CA1245651A - Pyridazinones, preparation process thereof and utilization thereof, drugs containing pyridazinones - Google Patents
Pyridazinones, preparation process thereof and utilization thereof, drugs containing pyridazinonesInfo
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- CA1245651A CA1245651A CA000481149A CA481149A CA1245651A CA 1245651 A CA1245651 A CA 1245651A CA 000481149 A CA000481149 A CA 000481149A CA 481149 A CA481149 A CA 481149A CA 1245651 A CA1245651 A CA 1245651A
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- compound
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- general formula
- acid
- alkoxy
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
- C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
- C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
- C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members 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
- C07D237/14—Oxygen atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- 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
-
- 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
- A61P9/08—Vasodilators for multiple indications
-
- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
Abstract of the Disclosure 6-aryl-3[2H]pyriaazinones of the general formula I
Description
~ S6S~ 0485 an~ utilization thereof ~rugs containing pyridazinones Fielcl of the invention ,_ ~
The invention reLates to pyridazinones, the preparation ana utilization thereof, ana to drugs contain-ing pyridazinones.
Prio 6-Aryl-3C2H]pyridazinones as starting materials or intermediates for the synthesis of pharmaceuticals and plant protec~ion agents and a process for their preparation are described, for example, by Baddar et al. tJ.Chem.Soc.
1965, 3342), Steck (J.Heterocycl.Chem. 11~1974)755), Albright 15 et al. (J.Heterocycl.Chem. 15(1978)881), Schrei~er et al.
(Bull.Soc.Chim.France Z(1973)625), Pitarch et al. (Eur.J.
Med.Chem.-Chimica Therapeutica 9(1974)644) and Curran et al.
(J.Med.Chem. 17(1974~273) or are known, inter aliaO from the following descriptions: German Offenlegungsschrift 2,435,244, 20 6erman Offenlegungsschrift 2,445,681 and German Offenlegungs-schrift 2,757,923.
6-Aryl-3-C2H]pyridazinones with a certain action are kno~n from, for example, the following descrip~ions:
German Offenlegungsschrift 2~427,943, German Offenlegungs-25 schrift 2,810,267, 6erman Offenlegungsschrift 2,845,220, European Offenlegungsschrift 8,391, European OffenLegungs-schrift 10,156, Japanese Preliminary Published Application 58,008,105 and U.S. Patent Specification 4,397,854 Detailed Description Certain 6-aryl-3C2H~-pyridazinones of the general formula I no~ have an advantageous pharmacological action.
The invention relates to compounds of the general formula I Rl H
RZ ~ O ~I) in ~hich one of the substituents R1 and R2 denotes hy~rogen `''~
S65~ .
or C1-C~-alkoxy, ana the other denotes polyfluoro-C1-C4-alkoxy~ and to their pharmacologically ~olerated salts with bases.
Polyfluoro-C1-C4-alkoxy is to be understood to ~e a straight-chain or branchea C1-C4-alkoxy group in which at least two hydrogen atoms are replaced by fluo-rine. A straight-chain C1-C3-alkoxy group in ~hich at least t~o hydrogen atoms are replaced by fluorine is preferre~. Preferred polyfluoroalkoxy groups are ai-fluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoro-ethoxy ana 1,1,1-trifluoroe~hoxy.
C1-C4-alkoxy is straight-chain or branched.
The methoxy group is preferred.
Suitable salts are salts ~ith inorganic bases.
The cations used for the salt formation are particu~
Larly the cations of the alkali metals or alkaline earth metalsl The invention also relates to the use of the compoun~s as claimea in claim 1 for the preparation of medicaments for the ~reatment or prophylaxis of disea-ses based on disorders of the bronchi an~/or cardiac insufficiency, or for strengthening the heart.
The invention furthermore relates to a process for ~he preparation of the 6-aryl-3~2H~pyri~azinones of the general formula I and of their pharmacologically tolerated salts with bases, ~hich comprises a) oxi~i~ing a 6-aryltetrahydropyridazinone of the general formula II
R2 ~3~ )= 111), in ~hich R1 and R2 have the abovementioned meaning, and, if desired, then converting the resulting pyrid~
azinone into a salt, or : b) reacting a morpholinobutyric acid of the ~ general formula III
565~
~ 3 -R2 ~ COON
in ~hiCh R1 an~ R2 have the a~o~ementioned meaning, with hydrazine and, if desired, then converting the resu~ting pyridazinone into a salt, or c) reactin~ an acrylic acid of the general formula IV R1 R2 ~ CD-C--CH-COOr IIV) in ~hich R1 and R2 have the abovementioned meaning, ~ith hy~razine and~ if desired, then converting the resulting pyri~azinone into a salt.
The oxidation tdehydrogenation) according to process variant a) is carried out by methods which are kno~n to the expert. For example, the dehy~rogenation can ~e carried out in the presence o~ noble metals of the eightn subgroup, for exampLe palladium or platinum (German Offenlegungsschrift 2,757,923); using chromium trioxide (Overen~ et al. J.Chem.Soc. 1947, 239) using nitrobenzenesulfonic acids or nitronaphthalenesulfonic acids, preferaDly using their sodium or ammonium salts 20 (British Patent Specification 1,168,291).
The reaction according to process variant b) is carried out ~y a method analogous to that of Schrei~er et al. (~ull.Soc.ch~m.France 2(1973)625). For example, the morpholinobutyric acid III, ~hich is formed as an interme~iate, is reacted ~ith hydrazine hydrate under reflux in a lo~er alkanol, for example n-~utanol.
Alternatively, the morpholinium salt of the compound III, o~ta~ned by reaction of the appropria~e aceto-phenone ~1th glyoxylic acia and morpholine, can be :
:~LZ~
reacted with hydrazine hydrate in acid solution.
The reaction according to process variant c) is carried out by methods which are known to the expert. For example, the compounds IV are reacted, in a manner analogous to that in German Offenlegungsschrift 2,445,681, with methanol or aqueous methanol at room temperature or slightly elevated temperature in the presence of basic compounds, such as alkyl metal carbonates, hydroxides or lower alkanolates, or tert.-amines or ammonium hydroxide, the acid is liberated from the resulting salt, and this acid is heated with 1 to 1.5 mol of hydrazine hydrate, at least a neutral medium, preferably an acid medium, being maintained.
The 6-aryl-3[2H]pyridazinones I are converted into the salts by methods which are known to the expert. The alkaline reactant which is used is that inorganic or organic base whose salt is desired. The salts are obtained by, for example, reacting the pyridazinones I with the stoichiometric equivalent of the appropria~e base, for example sodium hydroxide or sodium methanolate, or by converting readily soluble salts into sparingly soluble salts by double decomposition.
The compounds II, III and IV are known or can be prepared by known processes.
The examples which follow serve to illustræte the invention in detail. M.P. denotes melting point, and temperatures are given in C. The yields are given as a percentage of the theoretically calculated amount (% of theory).
Examples Example 1 6-(4-trifluoromethoxyphenyl~-3[211]pyridazinone ~2~L56S~
a) 27 g of 4-trifluoromethoxyacetophenone are heated with 13.7 g of glyoxylic acid monohydrate at 110 for 2 hours.
The melt, containing ~ -(4-trifluoromethoxybenzoyl)-acrylic acid, is cooled to 50, dissolved in 100 ml of water and 14 ml of aqueous 25% strength ammonia solution, and 7 ml of hydrazine hydrate are added and the mixture is boiled under reflux - 4a -.~ .
` 5 ~ 565~
for 1 hour. The tit~e compound crystallizes out on cooling. It is filtere~ off ~ith suction, dried in vacuo and recrystallized from isopropanol. 15.9 9 (62.1% of theory) are obtainea with an M.P. of 200.
The follo~ing are prepared ~y the same metho~:
6-c4~ 2~2-tetrafluoroethoxy)phenyl]-3~2H~pyridazin one, M.P. 173 (80.4% of theory), 6-C3 (1~1,2,Z-tetrafluoroethoxy)phenyl~-3C2H~pyri~azin-one~ M~Po 155 (70.7% of theory).
~) 4-Trifluoromethoxyacetophenone 40 9 of 4-trifluoromethoxybenzoic acid are boiled under reflux in 120 ml of thionyl chloride for 3 hours. Excess thionyl chloride is removed by distil-lation under atmospheric pressure, and the 4-trifluoro-methoxybenzoyl chloride is fractionally distilled in vacuo. 37.9 q (~7X of theory) of boiling point ~2 at 3.3 kPa are obtained.
A solution of magnesium di methyl malonate is prepared from 4.1 9 of magnesium turnings in 25 ml of absolute ethanol and 19~9 ml of dimethyl malonate and 1 ml of car~on tetrachlori~e. 37.9 9 of 4-trifluoro-methoxybenzoyl chloride in 85 ml of absolute ether are added ~rop~ise to this solution, ~hile coolin~ in ice, then the cooling bath is removed and the reaction mix-ture is stirred at 20 overnight. Then, ~hile cool-ing in ice, 25 ml of 25Z strength sulfuric acid are aa~ed dropwise, the ether layer is removed, and the ~ aqueous phase is extracted twice more l~it~ ether. The ; com~ined ether extracts are ~ashed ~ith water to neu-trality, dried over sodium sulfate and evaporated. Tne remaining yellow oil is ~oile~ in 300 ml of 6N hy~ro-chloric acid under reflux for 12 hours. After cooling~
the oil is removed, the aqueous pnase is ex~racte~ 6 times ~ith 100 ml of dichloromethane each time, and the oil and the ~ichloromethane extracts are com~ine~, ~ried over sodium sulfate and evaporated. The remain-ing oil is distilled at 1.6 kPa. ~6.85 9 ~77.~X of theory) of the title compound, of ~oiling point 94-96, are o~eained.
- ~2~S6S~
EKample 2 6~(4-trifluoromethoxyphenyl)-3~2~3pyrid~zinone 8L7 9 of glyoxylic ac~d monohy~rate are ~oiled in 50 ml of ethanol until dissolution is complete, then 16.5 9 of morpholine and 19.5 9 of 4-trifluoromethoxy-acetophenone are added, and the mixture is s~irred at 50 for 1~ hours. The reaction mixture is evapor-ated in vacuo, and the semisolid residue is dissolved in 50 ml of n-butanol, 7.0 9 of hydrazine hydrate are added, and the mixture is boile~ under reflux for 8 hours. Then the reaction mixture is evaporated in uacuo, and the residue is ~oiled in 100 ml of 2N hydro-chloric acid, filterea off ~ith suction and washed ~ith water until free of acid~ After drying and crystal-15 lization from isopropanol, 8.4 9 (45.4% of theory) of the ~itle compound are obtained with M.P~ 200.
Example 3 6-C4-tl,1~2,2-tetrafluoroethoxyphenyl)-3~2H~pyri~azin-one 11.8 9 of 4-(1,1,2,2-tetrafluoroethoxy)aceto-phenone an~ 4.6 9 of glyoxylic acid monohydrate are mixed an~ heated at 120 for 1.5 hours. The melt is cooled, dissolve~ in 1ûO ml of methanol, an~ 7.5 9 of potassium carbonate are adde~ and the mixture is heated 25 at 50-60 for 1 hour. After stan~in~ overnight, the mixture is acidified with 9.1 ml of concentrated hydro-chloric acid, 2~6 mL of nydrazine hydrate are added~
and the mixture is boiled under reflux for 3 hours.
Then it is acidified to pH 1 ~ith hydrochloric acid, and 75 ml of methanol are distilled out over the course of 2 hours. The mixture is allowed to cool, and the mass of crystals is filtered off ~ith suction, suspen-; ded several times in water~ filtered off hith suction and finally dried in vacuo. 8.2 9 (56.9X of theory) of the title compound are obtainea ~ith M.P 178.
Example 4 _ 6-~4-difluoromethoxy-3-methoxyphenyl)-3C2H3pyrid3zin-one a) 15 9 of 4-difluoromethoxy-3-methoxyaceto-~ r;
. _ ~Z9~i65~
- 7 ~
phenone are heated with 5.9 9 of glyoxylic acid mono-hyarate at 110 for 2 hours. The melt is then cooled to 60, 30 ml of water are added, and dissolution is broùght a~out ~y addition of 10 ml of concentratea aqueous ammonia solution. 3.2 9 of hyclrazine hydrate are aaded, and the mixture is boiled uncler reflux for 2 hours, during which the title compound gradually crys-tallizes out. After cooling, the precipitate is fil-tered off ~ith suction, ~horoughly ~ashed ~ith water, dried ana recrystallizea from isopropanol. 10.8 g t58~1X of theory) of the title compound are ob~ained ~ith M.P. 204.
The follouing are prepared by the same method:
6-(3-d1fluoromethoxy-4-methoxyphenyl)-3c2H~pyridazin one, M.P. 176 (42.2Z of theory), 6-(4-difluoromethoxyphenyl)-3C2H]pyridazinone, M.P.
168 ~53.9X of theory)~
6 ~3-difluoromethoxyphenyl)-3C2H]pyridazinone, M.P.
170 (87.5X of theory).
b) 4-Difluoromethoxy-3-methoxyacetophenone 20.8 9 of 4-hydroxy-3-methoxyacetophenone are dissolved in 350 ml of dioxane and 350 ml of water by the addition of 30 9 of sodiu~ hyaroxide, ancl ~he solu-tion is heated to 60. While stirring continuously, chlorodifluoromethane i~ passed into the solution until uptake of the gas stops (about 4 hours). The solution is cooled, and the reculting precipitate is filtered off ~ith suction and ~ashecl three times ~ith 40 ml of diethyl ether each time. The solution is di luted ~ith water to twice the volume and like~ise extracted three times ~ith 100 ml of diethyl ether each time. The com-bine~ ether extracts are dried over magnesium sulfate, eYaporated in Yacuo, and the resi~ue is crysta~izecl from petroleum ether ~boiling point 50-70). 19 9 (70.4X of theory) o~ 4-difluoromethoxy-3-methoxyaceto-phenone are obtained of M.P. 68.
The follo~ing are prepared ~y the same methoa:
3-difluoromethoxy-4-methoxyacetophenone, M.P. 74 (7798X of theory)~
~Z~565:~L
4-difluoromethoxyacetophenone, oil ~78.4X of theory), 3-di fluoromethoxyacetophenone, oil ~85.7% of theory).
C mercia~ us~fuLness The 6-ar~l-3C2H]pyri~azinones of the general formula I have valuable properties ~hich renaer them commercially useful. Surprisingly, they are distin~
guished by a Dronchospasmolytic an~/or car~iotonic action ~hich is in some cases considera~ly superior to that of theophylliner The ~ronchospasmolytic activity of the 6-aryl-3C2H~pyridazinones makes it possible to use them in human and veterinary medicine, where they are used for the treatment ana prophylaxis of ~iseases ~asea on diS-orders of the bronchi. For example, chronic o~struct-ive respiratory ~iseases of various origins (~ronchi-tis, ~ronchial asthma) can ~e treatea in humans and animals.
The positive inotropic activity of the 6-aryl-3C2H~pyri~azinones makes it possi~le to use them in human or veterinary medicine, ~here they are used for treatment of ~iseases ~hich are based on cardiac insuf-ficiency~ or for strengthening the heart. For example, myocardial insufficiency, caraiac insufficiency, ~eriatric heart, myocardial infarct~ cardiovascular insufficiency, stenocardia associated with def1Gient ;~ cardiac output and coronary insufficiency can be trea-tea jn humans ana animals.
Thus the invention further relates to a proce-aure for the treatment of mammals ~hich are suffering from one of the abovementioned aiseasesO The procedure comprises the administration to the unwell mammal of a therapeutically effective and pharmacologically toler-; ated amount of one or more of the compounds according to the invention.
The invention further relates to me~icaments containing one or more of the 6-aryl-3C2H~pyridazinones of the general formula I.
The medicaments are prepared by processes which ; are known per se, the compounas ~eing usea as SUCh or~
~ .
~S65:1 _ 9 if appropriate~ in combination ~ith ~uita~le pnarma-ceutical vehicles. If tne new pharmaceut~ca~ formul-ations contain pharmac~utical vehicles in aadieion to the active compoun~s, the content of active compound in S these mixtures is 0.5 to 95, prefera~ly 15 to 75, per-cent by weight of the total mixture.
The active compounds or the ~e~icaments are use~ in any suita~le formulation, provided that the esta~lishment and maintenance of sufficient levels of active compound are ensured. This can ~e achieved by, for example, oral or parenteral administraeion in suit-a~le doses. The pharmaceutical formulation of the active compoun~ is usually in the form of unit doses appropriate for ehe desired administration. A unit ~ose can be, for example, a tablet, a coated taDlet~ a capsule, a suppository or a measured volume of a pow-der, of a granular material, of a solution, of an emulsion or of a suspension.
"Unit dose" in the conte~t of the present in-vention is to be understood to ~e a physically discreteunit which contains an indivi~ual amount of the active constituent in com~ination ~it~ a pharmaceutical vehi-cle, the content of active compound in the unit dose cor-responaing to a fraction or a multiple of a therapeu-tic individual ~ose. An indivi~ual dose preferablycontains the amount of active compound ~hich is given in one administration and ~hich usualLy corresponds to a ~hole daily dose or a half, one-third or one-quarter of the daily dose. If only a fraction, such as a half or one-quarter, of the unit dose is required for an in-dividual therapeutic administration~ the unit dose is advantageously divisible, for example in the form of a tablet with a ~reaking groove.
~hen in the form of unit doses and intended, for example, for administration to humans, the pharma-ceutical formulations according to the invention can contain about S to 250 mg~ advantageously 19 to 200 mg, and in particular 20 to 100 mgO of active compound.
Parenteral formulations can contain a~out 1 to 50 mg, '' .;
, . , ~
5~5~L
advantageously 3 ~o 30 mg, and in particular 5 to 25 mg, of active compound. In human medicine, the active compoun~ or compounds are generally aministerea in a daily dose of 0.1 ~o 1û, preferably 0.3 to S, in particular 0.5 to 3, mg/kg of bo~y ~eight, if approp-riate in the form of several, preferably 1 to 3, in-aiviaual administrations~ to achieve the desire~
results. An individual a~ministration contains the active compound or compounds in amounes of 0.1 to 5~
prefera~ly 0~2 to 3, in par~icular 0.4 to 2, mg/kg of ~o~y weight. For administration by inhalation, it is advantageous to administer the active compound or com-pounds in a aaily dose of 0.1 to 10 mg, preferably û.5 to 5 mg, in particular 1 to 3 m~, if appropriate in the form of several, preferably 1 to 3, individual ~oses.
Formulations for intravenous administration are expedient, in particular, for acute treatment, for example emergency treatment.
The therapeu~ic administration of the pharma-2D ceutical formulation can take place 1 to 4 times dailyat fixed or varying points in ti~e, for example before each meal and/or in the evening. However, it may be necessary to deviate from the dosages mentioned, and in particular to ao so as a function of the nature, body ~eight and age of the individual to ~e treated~ the nature and severity of the disorder, the type of formu-lation and of administration of the medica~ent, an~ the period or interval ~ithin ~hich administration takes place. Thus, in some cases ie may be sufficien~ to manage ~ith less than the abovementioned amount of active compound, ~hile in other cases the abovementioned amount of active compound must ~e exceeded. In acute cases~ a higher dose is administered at the start of the treatment. After the onset of the desired effect, the ; 35 dose is re~uced to a lo~er level.
The optimum dosage and type of administration of the active compounds require~ in each particuLar case can be determined by any expert on the basis of his expert kno~Leage.
''.,;
;, S65~
The pharmaceutical formulations as a rule con-sist of the active compounds according to the invention an~ non-toxic pharmaceutically tolerated nedicament vehicles, which are used as an admixture or ~iluent in soli~, semisolid or liquid form, or as a means of en-casing, for example in the form of a capsule, a tablet coating, a sachet or some o~her container for the therapeutically active constituent. A vehicle can, for example, serve as a promo~er of the a~sorption of the meaicament by the body, as a formulating auxiliary, as a s~eetener, as a flavor correctant, as a colorant or as a preservative.
Examples of forms ~hich may ~e used orally are tablets, coated tablets, ~ard and soft capsules, for example made of gelatin, dispersible po~ders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
Tablets may contain inert diluents, for example calcium car~onate, calcium phosphateO sodium phosphate or lactose; granulating and dispersing agents, for example corn starch or alginates; binders, for example starch, gelatin or gum arabic; and lubricants, for example aluminum stearate or magnesium stearate~ talc or silicone oil. ~hey may additionally be provided ~ieh a coating which can also be such that delaye~
dissolution and absorption of the medicamen~ in the gastrointestinal tract, an~ hence, for example, ~etter tolerance, a protracted effect or a retarded effect, are achieved. Gelatin capsules can contain the medica-ment mixed ~ith a solid diluent, for example calciumcarbonate or kaolin, or an oily diluent, for example olive oil, peanut oil or paraffin oil.
Aqueous suspensions, ~hich, if appropriate, are prepared at short notice, may contain suspending agents, for example sodium carboxymethylcellulose, methylcellu-lose, ~ydroxypropylcellulose, sodium alginate~ polyvinyl pyrrolidone, gum tragacanth or gum ara~ic; dispersing agents and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol~ polyoxyethylene ~2a~65~L -sor~itol monooleate, po~yoxyethylene sor~itan mono-oleate or leci~hin; preservatives, for example methyl or propyl hy~roxybenzoate; flavorin~ agen~s; and s~eeteners, for example sucrose, lactose, so~ium S cyc~amate, dextrose or invert sugar syrup.
Oily suspensions may contain, for example, peanut oil, olive oil~ sesame oil, cocon~t oil or paraf-fin oil, and th1ckeners, such as, for example, bees~a~, hard paraffin or cetyl alcohol; and furthermore sweeteno ers, flavoring agents and antioxidants.
~ ater-dispersi~le powaers and granules may con-tain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those mentioned above, as well as with s~eeteners, flavoring agents ana colorants.
Emulsions may contain, for example, olive oil, peanut oil or paraffin oil, in addition to emulsifying agents, such as, for example, gum arabic, gum traga-canth~ phosphatides, soroit3n monoolea~e or polyoxy-ethylene sor~itan monooleate, and sweeteners an~ flav-oring agents.
For rectal administration of the medicaments, suppositories ~hich are preparea uith the aid of bind-ers which melt at the rectal temperature, for example ~ 25 cacao butter or polyethylene glycol, are used.
; For paren~eral administration of the medica-ments, sterile, injecta~le aqueous suspensions, isotonic salt solutions or other solutions ~hich, if appropri-ate, are to be prepare5 at short notice ana ~hich con-tain dispersing agents or uetting agents and/or phar-macologically tolerated ailuents, for example propylene glycol or butylene g~ycol, are used.
Oral administration of the medicaments is pr~-ferred.
Administration of the compounds according to the invention by inhalation is also preferred for the use as a bronchospasmolytic. These compoun~s are administered either directly as powders or ~y atomizing solutions or suspensions containing the compounds according to the :~L2~5~Sl invention. In this context, atomizin~ can be effected in the convent10nal manner, for example by compressed-air atomizers or ultrasoun~ atomizers. Administration from spray cans, especially t~ose ~ith a conventional metering valve (metered aerosols) is particularly advantageous. By means of meterea aerosols it is pos-sible to provide a defined amount of active compound per actuation of the spray. So-called synchronous inhalers, using ~hich administration of the active compound can ~e synchronized ~ith inhalation, are of particular aavantage here. Suitable synchronous inhalation devices are disclosed, for example, in German Patent Specification 1,945,257, German Patent Specification 1~917,911 and German Offenlegungsschrif~
The invention reLates to pyridazinones, the preparation ana utilization thereof, ana to drugs contain-ing pyridazinones.
Prio 6-Aryl-3C2H]pyridazinones as starting materials or intermediates for the synthesis of pharmaceuticals and plant protec~ion agents and a process for their preparation are described, for example, by Baddar et al. tJ.Chem.Soc.
1965, 3342), Steck (J.Heterocycl.Chem. 11~1974)755), Albright 15 et al. (J.Heterocycl.Chem. 15(1978)881), Schrei~er et al.
(Bull.Soc.Chim.France Z(1973)625), Pitarch et al. (Eur.J.
Med.Chem.-Chimica Therapeutica 9(1974)644) and Curran et al.
(J.Med.Chem. 17(1974~273) or are known, inter aliaO from the following descriptions: German Offenlegungsschrift 2,435,244, 20 6erman Offenlegungsschrift 2,445,681 and German Offenlegungs-schrift 2,757,923.
6-Aryl-3-C2H]pyridazinones with a certain action are kno~n from, for example, the following descrip~ions:
German Offenlegungsschrift 2~427,943, German Offenlegungs-25 schrift 2,810,267, 6erman Offenlegungsschrift 2,845,220, European Offenlegungsschrift 8,391, European OffenLegungs-schrift 10,156, Japanese Preliminary Published Application 58,008,105 and U.S. Patent Specification 4,397,854 Detailed Description Certain 6-aryl-3C2H~-pyridazinones of the general formula I no~ have an advantageous pharmacological action.
The invention relates to compounds of the general formula I Rl H
RZ ~ O ~I) in ~hich one of the substituents R1 and R2 denotes hy~rogen `''~
S65~ .
or C1-C~-alkoxy, ana the other denotes polyfluoro-C1-C4-alkoxy~ and to their pharmacologically ~olerated salts with bases.
Polyfluoro-C1-C4-alkoxy is to be understood to ~e a straight-chain or branchea C1-C4-alkoxy group in which at least two hydrogen atoms are replaced by fluo-rine. A straight-chain C1-C3-alkoxy group in ~hich at least t~o hydrogen atoms are replaced by fluorine is preferre~. Preferred polyfluoroalkoxy groups are ai-fluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoro-ethoxy ana 1,1,1-trifluoroe~hoxy.
C1-C4-alkoxy is straight-chain or branched.
The methoxy group is preferred.
Suitable salts are salts ~ith inorganic bases.
The cations used for the salt formation are particu~
Larly the cations of the alkali metals or alkaline earth metalsl The invention also relates to the use of the compoun~s as claimea in claim 1 for the preparation of medicaments for the ~reatment or prophylaxis of disea-ses based on disorders of the bronchi an~/or cardiac insufficiency, or for strengthening the heart.
The invention furthermore relates to a process for ~he preparation of the 6-aryl-3~2H~pyri~azinones of the general formula I and of their pharmacologically tolerated salts with bases, ~hich comprises a) oxi~i~ing a 6-aryltetrahydropyridazinone of the general formula II
R2 ~3~ )= 111), in ~hich R1 and R2 have the abovementioned meaning, and, if desired, then converting the resulting pyrid~
azinone into a salt, or : b) reacting a morpholinobutyric acid of the ~ general formula III
565~
~ 3 -R2 ~ COON
in ~hiCh R1 an~ R2 have the a~o~ementioned meaning, with hydrazine and, if desired, then converting the resu~ting pyridazinone into a salt, or c) reactin~ an acrylic acid of the general formula IV R1 R2 ~ CD-C--CH-COOr IIV) in ~hich R1 and R2 have the abovementioned meaning, ~ith hy~razine and~ if desired, then converting the resulting pyri~azinone into a salt.
The oxidation tdehydrogenation) according to process variant a) is carried out by methods which are kno~n to the expert. For example, the dehy~rogenation can ~e carried out in the presence o~ noble metals of the eightn subgroup, for exampLe palladium or platinum (German Offenlegungsschrift 2,757,923); using chromium trioxide (Overen~ et al. J.Chem.Soc. 1947, 239) using nitrobenzenesulfonic acids or nitronaphthalenesulfonic acids, preferaDly using their sodium or ammonium salts 20 (British Patent Specification 1,168,291).
The reaction according to process variant b) is carried out ~y a method analogous to that of Schrei~er et al. (~ull.Soc.ch~m.France 2(1973)625). For example, the morpholinobutyric acid III, ~hich is formed as an interme~iate, is reacted ~ith hydrazine hydrate under reflux in a lo~er alkanol, for example n-~utanol.
Alternatively, the morpholinium salt of the compound III, o~ta~ned by reaction of the appropria~e aceto-phenone ~1th glyoxylic acia and morpholine, can be :
:~LZ~
reacted with hydrazine hydrate in acid solution.
The reaction according to process variant c) is carried out by methods which are known to the expert. For example, the compounds IV are reacted, in a manner analogous to that in German Offenlegungsschrift 2,445,681, with methanol or aqueous methanol at room temperature or slightly elevated temperature in the presence of basic compounds, such as alkyl metal carbonates, hydroxides or lower alkanolates, or tert.-amines or ammonium hydroxide, the acid is liberated from the resulting salt, and this acid is heated with 1 to 1.5 mol of hydrazine hydrate, at least a neutral medium, preferably an acid medium, being maintained.
The 6-aryl-3[2H]pyridazinones I are converted into the salts by methods which are known to the expert. The alkaline reactant which is used is that inorganic or organic base whose salt is desired. The salts are obtained by, for example, reacting the pyridazinones I with the stoichiometric equivalent of the appropria~e base, for example sodium hydroxide or sodium methanolate, or by converting readily soluble salts into sparingly soluble salts by double decomposition.
The compounds II, III and IV are known or can be prepared by known processes.
The examples which follow serve to illustræte the invention in detail. M.P. denotes melting point, and temperatures are given in C. The yields are given as a percentage of the theoretically calculated amount (% of theory).
Examples Example 1 6-(4-trifluoromethoxyphenyl~-3[211]pyridazinone ~2~L56S~
a) 27 g of 4-trifluoromethoxyacetophenone are heated with 13.7 g of glyoxylic acid monohydrate at 110 for 2 hours.
The melt, containing ~ -(4-trifluoromethoxybenzoyl)-acrylic acid, is cooled to 50, dissolved in 100 ml of water and 14 ml of aqueous 25% strength ammonia solution, and 7 ml of hydrazine hydrate are added and the mixture is boiled under reflux - 4a -.~ .
` 5 ~ 565~
for 1 hour. The tit~e compound crystallizes out on cooling. It is filtere~ off ~ith suction, dried in vacuo and recrystallized from isopropanol. 15.9 9 (62.1% of theory) are obtainea with an M.P. of 200.
The follo~ing are prepared ~y the same metho~:
6-c4~ 2~2-tetrafluoroethoxy)phenyl]-3~2H~pyridazin one, M.P. 173 (80.4% of theory), 6-C3 (1~1,2,Z-tetrafluoroethoxy)phenyl~-3C2H~pyri~azin-one~ M~Po 155 (70.7% of theory).
~) 4-Trifluoromethoxyacetophenone 40 9 of 4-trifluoromethoxybenzoic acid are boiled under reflux in 120 ml of thionyl chloride for 3 hours. Excess thionyl chloride is removed by distil-lation under atmospheric pressure, and the 4-trifluoro-methoxybenzoyl chloride is fractionally distilled in vacuo. 37.9 q (~7X of theory) of boiling point ~2 at 3.3 kPa are obtained.
A solution of magnesium di methyl malonate is prepared from 4.1 9 of magnesium turnings in 25 ml of absolute ethanol and 19~9 ml of dimethyl malonate and 1 ml of car~on tetrachlori~e. 37.9 9 of 4-trifluoro-methoxybenzoyl chloride in 85 ml of absolute ether are added ~rop~ise to this solution, ~hile coolin~ in ice, then the cooling bath is removed and the reaction mix-ture is stirred at 20 overnight. Then, ~hile cool-ing in ice, 25 ml of 25Z strength sulfuric acid are aa~ed dropwise, the ether layer is removed, and the ~ aqueous phase is extracted twice more l~it~ ether. The ; com~ined ether extracts are ~ashed ~ith water to neu-trality, dried over sodium sulfate and evaporated. Tne remaining yellow oil is ~oile~ in 300 ml of 6N hy~ro-chloric acid under reflux for 12 hours. After cooling~
the oil is removed, the aqueous pnase is ex~racte~ 6 times ~ith 100 ml of dichloromethane each time, and the oil and the ~ichloromethane extracts are com~ine~, ~ried over sodium sulfate and evaporated. The remain-ing oil is distilled at 1.6 kPa. ~6.85 9 ~77.~X of theory) of the title compound, of ~oiling point 94-96, are o~eained.
- ~2~S6S~
EKample 2 6~(4-trifluoromethoxyphenyl)-3~2~3pyrid~zinone 8L7 9 of glyoxylic ac~d monohy~rate are ~oiled in 50 ml of ethanol until dissolution is complete, then 16.5 9 of morpholine and 19.5 9 of 4-trifluoromethoxy-acetophenone are added, and the mixture is s~irred at 50 for 1~ hours. The reaction mixture is evapor-ated in vacuo, and the semisolid residue is dissolved in 50 ml of n-butanol, 7.0 9 of hydrazine hydrate are added, and the mixture is boile~ under reflux for 8 hours. Then the reaction mixture is evaporated in uacuo, and the residue is ~oiled in 100 ml of 2N hydro-chloric acid, filterea off ~ith suction and washed ~ith water until free of acid~ After drying and crystal-15 lization from isopropanol, 8.4 9 (45.4% of theory) of the ~itle compound are obtained with M.P~ 200.
Example 3 6-C4-tl,1~2,2-tetrafluoroethoxyphenyl)-3~2H~pyri~azin-one 11.8 9 of 4-(1,1,2,2-tetrafluoroethoxy)aceto-phenone an~ 4.6 9 of glyoxylic acid monohydrate are mixed an~ heated at 120 for 1.5 hours. The melt is cooled, dissolve~ in 1ûO ml of methanol, an~ 7.5 9 of potassium carbonate are adde~ and the mixture is heated 25 at 50-60 for 1 hour. After stan~in~ overnight, the mixture is acidified with 9.1 ml of concentrated hydro-chloric acid, 2~6 mL of nydrazine hydrate are added~
and the mixture is boiled under reflux for 3 hours.
Then it is acidified to pH 1 ~ith hydrochloric acid, and 75 ml of methanol are distilled out over the course of 2 hours. The mixture is allowed to cool, and the mass of crystals is filtered off ~ith suction, suspen-; ded several times in water~ filtered off hith suction and finally dried in vacuo. 8.2 9 (56.9X of theory) of the title compound are obtainea ~ith M.P 178.
Example 4 _ 6-~4-difluoromethoxy-3-methoxyphenyl)-3C2H3pyrid3zin-one a) 15 9 of 4-difluoromethoxy-3-methoxyaceto-~ r;
. _ ~Z9~i65~
- 7 ~
phenone are heated with 5.9 9 of glyoxylic acid mono-hyarate at 110 for 2 hours. The melt is then cooled to 60, 30 ml of water are added, and dissolution is broùght a~out ~y addition of 10 ml of concentratea aqueous ammonia solution. 3.2 9 of hyclrazine hydrate are aaded, and the mixture is boiled uncler reflux for 2 hours, during which the title compound gradually crys-tallizes out. After cooling, the precipitate is fil-tered off ~ith suction, ~horoughly ~ashed ~ith water, dried ana recrystallizea from isopropanol. 10.8 g t58~1X of theory) of the title compound are ob~ained ~ith M.P. 204.
The follouing are prepared by the same method:
6-(3-d1fluoromethoxy-4-methoxyphenyl)-3c2H~pyridazin one, M.P. 176 (42.2Z of theory), 6-(4-difluoromethoxyphenyl)-3C2H]pyridazinone, M.P.
168 ~53.9X of theory)~
6 ~3-difluoromethoxyphenyl)-3C2H]pyridazinone, M.P.
170 (87.5X of theory).
b) 4-Difluoromethoxy-3-methoxyacetophenone 20.8 9 of 4-hydroxy-3-methoxyacetophenone are dissolved in 350 ml of dioxane and 350 ml of water by the addition of 30 9 of sodiu~ hyaroxide, ancl ~he solu-tion is heated to 60. While stirring continuously, chlorodifluoromethane i~ passed into the solution until uptake of the gas stops (about 4 hours). The solution is cooled, and the reculting precipitate is filtered off ~ith suction and ~ashecl three times ~ith 40 ml of diethyl ether each time. The solution is di luted ~ith water to twice the volume and like~ise extracted three times ~ith 100 ml of diethyl ether each time. The com-bine~ ether extracts are dried over magnesium sulfate, eYaporated in Yacuo, and the resi~ue is crysta~izecl from petroleum ether ~boiling point 50-70). 19 9 (70.4X of theory) o~ 4-difluoromethoxy-3-methoxyaceto-phenone are obtained of M.P. 68.
The follo~ing are prepared ~y the same methoa:
3-difluoromethoxy-4-methoxyacetophenone, M.P. 74 (7798X of theory)~
~Z~565:~L
4-difluoromethoxyacetophenone, oil ~78.4X of theory), 3-di fluoromethoxyacetophenone, oil ~85.7% of theory).
C mercia~ us~fuLness The 6-ar~l-3C2H]pyri~azinones of the general formula I have valuable properties ~hich renaer them commercially useful. Surprisingly, they are distin~
guished by a Dronchospasmolytic an~/or car~iotonic action ~hich is in some cases considera~ly superior to that of theophylliner The ~ronchospasmolytic activity of the 6-aryl-3C2H~pyridazinones makes it possible to use them in human and veterinary medicine, where they are used for the treatment ana prophylaxis of ~iseases ~asea on diS-orders of the bronchi. For example, chronic o~struct-ive respiratory ~iseases of various origins (~ronchi-tis, ~ronchial asthma) can ~e treatea in humans and animals.
The positive inotropic activity of the 6-aryl-3C2H~pyri~azinones makes it possi~le to use them in human or veterinary medicine, ~here they are used for treatment of ~iseases ~hich are based on cardiac insuf-ficiency~ or for strengthening the heart. For example, myocardial insufficiency, caraiac insufficiency, ~eriatric heart, myocardial infarct~ cardiovascular insufficiency, stenocardia associated with def1Gient ;~ cardiac output and coronary insufficiency can be trea-tea jn humans ana animals.
Thus the invention further relates to a proce-aure for the treatment of mammals ~hich are suffering from one of the abovementioned aiseasesO The procedure comprises the administration to the unwell mammal of a therapeutically effective and pharmacologically toler-; ated amount of one or more of the compounds according to the invention.
The invention further relates to me~icaments containing one or more of the 6-aryl-3C2H~pyridazinones of the general formula I.
The medicaments are prepared by processes which ; are known per se, the compounas ~eing usea as SUCh or~
~ .
~S65:1 _ 9 if appropriate~ in combination ~ith ~uita~le pnarma-ceutical vehicles. If tne new pharmaceut~ca~ formul-ations contain pharmac~utical vehicles in aadieion to the active compoun~s, the content of active compound in S these mixtures is 0.5 to 95, prefera~ly 15 to 75, per-cent by weight of the total mixture.
The active compounds or the ~e~icaments are use~ in any suita~le formulation, provided that the esta~lishment and maintenance of sufficient levels of active compound are ensured. This can ~e achieved by, for example, oral or parenteral administraeion in suit-a~le doses. The pharmaceutical formulation of the active compoun~ is usually in the form of unit doses appropriate for ehe desired administration. A unit ~ose can be, for example, a tablet, a coated taDlet~ a capsule, a suppository or a measured volume of a pow-der, of a granular material, of a solution, of an emulsion or of a suspension.
"Unit dose" in the conte~t of the present in-vention is to be understood to ~e a physically discreteunit which contains an indivi~ual amount of the active constituent in com~ination ~it~ a pharmaceutical vehi-cle, the content of active compound in the unit dose cor-responaing to a fraction or a multiple of a therapeu-tic individual ~ose. An indivi~ual dose preferablycontains the amount of active compound ~hich is given in one administration and ~hich usualLy corresponds to a ~hole daily dose or a half, one-third or one-quarter of the daily dose. If only a fraction, such as a half or one-quarter, of the unit dose is required for an in-dividual therapeutic administration~ the unit dose is advantageously divisible, for example in the form of a tablet with a ~reaking groove.
~hen in the form of unit doses and intended, for example, for administration to humans, the pharma-ceutical formulations according to the invention can contain about S to 250 mg~ advantageously 19 to 200 mg, and in particular 20 to 100 mgO of active compound.
Parenteral formulations can contain a~out 1 to 50 mg, '' .;
, . , ~
5~5~L
advantageously 3 ~o 30 mg, and in particular 5 to 25 mg, of active compound. In human medicine, the active compoun~ or compounds are generally aministerea in a daily dose of 0.1 ~o 1û, preferably 0.3 to S, in particular 0.5 to 3, mg/kg of bo~y ~eight, if approp-riate in the form of several, preferably 1 to 3, in-aiviaual administrations~ to achieve the desire~
results. An individual a~ministration contains the active compound or compounds in amounes of 0.1 to 5~
prefera~ly 0~2 to 3, in par~icular 0.4 to 2, mg/kg of ~o~y weight. For administration by inhalation, it is advantageous to administer the active compound or com-pounds in a aaily dose of 0.1 to 10 mg, preferably û.5 to 5 mg, in particular 1 to 3 m~, if appropriate in the form of several, preferably 1 to 3, individual ~oses.
Formulations for intravenous administration are expedient, in particular, for acute treatment, for example emergency treatment.
The therapeu~ic administration of the pharma-2D ceutical formulation can take place 1 to 4 times dailyat fixed or varying points in ti~e, for example before each meal and/or in the evening. However, it may be necessary to deviate from the dosages mentioned, and in particular to ao so as a function of the nature, body ~eight and age of the individual to ~e treated~ the nature and severity of the disorder, the type of formu-lation and of administration of the medica~ent, an~ the period or interval ~ithin ~hich administration takes place. Thus, in some cases ie may be sufficien~ to manage ~ith less than the abovementioned amount of active compound, ~hile in other cases the abovementioned amount of active compound must ~e exceeded. In acute cases~ a higher dose is administered at the start of the treatment. After the onset of the desired effect, the ; 35 dose is re~uced to a lo~er level.
The optimum dosage and type of administration of the active compounds require~ in each particuLar case can be determined by any expert on the basis of his expert kno~Leage.
''.,;
;, S65~
The pharmaceutical formulations as a rule con-sist of the active compounds according to the invention an~ non-toxic pharmaceutically tolerated nedicament vehicles, which are used as an admixture or ~iluent in soli~, semisolid or liquid form, or as a means of en-casing, for example in the form of a capsule, a tablet coating, a sachet or some o~her container for the therapeutically active constituent. A vehicle can, for example, serve as a promo~er of the a~sorption of the meaicament by the body, as a formulating auxiliary, as a s~eetener, as a flavor correctant, as a colorant or as a preservative.
Examples of forms ~hich may ~e used orally are tablets, coated tablets, ~ard and soft capsules, for example made of gelatin, dispersible po~ders, granules, aqueous and oily suspensions, emulsions, solutions or syrups.
Tablets may contain inert diluents, for example calcium car~onate, calcium phosphateO sodium phosphate or lactose; granulating and dispersing agents, for example corn starch or alginates; binders, for example starch, gelatin or gum arabic; and lubricants, for example aluminum stearate or magnesium stearate~ talc or silicone oil. ~hey may additionally be provided ~ieh a coating which can also be such that delaye~
dissolution and absorption of the medicamen~ in the gastrointestinal tract, an~ hence, for example, ~etter tolerance, a protracted effect or a retarded effect, are achieved. Gelatin capsules can contain the medica-ment mixed ~ith a solid diluent, for example calciumcarbonate or kaolin, or an oily diluent, for example olive oil, peanut oil or paraffin oil.
Aqueous suspensions, ~hich, if appropriate, are prepared at short notice, may contain suspending agents, for example sodium carboxymethylcellulose, methylcellu-lose, ~ydroxypropylcellulose, sodium alginate~ polyvinyl pyrrolidone, gum tragacanth or gum ara~ic; dispersing agents and wetting agents, for example polyoxyethylene stearate, heptadecaethyleneoxycetanol~ polyoxyethylene ~2a~65~L -sor~itol monooleate, po~yoxyethylene sor~itan mono-oleate or leci~hin; preservatives, for example methyl or propyl hy~roxybenzoate; flavorin~ agen~s; and s~eeteners, for example sucrose, lactose, so~ium S cyc~amate, dextrose or invert sugar syrup.
Oily suspensions may contain, for example, peanut oil, olive oil~ sesame oil, cocon~t oil or paraf-fin oil, and th1ckeners, such as, for example, bees~a~, hard paraffin or cetyl alcohol; and furthermore sweeteno ers, flavoring agents and antioxidants.
~ ater-dispersi~le powaers and granules may con-tain the medicaments mixed with dispersing agents, wetting agents and suspending agents, for example those mentioned above, as well as with s~eeteners, flavoring agents ana colorants.
Emulsions may contain, for example, olive oil, peanut oil or paraffin oil, in addition to emulsifying agents, such as, for example, gum arabic, gum traga-canth~ phosphatides, soroit3n monoolea~e or polyoxy-ethylene sor~itan monooleate, and sweeteners an~ flav-oring agents.
For rectal administration of the medicaments, suppositories ~hich are preparea uith the aid of bind-ers which melt at the rectal temperature, for example ~ 25 cacao butter or polyethylene glycol, are used.
; For paren~eral administration of the medica-ments, sterile, injecta~le aqueous suspensions, isotonic salt solutions or other solutions ~hich, if appropri-ate, are to be prepare5 at short notice ana ~hich con-tain dispersing agents or uetting agents and/or phar-macologically tolerated ailuents, for example propylene glycol or butylene g~ycol, are used.
Oral administration of the medicaments is pr~-ferred.
Administration of the compounds according to the invention by inhalation is also preferred for the use as a bronchospasmolytic. These compoun~s are administered either directly as powders or ~y atomizing solutions or suspensions containing the compounds according to the :~L2~5~Sl invention. In this context, atomizin~ can be effected in the convent10nal manner, for example by compressed-air atomizers or ultrasoun~ atomizers. Administration from spray cans, especially t~ose ~ith a conventional metering valve (metered aerosols) is particularly advantageous. By means of meterea aerosols it is pos-sible to provide a defined amount of active compound per actuation of the spray. So-called synchronous inhalers, using ~hich administration of the active compound can ~e synchronized ~ith inhalation, are of particular aavantage here. Suitable synchronous inhalation devices are disclosed, for example, in German Patent Specification 1,945,257, German Patent Specification 1~917,911 and German Offenlegungsschrif~
2,055,734.
For inhalation purposes, the active compounds are preferably usea in micronized forms, particle sizes of less than 10 ~um being advantageous. For administra-tion from spray cans, the active compounds are dispersed in customary propellants, prefera~lj with the aid of a ~ispersing agent. Possi~le propellants are, for example, mixtures of trichlorofluoromethane (Frigen~12), it being possible for all or some of the trichlorofluoromethane to De replaced ~y 1,1,2-trichlorotrifluoroethane (Frigen~113).
Possi~le dispersing agents are~ in particular, the sor-~i~an esters customary for these purposes (Span ~ from Atlas Gm~H) and lecithin. The dispersing agent is dis-solved in the propellant component of lo~er volatility, ~hich has been initially intro~uced in cooled form. The ; 30 micronized active compound is stirred, or the micronized active compounds are stirre~, into the solution. The dispersion is filled into spray cans. After crimping, the ~ore volatile propellant component i5 forced in.
The active compound or compounds can also be formu-lated in micro-encapsulated form~ if appropriate together ~itn one or more of ~he vehicles or addi~ives mentioned.
~=
40 kg of active compound, 24 kg of lactose ana ~ZgL565~
16 kg of corn starch are ~ranulated with 4 kg of poly~
vinyl pyrrolidone (molecular ~eighe 25,000) in 5.5 liters of water, and the granules are forced throu~h a sieve of 1.25 mm mesh. After drying, 10 kg of carboxy-methyl cellulose, 4 kg of talc ana 2 kg of magnesiumstearate are added. The granules are compressed on a cam~type machine to form tablets of diameter 9 mm, ~eight Z50 mg and hardness 4 to 5 k~.
Capsules contalning 15 mg of 6~(3-difluoromeehoxyphenyl)-3t2H]pyridazinone 150 mg of active co~pound, 845 m9 of micro-crystalline cellulose and 5 mg of amorphous silica are finely po~dered, the poHder is mixed thoroughly~ and size 4 hard geLatin capsules are filled ~ith the mix-ture.
~_ 0.540 9 of Spa~ - ~S and 0.135 9 of aroma are dissolved in 10.215 g of coolea Frigen~ 1. 0.270 9 of micronized active compound is stirred into the solution, and 24 ml cans are filled with the mixture.
After crimping, 14.971 9 of Frige ~ 2 are forcea in.
~ith a chamber volume of the metering valve of 125 ul, ~; 1.6 mg of active compound are released as an aerosol per valve stroke.
The b-aryl-3C2H]pyridazinones of the general formula I have a bronchospasmolytic action ~hich in some cases is considerably superior to ~hat of theo-phylline. In addition, compared with theophylline,their action is more organ-selective, as is evident from comparison of the bronchospasmolysis on the iso-lated, spontaneously contracted chain o1 tracheal rings of the guinea pig ~ith the positive inotropic action on the electrically stimula~ed left atrium of the rat~
Theophylline has been used for a long time as a broncho-spasmolytic for the treatmen~ of bronchial asthma and other spastic states of the smooth muscle of the bronchi.
~2a~S165~
Its si~e effects, ~specially those on the heart an~
circulation, are known (cf. Ehrhart/Ruschig~ Arznei-mittel (Me~icaments), Verlag Chemie ~einheim/
Bergstrasse 1972, Vol. 1, page 341, Vol. 2, page 258;
Schulze-Wernighaus Pharmakotherapie 4(1981)168 to 177).
In the Ta~les ~hich follo~ the compounds are identified by a serial num~er:
1: 6-~4-trifluoromethoxyphenyl~-3t2H~pyridazinone 2: 6-t3-(1,1,2,2~te~rafluoroethoxy)phenyl]-3C2H~pyri-dazinone
For inhalation purposes, the active compounds are preferably usea in micronized forms, particle sizes of less than 10 ~um being advantageous. For administra-tion from spray cans, the active compounds are dispersed in customary propellants, prefera~lj with the aid of a ~ispersing agent. Possi~le propellants are, for example, mixtures of trichlorofluoromethane (Frigen~12), it being possible for all or some of the trichlorofluoromethane to De replaced ~y 1,1,2-trichlorotrifluoroethane (Frigen~113).
Possi~le dispersing agents are~ in particular, the sor-~i~an esters customary for these purposes (Span ~ from Atlas Gm~H) and lecithin. The dispersing agent is dis-solved in the propellant component of lo~er volatility, ~hich has been initially intro~uced in cooled form. The ; 30 micronized active compound is stirred, or the micronized active compounds are stirre~, into the solution. The dispersion is filled into spray cans. After crimping, the ~ore volatile propellant component i5 forced in.
The active compound or compounds can also be formu-lated in micro-encapsulated form~ if appropriate together ~itn one or more of ~he vehicles or addi~ives mentioned.
~=
40 kg of active compound, 24 kg of lactose ana ~ZgL565~
16 kg of corn starch are ~ranulated with 4 kg of poly~
vinyl pyrrolidone (molecular ~eighe 25,000) in 5.5 liters of water, and the granules are forced throu~h a sieve of 1.25 mm mesh. After drying, 10 kg of carboxy-methyl cellulose, 4 kg of talc ana 2 kg of magnesiumstearate are added. The granules are compressed on a cam~type machine to form tablets of diameter 9 mm, ~eight Z50 mg and hardness 4 to 5 k~.
Capsules contalning 15 mg of 6~(3-difluoromeehoxyphenyl)-3t2H]pyridazinone 150 mg of active co~pound, 845 m9 of micro-crystalline cellulose and 5 mg of amorphous silica are finely po~dered, the poHder is mixed thoroughly~ and size 4 hard geLatin capsules are filled ~ith the mix-ture.
~_ 0.540 9 of Spa~ - ~S and 0.135 9 of aroma are dissolved in 10.215 g of coolea Frigen~ 1. 0.270 9 of micronized active compound is stirred into the solution, and 24 ml cans are filled with the mixture.
After crimping, 14.971 9 of Frige ~ 2 are forcea in.
~ith a chamber volume of the metering valve of 125 ul, ~; 1.6 mg of active compound are released as an aerosol per valve stroke.
The b-aryl-3C2H]pyridazinones of the general formula I have a bronchospasmolytic action ~hich in some cases is considerably superior to ~hat of theo-phylline. In addition, compared with theophylline,their action is more organ-selective, as is evident from comparison of the bronchospasmolysis on the iso-lated, spontaneously contracted chain o1 tracheal rings of the guinea pig ~ith the positive inotropic action on the electrically stimula~ed left atrium of the rat~
Theophylline has been used for a long time as a broncho-spasmolytic for the treatmen~ of bronchial asthma and other spastic states of the smooth muscle of the bronchi.
~2a~S165~
Its si~e effects, ~specially those on the heart an~
circulation, are known (cf. Ehrhart/Ruschig~ Arznei-mittel (Me~icaments), Verlag Chemie ~einheim/
Bergstrasse 1972, Vol. 1, page 341, Vol. 2, page 258;
Schulze-Wernighaus Pharmakotherapie 4(1981)168 to 177).
In the Ta~les ~hich follo~ the compounds are identified by a serial num~er:
1: 6-~4-trifluoromethoxyphenyl~-3t2H~pyridazinone 2: 6-t3-(1,1,2,2~te~rafluoroethoxy)phenyl]-3C2H~pyri-dazinone
3: 6-~4-S1,1,2,2-tetrafluoroethoxy)phenyl]-3C2H~pyri-dazinone
4: 6-(3-difluoromethoxy-4-methoxyphenyl)-3C2H~pyri~az-inone S: 6-t4 difluoromethoxy-3-methoxyphenyl~-3C2H~pyridaz-inone 6: 6-(4-difluoromethoxyphenyl~-3C2H~pyrjdazinone 7: 6-(3-difluoromethoxyphenyl)-3C2H~pyridazinone The bronchospasmolytic action of the compounds in vitro ~as eested on a chain of tracheal rings of ~he guinea pig as follows:
Four parallel chains of tracheal rings, each consisting of 6 inaividual rings, of guinea pigs ~ and ~o, 430-600 9) in an organ bath (5 ml, Krebs-Henseleit solution ~ith added phentolamine (10 5 mol/l~, 37, initial tension of the organs Z 9, gassing with carbo-gen), develop a stable, spontaneous tonic contraction af~er about Z0 to 30 minutes. Relaxation of these permanently contracted organs can be caused, under iso-metric measurement conaitions, ~y administration of the ; test substance in concentrations ~hich increase semi-logarithmically and cumulatively (for example 1 x 10 2 x 10 6 ~ 7 x 10 6 ~ 2 x 10 5 etc. mol~l), a con-stant relaxation response being waited for after each individual dose of the test substance before the next higher concentration is administered. Over a period of 20 to 30 minutes, a complete dose/action curve of the test substance is thus obtained~ The particular ~ ;29LS65~
relaxation is expressea as a percentage fraction of the maximum relaxation ~hich can be achieved by adminis~
tration of (-~isoprenaline ~10 6 mol/l). The con-centration of the tes~ subs~ance which ~rings about 50X of the ma~imum relaxation ~hich can be achieved, expressed ~y the negative logarithm of the EC50 molll: -lg~EC50), is a m~asure of the broncho-dilator activity.
The positive inotropic action of the compoun~s was tested in vitro on the electrically stimulated left atrium of the rat, 3S follo~s:
Isometric contractions tHSE force sensor K-30;
~atanabe recorder, Linear Coraer Mark 5) of isolated left atria of rats t~, 250-300 9) in an organ bath t10 ml, Tyrode nutrient solution, 31, gassin~ ~ith carbo-gen, initial tension of the organs 0.25 9) ~ith electric stimulation tHSE stimulator, 7 V, 3 ms, 2 Hz) ~ere recordea. After an equilibration period of 30 minutes, a dose-dependent increase in the contraction force can ~e brought about by administration of the test substance in concentrations ~hich increase semilogarith~ically an~ cumulatively (for example 1 x 10 6 + 2 x 10 6 ~
7 x 10 6 ~ 2 x 10 5 etc. mol/l), a constant inotropic response oeing ~aited for after each individuaL dose of the test su~stance ~efore the next higher concentration is administered. The particular increase in the con-traction force is expressed as a X of the initial value ~efore administration of the substance. The concentration of the test subs~ance ~hich potentiates the contraction force of the atrium by 40% compared ~ith the initial value tEC40pot mol/l), expressed by the negat1ve logarithm of the (EC40pot.mo~l) l5(Ec40pot.
serves as a ~easure of the cardiotonic activity.
The measure used for the or~an-selective activ-ity is the ratio bet~een (EC40pot~)left atrium andtEC50)trachea. As a measure of the activity, the ratios bet~een the (ECso)trachea values an~ (EC40pot ) ~eft atrium values of theophylline and the tested com-pound are given.
~` ;
~516S~L
The values which ~ere found are listed in Table 1 ~elo~:
Table 1: 3ronchospasmolytiG ana positive inotropic action Serial No. A B C D E
1 4.60 4.0 4.0 5O4 4.2 2 5.11 4.66 2.8 17.. 4 19 3 5.04 4.21 6.8 ~3.26.8 4 5.80 5.76 1.1 85 240
Four parallel chains of tracheal rings, each consisting of 6 inaividual rings, of guinea pigs ~ and ~o, 430-600 9) in an organ bath (5 ml, Krebs-Henseleit solution ~ith added phentolamine (10 5 mol/l~, 37, initial tension of the organs Z 9, gassing with carbo-gen), develop a stable, spontaneous tonic contraction af~er about Z0 to 30 minutes. Relaxation of these permanently contracted organs can be caused, under iso-metric measurement conaitions, ~y administration of the ; test substance in concentrations ~hich increase semi-logarithmically and cumulatively (for example 1 x 10 2 x 10 6 ~ 7 x 10 6 ~ 2 x 10 5 etc. mol~l), a con-stant relaxation response being waited for after each individual dose of the test substance before the next higher concentration is administered. Over a period of 20 to 30 minutes, a complete dose/action curve of the test substance is thus obtained~ The particular ~ ;29LS65~
relaxation is expressea as a percentage fraction of the maximum relaxation ~hich can be achieved by adminis~
tration of (-~isoprenaline ~10 6 mol/l). The con-centration of the tes~ subs~ance which ~rings about 50X of the ma~imum relaxation ~hich can be achieved, expressed ~y the negative logarithm of the EC50 molll: -lg~EC50), is a m~asure of the broncho-dilator activity.
The positive inotropic action of the compoun~s was tested in vitro on the electrically stimulated left atrium of the rat, 3S follo~s:
Isometric contractions tHSE force sensor K-30;
~atanabe recorder, Linear Coraer Mark 5) of isolated left atria of rats t~, 250-300 9) in an organ bath t10 ml, Tyrode nutrient solution, 31, gassin~ ~ith carbo-gen, initial tension of the organs 0.25 9) ~ith electric stimulation tHSE stimulator, 7 V, 3 ms, 2 Hz) ~ere recordea. After an equilibration period of 30 minutes, a dose-dependent increase in the contraction force can ~e brought about by administration of the test substance in concentrations ~hich increase semilogarith~ically an~ cumulatively (for example 1 x 10 6 + 2 x 10 6 ~
7 x 10 6 ~ 2 x 10 5 etc. mol/l), a constant inotropic response oeing ~aited for after each individuaL dose of the test su~stance ~efore the next higher concentration is administered. The particular increase in the con-traction force is expressed as a X of the initial value ~efore administration of the substance. The concentration of the test subs~ance ~hich potentiates the contraction force of the atrium by 40% compared ~ith the initial value tEC40pot mol/l), expressed by the negat1ve logarithm of the (EC40pot.mo~l) l5(Ec40pot.
serves as a ~easure of the cardiotonic activity.
The measure used for the or~an-selective activ-ity is the ratio bet~een (EC40pot~)left atrium andtEC50)trachea. As a measure of the activity, the ratios bet~een the (ECso)trachea values an~ (EC40pot ) ~eft atrium values of theophylline and the tested com-pound are given.
~` ;
~516S~L
The values which ~ere found are listed in Table 1 ~elo~:
Table 1: 3ronchospasmolytiG ana positive inotropic action Serial No. A B C D E
1 4.60 4.0 4.0 5O4 4.2 2 5.11 4.66 2.8 17.. 4 19 3 5.04 4.21 6.8 ~3.26.8 4 5.80 5.76 1.1 85 240
5.91 6.06 0.7 110 469
6 4.. 92 4~49 2.7 11.2 12.9
7 4.84 < 4.~ > 6.9 9.3 Theophylline 3.87 3.38 3.1 Column A: ~l9tECsO)trachea Column a: -~9 (Ec4opot.)left atrium Column C: (EC~opot~)left atrium/tEc5o)tracnea 50 theophylline 50 substance Column E (EC40pot.)theophylline/(EC40pot.)su~stance The protective action against acetylcholine-induced bronchospasm ~as determined on conscious guinea 20 pigs by a method derived from ~hat of T. Olsson, Acta Allergologi ca 26, 438-447 (1971)~ as follows:
6uin~a pigs (250-350 9) in a closed plexiglass cylinder tvolume: 5 l) are exposed to a mist of acetyl-choline (0.06% in 0.9% sodium chloride solution; Heyer Use 77 ultrasonic atomizer) t~ice at an interval of ZO
minutes. The time from the s~art of atomization until there is onset of a marked struggle to breathe (in certain circumstances, a hypoxic convulsion in the i lateral position) is measured and designate~ the latency perio~. The latency period in a control experi~ent twithout administra~ion of su~stance) is 2 minutes. The test substance is administerea orally by gava~e (standard dose 100 ~moL/kg, volume 1 ml of 4% strength methocel suspension in 0.9% strength sodium chloride solution/kg.
After 30 minutes, the animals are again exposed to the mist of acetylcholine, and the latency periods are .~ .
~, ..
::
~2~;65~
measured. A prolongation of the latency perioa to at ~east dou~le is regarded as a protective action.
The values ~hich ~ere foun~ are listed in Table 2 ~elo~:
Table 2: Protective action against acetylcholine-induced ~ronchospasm in conscious guinea pigs Serial Dose (~mol/kg)p~o.* Test 30 min. p~. (sic~
No. Triplins of the latency period in N of 10 animals 6 1ûO 8 15 Theophylline 100 3 * administered in 4X Me~hocel suspension It is evident from Table 2 that the protective action against the ~ronchospasm, induced ~y acetyl-choline atomization in conscious guinea pigs, brought about by the compounds investigated was greater than that of the comparison su~stance theophylline.
.
6uin~a pigs (250-350 9) in a closed plexiglass cylinder tvolume: 5 l) are exposed to a mist of acetyl-choline (0.06% in 0.9% sodium chloride solution; Heyer Use 77 ultrasonic atomizer) t~ice at an interval of ZO
minutes. The time from the s~art of atomization until there is onset of a marked struggle to breathe (in certain circumstances, a hypoxic convulsion in the i lateral position) is measured and designate~ the latency perio~. The latency period in a control experi~ent twithout administra~ion of su~stance) is 2 minutes. The test substance is administerea orally by gava~e (standard dose 100 ~moL/kg, volume 1 ml of 4% strength methocel suspension in 0.9% strength sodium chloride solution/kg.
After 30 minutes, the animals are again exposed to the mist of acetylcholine, and the latency periods are .~ .
~, ..
::
~2~;65~
measured. A prolongation of the latency perioa to at ~east dou~le is regarded as a protective action.
The values ~hich ~ere foun~ are listed in Table 2 ~elo~:
Table 2: Protective action against acetylcholine-induced ~ronchospasm in conscious guinea pigs Serial Dose (~mol/kg)p~o.* Test 30 min. p~. (sic~
No. Triplins of the latency period in N of 10 animals 6 1ûO 8 15 Theophylline 100 3 * administered in 4X Me~hocel suspension It is evident from Table 2 that the protective action against the ~ronchospasm, induced ~y acetyl-choline atomization in conscious guinea pigs, brought about by the compounds investigated was greater than that of the comparison su~stance theophylline.
.
Claims (12)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A compound of the general formula I
(I) in which one of the substituents R1 and R2 denotes hydrogen or C1-C4-alkoxy, and the other denotes polyfluoro-C1-C4-alkoxy, or a pharmacologically tolerated salt with a base.
(I) in which one of the substituents R1 and R2 denotes hydrogen or C1-C4-alkoxy, and the other denotes polyfluoro-C1-C4-alkoxy, or a pharmacologically tolerated salt with a base.
2. A compound as claimed in claim 1, wherein one of the substituents R1 and R2 denotes hydrogen or straight-chain C1-C3-alkoxy, and the other denotes polyfluoro-C1-C2-alkoxy.
3. A compound as claimed in claim 1, wherein one of the substituents R1 and R2 denotes hydrogen or methoxy, and the other denotes difluoromethoxy, trifluoromethoxy, 1,1,2,2-tetrafluoroethoxy or 1,1,1-trifluoroethoxy.
4. A compound as claimed in claim 1 wherein R1 denotes hydrogen and R2 denotes trifluoromethoxy.
5. The compound 6-(4-trifluoromethoxyphenyl)-3 [2H]
pyridazinone
pyridazinone
6. A process for preparing a compound of general formula I as defined in claim 1 or a pharmacologically tolerated salt with a base, which process comprises a) oxidizing a 6-aryltetrahydropyridazinone of the general formula II
(II) in which R1 and R2 have the abovementioned meaning, and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt, or b) reacting a morpholinobutyric acid of the general formula III
(III) in which R1 and R2 have the abovementioned meaning, with hydrazine and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt, or c) reacting an acrylic acid of the general formula IV
(IV) in which R1 and R2 have the abovementioned meaning, with hydrazine, and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt.
(II) in which R1 and R2 have the abovementioned meaning, and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt, or b) reacting a morpholinobutyric acid of the general formula III
(III) in which R1 and R2 have the abovementioned meaning, with hydrazine and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt, or c) reacting an acrylic acid of the general formula IV
(IV) in which R1 and R2 have the abovementioned meaning, with hydrazine, and, if required, then converting the resulting pyridazinone into a pharmacologically tolerated salt.
7. A process according to claim 6 wherein process b) is used and the morpholinobutyric acid of formula (III) is provided in the form of a morpholinium salt prepared by reaction of an appropriately substituted acetophenone, glyoxylic acid and morpholine.
8. A process according to claim 6 wherein process c) is used and the acrylic acid of formula (IV) is prepared by reaction of an appropriately substituted acetophenone with glyoxylic acid.
9. A process for preparing 6-(4-trifluoromethoxyphenyl)-3 [2H] pyridazinone which comprises reacting .beta.-(4-trifluoromethoxybenzoyl)-acrylic acid with hydrazine.
10. A process according to claim 9 wherein the .beta.-(4-trifluoromethoxybenzoyl)-acrylic acid is obtained in situ by reacting 4-trifluoromethoxyacetophenone with glyoxylic acid.
11. A pharmaceutical composition which comprises a compound as claimed in claim 1, 2 or 3, or a pharmacologically tolerated salt with a base, in association with a suitable diluent or carrier.
12. A process for preparing a pharmaceutical composition for the treatment of prophylaxis of diseases based on disorders of the bronchi or cardiac insufficiency or for strengthening the heart, characterised in that a compound as claimed in claim 1, 2 or 3 is incorporated as active ingredient in the pharmaceutical composition.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH229784 | 1984-05-10 | ||
| CH2297/84-4 | 1984-05-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1245651A true CA1245651A (en) | 1988-11-29 |
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ID=4230485
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|---|---|---|---|
| CA000481149A Expired CA1245651A (en) | 1984-05-10 | 1985-05-09 | Pyridazinones, preparation process thereof and utilization thereof, drugs containing pyridazinones |
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|---|---|
| US (1) | US4665074A (en) |
| EP (1) | EP0163965B1 (en) |
| JP (1) | JPH062750B2 (en) |
| AT (1) | ATE47844T1 (en) |
| AU (1) | AU578947B2 (en) |
| CA (1) | CA1245651A (en) |
| DE (1) | DE3574137D1 (en) |
| DK (1) | DK159431C (en) |
| ES (1) | ES8607950A1 (en) |
| GR (1) | GR851039B (en) |
| IE (1) | IE58033B1 (en) |
| IL (1) | IL75070A (en) |
| NZ (1) | NZ211995A (en) |
| PT (1) | PT80426B (en) |
| ZA (1) | ZA853504B (en) |
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| JPH06501941A (en) * | 1990-10-16 | 1994-03-03 | ビイク グルデン ロンベルク ヒエーミツシエ フアブリーク ゲゼルシヤフト ミツト ベシユレンクテル ハフツング | Arylpyridazinone |
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| SI0706513T1 (en) * | 1993-07-02 | 2002-10-31 | Altana Pharma Ag | Fluoroalkoxy-substituted benzamides and their use as cyclic nucleotide phosphodiesterase inhibitors |
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| WO1998055481A1 (en) | 1997-06-03 | 1998-12-10 | Byk Gulden Lomberg Chemische Fabrik Gmbh | Benzonaphthyridine |
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| US20090247488A1 (en) * | 2003-04-25 | 2009-10-01 | Carina Cannizzaro | Anti-inflammatory phosphonate compounds |
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| DE2435244A1 (en) * | 1974-07-22 | 1976-02-05 | Lentia Gmbh | PROCESS FOR THE PREPARATION OF 3-PHENYLPYRIDAZONES |
| DE2445681A1 (en) * | 1974-09-25 | 1976-04-15 | Lentia Gmbh | 3-Phenyl pyridaz-6-ones prodn. - from benzoylacrylic acids by base-catalysed prodn. of methanol then cyclisation with hydrazine |
| JPS6037101B2 (en) * | 1977-03-09 | 1985-08-24 | 三共株式会社 | Method for producing phenylpyridazinone derivatives |
| DE2757923A1 (en) * | 1977-12-24 | 1979-06-28 | Hoechst Ag | PROCESS FOR THE PRODUCTION OF 3-PYRIDAZONES |
| US4397854A (en) * | 1981-05-14 | 1983-08-09 | Warner-Lambert Company | Substituted 6-phenyl-3(2H)-pyridazinones useful as cardiotonic agents |
| PT78566B (en) * | 1983-05-11 | 1986-07-17 | Byk Gulden Lomberg Chem Fab | PYRIDAZINONE THEIR PREPARATION AND USE OF PYRIDAZINONE-CONTAINING MEDICINAL PRODUCTS |
| IT1173591B (en) * | 1983-05-11 | 1987-06-24 | Byk Gulden Lomberg Chem Fab | PIRIDATIONS, THEIR PREPARATION AND USE, DRUGS CONTAINING PIRIDATIONS |
-
1985
- 1985-04-19 DK DK177585A patent/DK159431C/en not_active IP Right Cessation
- 1985-04-29 AU AU41775/85A patent/AU578947B2/en not_active Ceased
- 1985-04-29 GR GR851039A patent/GR851039B/el unknown
- 1985-05-02 IL IL75070A patent/IL75070A/en unknown
- 1985-05-06 NZ NZ211995A patent/NZ211995A/en unknown
- 1985-05-07 US US06/731,580 patent/US4665074A/en not_active Expired - Fee Related
- 1985-05-07 DE DE8585105535T patent/DE3574137D1/en not_active Expired
- 1985-05-07 EP EP85105535A patent/EP0163965B1/en not_active Expired
- 1985-05-07 AT AT85105535T patent/ATE47844T1/en not_active IP Right Cessation
- 1985-05-09 IE IE114685A patent/IE58033B1/en not_active IP Right Cessation
- 1985-05-09 ZA ZA853504A patent/ZA853504B/en unknown
- 1985-05-09 CA CA000481149A patent/CA1245651A/en not_active Expired
- 1985-05-09 PT PT80426A patent/PT80426B/en not_active IP Right Cessation
- 1985-05-09 ES ES542979A patent/ES8607950A1/en not_active Expired
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Also Published As
| Publication number | Publication date |
|---|---|
| DK177585D0 (en) | 1985-04-19 |
| IE58033B1 (en) | 1993-06-16 |
| PT80426A (en) | 1985-06-01 |
| IE851146L (en) | 1985-11-10 |
| US4665074A (en) | 1987-05-12 |
| DK177585A (en) | 1985-11-11 |
| DK159431C (en) | 1991-03-18 |
| EP0163965B1 (en) | 1989-11-08 |
| NZ211995A (en) | 1987-11-27 |
| EP0163965A2 (en) | 1985-12-11 |
| IL75070A0 (en) | 1985-09-29 |
| ZA853504B (en) | 1985-12-24 |
| PT80426B (en) | 1987-04-16 |
| JPS60246375A (en) | 1985-12-06 |
| JPH062750B2 (en) | 1994-01-12 |
| EP0163965A3 (en) | 1987-06-24 |
| IL75070A (en) | 1988-11-15 |
| ATE47844T1 (en) | 1989-11-15 |
| AU578947B2 (en) | 1988-11-10 |
| ES8607950A1 (en) | 1986-06-16 |
| DK159431B (en) | 1990-10-15 |
| ES542979A0 (en) | 1986-06-16 |
| AU4177585A (en) | 1985-11-14 |
| GR851039B (en) | 1985-05-28 |
| DE3574137D1 (en) | 1989-12-14 |
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