SU1676453A3 - Method for preparation of fused pyrasol derivatives or theirs pharmaceutically accessible salts - Google Patents

Abstract

The invention relates to heterocyclic substances, in particular the preparation of compounds of the general f-ly I: where E is O or K C Su-alkyl, phenyl; RJ (independent) -H, halogen,.-Alkyl, C C -agasoxy; Q-H, C (0) -NHR & when Kv-C, -C-alkyl or (CHj) n-RJ- with RjT-phenyl (possibly mopo-or disubstituted with halogen, CFj, N0, C-alkyl) and n 0 or 1, or their pharmaceutically acceptable salts with immunomodulatory activity that can be used in medicine. The goal is to create new, more active substances of the specified class. Synthesis is carried out by the reaction of compounds; Nenya f-ly II with the compound f-ly III: NЈC-CH2-Q, VN-NR2-R3 C where Y is a chemically active substituent of the carboxy group; in an inert solvent in the presence of a basic agent at a temperature of from room temperature to 60 ° C. If necessary, the obtained compound with Q-H is reacted with compound f-ly IV:. The preparation of the necessary salts is carried out by the appropriate treatment of compound F. I. New compounds have low toxicity (mice over 400 mg / kg) and are active at a dose of 0.5-10 mg / kg. 1 tab. (Л С о VJ Ол GJ СО

Description

This invention relates to a process for the preparation of novel fused pyrazole derivatives having immuno-modulating activity.

The purpose of the invention is the synthesis of new compounds in a series of condensed derivatives of pyrosol, which in their activity are superior to a structural analogue possessing the same type of activity.

Example 1. To a suspension of 50% sodium hydride (7.4 g) in anhydrous dioxane (50 ml) under nitrogen atmosphere

with stirring at room temperature, a solution of diethyloxalate (34.5 g) in anhydrous dioxane (20 ml) is added, and then a solution of 2a, 5 3,4,5-tetrahydroacenaphthene-1-one (20.4 g) in anhydrous dnoxane (130 ml). The reaction mixture is kept under stirring at 25-45 ° C for

4 h, then it is diluted with ice

water (1500 ml) and acidified to fN 4 with 2N. HC1. The precipitate is filtered off with water, washed with water and then purified by treatment with methanol to give 2-ethoxy-2a, 3,4,5-tetrahydrocenaphene-1-one (30.8 g, mp 92-94 ° C, which is reacted with methyl hydrazine (5.7 g) in acetic acid (300 ml) at 50 ° C for 1 hour.

After cooling, the mixture is diluted with ice water, and the precipitate is filtered on a silica column using a 90:10 mixture of hexane and ethyl acetate, and then 80:20 as eluent, to give 3-ethoxycarbonyl-1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene (1,2-e) pyrazole (19.8 g), m.p. 115-117 ° C. This compound (3.2 g) is then reacted with acetonitrile (48 ml) dioxane (22 ml) in the presence of 50% sodium hydride (1.1 g) with stirring at 60 ° C for 45 minutes. After cooling, the reaction mixture is diluted with ice water and acidified to pH 4 with citric acid. The precipitate is filtered and washed with water until neutral. Crystallization from methanol gives 2.1 g of 3- (1-methyl-Sv, 4,5,6-tetra-hydro-1H-acenaphthyleno) 1,2-c (pyrazol-3-yl) -3-oxopropanenitrile, m.p. 225-227 ° C.

Using similar procedures, the following compounds can be obtained: 3- (1-phenyl-Sv, 4,5,6-tetra-hydro-1H-acenaphthyleno) 1,2-c (pyrazol-3-yl) -3- oxopropanenitrile, so pl. 143-1 46 ° C). 3- (9-methoxy-1-methyl-3b, 4,5,6-tetrahydro-1H-acenaphthylene) 1, 2-c (pyrazol-3-yl) -3-oxo-propanenitrile, m.p. 230-233 ° C.

PRI mme R 2. 3- (1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene) 1,2 -c (pyrazol-3-yl) -3-oxopropanenitrile (1.95 g ) is reacted with phenyl isocyanate (0.8 g) in the presence of triethylamine (0.75 g) in

, five ).

ten

15

20

thirty

)

a-25, -

6764534

dimethylformamide (20 ml) with stirring at 25-30 ° C for 90 minutes. The reaction mixture is diluted with ice water, acidified with HCl, and the precipitate is filtered and washed with water. Crystallization from a mixture of dichloromethane and methanol gives 1.8 g of 2-cyano-3- (1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene) 1,2-c (pyrazole-3- or) N-phenyl-3-oxopropanamide, mp 267-270 ° C, COTMCO-dg + CDC13 NMR, o, ppm: 3.61 (double doublet) (1H, C-Zv proton), 4.18 (singlet) (3N, CH3) 6.9-7.7 (multiplet) (8H, aromatic protons), 9.95 (broad singlet) (1H, -CONH-).

Using similar techniques, the following compounds can be obtained:

2-cyano-3- (1-phenyl-Sv, 4,5,6-tetra-hydro-1H-acenaphthyleno) 1,2-e (pyrazol-3-yl) -N - phenyl-3-oxopropanamide, t .pl. 250-252 ° C

2-cyano-3- (9-chloro-1-methyl-Sv, 4,5,6- -tetrahydro-1H-acenaphthyleno) 1,2-e (pyrazol-3-yl) -M-phenyl-3-oxopropanamide m.p. 275-278 ° C,

2-cyano-3- (9-methoxy-1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthyleno) 1,2-c (pyrazole-3-yl) -M-phenyl-3-oxopropane - mid, so pl. 275-277 ° C.

EXAMPLE 3. By performing procedures similar to those of Example 2, using the appropriate isocyanates, the following compounds can be obtained:

N- (4-chlorophenyl) -2-cyano-3- (1-methyl-Zv, 4,5,6-tetrahydro-1H-acenaphthyleno) 1, 2-e (pyrazole-3-yl) -Z-oxopropane - mid, tplo 275-278 0, N- (3-chlorophenyl) -2-cyano-3- (1-methyl-Zv, 4,5,6-tetrahydro-1H-acenaphthylene) 1,2-s (pyrazol-3-yl) -3-oxoprop-d5 namid, m.p. 270-272 ° C

2-cyano-M- (4-fluorophenyl) -3- (1-methyl-Zv, 4,5,6-tetrahydro-1H-acenaphthyleno) 1,2-e (pyrazol-3-yl) -3-oxopropane - mid, so pl. 289-290 ° C, 2-cyano-M- (4-methoxyphenyl) -3- (1-methyl-Sv, 4,5,6-tetrahydro-1 H-acenaphthyleno) 1,2-c (pyrazole -3-yl) -3-oxopropanamide, mp: 258-261 ° C, 2-cyano-3- (1-methyl-Sv, 4,5,6-tetrahydro -1H-acen aftile but) 1 , 2-c (pyrazol-3-yl) -M- (3-trifluoromethylphenyl) -3-oy-sopropanamide, m.p..275-276 ° C, N-butyl-2-cyano-3- (1- methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthyleno) 1,2-s (pi35

40

50

Razol-3-yl) -3-oxopropanamide, mp, 300 ° C, decomp.,

2-cyano-H- (3-nitrophenyl) -3- (1-methyl-Zv, 4,5,6-tetragvdro-1H-acenaphthylene) 1,2-e (pyrazol-3-yl) -oxopropane - mid, tp.251-253 ° C, 2-cyano-No- (3-methylphenyl) -3- (1-methyl-Sv, 4,5,6-those trahydro-1H-acenaphthylene) 1,2-e (pyrazol-3-yl) -3-oxopropanamide, m.p. 245-250 ° C. N-benzyl-2-cyano-3- (1-methyl-sv, 4,5,6-tetrahydro-1H-acenaphthyleno) 1,2-e (pyrazol-3-yl) -3-oxopropanamide, m.p. . 266-268 ° C.

Example 4. Adenaften-1-in (IACS, 62.432.1940) (4.1 g) is reacted with diethyloxalate (4.2 g in anhydrous ethanol (280 ml) containing sodium ethoxide (from 0.66 g sodium) at room temperature for 2 hours .. The precipitate is filtered and washed with hexane, then dissolved in water. The aqueous solution is acidified to pH 4 with citric acid, and the precipitate is filtered and washed with water. Crystallization from a mixture of chloroform and hexane gives 2-ethoxalyl adenaphthene 1-one, mp 101-1036 ° C (5.1 g), which is reacted with methyl hydrazide (1.3 g) in acetic acid (110 ml) n 60 ° C for 4 hours. After cooling, the reaction mixture is diluted with ice water and extracted with ethyl acetate.

The organic solution is evaporated to dryness in vacuo, and the residue is purified on an instant chromatography column using a mixture of 1: 1 hexane and ethyl acetate as eluent to give 3-ethoxycarbonyl-1-methyl-1H-α-enaphthylene (1,2-c) pyrazole, t .pl. 107-109 ° C (3 g), which hydrolyzes with heating with a 1% KOH solution in 95% ethanol (5.5 ml) at reflux temperature for 30 minutes. The reaction mixture is diluted with ice water and acidified to pH 3 with 37% HC1. The precipitate is filtered off, washed with water and crystallized from a mixture of chloroform and ethanol to give 1-methyl-1H-a-acetylene (1,2-c) pyrazole-3-carboxylic acid, mp. (2.4 g), which is reacted with thionyl chloride (1.3 ml) in dioxane (150 ml) at reflux temperature for 2 hours. After cooling, the solution is evaporated to dryness in vacuo.

five

0

Cuome, giving 1-methyl-IH-acenafth K1-but (1,2-c) pyrazole-3-carbonyl chloride (2.6 g). The crude product is dissolved in anhydrous dioxane (55 ml) and reacted for 20 minutes with stirring at room temperature with cyanoacetanilide carbanion (1.7 g) obtained by treatment with 50% sodium hydride (0.62%). d) in anhydrous dimethylformamide (30 ml) at room temperature. The reaction mixture is then diluted with ice water and acidified to pH 1 using normals. HClo The precipitate is filtered off and dissolved in chloroform, then the organic solution is washed with normal NNS and water until neutral. Crystallization from a mixture of chloroform and ethanol gives 3.1 g of 2-cyano-3- (1-methyl-1H-acena-naphleno II, 2-c} pyrazole-3-np) -H-phenyl-3-oxopropanamide, mp.275-278 C, NMR (CDS1),, ppm: 4.30 (syn5 gl) (3N, -CH3) 7.10-8.20 (multiplet) (12H), phenyl protons + (- COMN-), 16.5 (singlet) (1H-OH enol) „

By carrying out the process in a similar way can be obtained

0 the following compounds: 2-cyano-3- (1- -methyl-Sv, 4,5,6-those trahydro-1H-acenaphyleneo) 1,2-e (pyrazol-3-yl) -M-phenyl- 3- -oxopropanamide, m.p. 027-270 ° C. Example 5 p. 2-cyano-3- (1-me, thyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene) 1,2-e (pyrazol-3-yl) -M-phenyl- 3-α-oxopropanamide is dissolved by treatment with an equivalent amount of sodium ethylate in ethanol. Solution

0 is evaporated to dryness and the residue is treated with isopropyl ether and then filtered, giving the sodium salt of 2-cyano-3- (1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene) 1,2-e (pyrazole) 35-yl) -M-phenyl-3-oxopropanamide, m.p.LOZOO ° C.

By operating in a similar manner, the following compounds can be obtained: 2-cyano-3- (9-methoxy-1-methyl-Sv,

0 4,5,6-tetrahydro-1H-acenaphthyleno) 1,2- -c (pyrazol-3-yl) -N-phenyl-3-oxopropanamide, m.p. 290-295 ° C (decomposition).

Example H-Ethoxycarbonyl-9- -methoxy-1-netil-4,5-dihydro-1I, Sv I-15 -beneopyrano (4,5,6-e, f) cyclopentapyrazole (4.3 g), obtained according to Example 18, suspended in ethanol (160 ml), is reacted with a solution of KOH (1.9 g) in water

(12.5 ml). The reaction mixture is heated at reflux for 30 minutes. After cooling, the solution is diluted with ice water and acidified to pH 2 with 2N HCl. The precipitate is filtered and washed with water until neutral, then dried in vacuo to give 9-methoxy-I-methyl-A-dihydro-III, Zv H-1-benzopyrano (4,5,6-e, f) cyclopentapira sol-3-carboxylic acid, mp. 267-270 ° C (3.8 g), which is reacted with thionyl chloride (2.1 ml) in dioxane (150 ml) at reflux temperature for 1 hour. After cooling the solution is evaporated to dryness in vacuo to give 9 methoxy-1-methyl-4,5-dihydro-III, Zv H-benzopyrano (4,5,6-e, f) cyclopentapyrazole-3-carbonyl chloride (3, 9 g ). The crude product, dissolved in anhydrous dioxane (80 ml), is added with stirring at room temperature to a suspension of a carbanion prepared by treating cyanoacetanilide (2.32 g) with 50% sodium hydride (0.76 g) in anhydrous dimethylformamide (15 ml) and anhydrous dioxane (70 ml). The reaction mixture is stirred at room temperature for 45 minutes, then diluted with ice water and acidified to pH 2 with 2 n. HCl. The precipitate is filtered off, then dissolved in chloroform, and the organic solution is washed several times with a normal HCl solution and then with water until neutral. Evaporation to dryness in vacuum and crystallization from a mixture of methylene chloride and metha-nol give 2.7 g of 2-cyano-3- (9-methoxy--1-methyl-4,5-dihydro-1H, Zv H-1-benzopyrano) 4,5,6-е, f (-cyclopentapira-1-sol-3-yl) -M-phenyl-3-oxopropanamide, i.e. 262-264 ° С, NMR (СРС1), million ppm: 1.20-1.90 (multiplet) (1H, C-4 proton), 1.70 (multiplet) (1H, C-4 proton) , 3.50-4.80 (multiplet) (3N, N-CH3), 6.50-7.70 (multiplet) (7H, phenyl protons), 7.95 (singlet), (1H, -CONH-) , 16.20 (singlet) (1H, -OH enol).

By carrying out the process in the same way, the following compounds can be obtained: 2-cyano-3- (9-chloro-1-methyl-4,5-dihydro, 1H, Zv H-1-Bezopyrano) 4,5,6 -e, f (cyclopentapyrazol-3-yl) -N-phenyl-3-oxopropanamide 244-246 ° C.

5 0 g about 5 Q

five

Example 7. By carrying out the process according to Example 21, the result of suitable derivatives of 3-ethoxycarbonyl-4,5-dihydro-1H, Sv H1-benzothiopyrano (4,5,6-e, f) cyclopentapyrazole, The following compounds can be prepared:

2-cyano-3- (9-methoxy-1-methyl-4,5-di-hydro-1H, Zv H-1-benzothiopyrano) 4,5,6-e, f (cyclopentapyrazole-b-yl) - M-Phenyl-3-oxopropanamide, 270-273 ° C.

Try on 2-Cyano-3- (9-chloro--1-methyl-4,5-dihydro-1H, Zv H-1-benopypyrano) 4,5,6-e, f (cyclopentapiraeol-3-yl) The α-phenyl-3-oxopropanamide is dissolved by treatment with an equivalent amount of sodium ethylate in ethanol. The solution is evaporated to dryness and the residue is treated with isopropyl ether, and then filtered to give the sodium salt 2-cyano-3- (9-chloro-1-methyl-4,5-dihydro-1H, Zv H-1-benzopyrano) -4,5,6-е, f (cyclopentapyrazol-3-yl) -M-phenyl-3-oxopropanamide, mp above 300 ° C.

When carrying out the process in a similar way, sodium salts of the following compounds can be obtained: 2-cyano-H- (9-methoxy-1-methyl-4,5-dihydro-1H, Zv H-1-benzopyrano) 4,5, 6--е, f (cyclopentapyrazole-3-nl) -I-phenyl-3-oxopropanamide, m.p. 280-190 ° C (decomposed).

I

The immunomodulatory activity of the compounds of the invention is proved, for example, by the fact that they are effective in potentiating the cytotoxic activity of macrophages in relation to tumor cells and vitro. Below is an example of an experimental procedure that can be used to evaluate this activity: groups of four mice are treated with intraperitoneally tested compounds, and then after seven days the peritoneal cells are collected and poured into plates for 2 hours at 37 ° C. After this time periods, the walls are washed to remove non-adherent cells, then cells of the tumor being studied are added, and incubation is continued for 48 hours. At the end of this period, the viability of the test is evaluated. s cells using a calorimetric method, and determines a fkolichestvo e at 570 nm.

The table presents the data of representatives of the compounds of formula (I) on immunomodulatory activity in accordance with the procedure described above against the tumor of ACE cells.

In the experiment described above, the ratio of macrophages: tumor cells of an ACE is 5: 1.

The cytotoxic activity was calculated in% inhibition of tumor growth in the ACE tumor using the following formula:

, l (OD.A. - OD.V) - (OD.S. - OD.D.1% inhibition - ° --J--,

OH YEAH. - О.Д.В.

where is OD.A. - optical density in the joint growth of the ACE and

solvent-treated macrophages;

О.Д.В. - optical density for solvent-treated macrophages;

O.S. - optical density in the joint cultivation of the ACE and macrophages treated with the CEU compound

O.D.D. - optical density for macrophages treated with compound CE;

CE 25129 refers to 2-cyano-3- (1- -methyl-Sv, 4,5,6-tetrahydro-1H-acecenaphthylene, 2-cJpyrazol-3-yl) -N-phenyl-3-oxopropanamide;

CE 25479 is 2-cyano-3- (9- -methoxy-1-methyl-4,5-dihydro-1H-Zv H-1-benzopyrano 4,5,6-e, G cyclopentapyrazol-3-yl ) -P-phenyl-3-oxopropanamide;

CE 25513 denotes 2-cyano-Z- - (chloro-1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene 1,2-c pyrazol-3-yl) -N-phenyl-3- oxopropanamide;

CE 25566 denotes 2-cyano-Z- (9- -me-Goxy-1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene J, 2-pyrazole-3- -yl) -№-phenyl -3-oxopropanamide;

CE 25567 refers to M-benzyl-2-cyano-3- (1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene Tl, 2nd pyrazol-3-yl) -oxopr opanamide;

CE 25647 refers to N-butyl-2-cyano-3- (1-methyl-Sv, 4,5,6-those trahydro-1H-acenaphthylene 1,2-cj pyrazol-3-yl) -3- oxopropanamide;

CE 26124 denotes the number (3-chlorophenyl -2-cyano-3- (1-methyl-Sv, 4,5,6-tetrahyd ro-1H-acenaphthylene fl, 2-pyrazole 3 -yl) -3-oxopropanamide;

CE 26125 denotes 2-cyano-M- (4- -fluorophenyl) -3- (1-methyl-Sv, 4,5,6-those of t-hydra-1 H-acenaphthylene p, 2-c pyrazole-3 -yl) -3-oxopropanamide;

CE 26127 refers to 2-cyano-K- (3- -ni, trofenyl) -3- (1-methyl-Sv, 4,5, 6-tetrahydro-1H-acenaphthyleno Ј1,2-c pyrazol-3-yl) -3-oxopropanmid;

CE 26128 denotes 2-cyano-3- (1- -methyl-Sv, 4,5,6-tetrahydro-1 H-acenaf-tyleno 1,2-c pyrazol-3-yl) -H- (3-trn - fluoromethylphenyl) -3-oxopropanamide;

CE 26129 denotes 2-cyano-G - (3-methylphenll) -3- (1-methyl-Sv, 4,5,6-tetrahydro-1H-acenaphthylene 1,2-c1pyra-aol-3-yl) - 3-oxopropanamide;

CE 20696-6H, 6 (2-dimethylaminoethoxy carbonyl) -dibenzoЈv.dlnnpaH hydrochloride (known compound).

By virtue of the high therapeutic ratio, the compounds of the present invention can be safely used in medicine; in fact, they are low toxic compounds; stew.

For example, approximate sharp

toxicity (DD50 in M11e For the compound mentioned above under the CE 25129 cipher, which was determined when applied through the mouth with a single injection consistently increasing before and measured on the seventh day after use, is more than 400 mg / kg

Similar toxicity data were obtained for other compounds that are the subject of the present invention, for example, those listed in the table below.

The treatment regimen for cases of various clinical syndromes should be chosen depending on the type of pathology, also taking into account, as usual, the method of prescribing the form in which the compound is prescribed, and the age, weight and condition of the subject being treated.

Oral administration is generally used for all conditions in which such compounds are required. Preference is given to intravenous injection or infusion for the treatment of acute infections. For maintenance regimens, oral or parenteral, for example, intramuscular or subcutaneous method is preferred.

For these purposes, the compounds of the invention can be administered orally in doses of, for example, about 0.5-10 mg / kg of body weight per day for adults. Doses of active compounds that vary, for example, about 0.2-5 mg / kg body weight can be used for parenteral administration for adults. Of course, these dosage regimens can be adjusted to provide the optimum therapeutic response.

Claims (1)

Invention Formula Method for preparing condensed pyrazole derivatives of general formula I 2 1 N with (0) -sn-cm ;, Q where E is a CHe group or oxygen; C-C-alkyl or phenyl; V 35 R is each hydrogen, halogen, C, -C-alkyl, or C, -C-alkoxy; Q is hydrogen or -SOISHgroup; RB С-С-alkyl or (СН) у group where n 040 RC is phenyl, unsubstituted or substituted by one or two substituents, selected independently from halogen, CFj, nitro and C-C-alkyl, their pharmaceutically acceptable, corresponding to the fact that | 45 Compound 25129 25479 25513 25566 25567 reacting a compound of general formula II NGG-K R2 Q 5 0 five 0 35 40 45 where E, is the indicated value; Y is a chemically active derivative of the carboxy group, with a compound of the general formula III ch-01. Q where Q has the indicated values, in an inert solvent in the presence of a basic agent at a temperature from room temperature to, and, if necessary, the interaction of a compound of general formula Q is hydrogen with a compound of general formula IV RFC-N "4 0, where R. has the indicated values to obtain a compound of the general formula I, where Q is a -CONHRg group, where RJ has the indicated values and / or, if necessary, the preparation of a salt from the compound of the general formula I. Priority is based on: 09/18/87 with E — group R — C — Cf-alkyl or phenyl; R / and RJ- each is hydrogen, halogen, C | -C $ -alkyl or C -C-alkoxy; Q is hydrogen or —CONH Rg-group, where R is a kil or - (CH2) h-BRt group, where n or I; Ry is phenyl, unsubstituted or substituted with one or two substituents selected independently from halogen, CF, nitro or C, kela. 10.27.87 with E - oxygen. 13 167645314 Table continuation