CZ121895A3 - Symmetrically substituted chalcones and process for preparing thereof - Google Patents

Abstract

Symmetrically substituted antituberculotic chalcones of formula I wherein R is hydrogen or methyl, R 1 is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl or substituted phenyl of 1 to 2 halogens (F, Cl, Br, I) or hydroxy-, nitro-, cyano-, trichloromethyl-, or alkoxy containing 1 to 4 carbon atoms in the carbon chain, Ar denotes phenyl, or substituted phenyl with 1 to 3 halogens (F, Cl, Br, I), or nitro-, cyano-, hydroxy-, tetrahydro-2H-pyran-2-yloxy-, trifluoromethyl-, alkyl-, alkoxy-, alkoxycarbonyl-, acyloxy-, acylamino-, di- alkylamino- up to 6 carbon atoms in the alkyl chain or a 5 to 6 membered heteroaromatic system containing nitrogen, oxygen or sulfur as heteroatom, optionally containing nitrogen, oxygen or sulfur as heteroatom and substituted with alkyl, alkoxy or alkoxycarbonyl; a carbon atom having from 1 to 3 carbon atoms in the alkyl chain. The process for their preparation consists in treating the corresponding 3,5-diacetylpyridine of formula (II), wherein R and R 1 are as defined above, in a solution of lower alkanol at a temperature of 5 ° C with stirring of the ArCHO aldehyde of formula (III) where Ar as defined above, in the presence of a base-reacting catalyst in a molar ratio of reactants of 1: 2.5 to 5: 0.05 to 0.3, after which the reaction temperature is gradually raised to a condensation temperature after 2 to 5 hours of stirring at the above temperature 15 to 35 ° C and after 5 to 24 hours the reaction mixture is cooled and the crystallized portions are separated and further purified by recrystallization.

Description

Symmetrical substituted chalcones and methods for their preparation

I “Γ <=

Technical field

The invention relates to substituted chalcones with antituberculotic effects

BACKGROUND OF THE INVENTION

Substituted chalcones exhibit a wide and diverse biological effect (Dhar, DN: Chemistry of Chalcones and Related ⁴ Compounds, J. Viley, New York 1981, Chapter 26, p.213).

For example, various derivatives exhibit antibacterial (Oriental J. Chem. 1986, 2, 55), antiviral (Antimicrob. Agents Chemother.

1982, 22, 617, J. Antimicrob. Chemother. 1984, 14, 403; Antiviral Res. 1990, 13, 61), antimutagenic (Biochem. Biophys.Res.Commun.

1983, 112, 883), retinoid (J. Med. Chem. 1990, 33, 1430, J. Med. Chem. 1989, 32, 834), antimitotic (J. Med. Chem. 1984, 33, 1948, J. Med. Biol.Chem. 1989, 264, 21296), antineoplastic (EP Appl. 292576 A1 (1988)), anti-inflammatory (Pharmazie 1991, 46, 542, Carcinogenesis 1991, 12, 317, Planta Medica 1991, 57, 221, Arzneim. Forsch. 1987, 37, 435, P11), anti-ulcer activity (EP Appl. 412803 A1 (1992), EP Appl. 292576 A1 (1988), WO Appl. 8804288 A1 (1988), JPX 5106871 (1992)), and also are used to protect the gastrointestinal tract, skin protection _(Ε χ Ρ χ Appl. 502,205 Al (1992), WO Appl. 9205137 Al (1992)) and the treatment of multiple sclerosis (EP 286 083 A3 (1990)), and prostate (EP 224386 A2 (1984)).

A variety of methods for the preparation of chalcones are described in the literature (see above), the most suitable and most commonly used being undoubtedly the Claisen-Schmidt condensation of the corresponding substituted acetylphenones with substituted base-catalyzed benzaldehydes (eg hydroxides, alkoxides eg HCl, H2SO4, AlCl3, BF3, POCl3)

-2Friedel-Crafts acylation of substituted aromatic compounds with substituted cinnamoyl chlorides. Of the diverse series of hitherto synthesized chalcones, there are only a few reports describing the preparation of chalcones based on diacetylpyridine derivatives. They are mostly substances made from 2,

6-diacetylpyridine and 4-X-benzaldehydes (X = H, CH 3 CH-10 O, Cl),

Indian J. Chem. Sec., 30B (1) 46-51 (1991), Chem. Abstr. 114,

143230 (1991). When preparing a series of chalcones derived from 3,

The 5-disubstituted pyridine derivatives were under basic conditions in the base-catalyzed reaction (Collect

Czech.Chem.Commun. 57, 1937 (199 * 2) found that mostly undesired polymer products are formed which make product isolation difficult. Conversely, in the acid-catalyzed reaction (CH 3 COOH / H 2 SO 4), six chalcones were prepared from a series of formula I wherein Ar is unsubstituted phenyl, R is H and CH 3 and is hydrogen or phenyl. The disadvantage of this procedure was that it did not make it practically possible to prepare substituted derivatives and the product yields were only satisfactory (50%).

SUMMARY OF THE INVENTION

This drawback removes the invention of symmetrically substituted chalcones with antituberculotic effects of formula I wherein R is hydrogen or methyl,

R @ 1 denotes hydrogen, C1 -C4 alkyl or phenyl or substituted phenyl having 1 to 2 halogen substituents (F, Cl, Br, I) or hydroxy, nitro, cyano, trichloromethyl or trifluoromethyl groups or alkoxy containing from 1 to 4 carbon atoms in the carbon chain,

Ar is phenyl, or substituted phenyl with 1 to 3 halogen substituents (F, Cl, Br, I), or nitro-, cyano-, hydroxy-, tetrahydro-2H-pyran-2-yloxy-, trifluoromethyl, alkyl-, alkoxy-, alkoxycarbonyl-, acyloxy-, acylamino-, dialkylamino- having 1 to 6 carbon atoms in the alkyl chain

Or represents a 5-6 membered heteroaromatic system containing as heteroatom nitrogen, oxygen or sulfur optionally substituted by an alkyl, alkoxy or alkoxycarbonyl group containing from 1 to 3 carbon atoms in the alkyl chain.

against susceptible and antituberculotics resistant Mycobacterium tuberculosis strains and against non-tuberculous (atypical) mycobacteria.

An integral part of the present invention is a process for the preparation of said chalcones of formula (I), which are obtained by relatively simple basic catalysed Claisen-Schmidt reaction of the starting substituted 3,5-diacetylpyridine of formula (II) wherein R a is as hereinbefore defined. an aldehyde of formula III wherein Ar is as defined above.

According to the process of the invention, to the solution of the corresponding 3,5-diacetylpyridine of formula II in lower alkanol at 0 + 5 ° C, a mixture of the aldehyde of formula III and a solution of the basic reacting catalyst in a molar ratio of reactants of 1 is added under stirring. 2.5 to 5: 0.05 to 0.3, preferably 1: 3 to 4: 0.1 to 0.2. In the case where the ArCHO of the formula contains acidic reacting substituents (e.g. OH.COOH, SH group), an appropriately increased amount of the basic catalyst must be used. After stirring for 2 to 5 hours at the above temperature, the reaction mixture is slowly warmed to 15 to 35 ° C, preferably 20 + 5, and further stirred for 5 to 24 hours. The progress of the reaction can be controlled by thin layer chromatography. Often, during the reaction, a crystalline product precipitates, which is suctioned off after cooling the reaction mixture. For products containing acid reacting substituents, the reaction mixture is first acidified with dilute acid and the product is either filtered off with suction or extracted with a halogenated solvent, preferably chloroform, dichloromethane or dichloroethane, after which the combined extracts are worked up by standard procedures. Crystallization of the product from a suitable solvent such as methanol, ethanol, chloroform, diethyl acetate, pyridine, followed by a mixture thereof yields the product of formula I in the desired purity and very good yield (60-90%).

Preferably, methanol, ethanol, 2-propanol is used as the lower alcohol, and alkali metal (sodium, potassium), alkaline earth (calcium, barium) or sec. amines such as 1-methylpiperidine, dimethylcyclohexylamine, triethylamine, piperidine, diisopropylethylamine.

Results of biological evaluation

The substituted chalcones of formula (I) exhibit high mycobacterial activity in vitro as determined on the Sula broth by the dilution method. Activity of a compound of formula I wherein R is methyl and R1 is hydrogen against Mycobacterium tuberculosis H1 Rv (minimum inhibitory concentration - MIC 0.25 µg / ml) against M. kansasii PKGg (MIC 5 µg / ml) against M. avium 80/72 (MIC 50 µg / ml) is the same as for isonicotin hydrazide higher than antituberculotics

2-ethylisonicotinamide, p-aminosalicylic acid (PAS) and thiosemicarbazone p-acetamidobenzaldehyde. In an in vivo experiment, acute toxicity was found in mice (dosis maximum tolerant - indicative data 2000 mg / kg) i.e. 10-fold lower than that of isonicotin hydrazide (125mg / kg). In a chemotherapeutic experiment of experimental tuberculosis of mice induced by M. tuberculosis H37RV strain, this compound had a modest therapeutic effect after 21 days of oral administration at a concentration of 10 mg / mouse / day. The results were confirmed by histopathological examination of mouse organs.

The advantages of the process for the preparation of the compounds of the formula I are the easy isolation and high purity of the product, simple devices and readily available starting compounds.

Furthermore, relatively good antituberculotic activity against Mycobacteria tuberculosis which are resistant to Isomiazide and other aforementioned species of mycobacteria and last but not least, very low in vitro toxicity.

The process according to the invention is illustrated by means of several exemplary embodiments, which are illustrative only and do not limit the scope of the invention in any way.

-5ExampleExample

Example 1

1,1 '- (2,6-dimethyl-3,5-pyridinediyl) -bis [3- (4-chlorophenyl) - (E, E) -2-propen-1-one].

To a solution of 3,5-diacetyl-2,6-dimethylpyridine (2g, 10.5 mmol) in methanol (40 mL) was added p-chlorobenzaldehyde (5.6 g, 40 mmol) with stirring, the solution was cooled to ca. Potassium hydroxide (50 mg, 0.9 mmol) was added and the solution was stirred at about 5 ° C for 3 h. The mixture was allowed to warm to room temperature spontaneously and was further stirred at this temperature for 10 h. The resulting precipitate was aspirated and recrystallized from chloroform-methanol to give 3.2g (70%) of the desired product as yellowish crystals, mp = 175-177 ° C.

1 H NMR Spectrum:

2.71 s (6H, 2 x CH _3), 7.09 d (2H, = CH, J _HH = 16.22 Hz), 7.50 d (2H,

CH =, J? J? = 16.22 Hz), 7.89 s (1H, pyridine), 7.40 d (4H, benzene, JHH ⁼ 8.32Hz), 7.51 d (4H, benzene, J? 8.28 Hz).

The infrared spectrum in chloroform contains bands (cm *: 1591, 1644, 1667 (CH = CHCO-Ar group), 2971 (CH alif), 3013 (CH arom).

Example 2

1,1 '- (2,6-dimethyl-3,5-pyridindiyl) -bis [3- (4-methylphenyl) - (E, E) -2-propen-1-one].

To a solution of 3,5-diacetyl-2,6-dimethylpyridine (2 g, 10.5 mmol) in methanol (40 mL) was added p-methylbenzaldehyde (4, 80 g, 40 mmol) with stirring, the solution was cooled to ca. Potassium hydroxide (50 mg, 0.9 mmol) was added and the solution was stirred at ca. 5 ° C for 2 h. The solution was then allowed to warm to room temperature spontaneously and was further stirred at this temperature for 5 h. The resulting precipitate was aspirated and recrystallized from methanol to give 2.4g (58%) of crystals, mp = 122-124 ° C. The mother liquors were filtered off with suction and diluted with chloroform (40 ml) and washed with water (20 ml). The aqueous phase was washed with chloroform (2 x 10 mL), the combined chloroform portions were washed with saturated chloride solution

6-sodium (2 x 20 mL) and dried with calcined magnesium sulfate.

After evaporation of the solvents, the distillation residue (4.5 g) was chromatographed (180 g SiCl 2, eluent 3% methanol in chloroform) to give 1.11 g (28%) of the desired product m.p. = 123 to

124.5 ®C. A total of 3.51 g (86%) of white crystals were obtained.

NMR Spectrum:

2.39 s (6H, 2xCH ₃ ), 2.70 s (6H, 2xCH ₃ , pyridine), 7.07 d (2H, CH =, ^J H H ^{= 16 '12 Hz} ) ⁷ · ^{48 d} (2H, ^{CH =} ' ^J HH ^{= 16} ' ^{12 Hz} >> 7.87 ^s ( ^1H 'pyridine), 7.22 d (4H, benzene, 8.18Hz), 7.47 d (4H, benzene, ^J HH = ⁸ ' ^{19 Hz} ) ·

IR spectrum in chloroform showed absorptions (cm ^- @): 1596, 1639, 1685 (CH = CHC0-Ar), 2925, 2971 (CH aliph.), 3013 (CH arom.).

Example 3

1,1 '- (2,6-dimethyl-3,5-pyridindiyl) -bis [3- (4-nitrophenyl) - (E, E) -2-propen-1-one].

To a solution of 3,5-diacetyl-2,6-dimethylpyridine (2 g, 10.5 mmol) in methanol (40 ml) was added with stirring p-nitrobenzaldehyde (6 04 g, 40 mmol), cooled to about 0 ⁹ Potassium hydroxide (50 mg, 0.9 mmol) was added and the solution was stirred at ca. 5 ° C for 2 h. The solution was then allowed to warm to room temperature spontaneously and further stirred at this temperature for 2 h. the precipitate was aspirated and recrystallization from pyridine gave 3.4g (71%) of crystals tt = 260-262 ° C.

1 H NMR Spectrum:

2.75 s (6H, 2 x CH _3), 7.25 d (2H, = CH, J _HH = 15.94 Hz), 7.60 d (2H,

CH =, Jp | J | = 15.94 Hz), 7.97 s (1H, pyridine), 7.74 d (4H, benzene, JHH ⁼ 8.79Hz), 8.29 d (4H, benzene, δ H); ^{= 8.29} Hz).

Infrared spectrum in KBr contains bands (cm ^-1 ): 1347 (NO 2), 1518, 1602, 1670 (CH = CHCOAr group).

Example 4

1,1 '- (2,6-dimethyl-3,5-pyridinediyl) -bis [3- (4-hydroxyphenyl) - (E, E) -2-propen-1-one].

To a solution of 3,5-diacetyl-2,6-dimethylpyridine (2 g, 10.5 mmol) in methanol (40 mL) was added p-hydroxybenzaldehyde (4.88 g, 40 mmol) while stirring, the solution was cooled to ca. 0, potassium hydroxide (2.4 g, 43 mmol) was added and the solution was stirred at about 5 θθ for 2 h. The solution was then allowed to warm to room temperature spontaneously and stirred at this temperature for 24 h. Dilute with chloroform (50 mL) and acidify with dilute hydrochloric acid (1M) to pH = ca. 4. The aqueous layer was washed with chloroform (2 x 20 mL), the combined chloroform layers were washed with water (30 mL), brine (30 mL). ml) and were dried with magnesium sulfate. After evaporation of the solvents, the distillation residue (3.2g) was chromatographed (150g SiCl 2, eluent 10% methanol in chloroform) to give 1.23g (30%) of the desired product m.p. = 217-218 ° C <3.

1 H NMR Spectrum:

2.56 s (6H, 2 x CH _3), 7.21 d (2H, = CH, J _HH = 15.93 Hz), 7.49 d (2H,

CH = Jpju = 15.93 Hz), 8.15 s (1H, pyridine), 6.80 d (4H, benzene, ^J HH = 8,24Hz), 7.66 d (4H, benzene, J _HH = 8.36 Hz), 10.13 s (2H, OH). Infrared spectrum in KBr comprising bands (cm @ ^- @): 1514,1585,1649, 1668 (CH = CHCOAr), 2926 (CH aliph.), 3198, 3450 (OH).

Industrial applicability

The invention is useful in the pharmaceutical industry and in the manufacture of medicaments with antituberculotic effects.

Claims (8)

PATENT <T ι— X7 —4 - <-w. > * 'Zl J O o z < O -J n < (£ o £ £ Symmetrically substituted chalcones with antituberculotic effects of the general formula I, (i) wherein R represents hydrogen or methyl, R is hydrogen, alkyl of 1 to 4 carbon atoms or phenyl, or substituted phenyl of 1 to 2 substituents formed by halogen (F, Cl, Br, I), or hydroxy, nitro, cyano, trichloromethyl or trifluoromethyl, or alkoxy containing from 1 to 4 carbon atoms in the carbon chain, Ar is phenyl, or substituted phenyl with 1 to 3 halogen substituents (F, Cl, Br, I), or nitro, cyano, hydroxy, tetrahydro-2H-pyran-2-yloxy, trifluoromethyl, alkyl, an alkoxy-, alkoxycarbonyl-, acyloxy-, acylamino-, dialkylamino group containing a T 1-6 carbon atom in the alkyl chain or is a 5-6 membered heteroaromatic system containing nitrogen, oxygen or sulfur as the heteroatom, or a 5-6 membered heteroaromatic system, containing a nitrogen, oxygen or sulfur heteroatom and substituted with an alkyl, alkoxy or alkoxycarbonyl group containing from 1 to 3 carbon atoms in the alkyl chain. 2. A process for the preparation of symmetrically substituted compounds of the formula I as claimed in claim 1, characterized in that the method is as follows 3,5-diacetylpyridine of formula II wherein R a is as defined above in a lower alkanol solution acts at 0 + 5 ° C with stirring with an aldehyde of formula III, ArCHO where Ar is as defined above in the presence of a basically reacting of catalyst in a molar ratio of reactants of from 1: 2.5 to 5: 0.05 to 0.3, wherein for the aldehydes ArCHO containing acidic reactive substituents, the amount of basic catalyst is used at the upper end of the range, and after stirring for 2-5 hours the reaction temperature is gradually raised to a condensation temperature of 15 to 35 ° C and after 5 to 24 hours the reaction mixture is cooled, and the crystallized fractions are separated and further purified by recrystallization from a solvent selected from methanol, ethanol, chloroform, diethyl acetate, pyridine and / or mixtures thereof. The process (according to claim 2, characterized in that if the aldehyde (III) used contains an acidic substituent in the Ar group, the cooled reaction mixture is first acidified with dilute acid and the precipitated product is filtered off with suction or extracted into an organic solvent from the group. methanol, ethanol, chloroform, diethyl acetate, pyridine and / or mixtures thereof. The process according to claims 2 and 3, wherein the lower alkanol is methanol, ethanol, 2-propanol. 5. The process according to claims 2 to 4, characterized in that the molar ratio of the reactants and the basic catalyst is preferably 1: 3 to 4: 0, 1 to 0.2. The process according to claims 2 to 5, characterized in that the basic catalyst used is an alkali metal hydroxide, preferably sodium or potassium or alkaline caustic soils, preferably calcium, barium or secondary and tertiary amines. 2/1 Preferably 1-methylpiperidine, dimethylcyclohexylamine, triethylamine, diisopropylethylamine, piperidine. Method according to claims 2 to 6, characterized in that a 1M solution of hydrochloric, sulfuric or phosphoric acid is used as the dilute acid. , 8. A process according to claim 2, wherein the condensation reaction is carried out at a temperature of 20 + 5 ° C.