NZ214663A - Imidazo derivatives and pharmaceutical compositions - Google Patents

Imidazo derivatives and pharmaceutical compositions

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Publication number
NZ214663A
NZ214663A NZ214663A NZ21466385A NZ214663A NZ 214663 A NZ214663 A NZ 214663A NZ 214663 A NZ214663 A NZ 214663A NZ 21466385 A NZ21466385 A NZ 21466385A NZ 214663 A NZ214663 A NZ 214663A
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New Zealand
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groups
imidazo
group
methoxy
formula
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NZ214663A
Inventor
J Heider
V Austel
N Hauel
K Noll
A Bomhard
Meel J Van
W Diederen
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Thomae Gmbh Dr K
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Publication of NZ214663A publication Critical patent/NZ214663A/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D487/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/04Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number £14663 Nv/ Pricri,/ :i-n w Complete ::fication FiiecJ: \. .'r. A .
Class: Vf"! J-,?.7 P? 'f.
Af J k *} -J ? Pub'kC.'t 0:1 t?,!?•■•: . .
P.O. J. 3.f.V'. 1'2 FEB 1988' 2 14 66 AeCT xx _ j * l*20DEC1985J L*, il.
PATENTS FORM NO. 5 NEW ZEALAND PATENTS ACT 195 3 COMPLETE SPECIFICATION IMIDAZO DERIVATIVES X, WE DR. KARL THOMAE GmbH, a body corporate organised under the laws of the Federal Republic of Germany of D-7950 Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which 2/we pray that a patent may be granted to ixsc/us, and the method by which it is to be performed, to be particularly described in and by the following statement:- '(followed by page 1A.) f I 0 -2 J 4 6 6 - 1A- HV 149-473 Imidazo derivatives The present invention relates to certain new imidazo derivatives, their preparation and pharmaceutical compositions containing them.
Certain new imidazo derivatives have been found to possess valuable pharmacological properties, ^£7 particularly antithrombotic and cardiovascular properties such as a cardiotonic effect and/or an effect on blood pressure.
According to one aspect of the invention therefore we provide compounds of formula I (T) '■j J (wherein 1 or 2 of the groups A, B, C and D represent hydroxy-methine groups, 0, 1 or 2 of the groups 15 A, B, C and D represent methine groups, 0 or 1 of the groups A, B, C and D represent methine qroups substituted by an alkylmercapto group and the remaining 1 or 2 of the groups A, B, C and D represent nitrogen atoms, with the provisos that no group A, B, c 20 or D shall represent a methine group substituted by an alkylmercapto group unless it is located beside a nitrogen atom and that if 2 of the groups A, B, C and D represent hvdroxv-methine groups one shall be located beside a nitrogen atom; and ^ an<3 together with two carbon atoms of the phenyl ring between them represents a phenyl ring optionally substituted by an alkoxv group and R3 represents a hydrogen atom or an alkoxy A <2 1 46 6 3 group; or a first of the groups , R2 and R^ represents a hydroxy, phenylalkoxy, alkylmercapto, alkylsulphinyl, amino, alkylsulphonyloxy, sulphamyl, alkylaminosulphonyl, 5 dialkylaminosulphony1, alkylsulphonamido, N-alkyl-alkylsulphonamido, cyano, aminocarbonyl, alkylamino-carbonyl or dialkylaminocarbonyl group, or if the g remaining two of the groups R^, R2 and R3 do not both Jt represent hydrogen atoms or if A, B, C and D together 1 10 with the imidazole ring do not represent imidazo[1,2-b]- \ pyridazin-6(5H)-ones, imidazo[l,2-c]pyrimidin-5(6H)-ones and 5-alkylmercapto-imidazo[1,2-c]pyr imid in-7(8H)-ones, said first of the groups R^, R2 and R^ may also represent an alkoxy or alkylsulphonyl group, a second of the groups R^, R2 and R3 represents a hydrogen atom or a hydroxy or alkoxy group, and the third of the groups R^, R2 and R^ represents a hydrogen atom or an alkoxy group; and wherein any alkyl moiety of any said group contains one 20 or two carbon atoms) and the tautomers and acid addition salts thereof, particularly favourably physiologically acceptable acid addition salts thereof.
Thus, the present invention relates particularly 25 to imidazo[1,2-a]pyrimidin-7-ones and -5,7-diones, imidazo[1,2-c]pyrimidin-5-ones and -7-ones, imidazo[2,1-f]-[1,2,4]triazin-2-ones, -4-ones and -2,4-diones, imidazo[l,2-b]-pyr idaz in-6-ones, imidazo[l,2-a][1,3,5]-triazin-2-ones, -4-ones and -2,4-diones, imidazo[l,2-30 a]-pyrazin-6-ones and -8-ones, imidazo[1,2-d][1,2,4]triazin-5-ones, -8-ones and -5,8-diones, imidazo[1,2-b][1,2,4]-triazin-2-ones and -3-ones, and imidazo [ 2,1-c][1,2 , 4 ] -triazin-3-ones, the tautomers and the acid addition salts thereof, particularly the physiologically 35 acceptable acid addition salts thereof.
Thus, in the compounds of the invention the *- .•VI v: © 2 1466 groups to R^ may Cor example be as follows: A. R^ and R2 together with the phenyl ring to which they are attached may represent, in particular, a naphth-l-yl, naphth-2-yl, 2-methoxy-naphth-l- yl, 3-methoxy-naphth-l-yl, 4-methoxy-naphth-l-yl, l-methoxy-naphth-2-yl, 3-methoxy-naphth-2-yl, 4-methoxy-naphth-2-yl, 5-methoxy-naphth-2-yl, 6-methoxy-naphth-2-yl, 7-methoxy-naphth-2-yl, or 8-methoxy-naphth-2-yl group, and 10 R^ may represent a hydrogen atom, or a methoxy or ethoxy group, or B. R^ may represent a hydroxy, methoxy, ethoxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, methyl-mercapto, ethylmeccapto, methylsulfinyl, ethylsulfinyl, methylsulfonyl, ethylsulfonyl, amino, methylsulphonyloxy, ethylsulphonyloxy, sulfamyl, methylaminosulphonyl, ethylaminosulphony1, dimethylaminosulphonyl, diethyl-aminosulphonyl, N-methyl-ethylaminosulphonyl, methyl-sulphonamido, ethylsulphonamido, N-methy1-methylsul-20 phonamido, N-ethyl-methylsulphonamido, N-methyl- ethylsulphonamido, N-ethyl-ethylsulphonamido, cyano, aminocarbonyl, methylaminocarbony1, ethylaminocarbonyl, dimethylaminocarbonyl, diethylaminocarbonyl or N-methylethylaminocarbonyl group, R2 may represent a hydrogen atom or a methoxy or ethoxy group, and R^ may represent a hydrogen atom, a methoxy or ethoxy group.
Preferred compounds of the invention include 30 those of formula I wherein none of the groups A, B, C and D carries an alkylmercapto substituent; w i . -'RWwPCW*Nfc**j»v«^v^.>..._ ^ ^ 46 6 R^ and R2 together with two carbon atoms of the phenyl ring between them represent a phenyl or a raethoxy-phenyl ring and R^ represents a hydrogen atom or a methoxy 5 group; or a first of the groups R^, R2 and R^ represents a hydroxy, benzyloxy, methylmercapto, methylsulfinyl, methylsulfonyl, amino, methylsulphonyloxy, methylsulphon-amido, N-methyl-methylsulphonamido, sulfamyl, methylamino-10 sulphonyl, dimethylaminosulphonyl, cyano, aminocarbonyl, methylaminocarbonyl or dimethylaminocarbonyl group, or if the remaining two of the groups R^, r2 and R^ do not both represent hydrogen atoms or if A, B, C and D together with the imida2ole ring do 15 not represent imidazo[1,2-b]pyridazin-6-(5H)-ones and imidazo [1,2-c]pyrimidin-5(6H)-ones, said first of the groups , R2 and R^ may also represent a methoxy group, a second of the groups R^, R2 and R^ represents 20 a hydrogen atom or a methoxy group, and the third of the groups R^, R2 and R^ represents a hydrogen atom or a methoxy group, but particularly those compounds wherein R^ is in the 4 position and R2 is in the 2 position, and the tautomers and the acid addition salts thereof particularly the physiologically acceptable acid addition salts thereof.
However, particularly preferred compounds of the invention include those of formula I wherein 30 A, B, C and D are defined as hereinbefore; R^ in the 4 position represents a cyano, dimethylaminocarbonyl, methylsulphonyloxy, methylsul-phonamido, N-methyl-methylsulphonamido, sulfamyl, methylaminosulphonyl or dimethylaminosulphonyl 35 group, or • - * 2 1 46 6 if Rj and do not both represent hydrogen atoms or if A, B, C and D together with the imidazole ring do not represent imidazo[1,2-b]pyridazin-6(5H)-ones and imidazo [1,2-c]pyrimidin-5(6H)-ones, may also represent a methoxy group; R2 in the 2 position represents a methoxy group; and Rj represents a hydrogen atom; and the tautomers and the acid addition salts thereof, particularly the physiologically acceptable acid addition salts thereof.
According to a further aspect of the invention, we also provide a process for the preparation of the compounds of the invention which process comprises at least one of the following steps: a) reacting a compound of formula II A NH. rY c . N D (II) W (wherein A, B, C and D are as hereinbefore defined) 20 with a compound of formula III 0 = C X - CH.
(Ill) I .
I ' © I ^ Iv. 2 1 46 6 3 (wherein R^, R2 and R^ are as hereinbefore defined and X represents a nucleophilically exchangeable group, such as for example a halogen atom, e.g. a chlorine or bromine atom); b) (to prepare compounds o£ formula I wherein one of the groups R^, R2 and R^ represents an alkylsulphonyloxy, ^ alkylsulphonamido or N-alkyl-alkylsulphonamido group) reacting a compound of formula IV (IV) (wherein A, B, C and D are as hereinbefore defined and the groups R^1, R2' and R^ ' may represent the groups or atoms represented by R^, R2 and R3 {as hereinbefore defined) with the exception of alkylsulphonyloxy, alkylsulphonamido and N-alkyl-alkyl-15 sulphonamido groups, and with the proviso that one of the groups R^', R2' and R^1 must represent a hydroxy, amino, methylamino or ethylamino group) with a compound of formula V R4 - S02 - Y (V) (wherein R^ represents a methyl or ethyl group and Y represents a nucleophilically exchangeable group, such as for example a halogen atom or an alkoxy group, e.g. a chlorine or bromine atom or 25 a methoxy, ethoxy or benzyloxy group); r 7 2 1 466 3 c) (to prepare compounds of formula T wherein at least one of the qroups R^, r2 and R-j represents an alkoxy, phenylalkoxy, alkylmercapto or N-alkyl-alkylsulphonamido group) alkylating a compound of formula vi (wherein A, B, C and D are as hereinbefore defined and R^", R2" and R^" may represent the groups or atoms represented by R-j , R2 and R^ (as hereinbefore defined) but with the proviso that at least one of the groups R-^", R2" and R^" must represent a hydroxy, mercapto or alkylsulphonamido qroup) with a compound of formula wn (wherein R^ represents a methyl or ethyl group or a phenylalkyl qroup having 1 or 2 carbon atoms in the alkyl moiety and Z represents a nucleophilically exchanqeable qroup, such as for example a halogen atom or a sulphoryloxy qroup e.q. a chlorine, bromine or iodine atom or a methylsulDhonyloxv, methoxysulphonyloxy or p-tolvl-sulphony.loxy qroup); d) (to prepare compounds of formula I wherein one of the qroups R^ , R2 and R^ represents an aminocarbonyl, alkylaminocarbonyl, dialky1 aminocarbony], sulfamyl, alkylaminosulDhonvl or dialkvlaminosu]ohonvl qrouo) 3 z (vil) O ' si & reacting a compound of formula vril W - U 2 14663 ("iin / (where i n A, B, C and D are as hereinbefore defined, 1*2" ' and R^"' may represent the groups or atoms represented by R^, Rj and R-j (as hereinbefore defined) with the exception of aminocarbonyl, aIkylaminocarbonyl, dialkylaminocarbonyl, sulfamyl, alkylaminosulphonyl and dialkylamino-10 sulphonyl qroups, W represents a carbonyl or sulfonyl qrouD, and U represents a nucleophilicallv exchangeable group, such as for example a halogen atom or an 15 alkoxy group, e.g. a chlorine atom or a methoxy or ethoxy group) with an amine of formula IX ? H - N (IX) (wherein Rg and Rg which may be the same or different, each represents a hvdrogen atom or a methyl or ethyl group); tip v: 2 14663 e) (to prepare compounds of formula I wherein at least one of the qroups Rj, r2 and R3 represents an amino, hvdroxy or aminocarbonyl group or wherein at least one of the groups A, B, C. and D represents a hydroxymethine group) hydrolysing a compound of formula X (X) (wherein R^, Rj and R^ are as hereinbefore defined and A' ,B', C and D' may represent the qroups or 10 atoms represented by A, B, C and D as hereinbefore defined, but wherein e i ther at least one of the groups A', B', C and D' represents a methine group substituted by a hydrolytically removable group (such as for example a halogen atom, an alkoxy 15 or alkylmercapto group, e.g. a chlorine or bromine atom or a methoxy or methvlmercapto group) or^ at least one of the groups R^, R2 and R^ represents an alkanoylamino, cyano or alkylsulfonvloxy group); f) (to prepare compounds of formula I wherein one or two of the qroups A, B, C and D represent nitrogen atoms, one of the qroups A, B, C and D represents a hydroxymethine or alkylmercaptomethine qroup and the remaining one or two of the qroups A, B, C and D represent methine groups) reductively splittina off one or two reductively cleavahle groups from a compound of formula XI <* 2 7 4 6 6 3 ■O ■wi. (wherein R1' r2 an(^ R3 are as hereinbefore defined, one or two of the qroups A", B", C and D" represent nitrogen atoms, one of the groups A", B", C and D" represents a hydroxymethine or alkylmercaptomethine group, 0 or 1 of the groups A", B", C" and D" represent methine qroups and the remaining one or two groups A", B", C" and n" represent methine groups substituted by a reductively cleavable grouD, e.g. a haloqen atom or an alkylmercapto group); g) (to prepare compounds of formula T wherein one of the groups R-^, R2 and R^ represents a cyano 15 group) converting a corresponding compound of formula I wherein a first of the qroups R-^ R2 and R^ represents an amino group via the diazonium salt into a compound of formula I wherein said first of the qroups R^, Rj and R^ represents a cyano group; and h) converting a compound of formula T into an acid addition salt thereof. ^he reaction of step (a) is conveniently carried out in a solvent or mixture of solvents such as ethanol, isopropanol, benzene, glycol, 25 glycolmonomethylether, dimethylformamide or dioxan, for example at temperatures of between 0 and ]^0°C, preferably at temperatures of between 20 and 100°C. 2 14 6 However, the reaction may also be carried out without a solvent.
The reaction of step (b) is conveniently carried out in a solvent or mixture of solvents 5 such as water, methanol, ethanol, isopropanol, methylene chloride, ether, tetrahydrofuran, dioxan, dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, triethylamine or pyridine, whilst the 10 latter two may simultaneously also be used as solvent, preferably at temperatures of between 0 and 100°C, e.g. at temperatures of between ambient temperature and 50°C.
The reaction of step (c) is carried out with 15 an alkylating agent such as methyliodide, ethyliodide, dimethylsulphate or methyl p-toluenesulphonate, conveniently in a solvent such as tetrahydrofuran, dioxan, dimethylformamide, sulfolan, dimethylsulphoxide or ethylene glycoldimethylether, optionally in 20 the presence of an acid-binding agent such as potassium carbonate, potassium tert.butoxide, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, at temperatures of between 0 and 100°C, preferably at temperatures of between 25 20 and 50°C.
The reaction of step (d) is conveniently carried out in a solvent or mixture of solvents such as water, methanol, ethanol, isopropanol, methylene chloride, ether, tetrahydrofuran, dioxan, 30 dimethylformamide or benzene, optionally in the presence of an acid binding agent such as sodium carbonate, triethylamine or pyridine, whilst the latter two may simultaneously also be used as solvent, preferably at temperatures of between 0 and 100°C, 35 e.g. at temperatures of between ambient temperature and 50°C. 2146 63 If W in the starting material of formula VIII represents a carbonyl group, U may also represent a hydroxy group. In this case the reaction of step (d) is preferably carried out in the presence 5 of a dehydrating agent, e.g. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl-carbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxy-succinimide, N,N1-carbonyIdiimidazole or N,N'-thionyl-10 diimidazole or triphenylphosphine/carbon tetrachloride, or an agent which activates the amino group, e.g. phosphorus trichloride, and optionally in the presence of an inorganic base such as sodium carbonate or a tertiary organic base such as triethylamine or 15 pyridine, which may simultaneously serve as solvents, at temperatures of between -25 and 250°C, but preferably at temperatures between -10°C and the boiling temperature of the solvent used, and any water formed during the reaction may be eliminated by azeotropic distillation, 20 e.g. by heating with toluene using a water separator, or by adding a drying agent such as magnesium sulfate or molecular sieve.
The reaction of step (e) is conveniently carried out either in the presence of an acid such 25 as hydrochloric, sulphuric, phosphoric or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide or the alkali metal salt of a corresponding alcohol in a melt or in a suitable solvent such as water, water/methanol, 30 ethanol, water/ethanol, water/isopropanol or water/dioxan at temperatures of between -10 and 120°C, e.g. at temperatures of between ambient temperature and the boiling temperature of the reaction mixture.
The partial hydrolysis of the cyano group 35 in step (e) is, however, preferably carried out with concentrated sulphuric acid or with an alkali metal hydroxide solution in the presence of hydrogen 2 7 4 6 6 peroxide, e.g. with sodium hydroxide solution/hydroqen peroxide, conveniently at ambient temperature.
The reductive cleaving of step (f) is preferably effected by hydrogenolysis. This is preferably carried 5 out in a solvent such as methanol, ethanol, isopropanol, glacial acetic acid, ethvl acetate, dimethylformamide or water, optionally in the presence of an inorganic acid such as hydrochloric or hydro-bromic acid at temperatures of between -10°C and 10 100°C, preferably at 0°C to 60°C in the presence of a catalyst such as Raney nickel, platinum, platinum oxide or palladium on charcoal. Any benzyloxy group present is converted into a hydroxy group during the reaction.
If according to the invention a compound of formula T is obtained wherein one of the groups Rj,, R2 and R^ represents an amino group, this may be converted via the corresponding diazonium salt into a compound of formula T wherein one of the 20 groups R^, R^ and represents a cyano group.
The subsequent reaction of a diazonium salt, e.q. the hydrosulfate in sulfuric acid or the hydrochloride, in the presence of the corresponding copper (X) salt such as copper (I) cyanide/hydrochloric 25 acid, is conveniently carried out at slightly elevated temperatures, e.g. between 15°C and 100°C. The diazonium salt required is conveniently prepared in a suitable solvent, e.g. in water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric 30 acid or dioxan/hydrochloric acid, by diazotisation of a corresponding amino compound with a nitrite, e.q. sodium nitrite, or an ester of nitrous acid, at low temperatures, e.g. between -10°C and 5°C.
The compounds of formula T obtained according 35 to the invention may, if desired, be converted into the acid addition salts thereof, preferably the physiologically accep^ble acid addition salts, e ^ 14663 with inorganic or organic acids. Examples of suitable acids include hydrochloric, hydrobromic, sulphuric, phosphoric, fumaric, succinic, tartaric, citric, lactic, maleic and methanesulphonic acid. While 5 such physiologically acceptable salts are clearly preferred, other acid addition salts may be useful in the preparation of the physiologically acceptable acid addition salts or of the free bases and so are deemed to fall within the scopeof the invention. 10 The compounds of formulae II to XI used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature.
Thus, for example, the compounds of formulae 15 IV, VI, VIII, X and XI used as starting materials may be obtained by reacting a corresponding amino compound with a corresponding a-bromo-acetophenone optionally followed by chlorosulphonation.
As already mentioned hereinbefore, the new 20 compounds of general formula I, the 1H tautomers and the physiologically acceptable acid addition salts thereof have superior pharmacological properties, particularly antithrombotic and cardiovascular properties such as a cardiotonic activity and/or 25 an effect on blood pressure.
For example, the following compounds: A = 2-(4-dimethylaminosulfonyl-phenyl)-8H-imidazo-[1,2-a]pyr imidin-7-one, B = 2-(4-methoxy-phenyl)-7H-imidazo[1, 2-a]pyrazin-30 8-one, C = 7-(4-me thoxy-phenyl)-lH,3H-imidazo[l,2-a][1^3,5]-triazin-2,4-dione 2 146 0 = 2-(2-methoxy-4-methylsulphonyloxv-phenyl)-8H- imidazo[.l, 2-a] pyr imidin-7-one, E = 2-(2-methoxy-4-cyanophenyl)-8H-imidazof1,2-a]-pyr imidin-7-one, F = 2-(2-methoxy-4-dimethylaminosulphonyl-phenyl)-8H-imidazonr2-a]pyrimidi n-7-one, G = 2-(2-methoxy-4-methylaminosulphonyl-phenyl)-8H-imidazo[l,2-a]pyr i mi din-7-one, H = 2-(2-methoxy-4-dimethylaminocarbonyl-phenyl)-10 8H-imidazo[1,2-a]pyrimidin-7-one and 1 = 2-(2-methoxy-4-methylsulphonyloxyl-phenyl)- 7H-imidazof1,2-a]pyrazin-8-one, were tested for their bioloqical properties as follows: Determining the positive inotropic effect on pithed guinea pigs The tests were carried out on pithed quinea pigs. The animals were respirated with 50% + 50% 20 Nj. The arterial blood pressure was measured in the right carotid artery using a Bell and Howell pressure transducer (4-327-1). To determine the positive inotropic effect, the pressure in the left ventricle (LV) was measured with a catheter-25 tip manometer (Millar PR-249). The I/r-dp/dtmax was obtained using a differentiator. ^he substances being tested were iniected into a iugular vein. 0.9% NaCl+oolydiol 200 (1:1) was used as solvent. Each substance was tested on 3 quinea piqs. 30 The doses were 0.1 - 3 mq/kq i.v. The following Table contains the average values at 1 mg/kg i.v. 2 14663 .A •v.
Substance Dosage % Increase in mg/kg i.v.
LV-dp/dtmax A 1 32 B 1 45 C 1 86 0 1 63 E 1 44 F 1 47 G 1 75 H 1 33 I 1 98 <£/ The new compounds are well tolerated; when substances A to I were tested up to a dosage of 3 mg/kg i.v. no toxic effects on the heart or circulatory damage of any kind could be detected.
In view of their biological properties, the 20 compounds of general formula I prepared according to the invention and the physiologically acceptable acid addition salts thereof are suitable for treating cardiac insufficiency of various origins since they increase the contractile force of the heart 25 and partly by reducing blood pressure they facilitate the emptying of the heart.
For this purpose, the new compounds and the physiologically acceptable acid addition salts thereof, optionally together with other active 30 substances, may be incorporated in conventional pharmaceutical preparations such as plain or coated tablets, powders, suppositories, suspensions, ampoules or drops. The single dosage is from 0.1 - 15 mg/kg of body weight, preferably from 3-10 mg/kg of 35 body weight, 1-4 times a day.
According to a further aspect of the present 2 1466 invention we therefore provide pharmaceutical compositions containing a compound of formula I or a tautomer or physiologically acceptable acid addition salt thereof together with at least one carrier or diluent.
According to another aspect of the invention we provide the use of a compound of formula I (as hereinbefore defined) or a tautomer or physiologically acceptable acid addition salt thereof for the manufacture of a therapeutic agent for use in a method of treatment 10 of the human or non-human animal body for cardiac insuf f iciency.
According to a further aspect of the invention we provide the use of a compound of formula I (as hereinbefore defined) or a tautomer or physiologically 15 acceptable acid addition salt thereof for a method of treatment of the human or non-human animal body for cardiac insufficiency.
According to a yet further aspect of the invention we provide a method of treatment of the 20 human or non-human animal body for cardiac insufficiency comprising the administration to said body of a compound of formula I (as hereinbefore defined) or a tautomer or physiologically acceptable acid addition salt thereof.
The Examples which follow are intended to illustrate the invention: 214663 Example 1 2-(4-Methylsulfonyloxy-phenyl)-8H-imi dazo[l,2-a]pyrimidin-7-one 2.2 q (0.02 Mol) of 2-amino-4~hydroxy-pyrimidine and 5.9 g (0.02 mol) of ot-bromo-4-methylsul fonyloxy-acetophenone are stirred in 50 ml dimethylformamide at ambient temperature. After 6 hours the clear solution is evaporated to dryness J_n vacuo and 10 the crude product obtained is purified over a column (silica gel, particle size: 0.2 - 0.5 mm, eluant = methylenechloride /ethanol mixture). The desired end product is recrystallised from ethanol / dimethylformamide .
Yield: 37.7 % of theory, M.p.: 246-248 °C Calculated: C 51.14 H 3.63 N 13.76 R 10.50 Found: 51.06 3.58 13.76 10.70 Example 2 6-(4-Methylsulfonyloxy-phenyl)-3H-imidazo[2,1-f][1,2,4]-triazin -4-one 425 mg (1.86 mMol) 6-(4-hydroxyphenyl)-3H-imidazo-25 [2 ,1-f ] -[ 1, 2,4 ] tr iaz i n-4-one are dissolved in 20 ml of: IN sodium hydroxide solution. At ambient temperature, 456 mq of methane sulphonic acid chloride are added and the mixture is stirred for 2 hours at ambient temperature. ^he light vellow clear solution is 30 neutralized cold with 2N hydrochloric acid. The qrevish/white precipitate formed is suction filtered, washed with water, dried and dissolved in methylene chloride/ethanol =1:1; 10 q of silica qel are >vr 214663 added and the mixture is evaporated to dryness, the evaporation residue is placed on a silica gel column and eluted first with methylene chloride, then with methylene chloride/ethanol = 50:1 and 5 25:1. The desired eluates are concentrated by evaporation, the crystalline residue is triturated with ether, suction filtered and dried ui vacuo at 50°C.
Yield: 9.65 % of theory, M.p.: 304-306°C Calculated: C 47.07 H 3.29 N 18.30 S 10.45 Found: 47.44 3.58 18.04 10.06 Example 3 2-(3-Dimethylaminosulfonyl-4-methoxy-phenyl)-6H-imidazo-[1,2-c]pyr imidin-5-one a) 2- (3-ChIorosulfonyl-4-methoxy-phenyl)-6H-imidazo-[1,2-c]-pyr imidin-5-one 1.5 g (6.2 mMol) of 2-(4-methoxy-phenyl)-6H-imidazo[1,2-c]-pyrimidin-5-one are added to 15 ml of chlorosulphonic acid at 0-5°C with stirring. After standing for 3 hours at ambient temperature the reaction mixture is poured into ice water and the precipitated product 25 is suction filtered and dried. b) 2- (3-d iniet hy 1 am inosu If on yl-4-methoxy-phenyl)-6H-imidazo[l,2-c]pyrimidin-5-one 1.5 g (4.4 mMol) of the product obtained in a) are taken up in 30 ml of 40% aqueous dimethylamine 30 solution and heated to 50°C. After 30 minutes the clear solution is diluted with water, extracted with ethyl acetate and the combined extracts are "\ / 2 J46 dried over sodium sulphate, then concentrated by evaporation in vacuo. The crude product obtained is crystallised from ethanol.
Yield: 73.3 % of theory, M.p. : 288-290°C Calculated: C 51.71 H 4.63 N 16.08 S 9.20 O Found: 51.69 4.57 16.24 9.25 v Example 4 2-(4-Hydroxy-2-methoxy-phenyl)-5H-imidazo[1,2-b]-pyridazin-6-one 0.4 g (1.13 mMol) 6-chloro-2-(2-methoxy-4-methylsulfonyl oxyphenyl)imidazo[1,2-b]pyridazine are refluxed for 15 6.5 hours in 30 ml of 4N potassium hydroxide solution. After the hot solution has been filtered, the product is obtained by acidifying with concentrated hydrochloric acid.
Yield: 100 % of theory, M.p.: > 250°C NMR-Spectrum (Dimethylsulfoxide/Deuteromethanol): OCH^: 3.95 ppm (s) 3H H in phenyl ring: 6.65 ppm (dd) 1H 6.7 ppm (d) 1H 7.82 ppm (d) 1H H in 3-position: 8.45 ppm (s) 1H 7-position: 8.3 ppm (d) 1H 8-position: 7.4 ppm (d) 1H UV-Spectrum (ethanol): 256 nm (0. 19) 352 nm (0. 19) (Ethanol + KOH) : 275 nm (0. 26) 370 nm (0. 19) 2 14663 Example 5 6- (4-Hydroxy-phenyl)-3H-imidazo[2,1-f][l,2,4]triazin-4-one 1.37 g (0.005 mMol) of 6-(4-hydroxy-phenyl)-2-methyl-mereapto-3H-imidazo[2,1-f][ 1,2 , 4 ] t r iazin-4-one are dissolved in 60 ml of ethanol, mixed with 5g of Raney nickel and shaken for several hours in a Parr apparatus at 80°C under a hydrogen pressure 10 of 5 bar. Then the catalyst is filtered off, the residue is mixed with 20 g of silica gel, concentrated by evaporation and the residue obtained is purified over a silica gel column. It is eluted first with methylene chloride, then with methylene chloride/ethanol 15 = 5:1 and 25:1. The eluates containing the desired substance are concentrated by evaporation, the crystalline residue is triturated with ether, suction filtered and dried ui vacuo at 50°C.
Yield: 18.4 % of theory, M.p.: 314-316°C Calculated: C 57.89 H 3.53 N 24.55 Found: 57.70 3.74 24.50 Example 6 2-(4-Dimethylaminosulfonylphenyl)-8H-imidazo[l,2-a]-pyrimid in-7-one prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-4-dimethylaminosulfonyl-acetophenone analogously 30 to Example 1.
Yield: M. p. : Calculated: 27.3 % of theory, 300-302°C C 52.82 H 4.43 N 17.60 S 10.07 e 2 1466 © Found: 52.76 4.65 17.60 10.27 Example 7 2-(4-Dimethylaminosulfonyl-phenyl)-6H-imidazo[1,2-c]-pyr imidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and ct-bromo-4-dimethylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 28.7 % of theory, M.p.: 246-248°C Calculated: C 52.82 H 4.43 N 17.60 S 10.07 Found: 52.41 4.51 17.55 10.19 Example 8 2-(4-Methoxy-phenyl)-8H-imidazo[l,2-a]pyrimidin-7-one prepared from 2-amino-4-hydroxypyrimidine and a-bromo-20 4-methoxy-acetophenone analogously to Example 1.
Yield: 29.2 % of theory, M.p.: 290-295°C Calculated: C 64.72 H 4.60 N 17.42 Found: 64.60 4.60 17.16 Example 9 2- (4-Methylsulfonamido-phenyl)-6H-imidazo[1,2-c]pyr imidin-5-one prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-4-methylsulfonamido-acetophenone analogously to Example 1. 2 1 466 3 Yield: 34.6 % of theory, M.p.: 293-295°C Calculated: C 49.44 H 4.37 N 17.38 S 10.54 Found: 49.41 4.10 17.00 10.71 Example 10 2-(4-Methylsulfonyloxy-phenyl)-6H-[1,2-c]pyr imidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: 29.6 % of theory, M.p.: 30 2-305 °C Calculated: C 51.14 H 3.63 N 13.76 S 10.50 Found: 50.88 3.70 13.68 10.53 Example 11 2-(4-Methoxy-phenyl)-6H-imidazo[l,2-c]pyrimidin-5-one prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-6-methoxy-acetophenone analogously to Example 1.
Yield: 36.9 % of theory, M.p.: 255-258°C Calculated: C 64.72 H 4.60 N 17.42 Found: 64.81 4.60 17.67 Example 12 7-(4-Methylsulfonamido-pheny1)-lH,3H-imidazo[l,2-a][1,3,5]-triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4- _24_ 2 14663 dione and a-bromo-4-methylsulfonamido-acetophenone analogously to Example 1.
Yield: 28 % o£ theory, M.p.: > 300°C 5 value: 0.60 (methylene chloride/methanol = 7:3; Si02) Mass spectrum: M+ : 321 m/e CJV-Spectrum (ethanol): 278 nm (0.18) Example 13 7- (4-Methoxy-phenyl)-lH,3H-imidazo[l,2-a][l,3,5]triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4-15 dione and a-bromo-4-methoxy-acetophenone analogously to Example 1.
Yield: 31 % of theory, M.p.: > 300°C value: 0.70 (methylenechloride/methanol = 7:3; SiC^) 20 Mass spectrum: M+ : 258 m/e UV-Spectrum (ethanol): 274 nm (0.37) Example 14 2- (4-Methylsulf onamido-phenyl) -7H-irnidazo[l,2-a]pyrazin-8-one Prepared from 3-amino-lH-pyrazin-2-one and a-bromo-4-methylsulfonamido-acetophenone analogously to Example 1. -^4663 Yield: M.p. : % of theory, 323°C C 51.31 H 3.98 N 18.12 S 10.54 Calculated: Found: 50.97 4.32 18.12 10.78 Example 15 2-(4-Methoxy-phenyl)-7H-imidazo[1,2-a]pyrazin-8-one Prepared from 3-amino-lH-pyrazin-2-one and a-bromo-4-methoxy-acetophenone analogously to Example 1.
Yield: 25 % of theory, M.p.: > 300°C value: 0.65 (acetonitrile/formic acid = 9:1; SiC^) 15 Calculated: C 64.72 H 4.60 N 17.42 Found: 65.00 4.65 16.43 Example 16 2-(4-Methylsulfonyloxy-phenyl)-6H-imidazo[l,2-d][1,2,4]-tr iazin-5-one Prepared from 5-amino-2H-[1,2,4]triazin-3-one and a-bromo-4-methylsulfonyloxy-acetophenone in dimethylformamide analogously to Example 1.
Yield: 40.2 % of theory, M.p.: 286-287 °C Calculated: C 47.07 H 3.29 N 18.18 S 10.42 Found: 47.10 3.28 18.37 10.69 2 ■ '66 J Example 17 2-(4-Methoxy-phenyl)-6H-imidazo[lf 2-d][l,2,4]triazin-5-one Prepared from 5-amino-2H-[1,2,4]triazin-3-one and a-bromo-4-methoxy-acetophenone in dimethylformamide analogously to Example 1.
Yield: 42.4 % of theory, M.p.: 309-312°C Calculated: C 59.50 H 4.29 N 23.13 Found: 59.60 4.16 23.59 Example 18 2-(4-Methylsulfonamido-phenyl)-8H-imidazo[l,2-a]pyrimidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-4-methyIsulfonamido-acetophenone analogously 20 to Example 1.
Yield: 31.1 % of theory, M.p.: 308-309°C Calculated: C 51.31 H 3.98 N 18.61 S 10.54 Found: 51.00 3.98 18.08 10.65 Example 19 2- (2-Methoxy-4-methylsulfonyloxy-phenyl)-6H-imidazo-[1,2-c]pyrimidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-4-methy1su1fonyloxy-acetophenone analogously to Example 1.
'WWBftll'W.m - 1 *VT*r-:. v.-,. ^ i 4 6 6 3 Yield: 20 % of theory, M.p.: 264-266 °C Calculated: C 50.14 H 3.91 N 12.53 S 9.56 Pound: 49.71 3.95 12.19 9.95 Example 20 2 - (2,4-Dimethoxy-phenyl) -6H-imidazo[l,2-c]pyrimidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2,4-dimethoxy-acetophenone analogously to Example 1.
Yield: 23 % of theory, M.p.: 258-260 °C Calculated: C 61.98 H 5.85 N 15.49 Found: 62.08 5.86 15.24 Example 21 2-(4-Methylsulfonamido-phenyl)-5H-imidazo[l,2-b]pyridazin-6-one Prepared from 2-(4-methlysulfonamido-phenyl)-6-methyl-sulfonyloxy-imidazo[1,2-b]pyridazine and sodium hydroxide solution analogously to Example 4.
Yield: M.p. : Calculated: Found: 39.2 % of theory, 315-318°C C 51.31 H 3.97 51.43 4.13 N 18.41 S 10.54 18.20 10.50 2 1 4 6 6 3 Example 22 2-(4-Amino-phenyl)-5H-imidazo[1,2-b]pyridaz in-6-one Prepared from 2-(4-acetamido-phenyl)-6-chloro-imidazo-5 [1,2-b]pyridazine and potassium hydroxide solution analogously to Example 4.
Yield: 95.2 % of theory, M.p.: > 3 30 °C Analysis of the monohydrate: Calculated: C 59.02 H 4.95 Found: 59.47 4.87 Example 23 2-(4-Methoxy-2-methylsulfonamido-phenyl)-5H-imidazo-[1,2-b]pyr idaz in-6-one Prepared from 6-chloro-2-(4-methoxy-2-methylsulfonamido-phenyl)-imidazo[1,2-b]pyridazine and sodium hydroxide solution analogously to Example 4.
N 22.95 22.63 Yield: 78 % of theory, M.p.: 267-276°C Calculated: C 50.29 H 4.22 N 16.76 S 9.59 Found: 49.97 4.10 16.95 9.83 Example 24 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-5H-imidazo-[1,2-b]pyr idazin-6-one Prepared from 2-(2-methoxy-4-methylsulfonyloxy-30 phenyl)-6-methylsulfonyloxy-imidazo[1,2-b]-pyridazine and ethanolic hydrochloric acid analogously to Example 4. 2 1466 55 % of theory, 265-275°C (decomposition) C 48.82 H 4.10 N 12.20 48.27 4.11 11.34 Yield: M.p. : Calculated: Found: Example 25 6- (4-Hydroxy-phenyl) -2-niethylmercapto-3H-imidazo[ 2,1-f]-[1,2,4]tr iazin-4-one Prepared from 6-(4-methoxy-phenyl)-2,4-bis(methylmer-capto)-imidazo[2,1-f][1,2,4]triazine and concentrated hydrochloric acid analogously to Example 5.
Y i e Id : M.p.: 15 Calculated: Found: 47.5 % of theory, 307-309°C C 52.56 H 3.68 52.26 3.78 N 20.43 S 11.70 20.66 11.73 Example 26 7-(4-Methylsulfonyloxy-phenyl)-1H-imidazo[1,2-a][1? 3 ?5]-tr iazin-2-one Prepared from 2-amino-4-hydroxy-l,3,5-triazine and a-bromo-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: 29.8% of theory, M.p.: 234-236°C Calculated: C 47.05 H 3.29 N 18.29 S 10.47 Found: 47.03 3.27 18.66 10.49 2 14 6 Example 27 7-(4-Pimethylaminosulfonyl-phenyl)-lH-imidazo[1,2-a] [l;t3j5]-tr iazin-2-one Prepared from 2-amino-4-hydroxy-l,3,5-triazine and a-bromo-4-dimethylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 39.1 % of theory, M.p.: 283-285°C Calculated: C 48.89 H 4.10 N 21.93 S 10.04 ^ Found: 49.32 4.30 21.74 10.23 Example 28 2-(2-Methoxy-4-methylsulfonamido-phenyl)-8H-imidazo-[1,2-a]pyrimidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-4-methylsulfonamido-acetophenone analogously to Example 1.
Yield: M.p.: Analysis of Calculated: Found: 36.6 % of theory, 314-316°C the monohydrate: C 47.71 H 4.57 47.80 4.37 N 15.90 S 9.09 15.89 9.34 Example 29 2-(2-Methoxy-4-methylsulfonyl-phenyl)-7H-imidazole 1, 2-a] pyrazin-8-one Prepared from 3-amino-lH-pyrazin-2-one and a-bromo- 4-methylsulfonyl-acetophenone analogously to Example 1. ^ 14i Yield: 56 % of theory, M.p.: 283-286°C (Decomposition) UV-Spectrum (ethanol): 268 nm (0.56) 308 nm (0.48) 320 nm (0.45) Example 30 7-(2-Methoxy-4-methylsulfonyl-phenyl)-1H,3H-imidazo-[l,2-a]-[lf3j5]triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3j5]-triazin-2,4- dione and a-bromo-2-methoxy-4-methylsulfonyl-acetophenone analogously to Example 1.
Yield: 22 % of theory, M.p.: > 300 °C Mass spectrum: M+ : 336 m/e UV-Spectrum (ethanol + NaOH): 245 nm (0.46) 330 nm (0.28) Example 31 7-(2-Methoxy-4-methylsulfonyloxy-phenyl)-1H,3H-imidazo-[1,2-a][l,3j5]triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4-dione and a-bromo-2-methoxy-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: 22 % of theory, M.p.: > 300°C 30 Calculated: C 44.32 H 3.43 N 15.90 15.78 Found: 44.51 3.55 Mass spectrum: M+ : 352 m/e 2 1466 UV-Spectrum (ethanol): 290-304 (0.09) Example 32 2-(2-Methoxy-4-methylsulfonyloxy-phenvl)-7H-imidazo [1, 2-a]-pyrazin-8-one prepared from 3-amino-lH-pyrazin-2-one and a-bromo-2-methoxy-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: M.p.: Calculated: Found: 43 % of theory, 273-275°C C 50.11 H 3.91 49.90 3.99 N 12.52 S 9.55 12.82 9.61 Example 33 2-(2-Methoxy-4-me thylsulfonamido-phenyl)-6H-imidazo [1,2-c]-pyrimidin-5-one prepared from 2-hydroxy-4-amino-pyrimidine and 20 a-bromo-2-methoxy-4-methyIsulfonamido-acetophenone analogously to Example 1.
Yield: 28.4 % of theory, M.p.: 240-24 3 °C Calculated: C 50.29 H 4.22 N 16.76 S 9.59 Found: 49.90 4.31 16.54 9.65 Example 34 7-(2-Methoxy-4-methylsulfonamido-phenyl)-1H-imidazo 30 [1,2-a][1,3,5]tr iazin-2-one Prepared from 2-amino-6-hydroxy-[1?3,5]triazine and a-bromo-2-methoxy-4-methylsulfonamido-acetophenone 'x^ analogously to Example 1. 2 146 Yield: 25.4 % of theory, M.p.: 245-248°C Calculated: C 46.56 H 3.91 N 20.09 S 9.56 Found: 46.31 4.03 20.38 9.37 •Qi Example 35 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-8H-imidazo 10 [1,2-a]pyr imid in-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2-methoxy-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: 24 % of theory, M.p.: 253-255°C Calculated: C 50.14 H 3.90 N 12.53 S 9.56 Found: 50.30 3.73 12.33 9.44 Example 36 2-(2-Methoxy-4-methylaminosuIfonyl-phenyl)-6H-imidazole 1 , 2-c] -pyr imidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-methylaminosulfonyl-acetophenone 25 analogously to Example 1.
Yield: 37 % of theory, M.p.: > 300°c Calculated: C 47.91 H 4.57 N 15.90 S 9.09 Found: 48.00 4.43 15.79 9.27 o Example 37 2 146 2-(2-Methoxy-4-methylsulfonamido-phenyl)-6H-imidazo-[1,2-c]-pyr imidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-methylsulfonamido-acetophenone © analogously to Example 1.
Yield: 22.7 % of theory, M.p.: > 300°c Calculated: C 47.71 H 4.57 N 15.90 S 9.09 Found: 47.45 4.46 15.75 8.92 Example 38 7-(2-Methoxy-4-methylaminosulfonyl-phenyl)-lH-imidazo-[1,2-a][1,3,5]triazin-2-one Prepared from azacytosine and cx-bromo-2-methoxy-4-methylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 43-7 % of theory, M.p.: > 300°c Calculated: C 44.18 H 4.28 N 19.82 S 9.07 Found: 43.91 4.42 19.46 9.12 Example 39 7-(2-Methoxy-4-methylsulfonamido-phenyl)-lH-imidazo-[1,2-a][1,3,5]triazin-2-one Prepared from azacytosine and a-bromo-2-methoxy-30 4-methylsulfonamido-acetophenone analogously to Example 1.
Yield: 40.6 % of theory, M.p.: > 300°c Calculated: C 44.18 H 4.28 N 19.82 S 9.07 35 Found: 43.99 4.35 20.02 9.02 2 1466 - 35 -Example 40 2- (Methoxy-4-cyarto-phenyl) -8H-imidazo[ 1, 2-a]pyr imidin-7-one • * o Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2-methoxy-4-cyano-acetophenone analogously to Example 1.
Yield: 42.1 % of theory, M.p.: 308-310°C Calculated: C 61.74 H 4.03 N 20.37 Found: 62.01 4.03 20.03 1 Example 41 2-(2-Methoxy-4-d imethylaminocarbonyl-phenyl)-6H-imidazo-[1,2-c]pyr imidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-d imethylaminocarbony1-acetophenone analogously to Example 1.
Yield: 21.6 % of theory, M.p.: 245-250°C Calculated: C 61.53 H 5.16 N 17.94 Found: 61.26 5.19 17.98 Example 42 2-(2-Methoxy-4-methylaminocarbonyl-phenyl)-8H-imidazo-[1,2-a]pyr imidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and 30 a-bromo-2-methoxy-methylaminocarbony1-acetophenone analogously to Example 1.
Yield: 41.6 % of theory, M.p. of the hydrate: 272-274°C % 2 7 466 Calculated: C 56.96 H 5.10 N 17.71 Found: 56.70 4.99 18.01 Example 43 2- (2-Methoxy-4-inethylaminocarbony 1-phenyl) -6H-imidazo-[1,2-c]pyrimidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-methylaminocarbony1-acetophenone 10 analogously to Example 1.
Yield: 39.2 % of theory, M.p.: 277-279°C Calculated: C 58.62 H 4.92 N 18.23 Found: 58.58 4.95 18.25 Example 44 2- (2-Methoxy-4-dimethylaminocarbonyl-phenyl)-8H-imidazo-[1,2-a]pyr imidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and ct-br omo-2 -methoxy-4-d ime thy lam inocar bony 1-ace tophenone analogously to Example 1.
Yield: 38.1 % of theory, M.p.: 248-251°C Calculated: C 61.53 H 5.16 N 17.94 Found: 61.65 5.17 17.81 • - Example 45 2 J 46 6 3 2- (2,4-Dimethoxy-5-dimethylaminosulfonyl-phenyl)-8H-imidazo-[1,2-a]pyrimidin-7-one Prepared from 2-(2,4-dimethoxy-phenyl)-8H-imidazo-[1,2-a]-pyrimidin-7-one and chlorosulfonic acid 1^' and subsequent reaction with 40% dimethylamine analogously to Example 3.
Yield: 45 % of theory, M.p.: 300-303°C Calculated: C 48.47 H 5.08 N 14.90 S 8.62 O Found: 48.41 5.29 14.90 8.62 Example 46 7-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-1H-imidazo-[l,2-a][ lj 3,5]tr iazin-2-one Prepared from azacytosine and a-bromo-2-methoxy-4-dimethylaminosulfonyl-acetophenone analogously 20 to Example 1.
Yield: 28 % of theory, M.p.: 285-287°C Calculated: C 45.76 H 4.66 N 19.06 S 9.18 Found: 45.52 4.68 18.91 9.67 Example 47 2-(2-Methoxy-4-sulfamyl-phenyl)-8H-imidazo[l,2-a]-pyr imidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2-methoxy-4-sulfamy1-acetophenone analogously to Example 1.
Yield: 43.7 % of theory, T 2 7 4 6 I M.p.: 284-286°C Calculated: C 48.74 H 3.78 N 17.49 S 10.01 Found: 48.69 3.87 17.30 10.17 Example 48 2-(2-Methoxy-4-sulfamyl-phenyl)-6H-imidazo[1,2-c]-pyrimidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-suIfamy1-acetophenone analogously to Example 1.
Yield: 39.4 % of theory, M.p.: 284-286°C Calculated: C 48.74 H 3.78 N 17.49 S 10.01 Found: 48.59 3.97 17.40 10.21 Example 49 2-(2-Methoxy-4-methylaminosulfonyl-phenyl)-8H-imidazo-[1,2-a]-pyrimidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2-methoxy-4-methylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 22% of theory, M.p.: 300-302°C Calculated: C 50.28 H 4.22 N 16.76 S 9.59 Found: 50.15 4.39 16.65 9.68 Example 50 2-(2-Methoxy-4-aminocarbony1-phenyl)-8H-imidazo[1,2- a]pyr imidin-7-one-hydrate Prepared from 2-amino-4-hydroxy-pyrimidine and n 2 14663 a-bromo-2-methoxy-4-aminocarbony1-acetophenone analogously to Example 1.
Yield: 35 % of theory, M.p.: > 330°C 5 Calculated: C 55.63 H 4.67 N 18.53 Found: 5 5.38 4.58 18.29 Example 51 7-(2-Methoxy-4-cyano-phenyl)-1H-imidazo[1,2-a][1,3,5] tr iazin-2-one Prepared from azacytosine and a-bromo-2-methoxy-4-cyano-acetophenone analogously to Example 1.
Yield: 36.8 % of theory, M.p.: 270-272°C Calculated: C 51.48 H 3.98 N 23.09 Found: 51.80 3.98 22.80 Example 52 2- (2, 4-Dimethoxy-phenyl) 8H-imidazo[l,2-a]pyrimidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2,4-dimethoxy-acetophenone analogously 25 to Example 1.
Yield: 55.8 % of theory, M.p.: 270-273°C Calculated: C 61.99 H 4.83 N 15.49 Found: 61.68 4.91 15.46 2 146 Example 53 2-(2-Methoxy-4-aminocarbonyl-phenyl)-6H-imidazo[1,2-5 c]pyrimidin-5-one Prepared from 2-hydroxy-4-amino-pyrimidine and a-br omo-2-met hoxy-4-ami nocarbonyl-ace tophenone analogously to Example 1.
Yield: 30 % of theory, M.p.: 240-245°C O Calculated: C 59.15 H 4.26 N 19.71 ~ Found: 59.39 4.21 19.62 Example 54 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-6H-imidazo-[l,2-c]pyrimidin-5-one prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-dimethylaminosulfonyl-acetophenone 20 analogously to Example 1.
Yield: 30.6 % of theory, M.p.: 219-221°C Calculated: C 49.71 H 4.98 N 15.37 S 8.97 ^ Found: 49.69 5.01 15.27 9.03 Example 55 2-(2-Methoxy-4-cyano-phenyl)-6H-imidazo[1,2-c]pyrimidin - i- -one prepared from 2-hydroxy-4-amino-pyrimidine and a-bromo-2-methoxy-4-cyano-acetophenone analogously to Example 1. o 2 1466 3 Yield: 27 % of theory, M.p.: 308-310°C Calculated: C 61.08 H 4.02 N 20.35 Found: 61.15 3.98 19.97 Example 56 2- (2-Methoxy-4-dimethylaminosulf onyl-phenyl) -8H-imidazo-[1,2-a]pyr imidin-7-one Prepared from 2-amino-4-hydroxy-pyrimidine and a-bromo-2-methoxy-4-d imethylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 39.4 % of theory, M.p.: 297-300°C Calculated: C 51.86 H 4.35 N 16.13 S 9.23 Found: 51.58 4.54 16.10 9.15 Example 57 7-(2-Methoxy-4-methylsulfonyloxy-phenyl)-lH-imidazo[1,2-a]-[l>3,5]tr iazin-2-one Prepared from 2-amino-4-hydroxy-[1,3,5]triazine and a-bromo-2-methoxy-4-methyIsulfonyloxy-acetophenone analogously to Example 1.
Yield: 17.5 % of theory, M.p.: 258-261°C Calculated: C 44.06 H 3.98 N 15.81 S 9.14 Found: 43.86 3.93 15.64 9.21 Kits 2 14663 Example 58 7-(2-Methoxy-4-methylsulfonyl-phenyl)-lH,3H-imidazo[l,2-a]-[l,3,5]triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4- dione and a-bromo-2-methoxy-4-methylsulfonyl-acetophenone analogously to Example 1.
Yield: 22 % of theory, M.p.: > 300°C Calculated: C 46.42 H 3.59 N 16.66 Found: 46.38 3.71 16.78 Mass spectrum: M+ = 336 m/e.
Example 59 7-(2-Methoxy-4-methylsulfonyloxy-phenyl)-1H,3H-imidazo-[1,2-a][l,3,5]triazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4-dione and a-bromo-2-methoxy-4-methylsulfonyloxy-20 acetophenone analogously to Example 1.
Yield: 22 % of theory, M.p.: > 300 °C Calculated: C 44.32 H 3.43 N 15.90 Found: 44.51 3.55 15.68 Mass Spectrum: M+ = 352 m/e.
Example 60 7-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-1H,3H-30 imidazo-[l,2-a][l,3,5]tr iazin-2,4-dione Prepared from 6-amino-lH,3H-[1,3,5]triazin-2,4-dione and a-bromo-2-methoxy-4-dimethylaminosulfonyl-acetophenone analogously to Example 1.
Yield: 12 % of theory, M.p.: 7 300°C 2 146( R^ value: 0.6 (silica gel, eluant: Methylene chloride/ methanol = 10:2) UV Spectrum (ethanol): 300-320 nm (0.075) Example 61 2-(2-Methoxy-4-methylsulfonyl-phenyl)-7H-imidazo-[ 1, 2-a] -pyrazin-8-one Prepared from 3-amino-lH-pyrazin-2-one and ot-bromo-10 2-methoxy-4-methylsulfonyl-acetophenone analogously to Example 1.
Yield: 56 % of theory, M.p.: 283-286°C (decomp.) Example 62 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-7H-imidazo-[1,2-a]-pyrazin-8-one prepared from 3-amino-lH-pyrazin-2-one and a-bromo-20 2-methoxy-4-methylsulfonyloxy-acetophenone analogously to Example 1.
Yield: 43 % of theory, M.p.: 273-275°C Calculated: C 50.11 H 3.91 N 12.52 S 9.55 25 Found: 49.80 3.99 12.82 9.61 Example 63 2- (2-Napthyl) -7H-intidazo[ 1, 2-a3pyrazin-8-one Prepared from 3-amino-lH-pyrazin-2-one and 2-(2- bromo-acety1)-naphthalene analogously to Example 1.
T 2 14 6 Yield: 47 % of theory, M.p.: >300°C Calculated: C 75.55 H 4.24 N 16.08 Found: 75.17 4.14 15.83 Example 64 6-(4-Hydroxy-2-methoxy-phenyl)-2-methylmercapto-lH-imidazo-[2,1-f][l,2,4]tr iazin-4-one Prepared from 6-(2-methoxy-4-hydroxy-phenyl)-2,4-bis-methylmercapto-imidazo [2,1-f][1,2,4] triazine and concentrated hydrochloric acid analogously to Example 4.
Yield: 28.1 % of theory, M.p.: 307-309 °C Calculated: C 51.32 H 3.98 N 18.41 S 10.52 Found: 51.21 4.10 18.15 10.85 Example 65 2-(l-Methoxy-naphth-4-yl)-8H-imidazo[1,2-a]pyrimidin-7-one Prepared from a-bromo-4-(1-methoxy)-acetonaphthone and 2-amino-4-hydroxy-pyrimidine analogously to 25 Example 1.
Yield: 15% of theory, M.p.: 300-301°C (decomposition) Calculated C 70.09 H 4.50 N 14.42 Found: 69.87 4.49 14.31 - 4 5 - J Example 66 2-(2-Methoxy-naphth-6-yl)-6H-im idazo[1,2-c]pyr inn d i n-5-one Prepared from a-bromo-6-(2-methoxy)-acetonaphthone and 2-hydroxy~4-amino-pyrimidine analoqouslv to Example 1.
Yield: 15.3% of theory, M.p.: > 300°C Calculated: C 70.09 H 4.50 N 14.42 Pound: 70.29 4.62 14.54 Example 67 2-(l-Methoxy-naphth-2-yl)-8H-imidazo[1,2-a]pyrimidin-7-one Prepared from l-bromo-2-(1-methoxy)-acetonaphthone and 2-amino-4-hydroxy-pyrimidine analogously to Example 1. 2Cf Yield: 3.1% of theory, M.p.: 215-216°C Calculated: C 70.09 H 4.50 N 14.43 Found: 70.06 4.39 14.11 Example 68 2- (Naphth-2-yl) -8H-imiciazo[l,2-a] pyr imid in-7-one Prepared from a-bromo-2 -acetonaphthone and 2-amino-4-hydroxy-pyrimidine analogously to Example 1.
Yield: 11% of theory, M.p.: > 250 °C c 2f44$J Calculated: C 73.55 H 4.24 N 16.08 Found: 73.26 4.30 15.82 Example 69 2- (4-Aniino-2-methoxy-phenyl) -5H-imidazo[l, 2-b] pyridazin-6-one ,-ii 1.7 g (5.36 mMol) of 2-(4-acetamino-2-methoxy-phenyl)-6-chloro-imidazo[1,2-b]pyridazine are refluxed 10 for 32 hours in 150 ml of 4N potassium hydroxide solution. After cooling and filtering, the pH is adjusted to 6.5 with glacial acetic acid. The precipitate formed is suction filtered, washed with water and dried in a vacuum drying cupboard 15 over phosphorus pentoxide.
Yield: 84 % of theory, M.p.: 243-250°C (decomposition) Calculated: C 60.93 H 4.72 N 21.86 Found: 60.76 4.67 20.50 Example 70 2-(2-Methoxy-4-sulfamyl-phenyl)-5H-imidazo[1,2-b]-pyr idazin-6-one Prepared from 6-chloro-2-(2-methoxy-4-sulfamyl-phenyl) -imidazo[1,2-b]pyridazine and 4N potassium hydroxide solution analogously to Example 4.
Yield: 38 % of theory, M.p.: 297-300°C (decomposition) Calculated: C 46.15 H 4.17 N 16.56 S 9.48 Found: 46.36 4.09 16.70 9.99 Mass Spectrum: M+ = 320 m/e. 2 14 66 Example 71 2-(2-Methoxy-4-methylsulfonamido-phenyl)-5H-imidazo-[1,2-b]-pyridazin-6-one prepared from 6-chloro-2-(2-methoxy-4-methylsulfonamido-phenyl)-imidazo[1,2-b]pyridazine and 4N potassium hydroxide solution analogously to Example 4.
Yield: 64 % of theory, M.p.: 303-305°C (decomposition) Calculated: C 50.29 H 4.22 N 16.76 S 9.59 Found: 50.29 4.09 16.81 9.81 Example 72 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-6H-imidazo-[l,2-d]-[l,2,4]triazin-5-one 336 mg (3 mMol) of 5-amino-2H-l,2,4-triazin-3-one are suspended in 20 ml of absolute dimethylformamide, then 1.14 g (3.5 mMol) of -bromo-2-methoxy-4-20 methylsulfonyloxy-acetophenone are added. The mixture is then heated for 2 hours to 120°C with stirring, whereupon the yellow suspension changes into a clear reddish-orange solution. The reaction solution is stirred into 100 ml of ice water, and 25 the initially viscous oil slowly crystallizes out. The crystalline crude product is suction filtered and then recrystallised once again from ethanol/dimethyl-formamide (3:1) with the addition of activated charcoal.
Yield: 145 mg (14.3 % of theory), M.p.: 262-264°C (decomposition) Calculated: C 46.44 H 3.60 N 16.66 S 9.54 Found: 46.45 3.72 16.70 9.50 ^ M66 Example 73 2-(4-Dimethylaminosulfonyl-2-methoxy-phenyl)-5H-imidazo-[1,2-b1pyr idazin-6-one prepared from 6-chloro-2-(4-dimethylaminosulfonyl-2-methoxy-phenyl)-imidazo[1,2-b]pyridazine and 4N potassium hydroxide solution analogously to Example 4.
Yield: 49 % of theory, M.p.: 285-287°C (decomposition) Calculated: C 51.71 H 4.63 N 16.08 S 9.20 Found: 51.48 4.71 16.17 9.44 Example 74 The following compounds are obtained analogously to the preceding examples: 2-(4-Aminocarbonyl-phenyl)-6H-imidazo[1,2-c]pyr imidin-5-one 7-(4-Methylaminocarbony1-phenyl)-lH-imidazo[1,2-a]-20 [1,3,5]-triazin-2-one 2-(2-Methoxy-4-methyIsulfonyl-phenyl)-6H-imidazo[1,2-c]-pyr imidin-5-one 2-(2,4-Dimethoxy-5-dimethylaminosulfonyl-phenyl)-6H-imidazo-[1,2-c]pyrimidin-5-one 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-8H-imidazole 1,2 -c] -pyr imid in-7-one 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-5H-imidazo-[1,2-b]-pyr idazin-6-one rtt$!#WW^SPI®i^9Rfi®@5SB95t8Ptt86#8»w«w-..*r*'' j © 2 1466 - 49 - - 2-(4-Methylsulfonamido-phenyl)-5H-imidazo[1,2-b]pyridazin 6-one 2-(4-Amino-phenyl)-5H-imidazo[1,2-b]pyridazin-6-one 6-(2-Methoxy-4-methylsulfonyloxy-phenyl)-1H-imidazo[2,1- 6-(4-Methylsulfonyloxy-phenyl)-lH-imidazo[2,1-f][1,2,4] tr iazin-2-one 6-(2-Methoxy-4-sulfamyl-phenyl)-lH-imidazo[2,1-f ]-10 [1,2,4]-triazin-2-one 6-(2-Methoxy-4-methylaminosulfonyl-phenyl)-lH-imidazo-C 2,1—f] — [1,2,4]triazin-2-one 6-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-1H-imidazo-[2,1-f][1,2,4]tr iazin-2-one 6-(2-Methoxy-4-methylmercapto-phenyl)-lH-imidazo[2,1-f ] -[1,2,4]-triazin-2-one 6-(2-Methoxy-4-methylsulfinyl-phenyl)-lH-imidazo[2,1-f]-[1,2,4]tr iazin-2-one 6-(2-Methoxy-4-methylsulfonyl-phenyl)-lH-imidazo[2,1-f]-20 [1,2,4]triazin-2-one 6-(4-Benzyloxy-2-methoxy-phenyl)-2-methylmercapto-3H-imidazo-[2,1-f][1,2,4]triazin-4-one f]-[1,2,4]triazin-2-one 6-(4-Benzyloxy-2~methoxy-phenyl)-1H,3H-imidazo [2,l-f][l,2,4]-triazin-2,4-dione o 6-tr 6- [1 6- Ci 6- im 2- [1 2- [1 2- [1 2- [1 2- im 2- [1 2- [1 2-[1 4-Hydroxy-2-methoxy-phenyl)-3H-imidazo[2,1-f][1,2,4]-azin-4-one 2-Methoxy-4-methylsulfonyloxy-phenyl)-3H-imidazo[2,1-f] 2,4]tr iazin-4-one 4-Hydroxy-2-methoxy-phenyl)-1H,3H-imidazo[2,1-f]-2,4]-triazin-2,4-dione 2-Methoxy-4-methylsulfonyloxy-phenyl)-1H,3H-dazo[2,l-f]-[l,2,4]triazin-2,4-dione 2-Methoxy-4-methylsulfonyloxy-phenyl)-7H-imidazo[1,2-d] 2,4]triazin-8-one 4-Methylsulfonyloxy-phenyl)-7H-imidazo[1,2-d]-2,4]triazin-8-one 2-Methoxy-4-sulfamyl-phenyl)-7H-imidazo[1,2-d]-2,4]-triazin-8-one 2-Methoxy-4-methylaminosulfonyl-phenyl)-7H-imidazo-2-d][l,2,4]triazin-8-one 2-Methoxy-4-dimethylaminosulfonyl-phenyl)-7H-dazo-[1,2-d][l,2,4]triazin-8-one 2-Methoxy-4-methylmercapto-phenyl)-7H-imidazo[1,2-d]-2,4]triazin-8-one 2-Methoxy-4-methylsulf inyl-phenyl)-7H-imidazo[1,2-d]-2,4]triazin-8-one 2-Methoxy-4-me thylsulfonyl-phenyl)-7H-imidazo[1,2-d]-2,4]tr iazin-8-one 2-(2-Methoxy-4-sulfamyl-phenyl)-6H-imidazo[1,2-d]-[1,2,4]-tr iaz in-5-one ft ^ 466 2-(2-Methoxy-4-methylaminosulfonyl-phenyl)-6H-imidazo-[1,2-d][1,2,4]tr iazin-5-one 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-6H-imidazo-[l,2-d][1,2,4]triazin-5-one 2-(2-Methoxy-4-methylmercapto-phenyl)-6H-imidazo[1,2-d]-[1,2,4]triazin-5-one 2-(2-Methoxy-4-methylsulfinyl-phenyl)-6H-imidazo[l,2-d]-[1,2,4]triazin-5-one 2-(2-Methoxy-4-methylsulfonyl-phenyl)-6H-imidazo[l,2-d]-10 [1,2,4]triazin-5-one 2-(2-Methoxy-4-methylsulfonamido-phenyl)-7H-imidazo[l,2-a pyrazin-8-one 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-7H-imidazo-[1,2-a]pyrazin-8-one 2-(2-Methoxy-4-methylsulfonyloxy-phenyl)-6H,8H-imidazo[1,2-a]-pyrimidin-5,7-dione 2-(2-Methoxy-4-methyIsulfonyl-phenyl)-6H,8H-imidazo-[1,2-a]-pyrimidin-5,7-dione 2-(2-Methoxy-4-methylsulfonamido-phenyl)-6H,8H-20 imidazo[l,2-a]-pyr imidin-5,7-dione 2-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-6H,8H-imidazo-[1,2-a]pyr imidin-5,7-dione 6-(2-Methoxy-4-methylsulfonyloxy-phenyl)-1H,3H-imidazo-[2,l-f][l,2,4]triazin-2,4-dione 6-(2-Methoxy-4-methylsulfonyl-phenyl)-1H,3H-imidazo- 2 J 4663 [2,1-f]-[1,2,4]triazin-2,4-dione 6-(2-Methoxy-4-methylsulfonamido-phenyl)-1H,3H-imidazo[2,l-f]-[l,2,4]triazin-2,4-dione 6-(2-Methoxy-4-dimethylaminosulfonyl-phenyl)-1H,3H-5 imidazo-[2,1-f][l,2,4]triazin-2,4-dione 7-(2-Methoxy-4-methylsulfonamido-phenyl)-1H,3H-imidazo[1,2-a]-[1,3,5]triazin-2,4-dione 2-(4-Methoxy-phenyl)-6H,8H-imidazo[1,2-a]pyr imidin-5,7-dione 2-(4-Methylsulfonamido-phenyl)-6H,8H-imidazo[1,2-a]-pyrimidin-5,7-dione 6-(4-Methoxy-phenyl)-lH,3H-imidazo[2,l-f][l,2,4]triazin-2,4-dione 6-(4-Methylsulfonyloxy-phenyl)-lH,3H-imidazo[2,1-f]-15 [1,2,4]-triazin-2,4-dione > o -74663 Example A Tablets containing 100 mg o£ 7-(4-methoxy-phenyl)-1H.3H-imidazo-[1,2-a][1,3,5]triazin-2,4-dione 5 Composition; 1 tablet contains: Active substance 100.0 mg ~ Lactose 50.0 mg Polyvinylpyrrolidone 5.0 mg Carboxymethylcellulose 19.0 mg Magnesium stearate 1.0 mg 175.0 mg preparation; The active substance and lactose are homogeneously 15 moistened with an aqueous solution of the polyvinylpyrrolidone. The mixture is then subjected to moist screening (1.5 mm), drying using a circulating air dryer (50°C) and dryscreening (1 mm). ■ jc •Zr The remaining excipients are added to the granules 20 and the final mixture is compressed to form tablets. Weight of tablet: 175 mg Punch: 8 mm Example B Coated tablets containing 50 mg of 7-(4-methoxy-phenyl) -1H,3H-imidazo-[1,2-a][l,3,5]triazin-2,4-dione Composition: 1 tablet contains: Active substance 50. .0 mg Dried corn starch . .0 mg Soluble starch 2. .0 mg Carboxymethylcellulose 7. .0 mg Magnesium stearate 1. .0 mg 80.0 mg ^wsssnjiww,..,.. o 2 1 466 Preparation: The active substance and starch are homogeneously moistened with an aqueous solution of the soluble starch. The mixture is then subiected to moist screening 5 (1 mm), drying using a circulating air dryer (50°C and dry screening (1 mm).
The Granulate and the remaining excipients are then mixed together and compressed to form tablet cores.
Weight of core: 80 mq Punch: 6 mm Radius of curvature: 5 mm The finished cores are provided with a suqar coating in a coating pan in a conventional mariner.
Weight of coated tablet: 120 mg Example C Suppositories containing 75 mg of 7-(4-methoxy-ohenyl)-1H/3H-imidazo-[I,2-a][1 ,3,5]triazin-2,4-20 dione Composition: 1 suppository contains: Active substance: 75.0 mg Suppository mass (e.g. Witepsol H 19 Q} and Witepsol W 45) 1 625.0 mq 1 700.0 mg Preparation: The suppository mass is melted. At 38°C the ground active substance is homogeneously dispersed in the melt. It is cooled to 35°C and poured into chilled suppository moulds.
Weight of suppository: 1.7 q * f O <2- Q ^ 14 6 6 Example D Ampoules containing 50 mg of 7-(4-methoxy-phenyl)-1H# 3H-imidazo-[1,2-a][l,3,5]triazin-2,4-dione Composition; 1 ampoule contains: Active substance 50. .0 mg Ethoxylated hydroxystearic acid 250. ,0 mg 1,2-Propylene glycol 1000. ,0 mg Distilled water ad . .0 ml Preparation The active substance is dissolved in 1,2-propylene 15 glycol and ethoxylated hydroxystearic acid, then made up to the specified volume with water and filtered ster ile.
Bottling: in 5 ml ampoules Sterilisation: 20 minutes at 120°C Example E 1H,3H-imidazo-[1,2-a][1,3,5]tr iazin-2,4 -d ione Composi tion: Active substance 1. 0 g Methyl p-hydroxybenzoate 0. 035 g Propyl p-hydroxybenzoate 0. 015 g Anisole 0. 05 g Menthol 0. 06 g Sodium saccharin 1. 0 g Glycerol . 0 g Ethanol 40. 0 g Distilled water ad 100. 0 ml

Claims (19)

n - 56 - 46 preparation The benzoates are dissolved in ethanol and then the anisole and menthol are added. The active substance, glycerol and sodium saccharin dissolved in water are 5 then added. The solution is filtered clear. « • - 57 - WHAT -f/WE CLAIM IS:- /*** 1 ^ m n Sw> icTnttj
1. Compounds of formula I 2 1 46 6 (wherein 1 or 2 of the groups A, B, C and D represent 5 hydroxy-methine groups, 0, 1 or 2 of the groups A, B, C and D represent methine groups, 0 or 1 of the groups A, B, C and D represent methine groups substituted by an alkylmercapto group and the remaining 1 or 2 of the groups A, B, C and D represent nitrogen 10 atoms, with the provisos that no group A, B, C or D shall represent a methine group substituted by an alkylmercapto group unless it is located beside a nitrogen atom and that if 2 of the groups A, B, C and D represent hydroxy-methine groups 15 one shall be located beside a nitrogen atom; and R^ and R2 together with two carbon atoms of the phenyl ring between them represents a phenyl ring optionally substituted by an alkoxy group and represents a hydrogen atom or an alkoxy 20 group; or a first of the groups , R2 and R^ represents a hydroxy, phenylalkoxy, alkylmercapto, alkylsulphinyl, amino, alkylsulphonyloxy, sulphamyl, alkylaminosulphonyl, dialkylaminosulphonyl, alkylsulphonamido, N-alkyl-25 alkylsulphonamido, cyano, aminocarbonyl, alkylamino-carbonyl or dialkylaminocarbonyl group,or if the remaining two of the groups R^, R2 and do not both represent hydrogen atoms or if A, B, hi .. 2 1 4 6 6 3 - 58 - C and D together with the imidazole ring do not represent imidazo(1,2-b]pyridazin-6(5H)-ones, imidazo[l,2-c]pyrimidin-5(6H)-ones and 5-alkylmercapto-imidazo[1,2-c]pyrimidin-7(8H)-ones, said first of the groups 5 , R2 ar|d R3 may also represent an alkoxy or alkylsulphonyl group, a second of the groups R^, r2 and R3 represents a hydrogen atom or a hydroxy or alkoxy group, and the third of the groups , r2 and R^ represents 10 a hydrogen atom or an alkoxy group; and wherein any alkyl moiety of any said group contains one or two carbon atoms) and tautomers and acid addition salts thereof.
2. Imidazo[1,2-ajpyrimidin-7-ones and -5,7-diones, 15 imidazo[1,2-c]pyrimidin-5-ones and -7-ones, imidazo-[2,1-f][1,2}4]triazin-2-ones, -4-ones and -2,4-diones, imidazo[1,2-b]-pyridazin-6-ones, imidazo[1,2-a]-[1,3,5]-triazin-2-ones, -4-ones and -2,4-diones, imidazo[l,2-a]-pyrazin-6-ones and -8-ones, imidazo[1,2-d]-20 [1,2,4]triazin-5-ones, -8-ones and -5,8-diones, imidazo[1,2-b][1,2,4]triazin-2-ones and -3-ones, and imidazo [2,1-c][1,2,4]triazin-3-ones of formula I as claimed in claim 1, and tautomers and acid addition salts thereof. 25 3. Imidazo derivatives of formula I as claimed in either of claims 1 and 2 wherein none of the groups A, B, C and D carries an alkylmercapto substituent; and and R2 together with two carbon atoms of the phenyl ring between them represent a phenyl 30 or methoxy-phenyl ring, and represents a hydrogen atom or a methoxy group; or a first of the groups R^, R2 and R^ represents a hydroxy, benzyloxy, methylmercapto, methylsulfinyl, 35 methylsul£onyl, amino, methylsulphonyloxy, methylsulphon- y. 2 1466 - 59 - amido, N-methyl-methylsulphonamido, sulfamyl, methylaminosulphonyl, dimethylaminosulphonyl, cyano, aminocarbonyl, methylaminocarbonyl or dimethylamino-carbonyl group, or if the remaining two of the groups R^,
R2 and R-j do not both represent hydrogen atoms or f A, B, C and D toqether with the imidazole ring do not represent imidazo[1,2-b]pyridazin-6-(5H)-ones or imidazo (1,2-c]pyrimidin-5(6H)-ones, said first of the groups R1# r2 and may also represent a methoxy qroup, a second of the groups R^, R2 and R^ represents a hydrogen atom or a methoxy group, and the third of the groups R^, R2 and represents a hydrogen atom or a metho,xv group, and tautomers and acid addition salts thereof.
4. Imidazo derivatives of formula I as claimed in any of claims 1 and 2 wherein R-j in the 4 position represents a cyano, dimethylaminocarbonyl, methylsulphonyloxy, methylsulphonamido, N-methvl-methylsulphon-amido, sulfamyl, methylaminosulphonyl or dimethylaminosulphonyl group, or if R2 and do not both represent hydrogen atoms or if A, B, C and n together with the imidazole ring do not represent imidazo[l,2-^7) b]pyridazin-6(5H)-ones or imidazo [1,2-c]pyrimidin- 5(6H)-ones, R^ may also represent a methoxy qrouo, R2 in the 2 position represents a methoxy qroup, and R^ represents a hydrogen atom, and tautomers and acid addition salts thereof.
5. A compound of formula T as claimed in claim o •—A* 2 146 - 60 - 1 being (a) 2-(2-methoxy-4-methylsulphonyloxy-phenyl)-8H-imidazo[1,2-a]pyr imidin-7-one, (b) 2- (2-methoxy-4-cyanophenyl)-8H-imidaro[1,2-5 a]pyrimidin-7-one, (c) 2-(2-methoxy-4-methylsulfonyloxyphenyl) -7H-imidazo[l,2-a]pyrazin-8-one, or a tautomer or acid addition salt thereof.
6. Compounds as claimed in any one of claims 10 1 to 5 being physiologically acceptable acid addition salts of compounds of formula I as defined in claim 1.
7. Pharmaceutical compositions containing a compound of formula I as claimed in any one of 15 claims 1 to 5 or a tautomer or physiologically acceptable acid addition salt thereof together with at least one carrier or diluent.
8. A process for the preparation of compounds as claimed in claim 1 which process comprises at 20 least one of the following steps: a) reactinq a compound of general formula TT B- 4 NH. Y ' (ii) D (wherein A, B, c and P are as defined in any one of claims 1 to 5)with a compound of formula Ttr „_ , . _«a»>Wi*ir<ll»» » >■ - 61 - 2 14663 o - c — X - CH I \ — (III) (wherein R^, R2 and R^ are as defined in any one of claims 1 to 5 and X represents a nucleophilically 5 exchangeable group); b) (to prepare compounds of formula I wherein one of the groups R.^ R2 and R3 represents an alkylsulphonyloxy, alkylsulphonamido or N-alkyl-alkylsulphonamido group) reacting a compound of formula IV 10 (IV) (wherein A, B, C and D are as defined in any one of claims 1 to 5 and the groups R-^', R2' and R3' may represent the groups or atoms represented by Rl' R2 anc^ R3 *as *n anY one claims 15 1 to 5) with the exception of alkylsulphonyloxy, alkylsulphonamido and N-alkyl-alkylsulphonamido groups, and with the proviso that one of the groups R1' ' R2' anc^ R3' must represent a hydroxy, amino, methylamino or ethylamino group) 20 with a compound of formula V R4 " S02 " Y (V) © '46 - 62 - (wherein R4 represents a methyl or ethyl group and Y represents a nucleophilically exchangeable group); o c) (to prepare compounds of formula I wherein at least one of the groups and R^ represents an alkoxy, phenylalkoxy, alkylmercapto or N-alkyl-alkylsulphonamido group) alkylating a compound of formula VI (VI) 10 (wherein A, B, C and D are as defined in any one of claims 1 to 5 and anc* **3" raay represent the groups or atoms represented by the groups R^, R2 and R^ (as defined in any one of claims 1 to 5) but with the proviso that at least one of the 15 groups R2" an<^ R3* must represent a hydroxy, mercapto or alkylsulphonamido group) ■ s Kds with a compound of formula VII R4 - Z (VII) (wherein R4 represents a methyl or ethyl group ^ 20 or a phenylalkyl group having 1 or 2 carbon atoms in the alkyl moiety and Z represents a nucleophilically exchangeable group); d) (to prepare compounds o£ formula I wherein one 63 of the groups R^, R2 and represents an aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, sulphamyl, alkylaminosulohonyl or dialkylaminosulohonyl grouo) reacting a compound of formula vili (wherein A, B, C and n are as defined in any one of claims 1 to 5, Rg"' and R3"' may represent the qroups or atoms represented by R^, R2 and R^ (as defined in any one of claims 1 to 5) with the exception of aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl sulphamyl, alkylaminosulphonyl and dialkyl-aminosulphonyl groups, W represents a carbonyl or sulfonyl qroup, and U represents a nucleophilically exchangeable group) with an amine of formula IX A N W - U (viri) ll I (IX) (wherein R^ and Rg , which may be the same or different, each represents a hydroqen atom or a methyl or ethyl group); rY 7 - 64 - o 2 J 46 e) (to prepare compounds of formula I wherein at least one of the groups R^, Rj and R^ represents an amino, hydroxy or aminocarbonyl group or wherein at least one of the groups A, B, C and D represents 5 a hydroxymethine group) hydrolysing a compound of formula X (X) (wherein R^, Rj and R^ are as defined in any one of claims 1 to 5 and 10 A'# B', C' and D' may represent the groups or atoms represented by A, B, C and D (as defined in claims 1 to 5) but wherein either at least one of the groups A', B', C' and D' represents a methine group substituted by a hydrolytically removable 15 group o£ at least one of the groups R^, Rj and R^ represents an alkanoylamino, cyano or alkylsulfonyloxy group) ; f) (to prepare compounds of formula I wherein one or two of the groups A, B, C and D represent nitrogen 20 atoms, one of groups A, B, C and D represents a hydroxymethine or alkylmercapto-methine group and the remaining one or two of the groups A, B, C and T> represent methine qroups) reductively splitting off one or two reductively cleaveable groups from 25 a compound of formula XI >. - 65 - ^ 146 6 R. (xi) (wherein R^, R2 and R3 are as defined in any one of claims 1 to 5, one or two of the groups A", 5 B", C" and D" represent nitrogen atoms, one of the groups A", B", C" and D" represents a hydroxymethine or alkylmercaptomethine group, 0 or 1 of the groups A", B", C" and D" represent methine groups and the remaining one or two groups A", Bn, C" and 10 d" represent methine groups substituted by a reductively cleavable grouD); g) (to prepare compounds of formula I wherein one of the groups R^, R2 and R^ represents a cyano group) converting a corresponding compound of formula 15 I wherein a first of the groups R^, R2 and R^ represents an amino group via the diazonium salt into a compound of formula T wherein said first of the groups R^, R2 and R^ represents a cyano group; and h) converting a compound of formula T into an acid 20 addition salt thereof.
9. A process as claimed in claim 8 wherein the reaction is carried out in a solvent. 25
10. A process as claimed in either of claims 8 and 9 wherein the reaction of step (a) is carried out at temperatures of between 0 and 150°C. —^vinmw** y,"wt ——. * • I - i 46 6 - 66 -
11. A process as claimed in either of claims 8 and 9 wherein the reaction of any of steps (b), (c) or (d) is carried out in the presence of an acid binding agent. 5
12. A process as claimed in any one of claims 8, 9 and 11 wherein the reaction of any of steps (b), (c) or (d) is carried out at temperatures of between 0 and 100°C.
13. A process as claimed in either of claims 10 8 and 9, the hydrolysis of reaction step (e) is carried out in the presence of an acid or in the presence of a base.
14. A process as claimed in any one of claims 8, 9 and 13 wherein the reaction of step (e) is 15 carried out at temperatures of between -10 and 120°C.
15. A process as claimed in either of claims 8 and 9 wherein the partial hydrolysis is carried out in reaction step (e} with concentrated sulphuric 20 acid or with an alkali metal hydroxide solution in the presence of hydrogen peroxide at ambient temperature.
16. A process as claimed in either of claims 8 and 9 wherein the reductive splitting off of 25 reaction step (f) is carried out by hydrogenolysis.
17. A process as claimed in any one of claims 8, 9 and 16 wherein the reaction of step (f) is carried out at temperatures of between -10 and 100°C. 30
18. A method of treatment of the non- human animal body for cardiac insufficiency comprising 67 the administration to said body oC a compound of formula I (as defined in any one of claims 1 to 5) or a tautomer or physiologically acceptable acid addition salt thereof.
19. Compounds of formula I as defined in claim 1, tautomers and salts thereof, substantially as herein disclosed in any one of the Examples.
NZ214663A 1984-12-21 1985-12-20 Imidazo derivatives and pharmaceutical compositions NZ214663A (en)

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PH27291A (en) * 1989-01-31 1993-05-04 Takeda Chemical Industries Ltd Imidazolpyrimidazines their production and use
EP0440119A1 (en) * 1990-01-31 1991-08-07 Takeda Chemical Industries, Ltd. Imidazopyridazine compounds, their production and use
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WO2007028051A2 (en) 2005-09-02 2007-03-08 Abbott Laboratories Novel imidazo based heterocycles
US7723336B2 (en) 2005-09-22 2010-05-25 Bristol-Myers Squibb Company Fused heterocyclic compounds useful as kinase modulators
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US7868001B2 (en) 2007-11-02 2011-01-11 Hutchison Medipharma Enterprises Limited Cytokine inhibitors
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