FI59406C - PROCEDURE FOR THE SUBSTANCE OF 2H-PYRAN-2,6 (3H) -DIONERATED WOOL INHIBERAR ANTIGEN-ANTIKROPPREAKTIONER - Google Patents

Description

R25CT ΓΒΙ f11, ADVERTISEMENT γλ λ Λ / 'JGTa m <11> utlAcgningsskrift 5 9 4 U 0 C (45) Patent granted tty 10 03 1931, ΛΑ'jjf Patent ceddelat VTV (51) Kv.ik? /Int.a. 3 C 07 D 309/36 FINLAND — FINLAND <*) PttanttlhakMiMi »- Pacantameknlng 752139 (22) Htkemtopllvl - An« 6ki »lng * d« g 2U.07.79 (23) AlkupUvl — Glltl | h «tad« g 2U.07.75 (41) Tullut lulkbakal - Bllvtt affantllg

Patented by the State Itua .... ________. ,, ......

- '(44) Diffuse »k» lp «noo μ date of issue. -

Patent · och regiateratyralaan 'Amoiun utbgd och utl. * Krift «n pubitcand 30. OU. 81

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23.0U.75 USA99U0, 570896 (71) Smithkline Corporation, 1500 Spring Garden Street, Philadelphia, Pennsylvania 19101, USA (72) Lawrence William Chakrin, Haddonfield, New Jersey, Kenneth Means Snader, Hatboro, Pennsylvania , USA (US), Chester Rhodes Willis,

Kingston, Jamaica-Jamaica (JM) (7U) Berggren Oy Ab (5U) Method for the preparation of substituted 2H-pyran-2,6 (3H) -dione derivatives acting as inhibitors of antigen-antibody reactions - Förfarande för framställning av substituerade 2H-pyran-- 2,6 (3H) -dione derivatives, vigorous in vivo antigenic antichroppreaktioner

The present invention relates to a process for the preparation of substituted 2H-pyran-2,6 (3H) -dione derivatives which are effective inhibitors of antigen-antibody reactions and have the following general structural formula:

Hl 13 nhr (i) oo ^ 0 wherein R is lower alkyl of 3 to 6 carbon atoms, hydroxyphenyl, alkanoyloxyphenyl, wherein the alkanoyl moiety has 2 to 7 carbon atoms, carbamoyloxyphenyl, N-benzylcarbamoyloxyphenyl, p-mercaptophenyl, aminophenyl or aminophenyl .

The process of the invention comprises reacting 3,5-diacetyl-N, 6-dihydroxy-2H-pyran-2-one with the amine RNH2, wherein R is as defined in formula I. The reactants are usually heated to reflux in a neutral organic solvent. such as benzene, toluene or alkanol, e.g. methanol or ethanol, for 2-12 hours to obtain the desired end products. Mono- and di-alkali metal salts of the products, such as mono- and disodium or potassium salts, can be readily obtained by treating the product with a suitable alkali metal alkoxide, for example methoxide in an alkanol solvent such as methanol.

Compounds in which R is alkanoyloxyphenyl are conveniently prepared starting from the corresponding hydroxyphenyl derivative by reacting it with a suitable alkanoyl chloride, preferably in an organic base such as triethylamine, and in an inert solvent such as tetrahydrofuran.

For convenience, the starting material used in this process is called 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one and is obtained by reacting acetone dicarboxylic acid with acetic anhydride at elevated temperature in sulfuric acid. However, the reaction product actually has the following tautomeric structure fj 0H? 0 OH 0 0 OH 0 X JL l II 1 II J 1> CHT ^ CH-. CH 2 Cl 2. C H ^ CH, '[I 2_ \ 5 3 _s, 3 | 3

^ "'O ^ O ^ o ^ O ^ O ^ O ^' ^ O '^ OH

This has been confirmed by NMR spectrometric and X-ray crystallographic studies of C4 atoms. The amount of tautomerism shown in Formulas A is affected by e.g. the solvent used in C1'5 spectral studies. Thus, the reaction of this compound with the amine RNH2 according to the invention provides a product having the following tautomeric structures: 59406 ®

O OH CH, O OH CH O OH CHT

H li3 11 X 1 P i | J

CH, ^ C ^ u nr CH, / C'VV ^ NsY ^ C ^ NHR ch, ^ 0 il II 3 I i HO ^ O ^ O ^ O- ^ O ^^ O ^ 0 ^^ O oh in which formulas R is defined in formula I.

Although it has not been possible to determine the exact tautomerism of the substance in solution by NMR spectrometry of cX4 atoms, X-ray crystal studies using solid compounds in which R is p-hydroxyphenyl have shown that, due to the very extensive conjugation, carbon-carbon the bonds are hybridized throughout the molecule, and as a result, the bond lengths are somewhere between the lengths of the double and single bonds. However, since one of the interchangeable hydrogens is located in this compound under nitrogen, for convenience we have chosen to use one tautomeric form of formula I, namely the intermediate enamine-pyran-2,6-dione structure, to represent all compounds formed by administering formula (A) react with the amine RNHE. However, it will be apparent to one skilled in the art that the structure of the compounds of formula I will be more fully manifested from the tautomeric forms shown in formula (b).

The compounds prepared by the method of the invention inhibit the release and / or formation of pharmacologically active mediators from effector cells which are retained by the interaction of the antigen and a specific antibody attached to the cellular structure. Thus, these compounds are valuable in the treatment of allergic diseases such as asthma, gout and urticaria.

The compounds prepared by the process of the invention are preferably used as pharmaceutical compositions containing a suitable amount of a substituted 2H-pyran-2,6 (3H) -dione derivative of formula I in association with a pharmaceutical carrier or diluent. The nature of the mixture and the pharmaceutical carrier or diluent H 59406 will, of course, depend on the desired route of administration, i. whether it is oral, parenteral or inhalation. The active drug is preferably administered in a mixture containing a sufficient amount of the compound to effect inhibition of the antigen-antibody reaction. When used in this way, the dosage of the mixture is such that 0.5 to 500 mg of active ingredient is administered in each dosage. The administration is preferably carried out by administering equal doses 1 to 4 times daily in a daily dosage amount of about 0.5 to 2000 mg.

The pharmaceutical preparations are prepared by conventional methods known from pharmaceutical chemistry, which include mixing, granulating and compressing, if necessary, or various mixing treatments and dissolving the ingredients to obtain the desired end product.

Pharmacological experiments

The inhibitory activity of the compounds of the invention on the release of neurotransmitters in sensitized tissues was measured by the ability of the active drug to inhibit passive cutaneous anaphylaxis (PCA) in rats. In this experimental set-up, a titrated and appropriately diluted serum (obtained from rats previously immunized by intraperitoneal injection of egg albumin aluminum hydroxide or egg albumin imbordatella pertussis USP and II brasiliensis) containing reactive antibodies, directed against egg albumin are injected intradermally into the four depilated areas of the back of normal adult male rats. 48 hours later, the animals are injected intravenously with 0.5 ml of isotonic saline containing 5 mg of egg albumin antigen and 5 mg of Evans blue dye. Chemical mediators such as histamine and serotonin, which are released at sensitized sites due to local cell anaphylaxis, cause an increase in capillary permeability, resulting in plasma leakage and blister formation. This blister can be detected by the blue color of Evans bound to plasma protein. Under the experimental conditions, the average size of the blister is about 12 x 12 mm. Thirty minutes after antigen sensitization, 5,590,406 animals are sacrificed, their dorsal skin is inspected, and bladder diameter is recorded. The test compound is administered intravenously (i.v.) initially 0.5 minutes before antigen administration. (This test can also be performed using other modes of drug administration, i.e., oral or intraperitoneal). The percentage inhibition is calculated from the mean difference in blister diameter between the treated group and the control group given saline or some suitable diluent.

Table 1 shows the results of the above experiment comparing the compounds prepared by the process of the invention with those described in Journal of Organic Chemistry, (21) (1956), 686-688, which are prepared by reacting pyran-2-ones with an amine.

Table 1 Inhibition of PCA reaction in rats R Dose Inhibit # (mg / kg, iv) a) p-hydroxyphenyl 5.0 73 p-mercaptophenyl 5.0 100 p-aminophenyl 0.5 58 b) phenyl 10.0 76 p -dimethylaminophenyl 100 (ip) 11 p-nitrophenyl 10.0 17 p-methoxyphenyl 5.0 27 a) compounds according to the invention b) known compounds

When the compounds were administered intravenously (i.v.), the pretreatment time was 1/2 minute and when administered intraperitoneally (i.p.), the pretreatment time was always 5 minutes.

6 59406

It can be seen from Table 1 that the compounds prepared by the process of the invention are considerably more active than the known compounds.

When the mechanism of action was tested, the compounds of formula I were not found to provide similar or comparable inhibition of vesicle formation in rats by intracutaneous administration of histamine and serotonin to rats, followed by i.v. using the test compound at the same dosage and pretreatment time that produced significant inhibition in the 48-hour PCA reaction in rats.

Oral administration of 5-acetyl-4-hydroxy-3 ', N- (p-hydroxyphenylamino) ethylidene-2H-pyran-2,6 (3H) -dione provided 58% inhibition in a 48-hour rat PCA system. at a dose of 25 mg / kg and a pretreatment time of 15 minutes. This compound is also active in vitro to inhibit antigen-mediated release of the neurotransmitter from monkey lung and skin and from the lung system of rats at β-x 3 to --3.3 x 10 M. Similarly, 5-acetyl-3- [1- -aminophenylamino) -ethylidene-4-hydroxy-2H-pyran-2,6 (3H) -dione provided oral inhibition of $ 32 in a 48-hour rat PCA system at a dose of 25 mg / kg and a pretreatment time of 5 minutes. A compound of formula I wherein R is hydroxyphenyl is preferred for oral administration.

The following examples illustrate the process of the invention and the preparation of compounds of formula I.

Example 1

To a boiling solution of 4.2 g (0.02 m) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of benzene-methanol is added 1.2 g (0.02 m ) n-propylamine and the resulting mixture was heated at reflux overnight. The reaction mixture is concentrated, filtered and the solid is treated with water to give pure 5-acetyl-4-hydroxy-3- [1- (n-propylamino) ethylidene] -2H-pyran-2,6 (3H) -dione, m.p. 145-148 ° C.

7 59406

Similarly, 1.8 g (0.025 m) of n-butylamine and 5.3 g (0.025 m) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one are heated under reflux overnight in 50 ml of: benzene and the resulting solid is filtered to give 5-acetyl-3- [N- (n-butylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. LL4 to 112 ° C.

Example 2

To a boiling solution of 4.2 g (0.02 m) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of benzene is added 2.0 g (0, 02 m) n-hexylamine and the mixture is concentrated and the oily residue is triturated with petroleum ether to give 5-acetyl-2- [N- (n-hexylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H ) -dionia, m.p. 80-82 ° C.

Example 5

To a boiling solution of 4.24 g (0.02 m) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 200 ml of methanol is added 2.18 g (0.02 m ) p-hydroxyaniline. The resulting mixture was heated at reflux overnight and filtered to give 5-acetyl-4-hydroxy-3-7Ϊ- (p-hydroxyphenylamino) ethylidene-2H-pyran-2,6 (3H) -dione, m.p. 223-225 ° C. Both mono- and disodium salts are prepared after treatment of the dione with sodium methoxide in methanol.

Similarly, m-hydroxyaniline or o-hydroxyaniline is reacted with an equimolar amount of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in methanol to give the corresponding products, 5-acetyl-4-hydroxy- 3- [T- (m-hydroxyphenylamino) -ethylidene] -2H-pyran-2,6 (3H) -dione, m.p. 213-216 ° C, and 5-acetyl-4-hydroxy-3- [N- (° -hydroxyphenylamino) -ethylidene] -2H-pyran-2,6 (3H) -dione, m.p.

210-212 ° C.

Example 4

A mixture of 2.12 g of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one, 1.25 g of p-aminothiophenol and 75 ml of methanol is heated under reflux for 2 hours, cooled and filtered. to give 5-acetyl-4-hydroxy-3- [N- (p-mercaphthenylamino) ethylidene] d.7-2H-pyraa-2,6-3H) -dione, m.p. 207-210 ° C.

Example 5 o-Phenylenediamine (2.1 g; 0.02 m) is added to a hot solution of 4.2 g (0.02 m) of 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2- on methanol and the resulting mixture is heated at reflux for 2 hours. The reaction mixture is cooled and filtered to give 5-acetyl-3- [N- (o-aminophenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. L8L ~ 179 ° C.

Similarly, reacting an equimolar amount of p-phenylenediamine as described above affords the corresponding 5-acetyl-3- [1- (p-aminophenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. 2L8 ~ 215 ° C.

Example 6

To a solution of 3.03 g (0.01 m) of 5-acetyl-4-hydroxy-3 - [(1-hydroxyphenylamino) ethylidene] -2H-pyran-2,6 (3H) -dione and 1, 0 g (0.01 m) of triethylamine in 150 ml of tetrahydrofuran, 0.78 g (0.01 m) of acetyl chloride are added. The resulting mixture is heated to reflux for 2 hours, cooled and filtered. The solid is recrystallized to give 3- [N- (p-acetoxyphenylamino) ethylene] -5-acetyl-4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. 199-201 ° C.

Similarly, equimolar amounts of 5-acetyl-4-hydroxy-3- [7 '(p-hydroxyphenylamino) ethylidene] -2H-pyran-2,6 (3H) -dione and the appropriate alkanoyl chloride are reacted as described above to give the following alkanoyloxy derivatives : 5-Acetyl-4-hydroxy-3 - [(p-propionyloxyphenylamino) ethylidene] -2H-pyran-2,6 (3H) -dione, m.p. 168-170 ° C, 5-acetyl-3- [N- (p-butyryloxyphenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. 158-160 ° C, 5-acetyl-4-hydroxy-3- [N- (p-pentanoyloxyphenylamino) ethylidene] -2H-pyran-2,6 (3H) -dione, m.p. 155-157 ° C, 5-acetyl-3- [N- (p-hexanoyloxyphenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. 148-149 ° 5-acetyl-3 - [[N- (p-heptanoyloxyphenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. L47-L48 ° C.

9 59406 and the solid is recrystallized from 5-acetyl-3- [1- (p-N-benzylcarbamoyloxyphenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione, m.p. 195-197 ° C.

Example 8

A solution of 1.88 g (0.01 m) of p-carbamoyloxyaniline hydrochloride and 1.0 g (0.01 m) of triethylamine in 50 ml of methanol is added to a hot solution of 2.21 g (0 , M) 3,5-diacetyl-4,6-dihydroxy-2H-pyran-2-one in 150 ml of methanol. The resulting mixture was heated at reflux for 2 hours, cooled and the filtered solid recrystallized to give 5-acetyl-3- [1- (p-carbamoyloxyphenylamino) ethylidene] -4-hydroxy-2H-pyran-2,6 (3H) -dione. , sp. 213-215 ° C.

Example 9

A solution of 1.5 g (0.01 m) of p-ureidoaniline in 50 ml of methanol is added to a solution of 2.1 g (0.01 m) of 3,5-diacetyl-4,6-dihydroxy-2H- pyran-2-one in 150 ml of methanol. A solid formed immediately and the mixture was heated to reflux for 12 hours. The filtered solid is recrystallized to give 5-acetyl-4-hydroxy-3- [1- (p-ureidophenylamino) ethylidene] -2H-pyran-2,6 (3H) -dione, m.p. 250-253 ° C.