro poxy)-phenyl]-lH-lmidazo[ 4,5-b] - pyridine and l-(2-phenyl-ethyl)-piperazine. M.p.: 236 to 238°C.
Example 161 2-f 4-Methoxy-2-(3-methylamlno-propoxy)-phenyl]-1H-15 imidazof4,5-b]pyridine hydrochloride Prepared analogously to Example 156 from 2-[4-raetho xy-2-(3-chloropropoxy)-pheny l]-lH-imidazo[ 4,5-b]-pyridine and methylamine.
M.p.t 215'C. 20 Example 162 2-f 4-Methoxy-2-(2-dlmethylamlno-ethoxy)-phenyl]-1H-lmldazof4.5-b]pyridine dlhydrochlorlde - 91- 39 0 00 Prepared analogously to Example .156 from 2-[4-methoxy-2-(2-chloro-ethoxy)-phenyl]-lH-lmidazo[4,5-b]-pyridine and dimethylamine.
M.p.: 240 to 242°C.
Example 163 2«»(2-Methylamlno-phenyl)-lH-imldazo[4,5-b1pyrldine 1.77 g of N-methyl- isatoic anhydride and 1.09 of 2,3-diaminopyridine were melted and heated for 10 minutes at 180°C. Recrystallization from ethyl acetate. M.p.: 262 to 263°C.
Example 164 2-( 2,4-Dlmethoxy-pheiryl)-3-( 2-pheny l-ethyl)-3H-Imldazo-f 4,5-b]pyridine 0.17 g of 2-(2-hydroxy-4-methoxy-phenyl)-3-(2-phenyl-ethyl)-3H-imidazo[4,5-b]pyridine were dissolved in 7 ml of dimethylformamide. The mixture was stirred for S minutes with 0.02 g of sodium hydride (80% suspension in oil) and reacted with 0.07 g of methyl iodide under ice-cooling. After 4 hours, water was added to the reaction mixture. The precipitated product was dissolved in ethyl acetate, and the organic layer was washed with 2N sodium hydroxide solution and water - 92 - and evaporated.
Recrystallization from ethanol/water.
M.p.: 157«C.
Example 16S 2»(2i 4-Dltnethoxy-pheny 1) - 3- T 2- (3.4-dlmethoxy-pheny1) -ethyl1»3H-lmlda»or4.5-b]pyrldlne hydrochloride Prepared analogously to Example 119 from 3-aoino-2- [2-(3»4-dimethoxy-phenyi)-ethylamino]f/ridlne and 2,4- dlmethoxy-benzoic acid. The hydrochloride was precipitated from ether.
M.p.: 195°C.
Example ?66 2-(2-Fluoro-5-methylmercapto-phenyl)-lH-imldazof4,5-b]-pyridine Prepared analogcusly to Example 119 from 2,3-diaminopyridine and 2-fluoro-5-methylmercapto-benzoic acid. M.p.: 195°C.
Example ^ 2-(2-Fluoro-5-roethylsulfinyl-phenyl)-IH-imldazor4.5-b1-pyridine Prepared from 2-(2-fluoro-5-methylmercapto-pheny 1)-lH-imidazo[4,5-b]pyridine by oxidation with hydrogen - 93 - 39000 peroxide in'glacial acetic 'acid at room temperature. The purification was effected fay column chromatography on silica gel with chlorofortn/oethanol 19:1 as eluent. M*p.> 190 to 192®C.
"• Example 168, 2-(2-»Fluoro»5-ciethylsulfonyl-pheiiyi)-lH-imi{iazo[ 4, S-b]- pyridine Prepared from 2-(2-fluoro-5-methylmercapto-pheny1)-lH-imidazo[4,5-b]pyridine according to Example 167. but at 40°C.
M.pii 242°C.
Example 169 2- ( 3,4-Dimethoxypheny 1) - 3- ( 3-mo rpho lino-propy 1)-3H- Imldazo-f4.5-b]pyridlne dlhydrochlorlde a) N '•»( 2-Chloro-3-pyrldy 1) -W' - ( 3-morphollnopropy 1) - 3,4-dlmethoxy-benzamidine 4.9 g of N- ( 3-morphol inopropy 1) - 3,4-dimc thoxy-benzamide and 2.04 g of 2-chloro-3-aminopyridine were refluxed for 2 hours In 85 ml of phosphorus oxychloride. After distilling off the excess of phosphorus oxychloride, the mixture was poured into water. The solution was made alkaline and extracted with ethyl acetate. After - 94 - 30060 evaporation of the residue, the product remained as 5 viscous oil. . b) 2-(3.4-»blAethoxyphenyl)-3-(3-morpho 1 ino-propy 1)-3H-iaddazoF*.5-b7bvridine dlhydrochlorlde pjrridylJ-N'-O-morphollno- propyi)-3,4-*dimethoxy-benza2&idine and 1.5 g of sodium hydride (801 suspension in oil) were heated in 100 ml of diotethylforoamide for 2 hours at 120°C. The dlhydrochlorlde was precipitated from ether vith io hydrochloric acid and recrystallized from ethanol/ cyclohexane.
M.p.t 180°C.
Example 17Q 2- ( 4-Methoxy-phenyl)-3- ( 3-morphol Ino-propoxy ) -3H- imldazo-15 f 4.5-blpyridlne dlhydrochlorlde Prepared analogously to Example 169 from N'-(2-chloro- 3-pyridyl)-.N -(3-n»rpholino-propyl)-5-methoxy-benzamidine. M.p.: 218°C.
Example 171 20 2-(4-Mathoxy-phenyl)-3-r 3-(4- phenvl-plpe razin-l-yl)- pgopyl1-3H-lmldazof4.5-blpyrldine dlhydrochlorlde hydrate Prepared analogously to Exa&pLe 169 from N'-(2-chloro-3-pyridyl) -N-[3-(4»phenyl-piperazin-l-yl)- - 95 - 390 6 G -propy1 ] - 4-methoxy-benzamidine.
M.p.: 100°C.
Example -172 2- ( 4-Methoxy-pheny 1) - 3 ( 2-morpho lino- ethy 1) - 3H- imidazo-f4.5-b1pyrldlne hydrochloride Prepared analogously to Example 169 from N'-(2-chloro-3-pyridyP -N- (2-morpholino-ethyl)-4-methoxy-benzamidine.
M.p.: 149°C.
Example 173 2-(4-Methoxy-phenyl) j-[3-(4-methy1-plperazln-l-yl)-propyl1-3H-laida»of4.5-blpyridlne trlhydrochloride Prepared analogously to Example 169 from N'-(2-chloro-3-pyridy 1) -H- [3-(4-methyl-pipeatd.n-l-yl)-propyl]-4-methoxy-benzamidine.
M.p.: 257°C.
Example 174 2-(4-Methoxv-phenyl)-3~r 2-(4-methy1-plperazln-1-y1)-ethy 1]-3H-lmldazof4,5-b1pyrldln< trlhydrochloride Prepared analogously to Example 169 from N'-(2-chloro-3-pyridyl)-N'-f2-(4-methy1-piperazin-1-yl)-ethy1 ]-4-methoxy-benzamidine.
M.p.: 225°C. - 96 - 390CC Example I{? H (4-Hetlioxy phtny I)- 3 ) J d imothy ium ino-piypy I) -3U-imtdazo fo;>5-b1 pyridine dih>d>^chlorfdc Prepared analogously to Example 169 from N'-(2-chloro -3-pyridyl)-N'-(3-dimethyl amino-propyl)-4-methoxy-benzamfde.
M.p.: 229°C.
Example 176 2-(4-Hethoxy-pheny1)-3-(3-p1per1d<no-propyl )-3H-im1da?o- Cff.5-h3 pyridine dlhydrochlorlde Prepared analogously to Example 169 from N'-(2- chloro-3-pyridyl)-N-(3-piperidino-propyl)-4-methoxy- benzamlde.
M.p.: H6°C.
Example 177 Z. •( 4-Methoxy-phenyl ) - 3-(4-giorphol inp-butyl )-3 H - imidazo-[^,5-61 pyridine dihydrochloride hydrate Prepared analogously to Example 169 from N ' - (2-chl o <-o-3-pyridyl)-N-(4-morpho1ino-butyl)-4-methoxy benzaminc M.P. : 1?6°C.
Example ?-K!- i-'ii i' l>. , 5 - £ - pyridine hydroch ! onc*o Prepared analogously U E*ample 11 -J from 2-fluoro -4-n;.-trty 1-mercapto-beiiio i c id and 2 , 3-d i ami'nopy r i d i nc-M o. ; ?S7°r. - i)7 - 390 lit» Example 179 2'{it -FVuoro-4-niethy 1 sul f inyl — phenyl )-lH-laldazo 5,5-bj- pyridine Prepared analogously to Example 167 fron 2-(?-fluoro-4-methyl-mercapto-phenyl)-lH-imidazo Gl»S-b }-pyridine. Crystallization by trituration in petroleum ether.
M.p. : 219°C.
Example 180 2-(4-Hethylmercapto-phenyl)-3-(3-norpho1ino-propyl -3H->midazo -4 ,_5_-b7pyr 1 di ne Prepared analogously to Lxample I6'i from N'-(i!-chloro-3-pyridyl)-N-(J-morpholine-propyI)-4-raethyl mercapto-benzamide. Recrystallized from ether/cyclohexane.
M.p.: 110°C. 3 8 0 6 l> Exaflplt 181 2-f 2-Propoxy-4-(4-methy1-plperarln-1-y1)-pheny1]-1H-lmldazof 4.5-b 1 pyridine dlhydrochlorlde Prepared analogously to Example 146 from 3-(4-me thy1-plperazln-1-y1)-l-propoxy-benzene.
M.p.: 237 to 238°C.
Example 1S2 Tablets containing 100 mg of 2-(2, 4-dime thoxy-phenyl)-lH-lmlda»of4,5-b1pyrldlns hydrochloride Composition: 1 tablet contains: Active ingredient 100.0 cog lactose 50.0 mg polyvinyl pyrrMidone 5.0 mg carboxymethylcellulose 19.0 mg magnesium stearate 1.0 mg 175.0 mg moist screening: 1.5 on Drying: in the circulating air drier at 50°C.
Dry screening: 1 mm The dry granulate was admixed with the remaining auxiliary products and pressed into tablets.
Veight of tablet: 175 mg Punch: 2mm 0 - 99- 3 0 0 0 0 Coated tablets containing 50 mg of 2-C2,4-dlmethoxy-pheny1)-IH-lmldazof4.5-blpyrldlne hydrochlorlde 1 coated tablet core contains: 5 Active ingredient 50.0 mg corn starch, dried 20.0 mg soluble starch 2.0 mg carboxymethylcellulose 7.0 mg magnesium stearate 1.0 mg lo 80-° The active Ingredient and com starch were homogeneously moister.cd with the aqueous solution of the soluble starch.
Hoist screening: 1.0 mm !5 Dry screening: 1.0 mm Drying: at 50°C in the circulating air drier The granulate and the remaining auxiliary products were mixed and pressed to form coated tablet cores.
Weight of core: 80 mg -o Punch: 6 ens, arched (5 mm) The finished cores were covered with a coat consisting essentially of sugar and talcum in conventional manner. The finished coated tablets were polished with - ;oo - J U 0 (i <> beeswax.
Weight of the coated tablet: 120 mg Example i Suppositories containing 75 mg of 2-(2,4-dimethoxy-pheny1)-S IH-lmldazo[4,5-b]pyridine hydrochlor ide 1 suppository contains: Active Ingredient 75.0 mg suppository mass (e.g.*Vitepsol H 19 and Witepsol W 45) 1 625.0 mg 10 1 700.0 mg Method of preparation: The suppository mass was melted. At 38rC the pulverized active ingredient was homogeneously dispersed in the melt. The suppository mass was cooled to 3 5"C iand poured into pre-cooled moulds.
Weight of suppository: 1.7 g Examp1e 135 Ampoules containing 50 mg of 2-(2,6-dlmethoxy-pheny1)-IH-lmidazo[4.5-blpyridine hydrochloride 2o 1 ampoule contains: Active ingredient 50.0 mg sorbitol 250.0 mg distilled water ad 5.0 ml •Witepsol is a Trade mark. - ioi - •J 0 0 0 Method of preparation: The active ingredient and the sorbitol were dissolved In distilled water. The solution was made up to the given volumn and filtered sterile.
Filling: into ampoules of 5 ml capacity Sterilisation: 20 minutes at 120°C.
Example 186 Drop solution containing 25 mg of 2-(2,4-dlmethoxy- phenyl)-lH-lmidazo("4,5-b1pyrldlne hydrochloride per 5 ml Active ingredient 5.0 g methyl £-hydroxybfcnzosLe 0.035 g propyl £-hydroxybenzoate 0.015 g aniseed oil 0.05 g menthol 0.06 g sodium saccharine 1.0 g glycerine 10.0 g ethanol 40.0 g distilled water ad 100.0 ml Method of preparation: The benzoic acid esters were dissolved in ethanol and subsequently the aniseed oil and the menthol were added. Active ingredient, glycerine and sodium saccharide dissolved in water and added. The solution was filtered Dure. 3 !) 0 « l»

Claims (1)

  1. CLAIMS 1. Compounds of general formula <* and isomers thereof of general formula R, 5 / * 2 (la) 3 (Wherein Rj , R^ and R^, which may be the sane or different, each represents a hydrogen or halogen atom; a hydroxy, alkyl, allylo*y, benzyloxy, alkylthio, alkylsulfinyl or alkylsulfonyl qrouD; an amino group optionally substituted by one or two alkyl groups; a morpholino or a plperazino group optionally substituted in the 4-position by a phenyl group or an alkyl group containing from 1 to 3 carbon atoms; or an alkoxy group containing from 1 to 4 carbon atoms, optionally substituted by a halogen atom or by a hydroxy, alkoxy, a lkyltn; alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, piperidino, morpholino, thiomorpholino, thiomorpholino - S - oxide, thiomorpholino -S,S - dioxide, 4 - alkylpiperazino, 3-phenyl-oiperazino, 4 - dimetho.iv-phenylpiperazino, 4 - phenylethylpiperazino, rhenylethylaraino, N - m.tnyl - phenyIethylamino or N - methyl - dimethoxy - phenylethylamino qroup with the proviso that if any two of the groups Rj, R7 and R^ represent, hydrogen atoms then the other group is other than a hydrogen or halogen atom or a methyl or unsubstituted amino group; or two of the groups R, to together represent a methylenedioxy group and the remaining R,, R? or s-:^ hroup is as hereinbefore defined; each of the above mentioned alkyl or')Ui>*. - 10} - containing from 1 to 4 carbon atoms R. represents a hydrogen atom; an alkyl group optionally substituted by a hydroxy, dialkylamino, phenyl, dlmethoxyphenyl, piperidino, morpholino, 4-methyl-plperazlno or 4-phenylpiperazlno group, each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms, or a phenyl group optionally substituted by one or more halogen atoms or methoxy groups, vith the proviso that when represents a hydrogen atom at least one of the groups R^ to R^ Is other than hydrogen; and R^ represents a hydrogen atom, a halogen atom or a lower alkyl group containing from 1 to 3 carbon atoms and the corresponding irndazo&.Sbl yridlne-tf-oxides and isomers thereof and acid addition salts thereof. 2. Compounds of general formula la wherein R^, R£, and R^ are as defined In claim! and R^ represents a hydrogen atom. 3. Compounds of general formula I wherein R^ to R,. are as defined in claim 1. 4. Compounds of general formula I and Isomers thereof of general formula la [wherein R^, R^ and R^ represent hydrogen atoms and R^ and R^, which may be the same or different, each represents a halogen atom or a methyl, methoxy, ethoxy, alkylthio, alkylsulfinyl, dlalkylamlno-alkoxy, morpholInoalkoxy, thiomorpholinoalkoxy, 4-methyl- - 104 - 3 9 0 6 l> piperazinoalkoxy, 4-phenylpiperazinoalkoxy or alkylsulf iny la lkoxy group (wherein each alkyl group contains from 1 to 3 carbon atoms and each alkoxy group contains 2 or 3 carbon atoms)] and physiologically compatible acid addition salts thereof. 5. 2-(2,4-Dimethoxy-phenyl)-lH-imidazoi 4,5-b]pyridine and physiologically compatible acid addition salts thereof. 6. 2-( 2-Methoxy-4-methylmercapto-phenyl)-lH« imidazole,5-b]pyridine and physiologically compatible acid addition salts thereof. 7. 2- ( 2-Methoxy-4-methylsuM.nyl-pheny 1) - IH- imidazo' 4.5- b ' -pyridine and physiologically compatible acid addition salts thereof. 8 . 2-( 2-Met^ixy-4-methy 1-phenyl)-IH-imidazo[ 4,5-b jpyridlne and physiologically compatible acid addition salts thereof. 9. 2-( 2-Me thoxy-5-methy lmercapto-phenyl)- IH- imidazo-[4,5-b]pyridine and physiologically compatible acid addition salts thereof. 10. 2-(2-Ethoxy-4-methyl-phenyl)-lH-imidazo[4,5-b]pyridine and physiologically compatible acid addition salts thereof. 11. Compounds of general formula R 1 R 5 (I) 3 - 105 - t«nd isomers thcu'ut <d general formula G»herein R^, R^ an<' "3* which may be the same or different, each represents a hydrogen or halogen atom; a hydroxy, allyioxy, benzyloxy, alkylthio, alkylsulfinyl or alkylsulfonyl grouD; an amino group optionally substituted by one or two alkyl groups; or an alkoxy group containing from 1 to 4 carbon atoms optionally substituted by a halogen atom or by a hydroxy, alkoxy , alkylthio, alkylsulfinyl, alkylsulfonyl, alkylamino, dialkylamino, morpholino, thiomorpholino, N - methyl piperazino or N - Dheny1piperazino group with tne proviso that if any two of the groups Rj, R^ and represent hydrogen atoms then the other group is other th.m a hydrogen or halogen atom or a methyl or unsubs t i tt< tod an 111*1 group; or two of the groups R^ to R^ together represent .1 methylenedioxy group and the remaining Rj, R2 or R^ group is as defined above; each of the above mentioned alkyl groups containing from 1 to 4 carbon atoms; R^ represents a hydrogen atom; an alkyl group optionally substituted by a hydroxyl, dialkylamino, phenyl or morpholino group, whereby each of the above mentioned alkyl groups contains from 1 to 4 carbon atoms; or a phenyl group optionally substituted by a halogen atom or a methoxy group; with the proviso that when represents a hydrogen atom at least one of the groups R1 to is other than hydrogen; - loh . 3 9 o U i; 10 20 and Rj represents a hydrogen or halogen atom or an alkyl group containing from 1 to 3 carbon atoms and physiologically compatible acid addition salts thereof. 12. Compounds of general formula (I) and isomers thereof of general formula R, J -t/ f JL (la) A ,y- t .. / \ .</ 'A- 3 [wherein Rj, R.,, and Rj, which may be the same or different each represents a hydrogen, fluorine or chlorine atom, a methyl or methyl-jmir-o group, a morpholino or p-?r5zino group optionally substituted in the 4-position by a phenyl group or by an alkyl group containing from 1 to 3 carbon atoms, or an alkoxy group containing from 2 to 4 carbon atoms substituted by a dimethylamino, diethylamino, piperidino. morpholino, thiomorpholino, phenylethylamino, N - methylphenylethylamino or N - methyldimethoxyphenylethylaraino group or by a piperazino group substituted in the 4-position by a methyl, phenyl, dimethoxy-phenyl or phenylethyl group with the proviso that if any two of the groups Rj, R£ and Rj represents hydrogen atoms, tnen the other group is other than a hydrogen or halogen atom or a methyl group; R^ represents a hydrogen atom, an alkyl group containing from 2 to 4 carbon atoms substituted by a phenyl, dimethoyyphenyl, piperidino, morpholino, N - metny1piperazino or N - - 107 - 3 9 0 t» 0 phenylpiperazino group; with the proviso that when represents a hydrogen atom at least one of the groups Rj to R^ is other than hydrogen; and R^ represents a hydrogen atom] and physiologically compatible acid addition salts thereof. 13. Compounds as claimed in claim 1 other than those claimed in claims S to 10 as herein specifically described. 14. Compounds as claimed in claim 11 other than those claimed in claims 5 to 10 as herein specifically described. 15. Compounds as claimed indaim 12 as herein specifically described. 16. A process for the preparation of compounds of general formula I and iosmere thereof of general formula la ns defined in claim 1 which c uprises reacting a compound of formula group of formula R.NH-(wherein R, is as defined in claim l)j u with a compound of formula R 5 (II) jwherein R^ is as defined in claim 1 and Y represents a (HI) - 108 - 3806G (wherein R^ to R^ arc as defined In claim 1 and X represents a carboxyl, thiocarboxyl or dithiocarboxyl group) or a functional derivative thereof. 17. A process as claimed in claim 16 wherein the 5 functional derivative is an acid halide, anhydride, ester or orthoester. 18. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim 1 which comprises reacting a compound of lo formula 15 If (wherein R^ is as defined in claim 1 and Y represents a halogen atom) with a compound of formula x-C?C[ <m) [wherein to R^ are as defined in claim 11 and X represents an appropriate -NR^- containing group (wherein R^ Is as defined in claim 1) which is derived from a carboxyl, thiocarboxyl or dithiocarboxyl group]. - 109 - 3 9 0 6 0 19. A process as claimed In claim 18 wherein the said -NR^- containing group Is a nltrile, amide, amldo ester, imido thloester, imido halide or aoidine group. 20. A process as claimed In any of claims 16 to 19 S wherein the reaction is effected in the presence of a solvent. 21. A process as claimed In any of claims 16 to 20 wherein the reaction is effected at temperatures from -20 to 250°C. lu 22. A process as claimed In either claim 16 or claim 18 wherein a compound of formula III wherein X represents a carboxyl or an amide group Is reacted with a compound of formula II as defined in claim 16 or claim 18 respectively in the presence of phosphorus oxychloride 15 or thionyl chloride and in the presence of pyridine or triethylamlne at temperatures from -20 to 120°C. 23. A process as claimed In claim 18 wherein a compound of formula III wherein X represents a nltrile group is reacted with a compound of formula II as defined in claim 18 in the presence of a catalytic quantity of p-toluene-sulfonic acid and at temperatures from 120 to 180°C. - 110 - 39066 26. A process as claimed in claim 18 wherein a compound of formula III wherein X represents a thioamide group Is reacted with a compound of formula II as defined in claim 18 at temperatures from 100 to 150°C. 25. A process as claimed in claim 18 wherein a compound of formula it wherein Y represents a chlorine atom is reacted with a compound of formula III as defined in claim 18 at temperatures from 100 to 200°C. 26. A process for- the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim 11 which comprises reacting a compound of formula (wherein R^ is as defined In claim 11 and Y represents a group of formula R^NH- (wherein R^ is as defined In claim 11)] with a compound of formula a carboxyl, thiocarboxyl or dithiocarboxyl group) or with a (II) (III) (wherein R^to are as defined in claim 11 and X represents - ill - 390CU functional derivative thereof. 27. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim 12 which comprises reacting a compound of formula (II) ! wherein R^ represents a hydrogen atom and Y represents a group of formula R^NH- (wherein R^ is as defined In claim 12)] with a compound of formula (I^, (wherein to are as defined in claim 12 and X represents a carboxy. thiocarboxy or dithlocarboxy group) or with a functional derivative thereof. 28. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim 11 which comprises reacting a compound of formula -CC "" (wherein R^ is as defined In claim 11 and Y represents a halogen atom) with a compound of formula - 112 - 3 9 0 0 1) 10 (III) [wherein R^ to are as defined in claim 11 and X represents an appropriate -NR^- containing group (wherein R, is as defined in claim 11) which is derived from a 4 carboxyl, thiocarboxyl or dithiocarboxyl group]- 29. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim 12 which comprises reacting a compound of formula (II) (wherein R^ rt*nr<-sents a hydrogen atom and Y represents a [wherein R(to are as defined in claim 12 and X represents 15 an appropriate -MR^- containing group (wherein R^ is as defined in claim 1) which is derived from a carboxyl, thiocarboxyl or dithiocarboxyl group]. - 113 - 30. A process as claimed In any of claims 16 to 25 wherein a compound of formula 1 or la containing a reactive halogen atom thereby obtained Is subsequently converted into the corresponding amino compound by reaction with an amine. 31. A process as claimed In any of claims 16 to 25 and 30 wherein a compound of formula I or la containing a reacting hydrogen atom thereby obtained is subsequently alkylated by reaction with an alkylating agent In the presence of a base. 32. A process as claimed in any of claims 16 to 25, 30 and 31 wherein a compound of formula I or la thereby obtained is subsequently converted into the corresponding N-oxide, S-oxide or S,S-dioxide compound by means of an oxidising agent. 33. A process as claimed in any of claims 16 to 25 and 30 to 11 wherein a compound of formula I or la thereby obtained is subsequently converted into a acid addition salt thereof. 34. A process as claimed in claim 33 wherein the compound of formula I or la is converted into a physiologically compatible acid addition salt thereof. - 114 - 30 0 6 li 35. A process ,is claimed in any of claims 30 to 34 wherein the compound of formula I or la is as defined in claim 11. 36. A process as claimed in any of claims 30 to 34 wherein the compound of formula I or la is as defined in claim 12. 37. A process for the preparation of compounds of general formula ! and isomers thereof of general formula la and the corresponding imidazo! 4,5-b]pyridine-N-oxides and isomers thereof as defined in claim I substantially as herein described. 38. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined in claim II substantially as herein described. 39. A process for the preparaMon of compounds of general formula I md i'-~ners thereof of general formula la as defined in claim 12 substantially as herein described. 40. A process for the preparation of compounds of general formula laid isomers thereof of general forrr.ula la and the corresponding imidazol4,5-b]pyridlne-N-oxides and isomers thereof as defined in claim I substantially as herein described with reference to Examples 1 to 181. 41. A process for the preparation of compounds of general formula L and isomers thereof of general formula la a3 defined in claim 11 substantially as herein described with reference to Examples I to ng * " * d 39066 42. A process for the preparation of compounds of general formula I and isomers thereof of general formula la as defined In claim 12 substantially as herein described with reference to Examples 119 to 181. 5 43. Compounds of general formula I and isomers thereof of general formula la and the corresponding imidazo! 4,5~.» pyridlne-N-oxides and Isomers thereof as defined in claim 1 and acid addition salts thereof whenever prepared by a process as claimed in any of claims 16 to 25, 30 to 10 34, 37 and 40. 44. Compounds of general formula I and Isomers thereof of general formula la as defined in claim 11 and physiologically compatible acid addition salts thereof whenever prepared by a process as claimed in any of claims 26, 28, 15 35, 38 and 41. 45. Compounds of general formula I and isomers thereof of general formula la as defined in claim 12 and physiologically compatible acid addition salts thereof whenever prepared by a process as claimed in any of claims 27, 29, 20 36, 39 and 42 . 46. Pharmaceutical compositions comprising as active ingredient at least one compound of formula I or isomer thereof of formula la or physiologically compatible acid addition salt thereof as claimed in claim ! in association t:, with a pharmaceutical carrier or excipient. -lie-
IE195/74A 1973-02-03 1974-02-01 Imidazo (4,5-b) pyridines IE39066B1 (en)

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DE2305339A DE2305339C3 (en) 1973-02-03 1973-02-03 Imidazo [4,5-b] pyridines, their preparation and their use as cardiotonica
DE2361757A DE2361757A1 (en) 1973-12-12 1973-12-12 Cardioactive imidazopyridines - substd. 2-phenyl 1H(or3H) imidazo (4,5,6) pyridines with positive inotropic and platelet aggregation inhibiting activity

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DE3132754A1 (en) * 1981-08-19 1983-03-03 Merck Patent Gmbh, 6100 Darmstadt 2-Arylimidazo[4,5-b]pyridines, pharmaceutical preparations containing these compounds, and processes for their preparation
ES517193A0 (en) * 1981-11-10 1983-12-01 Wellcome Found A PROCEDURE FOR THE PREPARATION OF NEW IMIDAZO DERIVATIVES (4,5-C) PIRIDINA.
ZA832938B (en) * 1982-05-03 1984-12-24 Lilly Co Eli 2-phenylimidazo(4,5-c)pyridines
US4772600A (en) * 1986-06-09 1988-09-20 A. H. Robins Company, Inc. Fused imidazoheterocyclic compounds and pharmaceutical compositions
JPH01190663A (en) * 1988-01-22 1989-07-31 Terumo Corp Cysteamine derivative and antirheumatic agent containing said derivative
US6653309B1 (en) 1999-04-26 2003-11-25 Vertex Pharmaceuticals Incorporated Inhibitors of IMPDH enzyme technical field of the invention
US9273027B2 (en) 2010-02-24 2016-03-01 Research Triangle Institute Arylpiperazine opioid receptor antagonists
CN103261170B (en) * 2010-12-24 2016-08-24 住友化学株式会社 Fused heterocyclic compound and the purposes for Pest control thereof
WO2013191189A1 (en) * 2012-06-21 2013-12-27 住友化学株式会社 Fused heterocyclic compound
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