JPH0335316B2 - - Google Patents

Description

[Detailed description of the invention]

Many [[(3-pyridinyl)methylene]amino]oxy derivatives have been reported in the Journal of the Chemical Society as intermediates or as compounds with plant growth inhibitory and vitamin K activities.
Perkin Transactions (J.Chem.
Soc., Perkin Trans.) I, (3), 984-987 (1981)
and Journal of Medicinal Chemistry (J.Med.Chem.) 7 (6), 824-826 (1964). Swiss Patent No. 616406 describes a number of [[(3-pyridinyl)methylene]amino]oxy derivatives useful as lipid-lowering agents and plant protection agents. In U.S. Pat. No. 4,518,602, thromboxane A ₂ synthetase (thromboxane A ₂
A number of vinyl carboxylic acid derivatives have been described that have inhibitory properties. In European Patent Application No. 0175304,
[[(methylene)amino]oxy]propionic acid is described. The compounds of the present invention, by virtue of their ability to specifically inhibit the enzymatic synthesis of thromboxane A ₂ and the nature of the substituent attached to the [(methylene)amino]oxy group, are distinct from the prior American compounds cited above. is different. The present invention is based on the structural formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
Novel [[[(3-pyridinyl ⁾ methylene]amino]oxy]alkanoic acids and esters thereof, which can be represented by N-oxide, pharmaceutically acceptable acid addition, metal or amine substituted salts and possible stereochemically isomeric forms thereof. In the above definitions, the term halo generally refers to fluoro, chloro, bromo and iodo; "C ₁
~C ₆ alkyl” refers to straight-chain and branched saturated hydrocarbon radicals having 1 to 6 carbon atoms, such as methyl, ethyl, 1-methylethyl, 1,1-dimethylethyl, propyl, butyl, pentyl , hexyl, etc.; " _C1 - _C10 alkyl" is meant to include straight and branched saturated hydrocarbon groups having from 1 to 10 carbon atoms;
And " _C2 - _C10 alkanediyl" has 2 carbon atoms
This means that divalent linear or branched alkanediyl groups having ~10 groups are included. N-oxide of a compound of formula () is meant to consist of a compound of formula () in which one or more nitrogen atoms, preferably pyridine nitrogen atoms, are oxidized to the so-called N-oxide form. Preferred compounds within the scope of the invention are the [[(3-
pyridinyl)methylene]amino]oxy group and -
COOR ¹ unit has at least 3 and at most 6
Compounds separated by carbon atoms. Particularly preferred compounds are those in which R is Ar or Ar(C ₁
~ _C4 alkyl). Further particularly preferred compounds are those in which R ¹ is hydrogen;
and R is phenyl or naphthalenyl,
The phenyl and naphthalenyl are each independently,
The above optionally substituted with up to 2 substituents which are _C1 - _C6 alkyl, _C1 - _C6 alkyloxy, di( _C1 - _C6 alkyloxy)methyl, formyl, halo or trifluoromethyl is a particularly preferred compound. Particularly preferred compounds within the scope of the invention include a pyridine ring in the oxime moiety and -O-Alk-
More particularly preferred are compounds as described above in which the COOR ¹ substituent is in the trans configuration. The most preferred compounds are (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid and (E)-5
-[[[(3-methylphenyl)(3-pyridinyl)
methylene]amino]oxy]pentanoic acid, its pharmaceutically acceptable salts and N-oxide forms. In general, compounds of formula () can be prepared by reaction of oximes of formula () or their N-oxides with intermediates of formula () according to O-alkylation methods known in the art. . In formula (), W represents a suitable reactive leaving group, such as halo, such as chloro, bromo or iodo, or a sulfonyloxy group, such as methylsulfonyloxy or 4-methylsulfonyloxy. The O-alkylation reaction is advantageously carried out in a suitable reaction-inert solvent or mixture of such solvents. Suitable reaction-inert solvents are, for example, aromatic hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, etc.; lower alkanols, such as methanol, ethanol, 1-butanol, etc.; acetone, such as 2-propanone, 4-methyl-2 - pentanone, etc.; ethers, such as 1,4-dioxane, 1,1'-oxybisethane, tetrahydrofuran, etc.; polar aprotic solvents, such as N,
N-dimethylformamide (DMF), N,N-dimethylacetamide (DMA), hexamethylphosphate triamide (HMPT), dimethyl sulfoxide (DMSO), nitrobenzene, 1-methyl-2
-pyrrolidinone, etc. In order to pick up the acid liberated during the reaction, a suitable base,
For example, alkali metal carbonates or bicarbonates, sodium hydride, or organic bases such as N,N
The addition of -diethylethanamine or N-(1-methylethyl)-2-propanamine can be used. The reaction rate can be increased by slightly raising the temperature. The oxime of formula () can be prepared by converting the starting oxime to an alkali metal hydride or an alkaline earth metal hydride, such as sodium hydride, calcium hydride, etc., or an alkali metal hydroxide, such as sodium hydroxide, potassium hydroxide, etc. It is advantageous to react and first convert it into a metal salt form, preferably an alkali metal salt form, and then use this metal salt form for the reaction with the compound of formula (). In addition, the compound of formula () is an aldehyde or ketone of formula () or its N-oxide.
(amino)oxyacid or ester, or preferably in its acid addition salt form; or when R ¹ is hydrogen,
The alkali metal salt form of formula () can be used most advantageously. For the reaction of formulas () and (), suitable inert solvents such as water; lower alkanols such as methanol, ethanol, 1-butanol, etc.; ethers such as 1,4-dioxane, 1,1'-oxy It can be carried out in bisethane, tetrahydrofuran, etc., or in aromatic hydrocarbons such as benzene, methylbenzene, dimethylbenzene, etc.; and mixtures of such solvents. A suitable base, such as an alkali metal hydroxide, carbonate or bicarbonate, or an organic base, such as a tertiary amine, such as N,N
-diethylethanamine, N-(1-methylethyl)-2-propanamine, etc., or addition of pyridine is preferred. Compounds of formula () can also be prepared by oxime rearrangement of aldehydes or ketones of formula () or their N-oxide forms and oximes of formula (). The oxime transfer reaction can be advantageously carried out by stirring the reactants together in an acidic solvent and optionally heating.
The by-product aldehyde or ketone of formula () is preferably removed from the reaction mixture by methods known in the art, such as fractional distillation. In formulas () and (), R ² and R ³ are each independently hydrogen or C ₁ -C ₆ alkyl. Compounds of formula () can also be prepared by reacting alkenes of formula () with oximes of formula () or their N-oxides in the presence of a catalytic amount of a suitable base in a suitable solvent. R ¹ OOC−C _2-10 alkenediyl-H()+()
→() Compounds of formula () can also be converted into each other according to functional group transformation methods known in the art. An example is shown below. Compounds of formula () containing an ester group can be converted to the corresponding carboxylic acid according to saponification methods known in the art, for example by treating the starting compound with an alkaline or acidic aqueous solution. Conversely, carboxylic acid groups can be converted to the corresponding ester groups according to esterification methods known in the art. For example, one can convert a carboxylic acid into the corresponding reactive derivative and then react this with the corresponding alkanol HOR ¹ ; alternatively, the carboxylic acid and the alkanol HOR ¹
with a suitable ester-forming reagent such as dicyclohexylcarbodiimide, 2-chloro-1-
By reacting with methylpyridinium iodide, etc. Compounds of formula () having a nitro substituent can be converted to the corresponding amine by methods known in the art for reduction of nitro to amine, for example by stirring in the presence of sodium hydrosulfite. can. Optionally, further amino substituents can be added by reacting the amine with a suitable acylating agent, such as an acyl halide or an acid anhydride, to give a compound of formula () having a _C1 - _C6 alkylcarbonylamino substituent. can be transformed. Compounds of formula () having a di( _C1 - _C6 alkoxy)methyl substituent can be deacetalized to generate the corresponding formyl group. The deacetalization can be carried out according to methods widely known in the art, for example by reacting the starting materials in an acidic aqueous medium. The formyl group can be further oxidized to the corresponding carboxyl group with a suitable oxidizing agent, such as potassium permanganate, mercury oxide (), etc. A compound of formula () can be converted to the corresponding N-oxide form according to methods known in the art for converting a pyridinyl nitrogen to its N-oxide form. Such N-oxidation reactions can generally be carried out by reacting the starting compound with a suitable organic or inorganic peroxide. Suitable acid-free peroxides can be, for example, hydrogen peroxide, alkali metal or alkaline earth metal peroxides, such as sodium peroxide, potassium peroxide, barium peroxide, etc.; suitable organic peroxides are Peracids, such as benzenecarboperoxoacid or halo-substituted benzenecarboperoxoacid, such as 3-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, such as peracetic acid, alkyl hydroperoxides, such as t-butyl hydroperoxide, etc. Can be done. Suitable solvents include, for example, water, lower alkanols such as methanol, ethanol, propanol, butanol, etc.
Hydrocarbons, such as benzene, methylbenzene, dimethylbenzene, etc., ketones, such as 2-propanol, 2-butanone, etc., halogenated hydrocarbons, such as dichloromethane, trichloromethane, etc., and mixtures of such solvents. In order to increase the reaction rate, it is appropriate to heat the reaction mixture. In all the preparations above and below, the reaction products can be isolated from the reaction mixture and further purified according to methods generally known in the art. From formula (), the compounds of the present invention are E- or Z
- type, the E and Z designations are described in Journal of Organic Chemistry (J.Org.Chem.), 35 , 2849-2867 (1970)
“International Union of Pure and Applied Chemistry; Union of
Pure and Applied Chemistry: Tentative
Rules for the Nomenclature of Organic
Chemistry.Section E.Fundamental
Depending on the nature of the substituents on the oxime moiety,
Before separating the pure geometric isomers, E- and Z-
It is advantageous to subject the mixture of isomers to an isomerization reaction. The isomerization reaction is an equilibrium reaction, and the reaction is generally carried out in the presence of a mineral acid. Pure stereochemically isomeric forms of compounds of formula ( ) and intermediates of formula ( can be obtained by high performance liquid chromatography. Stereochemically isomeric forms of compounds of formula () are, of course, intended to be included within the scope of the present invention. Compounds of formula () are treated with a suitable acid, e.g. an inorganic acid,
For example, hydrohalic acids, such as hydrochloric acid, hydrobromic acid, etc., and sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids, such as acetic acid, propionic acid, hydroxyacetic acid, 2-hydroxy-propionic acid, 2-oxopropionic acid, etc. acid, oxalic acid, propane dioic acid, butane dioic acid, butene dioic acid, (Z)-2-butene dioic acid, (E)-2-butene dioic acid, 2-hydroxybutane dioic acid, 2,3- Dihydroxybutanediuccinic acid, 2-hydroxy-1,2,3
-propanetricarboxylic acid, methanesulfonic acid,
Ethanesulfonic acid, benzenesulfonic acid, 4-methylbenzenesulfonic acid, cyclohexanesulfamic acid, benzoic acid, 3-phenyl-2-propenoic acid, α-hydroxybenzeneacetic acid, 2-hydroxybenzoic acid, 4-amino-2 It can be converted to its therapeutically active non-toxic acid addition salt form by treatment with -hydroxybenzoic acid or the like. Conversely, the salt form can be converted to the free base form by treatment with alkali. Compounds of formula () containing one or more acidic protons can also be converted to their therapeutically active non-toxic metal or amine substituted salt forms by treatment with a suitable organic or inorganic base. . Suitable inorganic bases are, for example, ammonia or bases derived from alkali metals or alkaline earth metals, such as alkali metal or alkaline earth metal oxides or hydroxides, such as lithium hydroxide, sodium hydroxide, potassium hydroxide, water. Magnesium oxide, calcium hydroxide, calcium oxide, etc.; alkali metal or alkaline earth metal hydrides, such as sodium hydride, potassium hydride, etc.; alkali metal bicarbonates or carbonates, such as sodium carbonate, potassium carbonate, sodium bicarbonate. , calcium carbonate, and the like.
Suitable organic bases are, for example, primary, secondary and tertiary aliphatic and aromatic amines, such as methylamine, ethylamine, propylamine, isopropylamine, the four butylamine isomers, dimethylamine, diethylamine, diethanolamine, dipropylamine. , diisopropylamine, di-n-
butylamine, pyrrolidine, piperidine, morpholine, N-methylmorpholine, triethylamine, tripropylamine, quinoclidine, pyridine, quinoline, isoquinoline, diethanolamine and 1,4-diazapicyclo[2,2,2]octane; or a quaternary ammonium base; For example, it can be tetramethylammonium hydroxide, trimethylbenzylammonium hydroxide, triethylbenzylammonium hydroxide, tetraethylammonium hydroxide and trimethylethylammonium hydroxide. Conversely, the salt form can be converted to the free acid form by treatment with acid. Certain intermediates and starting materials in the above preparations are known compounds, which can be made according to methods known in the art for making these or similar compounds. A number of such manufacturing methods are described in more detail below. Intermediates of formula () can be prepared from the corresponding carbonyl compounds of formula () or their N-oxides according to the methods described above for preparing compounds of formula () starting from formulas () and (). can be easily derived by reacting the carbonyl compound with hydroxylamine () or its acid addition salt form. Intermediates of formula () can be advantageously prepared according to methods known in the art, for example as described in Tetrahedron, 23 , 4441-4447 (1967). The compounds of formula (), their N-oxide forms, their acid addition, metal or amine substituted salts or stereochemically isomeric forms have useful pharmacological properties.
Said useful pharmacological properties include, for example, the "platelet malondialdehyde (MDA)" described below which describes the thromboxane synthetase inhibitory properties of the compounds of the invention.
“Platelet malondialdehyde (MDA)”
In addition to the above, a selective inhibitory effect on the biosynthesis of thromboxane A ₂ and an increased effect on the production of prostacyclin and prostaglandins D ₂ , E ₂ and F ₂ , e.g. in platelet aggregation experiments using various inducers such as collagen, arachidonic acid; or labeled arachidonic acid or radio-immunoassays (radio-immunoassays).
This can be demonstrated in experiments to measure intermediates in arachidonic acid metabolism using immunoassays. In view of its useful pharmacological properties, the present compounds can be formulated into various pharmaceutical forms for administration purposes. To prepare the pharmaceutical compositions of the present invention, an effective amount of a particular compound in base or acid addition salt form as the active ingredient is formulated in intimate admixture with a pharmaceutically acceptable carrier;
The carrier can take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in integrated dosage forms suitable for oral, rectal, transdermal administration, or parenteral injection. For example, in preparing compositions in oral dosage forms, common pharmaceutical vehicles such as water, glycols, oils, alcohols, etc. in the case of oral liquid preparations, such as suspensions, syrups, elixirs and solutions; Alternatively, in the case of powders, pills, capsules and tablets, solid carriers such as starch, sugar, carrion, lubricants, binders, disintegrants, etc. can be used. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. For parenteral compositions, the carrier usually consists of sterile water, at least in large part, although other ingredients can be included, eg, to aid solubility. For example, injectable solutions can be prepared with a carrier consisting of a saline solution, a glucose solution, or a mixture of saline and glucose solution. Injectable suspensions can also be prepared using suitable liquid carriers, suspending agents and the like. In compositions suitable for transdermal administration, the carrier may also consist of penetration enhancers and/or suitable humectants, optionally combined in minor proportions with suitable additives of any kind, which additives have a noticeable effect on the skin. It does not cause any harmful effects. The additives can facilitate administration to the skin and/or aid in the preparation of the desired composition. These compositions can be administered in a variety of ways, such as transdermal patches, infusions, and ointments. The acid addition salts of formula () are clearly more suitable in the preparation of aqueous compositions due to their increased solubility in water than the corresponding base forms. It is especially advantageous to formulate the above pharmaceutical compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form, as used herein, refers to physically discrete units suitable for unitary dosage, each unit being suitable for producing the desired therapeutic effect in combination with the required pharmaceutical carrier. Contains a predetermined amount of active ingredient calculated to. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers,
Injection solutions or suspensions, one teaspoonful, one tablespoonful, etc., and their divided doses. Compounds of formula (), their N-oxides, their pharmaceutically acceptable acid addition, metal or amine substituted salts and their possible stereochemically isomeric forms are:
Thromboxane acts on platelets and vascular walls.
selective inhibitory effect in the biosynthesis of _A2 and also prostacyclin and prostaglandin
Figure 2 shows an increased effect on the production of D ₂ , E ₂ and F ₂ 〓. In view of its ability to selectively inhibit the biosynthesis of thromboxane A ₂ and its increased effect on the production of prostacyclin and prostaglandins D ₂ , E ₂ and F ₂ It is known that it can be used as an inhibitor of platelet aggregation, the action of which is influenced by thromboxane A ₂ , prostacyclin, and/or prostaglandins D ₂ , E ₂ and F ₂ [ Science, 193 , 1135~
1137 (1976), Pharmacolog.Rev., 30 , 293-331 (1979)]. Compounds of formula (), their N-oxides, pharmaceutically acceptable acid addition salts thereof, metal In view of the utility of salts or amine-substituted salts and their possible stereochemically isomeric forms, methods are provided for treating clinical conditions in mammals, wherein the conditions are associated with thromboxane A ₂ , prostacyclin and/or prostacyclin. associated with the production of grandins D ₂ , E ₂ and F ₂ sexual ischemic attacks, migraines, ischemic diseases in the kidneys, lungs and other organs, peptic ulcers, vascular complications of diabetes, as well as cancer and its catabolism by blood flow.This method uses the formula () systemically administering to the mammal an effective amount of the compound, N-oxide, pharmaceutically acceptable acid addition, metal or amine substituted salt, or possible stereochemically isomeric forms thereof. For those familiar with treating clinical conditions, the effective amount can be easily determined from the test results described below. Generally, the effective amount is 0.005 mg/Kg.
Body weight to 20mg/Kg body weight, more preferably 0.01mg/Kg body weight
Kg body weight to 10 mg/Kg body weight. The following examples illustrate the invention:
It is not intended to limit the scope of the invention. All parts are parts by weight unless otherwise specified. A Intermediate Preparation Example 1 To a stirred and cooled (-78°C) mixture of 50 parts of 1-bromo-2-(dimethoxymethyl)benzene and 245 parts of 1,1'-oxybisethane is added 2.5 parts of 1-bromo-2-(dimethoxymethyl)benzene in hexane. 59 parts of M1-butyllithium solution was added dropwise. After the addition was complete, stirring was continued for 10 minutes at room temperature. A solution of 23.1 parts of 3-pyridinecarboxaldehyde in 42 parts of 1,1'-oxybisethane was added dropwise to the reaction mixture. After the addition was complete, the mixture was allowed to come to room temperature. The mixture was taken into ice water and the product was extracted with 1,1'-oxybisethane. The extract was dried, filtered and evaporated to give a residue of 56 parts (99.9%) of α-[2-dimethoxymethyl)phenyl]-3-pyridinemethanol (Intermediate 1). In a similar manner, also prepared: α-[3-(dimethoxymethyl)phenyl]-3
-pyridinemethanol as residue (intermediate 2). Example 2 To a stirred and cooled (-70 to 80°C) solution of 71.4 parts of a 1.6M 1-butyllithium solution in hexane in 105 parts of 1,1'-oxybisethane is added 1,1'-
3-bromopyridine in 70 parts of oxybisethane
40.6 parts of solution was added dropwise. After the addition is complete, stir for 15 minutes.
1,1'-oxybisethane at this low temperature for 1 min.
A solution of 30 parts of 2-(trifluoromethane)benznitrile in 35 parts was added dropwise. After the addition was complete, the mixture was stirred at this low temperature for 3 hours. The mixture was heated to room temperature and poured into 84 parts of 10N hydrochloric acid solution and a small amount of crushed ice. The aqueous layer was separated and heated to boiling point. After cooling, the mixture was made alkaline with ammonium hydroxide solution and the product was extracted with dichloromethane. The extract was dried, filtered, and concentrated. The residue was purified by filtration on silica gel using trichloromethane as eluent. Collect the pure fractions and concentrate the eluent to give (3-pyridinyl)[2-(trifluoromethyl) as an oily residue.
27.8 parts (63%) of phenyl]methanone were obtained (Intermediate 3). In a similar manner, the following was also prepared: [3,5-bis(trifluoromethyl)phenyl](3-pyridinyl)methanone as residue (intermediate 4). Example 3 To a stirred mixture of 12 parts of magnesium and 70 parts of 1,1'-oxybisethane was added dropwise 88 parts of 1-bromooctane under a nitrogen atmosphere while cooling.
After the addition was complete, the mixture was heated under reflux for 1 hour.
The 1,1'-oxybisethane was removed and a mixture of 40 parts of 3-pyridinecarbonitrile and 180 parts of benzene was added. The whole was heated under reflux for 2 hours and after cooling the mixture was poured into 300 parts of ice water. The separated aqueous phase was treated with ammonium hydroxide and the product was extracted three times with 150 parts of trichloromethane. The combined extracts were dried, filtered, and evaporated to leave a residue of 1
-(3-pyridinyl)-1-nonanone 70.7 parts (83.9
%) was obtained (Intermediate 5). Example 4 α-[3-(dimethoxymethyl)phenyl]-3
- Pyridine A mixture of 19 parts of methanol, 36 parts of activated manganese oxide and 280 parts of dichloromethane was stirred at room temperature over the weekend. The reaction mixture was filtered over silica gel and the filtrate was filtered again over diatomaceous earth and silica gel. Evaporate the filtrate;
The residue was distilled under vacuum. Collect the desired fraction,
15.7 parts (82%) of [3-(dimethoxymethyl)phenyl](3-pyridinyl)methanone was obtained (Intermediate 6). In a similar manner, the following was also prepared: [2-(dimethoxymethyl)phenyl](3-pyridinyl)methanone; boiling point 142-147°C (Intermediate 7). Example 5 2- in 225 parts of N,N-dimethylformamide
To a stirred and cooled (0°C) solution of 70 parts of phenyl-1-(3-pyridinyl)ethanone was added 2-methyl-2-propanol, potassium salt, under a nitrogen atmosphere.
46.9 parts were dropped. After the addition is complete, stir at 0℃ for 30 minutes.
Lasted for a minute. The reaction mixture was allowed to reach room temperature and 70 parts of iodomethane were added. The reaction mixture was allowed to reach room temperature for 8 hours. The mixture was poured into water and the product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated to dryness to give a residue of 30 parts (40%) of 2-phenyl-1-(3-pyridinyl)-1-propanone (intermediate 8). ). Example 6 [3-(trifluoromethyl)phenyl](3-
A mixture of 27.6 parts of pyridinyl)ethanone, 8.3 parts of hydroxylamine hydrochloride, 6.4 parts of sodium carbonate, and 160 parts of ethanol was stirred at reflux temperature for 24 hours.
After cooling, the precipitated product was filtered off (kept aside) and washed with water. The ethanol layer was concentrated and the residue was washed again with water, combined with the first fraction (described above) and crystallized from 120 parts of 4-methyl-2-pentanone. Filter the product,
Drying gave 20 parts (68%) of (E+Z)-(3-pyridinyl)[3-(trifluoromethyl)phenyl]methanone, oxime; melting point 185.4°C (Intermediate 9). In a similar manner, the following were also produced:

[Table] Example 7 70 parts of 1-(3-pyridinyl)-1-nonanone, 44.8 parts of hydroxylamine hydrochloride, potassium carbonate
A mixture of 88.2 parts and 320 parts of ethanol was stirred at reflux temperature for 2 hours. After evaporation to dryness, the residue was dissolved in water.
The product was extracted three times with 105 parts of 1,1'-oxybisethane. The combined extracts were filtered and evaporated, leaving 68.5 parts (91.6%) of 1-(3-pyridinyl)-1-nonanone and oxime.
(Intermediate 18) was obtained. In a similar manner, the following were also prepared: 1-(3-pyridinyl)-1-heptanone, oxime, as residue (intermediate 19); and (E+Z)-2-phenyl-1-(3-pyridinyl )-1-propanone, oxime (intermediate 20). Example 8 (4-methoxyphenyl)(3-pyridinyl)
Ethanone 4.3 parts, hydroxylamine hydrochloride 1.53 parts
N, N to a stirred mixture of 1 part and 80 parts of ethanol
-2.1 parts of diethylethanamine were added dropwise at room temperature.
After the addition was complete, stirring was continued at reflux temperature overnight. The reaction mixture was evaporated. The residue was taken into water with stirring. The product was filtered off, washed with water and crystallized twice, first from acetonitrile and then from ethyl acetate. The product was filtered off and treated with ethyl acetate and 2,
Washed with 2′-oxybispropane and dried under vacuum for 60 min.
Dry at °C, (E+Z)-(4-methoxyphenyl)
(3-pyridinyl)methanone, oxime; 1.68 parts (36.8%) was obtained. Melting point: 176.0°C (intermediate 21). Example 9 20.8 parts of hydroxylamine hydrochloride was added to a stirred mixture of 54.2 parts of (3-methylphenyl)(3-pyridinyl)methanone, 25.2 parts of sodium bicarbonate, and 480 parts of ethanol. Stirring was continued at reflux overnight. The precipitated product was filtered off (separate the filtrate) and stirred in water. The separate filtrate (see above) was evaporated. The residue was stirred in water. The aqueous solutions were combined. Filter the product,
Washing with water and 2,2'-oxybispropane and drying under vacuum at 65°C yielded (E+Z)-(3-methylphenyl)(3-pyridinyl)methanone, 52.1 parts (89.3%) of the oxime. ; Melting point 167.0℃ (intermediate
twenty two). In a similar manner, the following was also prepared: (E)-[2-(dimethoxymethyl)phenyl](3
-pyridinyl) methanone, oxime; melting point 124.2
(Intermediate 23); and (E+Z)-[3-(dimethoxymethyl)phenyl](3-pyridinyl)methanone, oxime; melting point 80.6°C (Intermediate 24). Example 10 [3,5-bis(trifluoromethyl)phenyl](3-pyridinyl)methanone 9 parts, hydroxylamine hydrochloride 2.09 parts, sodium acetate 2.46 parts
A mixture of 60 parts of methanol and 50 parts of water was stirred at reflux temperature for 8 hours. The ethanol layer was evaporated. The precipitated product was filtered off, washed successively with water, 2-propanol and 2,2'-oxybispropane, dried and yielded [3,5-bis(trifluoromethyl)phenyl](3-pyridinyl). methanone,
7.6% (81%) of oxime was obtained; melting point 188°C (intermediate 25). In a similar manner, the following was also prepared: (E+Z)-(3-pyridinyl)[2-trifluoromethyl)phenyl]methanone, oxime, as residue (intermediate 26). Example 11 A mixture of 40 parts of 2-phenyl-1-(3-pyridinyl)ethanone, 36.8 parts of 1-bromohexane, 2-methyl-2-propanol, 25 parts of potassium salt, and 200 parts of dimethyl sulfoxide was added under a nitrogen atmosphere. Stirred at room temperature for 2 hours. The product was extracted with ethyl acetate. The extract was washed with dilute sodium bicarbonate solution, dried, filtered and evaporated.
The residue was taken up in 160 parts of ethanol, and 32 parts of hydroxylamine hydrochloride were added. After stirring for 1 hour at 50°C, the mixture was evaporated and the product was extracted with ethyl acetate. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fraction was collected, the eluent was evaporated, and the residue (E+
Z)-2-phenyl-1-(3-pyridinyl)-1
- Octanone, 7.8 parts (13%) of oxime were obtained (intermediate 27). B Preparation Example 12 of Target Compound To a stirred mixture of (E)-3-pyridinecarboxaldehyde, 5 parts of oxime and 90 parts of N,N-dimethylformamide was added a portion of 4.02 parts of 50% sodium hydride dispersion at room temperature. Added one by one. After addition,
Stirring was continued at 40° C. until hydrogen gas evolution ceased. After cooling, N,N-dimethylformamide 13.5
A solution of 8.3 parts of 6-bromohexanoic acid in
It was dripped. After the addition was complete, the reaction mixture was stirred for 30 minutes. This was poured into water and acidified with hydrochloric acid to a pH value of 5. The precipitated product was filtered off and crystallized from a mixture of water and 2-propanol, giving (E)-6
- 6.37 parts (65.9%) of [[[(3-pyridinyl)methylene]amino]oxy]hexanoic acid was obtained; melting point
117.1°C (Compound 1). In a similar manner, the following were also prepared: (E)-5-[[[(3-pyridinyl)methylene]amino]oxy]pentanoic acid; mp 126.3°C (compound 2); and (E)-3 -[[[(3-pyridinyl)methylene]amino]oxy]propionic acid; melting point 155.5°C (compound 3). Example 13 To a stirred mixture of (E+Z)-phenyl(3-pyridinyl)methanone, 8 parts of oxime, and 108 parts of N,N-dimethylformamide was added 4.0 parts of 50% sodium hydride dispersion in portions at room temperature. .
After the addition was complete, stirring was continued until hydrogen gas evolution ceased. A solution of 8.3 parts of 5-bromopentanoic acid in 18 parts of N,N-dimethylformamide was added dropwise at room temperature. After the addition was complete, the reaction mixture was stirred and heated to 80° C. overnight. The solvent was evaporated. The residue was taken into an aqueous sodium bicarbonate solution and extracted three times with dichloromethane. Separated aqueous/NaHCO ₃ -phase
The pH value was brought to 5 with hydrochloric acid solution. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was taken up in 2-propanol and the 2-propanol was evaporated. The residue was stirred in a mixture of ethyl acetate and 2,2'-oxybispropane. The product was filtered off (separate filtrate), washed with 2,2'-oxybispropane, dried under vacuum at 70°C and as the first fraction (E+Z)-5-[[[ phenyl(3-pyridinyl)methylene]amino]oxy]
4.3 parts (35.8%) of pentanoic acid were obtained: melting point 97.4°C.
The separate filtrate was evaporated. The residue was dried under vacuum at 60 °C as a second fraction.
(E+Z)-5-[[[phenyl(3-pyridinyl)
0.8 part (6.6%) of methylene]amino]oxy]pentanoic acid was obtained; melting point 92.4°C (compound 4). In a similar manner, also prepared: (E+Z)-4-[[[phenyl](3-pyridinyl)methylene]amino]oxy]butyric acid; mp 88.2
(Compound 5); and (E+Z)-6-[[[phenyl](3-pyridinyl)methylene]amino]oxy]hexanoic acid; melting point 104.1°C (Compound 6). Example 14 To a stirred mixture of (E)-1-(3-pyridinyl)ethanone, 4.08 parts of oxime, and 45 parts of N,N-dimethylformamide was added portionwise 1.44 parts of 50% sodium hydride dispersion at room temperature. Ta. The mixture was stirred until complete reaction and heated briefly to 40-50°C in a water bath. After cooling, 6.9 parts of ethyl 5-bromopentanoate was added dropwise at room temperature (exothermic reaction). After the addition was complete, stirring was continued for 10 minutes. Upon standing at room temperature overnight, the reaction mixture was evaporated and water was added. The product was extracted with methylbenzene. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated to give 7.07 parts (89.5%) of ethyl (E)-5-[[[[1-(3-pyridinyl)ethylidene]amino]oxy]pentanoate as a residue. (Compound 7). In a similar manner, the following were also produced:

[Table] In a similar manner, the following were also prepared: Ethyl 5-[[[(2-furanyl)(3-pyridinyl)methylene]amino]oxy]pentanoate (compound 31); (4-methoxy-1-naphthalenyl)
(3-pyridinyl)methylene]amino]oxy]
Ethyl pentanoate (compound 32); 5-[[[(3-pyridinyl)(5-pyrimidinyl)
Ethyl methylene]amino]oxy]pentanoate (compound 33); 5-[[[(3,4,5-trimethoxyphenyl)
(3-pyridinyl)methylene]amino]oxy]
Ethyl pentanoate (compound 34); 5-[[[(2-dimethoxymethyl)-1-naphthalenyl](3-pyridinyl)methylene]amino]
oxy]ethyl pentanoate (compound 35); and 2-methyl-5-[[[(3-pyridinyl)[3-
Ethyl trifluoromethyl)phenyl]methylene]amino]oxy]pentanoate (compound 36). Example 15 (E+Z)-(3-pyridinyl)(3-thienyl)
To a stirred mixture of methanone, 10.2 parts of oxime, and 67.5 parts of N,N-dimethylformamide were added 2.4 parts of 50% sodium hydride dispersion in portions over 15 minutes at room temperature. After the addition was complete, stirring was continued until hydrogen evolution ceased. 12.5 parts of ethyl 5-bromopentanoate was added dropwise over 10 minutes. After the addition was complete, stirring was continued for 18 hours at room temperature. After evaporation under vacuum, the residue was stirred in water and the product was extracted with trichloromethane. The extract was dried, filtered and evaporated. The residue was purified twice by column chromatography on silica gel using a mixture of trichloromethane and ethyl acetate (90:10 by volume) as eluent. The first fraction was collected and the eluent was evaporated under vacuum, leaving (E)-5-[[[(3-pyridinyl)
5.5 parts (33.0%) of ethyl (3-thienyl)methylene]amino]oxy]pentanoate was obtained (compound
37). The second fraction was collected and the eluent was evaporated under vacuum, leaving (Z)-5-[[[(3
5 parts (30.0%) of ethyl pyridinyl)(3-thienyl)methylene]amino]oxy]pentanoate were obtained (compound 38). In a similar manner, the following were also produced:

[Table] Example 16 2-phenyl-1-(3-pyridinyl)ethanone, 7 parts of oxime, ethyl 6-bromohexanoate
A mixture of 8.7 parts of potassium carbonate, 10 parts of potassium carbonate, and 45 parts of N,N-dimethylformamide was stirred at room temperature overnight. After evaporation, the residue was taken up in ethyl acetate. The organic phase was washed with dilute aqueous sodium bicarbonate solution, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected, the eluent was evaporated, and the residue was 12 parts (95 %) was obtained (compound 47). In a similar manner, the following were also produced:

[Table] Example 17 Mixture of (E+Z)-2-phenyl-1-(3-pyridinyl)-1-octanone, 10 parts of oxime, 7.5 parts of ethyl 6-bromohexanoate, 10 parts of potassium carbonate, and 100 parts of dimethyl sulfoxide was stirred at room temperature overnight. The product was extracted with 1,1'-oxybisethane. The extract was washed with water, dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using trichloromethane as eluent. The pure fractions were collected, the eluent was evaporated, and the residue was (E+Z)-6-[[[2-phenyl-1
-(pyridinyl)octylidene]amino]oxy]
10 parts (68%) of ethyl hexanoate were obtained (compound
62). Example 18 4.3 parts of ethyl (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoate, 25 parts of 1N sodium hydroxide solution and 20 parts of ethanol mixture of at room temperature
Stirred for 2.5 hours. 25 parts of 1N hydrochloric acid was added and the ethanol layer was evaporated. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (98:2 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized from a mixture of 2,2'-oxybispropane and hexane (2:1 volume ratio). The product was filtered off, dried and (E)-5
1.7 parts (42.2 parts) of -[[[(3-pyridinyl)[3-trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid were obtained; melting point 70.3°C (compound 63). In a similar manner, the following were also produced:

【table】

[Table] In a similar manner, the following were also prepared: 5-[[[(2-furanyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid (compound
96); 5-[[[(4-methoxy-1-naphthalenyl)
(3-pyridinyl)methylene]amino]oxy]
Pentanoic acid (compound 97); 2-methyl-5-[[[(3-pyridinyl)[3-
(Trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid (compound 98); 5-[[[(3-pyridinyl)(5-pyrimidinyl)
methylene]amino]oxy]pentanoic acid (compound
99); and 5-[[[(3,4,5-trimethoxyphenyl)
(3-pyridinyl)methylene]amino]oxy]
Pentanoic acid (compound 100). Example 19 A mixture of 6 parts of ethyl 5-[[[2-methyl-1,2-di(3-pyridinyl)propylidene]amino]oxy]pentanoate and 80 parts of 3N sodium hydroxide solution was stirred at room temperature for 12 hours. . reaction mixture
Acidified with 3N hydrochloric acid. After evaporation to dryness, the residue was taken up in methanol and the precipitate was filtered off. The filtrate was evaporated and the residue was purified by column chromatography on silica gel using a mixture of trichloromethane, methanol and formic acid (90:10:1 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. 2 residues
- Converted to oxalate in a mixture of propanone and methanol. This salt is filtered off, dried and 5-
[[[2-methyl-1,2-di(3-pyridinyl)
4.2 parts (50%) of propylidene]amino]oxy]pentanoic acid oxalate (1:2) were obtained; melting point
134.8°C (compound 101). In a similar manner, the following were also produced:

[Table] Example 20 (E+Z)-5-[[[(3-pyridinyl)[3-
(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid 7.4 parts, sulfuric acid 2.16 parts,
80 parts of methanol and 2,2-dimethoxypropane
21.3 parts of the mixture was stirred at reflux temperature for 1 hour. After concentration, crushed ice was added to the concentrate and then ammonium hydroxide was added. The product was extracted with dichloromethane. The extract was dried, filtered, and concentrated. The residue was purified on silica gel with a mixture of trichloromethane and acetonitrile (80:20) as eluent.
and 85:15 volume ratio) and purified by column chromatography. The pure fractions were collected, the eluent was evaporated, and the residue was (E)−
4.7 parts (61%) of methyl 5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoate were obtained (compound
115). Example 21 (E+Z)-5-[[[[3-(dimethoxymethyl)
phenyl](3-pyridinyl)methylene]amino]
2.6 parts of ethyl oxy]pentanoate, 15 parts of 1N hydrochloric acid solution
and 13.5 parts of tetrahydrofuran were stirred at room temperature for 2 days (exothermic reaction: temperature rose to 40°C). Furthermore, 15 parts of 1N hydrochloric acid solution and 13.5 parts of tetrahydrofuran were added. After the reaction was completed, 30 parts of 1N sodium hydroxide solution was added, and then the tetrahydrofuran layer was separated. The aqueous phase was extracted with dichloromethane. The organic layer was dried, filtered and evaporated. The residue was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (90:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was crystallized at room temperature. The product was taken up into a mixture of ethyl acetate and 2,2'oxybispropane. The product was filtered off and the 2,2'-
Washed with oxybispropane and dried under vacuum at 60°C to give 0.55 parts (26.3%) of (E+Z)-5-[[[(3-formylphenyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid. obtained; melting point
111.4°C (compound 116). In a similar manner, the following was also prepared: 5-[[[(2-formyl-1-naphthalenyl)
(3-pyridinyl)methylene]amino]oxy]
Pentanoic acid (compound 171). Example 22 (E+Z)-5-[[[(4-nitrophenyl)(3
A mixture of 5.7 parts of ethyl -pyridinyl)methylene]amino]oxy]pentanoate, 13 parts of sodium hydrosulfite, 80 parts of ethanol and 65 parts of water was stirred at room temperature for 7 hours (slightly exothermic reaction). The mixture was left overnight. After evaporation, water was added and the product was extracted with dichloromethane. The extract was dried, filtered, and concentrated. The concentrate was purified by column chromatography on silica gel using a mixture of trichloromethane and methanol (95:5 volume ratio) as eluent. The pure fractions were collected, the eluent was evaporated, and the residue was 1.7 parts (33.1%) of ethyl (E+Z)-5-[[[(4-aminophenyl)(3-pyridinyl)methylene]amino]oxy]pentanoate. ) was obtained (compound 118). Example 23 (E+Z)-5 in 22.5 parts of tetrahydrofuran
-[[[(4-aminophenyl)(3-pyridinyl)
To a stirred solution of 1.7 parts of methylene]amino]oxy]pentanoic acid was added dropwise 0.56 parts of acetic anhydride at room temperature. After the addition was complete, stirring was continued for 2.5 hours at room temperature.
The mixture was left at room temperature over the weekend. After evaporation, the residue was purified on silica gel with a mixture of trichloromethane and methanol (90:10) as eluent.
It was purified by column chromatography using a volume ratio). Collect pure fraction,
The eluent was evaporated. The residue was stirred in 100 parts of a mixture of methylbenzene and 2,2'-oxybispropane (25:75 by volume). Filter the product, 2.
Washed with 2'-oxybispropane and dried, (E+Z)-5-[[[[4-(acetylamino)
phenyl](3-pyridinyl)methylene]amino]
1.2 parts (67.5%) of oxy]pentanoic acid were obtained; melting point 112.9°C (compound 119). Example 24 (E+Z)-6-[[[2-phenyl-1-(3-
A mixture of 7.6 parts of ethyl pyridinyl)propylidene]amino]oxy]hexanoate and 100 parts of 3N sodium hydroxide solution was stirred at room temperature overnight. The reaction mixture was neutralized to a pH value of 5.5 with 3N hydrochloric acid solution. The reaction mixture was concentrated and the concentrate was dissolved in 2-propanone. The inorganic salts were filtered off, the filtrate was dried, filtered and evaporated. The residue was placed on silica gel.
It was purified by column chromatography using a mixture of trichloromethane and ethyl acetate (95:5 volume ratio) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was dissolved in a solution of 0.56 parts sodium in methanol.
After evaporation to dryness, the residue was suspended in 1,1'-oxybisethane for 1 hour. The purified product was filtered off and dried under vacuum to give (E+Z)-6-[[[2-phenyl-1-(3-pyridinyl)propylidene]amino]
2.8 parts (38%) of sodium oxy]hexanoate were obtained; melting point 190.7°C (compound 120). Example 25 (E+Z)-5-[[[(3-
To a stirred solution of 1 part of pyridinyl)[3-trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid was added 2.94 parts of a solution of sodium methylate in methanol. The reaction mixture was evaporated. The precipitated product was filtered and dried at 60°C, and 0.6 part of sodium (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoate was added. (56.5%); melting point 215.9°C (compound 121). In a similar manner, the following was also prepared: (E)-5-[[[phenyl(3-pyridinyl)methylene]amino]oxy]sodium pentanoate;
Melting point 153.4°C (Compound 122); Sodium (E)-5-[[[(1-naphthalenyl)(3-pyridinyl)methylene]amino]oxy]pentanoate; Melting point 172.0°C (Compound 123); and in a similar manner , also prepared: (E)-Sodium 5-[[[(4-methoxy-1-naphthalenyl)(3-pyridinyl)methylene]amino]oxy]pentanoate (Compound 124). Example 26 To a stirred solution of 1 part (E)-5-[[[(1-naphthalenyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid in 75 parts trichloromethane is added 3-chlorobenzenecarboperoxoic acid. 0.625 parts were added in portions at 0-5°C. After the addition was complete, the reaction mixture was allowed to come to room temperature overnight. After evaporation, the residue was crystallized twice from ethyl acetate. The product was filtered off, washed with ethyl acetate and 2,2'-oxybispropane, dried under vacuum at 50 °C, and (E)
-5-[[[(1-naphthalenyl)(3-pyridinyl)
0.64 parts (61.1%) of methylene]amino]oxy]pentanoic acid, N-oxide were obtained; melting point 165.6°C (compound 125). Example 27 6.5 parts of silver oxide (), 50 parts of water, 63 parts of ethanol and 5-[[[(3-formylphenyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid
6.5 parts of the mixture was stirred at slightly elevated temperature for 1 hour, and 3
-[[(4-carboxybutoxy)imino](3-pyridinyl)methyl]benzoic acid was obtained (compound
126). C Pharmacological Examples Example 28 Platelet Malondialdehyde (MDA) Production As an indicator of thromboxane _A2 biosynthesis, MDA production by platelets in plasma was evaluated spectrofluorometrically. Citrated platelet-rich plasma (250 × ¹⁰ platelets/μ) in the presence of solvent (0.2% dimethyl sulfoxide) or compound solution was preincubated for 10 min at 37 °C, then
CaCl2 _1mM final concentration 50μ and thrombin 20N.I.
The final concentration of HU/ml was challenged to 50μ. 37
After 30 min at °C, 10% (w/v) trichloroacetic acid 1
The reaction was stopped by adding ml. After isolation of the supernatant by centrifugation at 320 g for 20 min, the thiobarbituric acid reaction on MDA was performed using acid-hydrolyzed 1,1,3,3-tetramethoxypropane as a standard. . After absorption at 510nm,
Fluorescence of the sample was measured at 553 nm. The result
It was calculated as nM MDA/10 ⁸ platelets/30 min and expressed as the percentage inhibition caused by the compound on the production of MDA after thrombin stimulation in vehicle. For in vitro experiments, human platelets in plasma were used. Percentage inhibition was calculated against solvent values. IC ₅₀ − values were determined as the dose in μM that resulted in 50% inhibition. For in vivo experiments, male Wistar
Rats were fasted overnight. 2 hours before blood collection
Animals were treated with test compound solution/suspension or vehicle. 50 on the MDA value obtained by the solvent
% inhibition was considered as a criterion for inhibitory activity. _ED50
- values were determined by probit analysis. The _IC50 -values of many compounds of formula () and
The _ED50 -values are shown in the table below. The compounds in this table are not shown for the purpose of limiting the invention thereto, but are merely illustrative of the useful pharmacological properties of all compounds within the scope of formula ().

[Table] Compound No. 4, 9, 63, 65, 68, 70, 72,
73, 74, 78, 84, 86, 89, 90, 92, 93 and 121
When toxicity tests were conducted on each of these, the LD ₅₀ for each was 40 mg/Kg body weight or higher. D Composition Examples The following preparations are illustrative of representative pharmaceutical compositions in dosage unit form suitable for systemic administration to animals and human patients in accordance with the present invention. The "active ingredient" (A.
I.) relates to compounds of formula () or pharmaceutically acceptable acid addition salts thereof. Example 29: Oral drop AI500g to 2-hydroxypropionic acid 0.5
and dissolved in polyethylene glycol 1.5 at 60-80°C. After cooling to 30-40°C, polyethylene glycol 35 was added and the mixture was thoroughly stirred. Then sodium saccharin in purified water 2.5
1750 g of the solution was added and, with stirring, 2.5 g of cocoa flavoring and enough polyethylene glycol to bring the volume to 50, producing an oral drop solution consisting of 10 mg of AI per ml. The resulting solution was filled into suitable containers. Example 30: Oral solution 9 g of methyl 4-hydroxybenzoate and 1 g of propyl 4-hydroxybenzoate were dissolved in 4 of boiling purified water. In this solution 3, first 2,
10 g of 3-dihydroxybutanedioic acid was dissolved, followed by 20 g of AI. The latter solution was combined with the remaining portion of the former solution and to this was added 12 1,2,3-propanetriol and 3 70% sorbitol solution. 40g of sodium saccharin in water
0.5, and added 2 ml of yellow strawberry essence and 2 ml of gooseberry essence. Combine the latter solution with the former and add enough water to make a volume of 20
to prepare an oral solution consisting of 20 mg of active ingredient per teaspoon (5 ml). The resulting solution was filled into suitable containers. Example 31: Capsule AI20g, sodium lauryl sulfate 6g, starch
56g, lactose 56g, colloidal silicon dioxide
0.8 g and 1.2 g of magnesium stearate were stirred together vigorously. The resulting mixture was then filled into 1000 suitable hard gelatin capsules each containing 20 mg of active ingredient. Example 32: Preparation of a film-coated tablet tablet core A mixture of 100 g AI, 570 g lactose and 200 g starch was thoroughly mixed, followed by 5 g sodium dodecyl sulfate and polyvinylpyrrolidone [Kollidon-K] in about 200 ml water. K) 90 ] 10
moistened with a solution of g. The wet powder mixture was sieved, dried and sieved again. Next, 100g of microcrystalline cellulose [Avicel]
and 15 g of hydrogenated vegetable oil (Sterotex) were added. The whole is mixed well and compressed into tablets, each containing 10 mg of active ingredient.
Obtained 10000 tablets. Coating To a solution of 10 g of methylcellulose (Methocel 60HG) in 75 ml of denatured ethanol was added a solution of 5 g of ethyl cellulose (Ethocel 22 cps) in 150 ml of dichloromethane.
Then 75 ml of dichloromethane and 2.5 ml of 1,2,3-propanetriol were added. Melt 10g of polyethylene glycol and 75ml of dichloromethane
dissolved in. The latter solution was added to the former, followed by 2.5 g of magnesium octadecanoate, 5 g of polyvinylpyrrolidone and 30 ml of a concentrated dye suspension (Opaspray K-1-2109) and the whole was homogenized. The tablet cores were coated with the mixture thus obtained in a coating device. Example 33: Injection solution 1.8 g of methyl 4-hydroxybenzoate and 4-
0.2 g of propyl hydroxybenzoate was dissolved in approximately 0.5 g of boiling water for injection. After cooling to about 50℃, add 4g of lactic acid and 0.05g of propylene glycol while stirring.
and 4 g of AI were added. Cool the solution to room temperature and
Add enough water for injection to make the volume 1,
A solution of 4 mg AI per ml was obtained. The solution was sterilized by filtration (USP p811) and filled into sterile containers. Example 34: Suppository 3 g of AI in 25 ml of polyethylene glycol 400 3 g of 2,3-dihydroxybutanediuccinic acid
was dissolved in a solution of Surfactant [SPAN
)] 12g and 300g of triglyceride [Witepsol 555]
were melted together. The latter mixture was thoroughly mixed with the former solution. The mixture thus obtained is 37-38
100 suppositories were produced, each containing 30 mg of active ingredient, by pouring into molds at a temperature of °C.

Claims (1)

[Claims] 1 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities stereochemically isomeric forms. 2 The [[(3-pyridinyl)methylene]amino]
2. A compound according to claim ¹ , wherein the oxy and -COOR groups are separated by at least 3 and at most 6 carbon atoms. 3. The compound according to claim 2, wherein R is Ar or Ar ( _C1 - _C4 alkyl). 4 R ¹ is hydrogen, and R is phenyl or naphthalenyl, and the phenyl and naphthalenyl are each independently C ₁ -C ₆ alkyl, C ₁ -
_C6 alkyloxy, di( _C1 - _C6 alkyloxy)
4. A compound according to claim 3, optionally substituted with up to two substituents which are methyl, formyl, halo or trifluoromethyl. 5 Pyridine ring and -O- in the oxime moiety
5. A compound according to claim 4, wherein the Alk-COOR ¹ substituent is in the trans configuration. 6 The compound is (E)-5-[[[(3-pyridinyl)[3
-(trifluoromethyl)phenyl]methylene]
The compound according to claim 1, which is amino]oxy]pentanoic acid. 7 The compound is (E)-5-[[[(3-methylphenyl)
(3-pyridinyl)methylene]amino]oxy]
The compound according to claim 1, which is pentanoic acid. 8 Inert carrier and formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities thromboxane A ₂ , prostacyclin and/or prostaglandin D ₂ in pharmaceutically acceptable amounts in stereochemically isomeric forms;
A pharmaceutical composition for the _treatment of clinical conditions associated with the production of E2 and _F2〓 . 9 The [[(3-pyridinyl)methylene]amino]
9. A pharmaceutical composition according to claim 8, wherein the oxy and ^-COOR groups are separated by at least 3 and at most 6 carbon atoms. 10. The pharmaceutical composition according to claim 9, wherein 10R is Ar or Ar ( _C1 - _C4 alkyl). 11 R ¹ is hydrogen, and R is phenyl or naphthalenyl, and the phenyl and naphthalenyl are each independently C ₁ -C ₆ alkyl, C ₁
Claim 10, optionally substituted with up to two substituents which are ~ _C6 alkyloxy, di( _C1 - _C6 alkyloxy)methyl, formyl, halo or trifluoromethyl. Pharmaceutical composition. 12 Pyridine ring and -O in oxime moiety
12. The pharmaceutical composition of claim 11, wherein the -Alk-COOR ¹ substituent is in the trans configuration. 13 The compound is (E)-5-[[[(3-pyridinyl)
The pharmaceutical composition according to claim 8, which is [3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid. 14. The pharmaceutical composition of claim 8, wherein the compound is (E)-5-[[[(3-methylphenyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid. 15 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities thromboxane A ₂ , prostacyclin and/or prostaglandin D ₂ , E ₂ and
Methods for treating clinical symptoms associated with the production of F ₂ 〓. 16 At least three of the [[(3-pyridinyl)methylene]amino]oxy groups and ^one -COOR group,
and separated by at most 6 carbon atoms. 17. The method of claim 16, wherein 17R is Ar or Ar ( _C1 - _C4 alkyl). 18 R ¹ is hydrogen, and R is phenyl or naphthalenyl, and the phenyl and naphthalenyl are each independently C ₁ -C ₆ alkyl, C ₁
Claim 17, optionally substituted with up to two substituents which are ~ _C6 alkyloxy, di( _C1 - _C6 alkyloxy)methyl, formyl, halo or trifluoromethyl. Method. 19 Pyridine ring and -O in oxime moiety
19. The method of claim 18, wherein the -Alk-COOR ¹ substituent is in the trans configuration. 20 The compound is (E)-5-[[[(3-pyridinyl)
16. The method according to claim 15, which is [3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid. 21. The method according to claim 15, wherein the compound is (E)-5-[[[(3-methylphenyl)(3-pyridinyl)methylene]amino]oxy]pentanoic acid. 22 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities In preparing stereochemically isomeric forms, the formula The oxime or its N-oxide or metal salt form is reacted with the formula W-Alk-COOR ¹ () where W represents a reactive leaving group, and the intermediate of O- or alkylating; or converting the compounds of formula () into each other, optionally according to group transfer methods known in the art, and optionally converting the compound of formula () into a solvent preferably inert to the reaction. and, if necessary, further treatment of the compound of formula () with a suitable acid or base to form a therapeutically active non-toxic acid addition. salt, metal salt or amine substituted salt; conversely, or acid addition salts are converted to the free base by an alkali, or metal salts or amine substituted salts are converted to the free acid form by an acid. and/or the above formula (), characterized in that it produces stereochemically isomeric forms thereof;
, its N-oxide form, its pharmaceutically acceptable acid addition, metal or amine substituted salts, or its possible stereochemically isomeric forms. 23 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities In preparing stereochemically isomeric forms, the formula of the aldehyde or ketone or its N-oxide form in a solvent inert to the reaction. (amino)oxy acids or esters of; or the compounds of formula () are optionally converted into each other according to group rearrangement methods known in the art; Conversion to the N-oxide form, preferably by treatment with a peroxide in a reaction-inert solvent; and, if necessary, further therapeutic conversion of the compound of formula () by treatment with a suitable acid or base. or convert the acid addition salt, metal salt or amine substituted salt to a non-toxic acid addition salt, metal salt or amine substituted salt active in The above formula () is characterized in that it is thus converted into the free acid form; and/or to produce stereochemically isomeric forms thereof.
, its N-oxide form, its pharmaceutically acceptable acid addition, metal or amine substituted salts, or its possible stereochemically isomeric forms. 24 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities In preparing stereochemically isomeric forms, the formula of the aldehyde or ketone or its N-oxide form in a solvent inert to the reaction. In the formula, R ² and R ³ are each independently hydrogen or
or React with an oxime of formula (), which is a _C1 - _C6 alkyl; or the compounds of formula () are optionally converted into each other according to group rearrangement methods known in the art and, if necessary, an oxime of formula () The compound of formula () is converted to the N-oxide form by treatment with a peroxide, preferably in a reaction-inert solvent; and further, if necessary, the compound of formula () is converted to the N-oxide form by treatment with a suitable acid or base. or convert the acid addition salts to the therapeutically active non-toxic acid addition salts, metal salts or amine substituted salts; conversely, or convert the acid addition salts to the free bases by means of alkali; the above formula (), characterized in that it is converted by an acid into the free acid form; and/or its stereochemically isomeric forms are produced.
, its N-oxide form, its pharmaceutically acceptable acid addition, metal or amine substituted salts, or its possible stereochemically isomeric forms. 25 formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities To prepare a stereochemically isomeric form, an alkene of the formula R ¹ OOC−C ₂ -C ₁₀ alkenediyl-H () is reacted with the formula () in an inert solvent. oxime or its N-oxide form; or the compounds of formula () are optionally converted into each other according to group rearrangement methods known in the art and, if necessary, the compounds of formula () are Conversion to the N-oxide form, preferably by treatment with a peroxide in a reaction-inert solvent; and, if necessary, further therapeutic conversion of the compound of formula () by treatment with a suitable acid or base. or convert the acid addition salt, metal salt or amine substituted salt to a non-toxic acid addition salt, metal salt or amine substituted salt active in The above formula () is characterized in that it is thus converted into the free acid form; and/or to produce stereochemically isomeric forms thereof.
, its N-oxide form, its pharmaceutically acceptable acid addition, metal or amine substituted salts, or its possible stereochemically isomeric forms. 26 (3-pyridinyl)[3-trifluoromethyl)phenyl]methanone, its oxime or metal salt, is reacted with 5-bromovaleric acid or its alkyl ester in a suitable reaction-inert solvent; and in the case of esters. the ester group is converted to the corresponding carboxylic acid by treatment with an aqueous alkaline solution; and, if necessary, the compound thus obtained is further treated with an acid or base to form a therapeutically active non-toxic acid addition. salt, metal salt or amine-substituted salt form; conversely, acid addition salts are converted to the free base by treatment with alkali, or metal salts or amine-substituted salts are converted by acid to the free acid form. (E)-5-[[[(3-pyridinyl)[3-(trifluoromethyl)phenyl]methylene]amino]oxy]pentanoic acid or its pharmaceutically acceptable acid addition salt, metal A method for producing a compound selected from the group consisting of salts or amine-substituted salts. 27 (3-methylphenyl)(3-pyridinyl)
Methanone, its oxime or metal salt form, is reacted with 5-bromovaleric acid or its alkyl ester in a suitable reaction-inert solvent; and in the case of an ester, the ester group is treated with an aqueous alkaline solution. converting it into the corresponding carboxylic acid; and further converting the compound thus obtained into the therapeutically active non-toxic acid addition salt, metal salt or amine substituted salt form by treatment with an acid or base; Conversely, (E)-5-[[[ (3-methylphenyl) (3
- A method for producing a compound selected from the group consisting of pyridinyl)methylene]amino]oxy]pentanoic acid or a pharmaceutically acceptable acid addition salt, metal salt or amine substituted salt thereof. 28 Inert carrier and formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities A composition for the treatment of thrombosis comprising a pharmaceutically acceptable amount of stereochemically isomeric forms. 29 Inert carrier and formula where R is hydrogen, _C1 - _C10 alkyl, trifluoromethyl, Ar or Ar( _C1 - _C10 alkyl); provided that Ar is phenyl, naphthalenyl, pyridinyl, pyrimidinyl, furanyl or thienyl; The phenyl and naphthalenyl each independently represent _C1 - _C6 alkyl, _C1 - _C6 alkoxy,
mono- and di( _C1 - _C6 alkyloxy)methyl,
optionally substituted with up to 3 substituents which are amino, _C1 - _C6 alkylcarbonylamino, carboxyl, formyl, halo, hydroxy, nitro or trifluoromethyl; ^R1 is hydrogen or C1- _{C6 6} alkyl; and Alk is a _C2 - _C10 alkanediyl group; with the proviso that [[(3-pyridinyl)methylene]
[amino]oxy group and ^one -COOR group shall not be bonded to the same carbon atom, N-oxide type, pharmaceutically acceptable acid addition salts, metal salts or amine substituted salts or their possibilities A composition for the treatment of ischemic diseases comprising a pharmaceutically acceptable amount of stereochemically isomeric forms.