HU204043B - Process for producing new chromene derivatives having analgetic effect and analgetic compositions comprising same as active ingredient - Google Patents

Abstract

Novel analgesic chromene derivs. (IV) are prepd. at 50-120 deg.C from chromanone derivs. (I) with a cpd. contg. a halogen atom (V), in polar-protic, bipolar-aprotic solvent in the presence of alkali-hydroxide or -carbonate bases and alkali-iodide catalysts. Chromanone derivs. (II) obtained are reduced to chromanol derivs. (III) by complex metal-hydrides in alcohols or ethers at their boiling pt. Cpds. (III) are dehydrated to chromene derivs. (IV), by a mineral acid. In all above formulae R = 1-4C-alkyl or alkoxy gps. and R1 = an aryl gp.

Description

The present invention relates to the preparation of novel chromene slides and analgesic compositions containing such compounds as active ingredients.

As used herein, variable substituents in the general formulas have the following meanings:

R is (C1-C4) -alkyl, (C1-C4) -alkoxy,

R 1 is a C 6 -C 10 homoaromatic group which may be optionally substituted by halogen,

X is halogen.

The novel compounds produced by the process of the present invention are so-called "isolated from nature". Analogues of Precocene-1 (P1) and Precocene-2 (P2). The biological activity of P1 and P2 on insects is known [Science, 193, 542 (1976)], and their use as a new type of environmentally friendly insecticide is expected.

Intensive research has been conducted over the last ten years to produce analogs with activity greater than that of natural P1 and P2 (U.S. Pat. No. 4,162,326, U.S. Pat. No. 4,542,150, U.S. Pat. No. 4,716,238, 194,214). descriptions).

The above patents disclose a number of synthetic P1 and P2 analogues which have activity beyond the insecticidal activity of natural compounds (P1 and P2) and have also recognized their nematicidal activity (Hungarian Patent No. 194,214).

In the course of our work, several novel chromene derivatives containing an acid amide side chain on the aromatic ring have been prepared by the methods described in the above mentioned scientific and patent literature. These compounds have been shown to be completely inactive in classical precocene tests (Hungarian Patent Specification No. 194,214). phenylquinone in the Writ-35 hing test.

Thus, the present invention is based on the discovery that the novel chromene slides of formula (IV) have an analgesic effect on the order of codeine, and compounds of this type are not known among the 40 analgesics.

SUMMARY OF THE INVENTION The present invention relates to a process for the preparation of novel compounds of formula (TV).

According to this method, the chromanone derivatives of the formula I, wherein R is as defined above, are prepared in accordance with the method described above

SHE

R1-NH-C-CH2-X - wherein R1 and X are reacted with the above compound in a polar protic, bipolar aprotic solvent, alkali hydroxides, alkali carbonates as bases, alkali iodides as catalysts in the presence of 50-120 [deg.] C., the chromanone derivatives of the general formula (H) in which R and R1 are as defined above are reduced with the complex metal hydride, alcohols, ethers at the boiling point of the solvents, followed by The chromanol derivatives of the formula wherein R and R 1 are as defined above are dehydrated with a mineral acid to give the chromene derivatives of the formula (TV) where R and R 1 are as defined above. 60

The present invention is further illustrated by the following examples, but is not limited to the examples. The purity of the compounds disclosed in the Examples was checked by thin layer gas chromatography. In addition to elemental analysis, the structure of the compounds was confirmed by their IR and PMR spectra.

The PMR spectra are given as:

ex: 5.50 (dd, 1H) multiplet notation:

5.50 - chemical shift dd-multiplicity 1H - number of protons belonging to the signal s-singlet d-doublet dd- double doublet t-triplet q-quartet m - higher multiplet sz - broad elongated signal

Examples

L 2 (2,8-Trimethyl-7- (phenylaminocarbonylmethyleneoxy) -4-chromanone

6.2 g of 2,2,8-trimethyl-7-hydroxy-4-chromanone, 6.0 g of N-chloroacetylaniline, 10.0 g of potassium carbonate, 0.2 g of sodium iodide and 300 ml of abs. the acetone mixture was refluxed for 6 hours, then the inorganic salt was filtered hot and the solvent evaporated in vacuo. The residue was crystallized from methanol to give a white crystalline solid.

Based on the above example, the chromanone derivatives of Table I were also prepared, the physical constants and yields of which are reported there.

2.2 (2,8-Trimethyl-4-hydroxy-7- (phenyl-oxy-aminocarbonyl mefdén) chroman

A mixture of 7.0 g of 2,2,8-trimethyl-7- (phenylaminocarbonylmethyleneoxy) chromanone, 5.0 g of sodium borohydride and 250 ml of methanol was refluxed for 1 hour and then cooled to room temperature with water. the solution was diluted. The precipitated solid was filtered, crystallized from methanol to give a white crystalline solid.

Based on the above example, a. Table III also describes the chromanol derivatives whose physical constants and yields are reported there.

3.2 (2,8-Trimethyl-7- (phenyl-aminocarbonyl-methylene) -2H-chromene

A mixture of 6.7 g of 2,2,8-trimethyl-4-hydroxy-7- (phenylaminocarbonylmethyl] -enoxy) chroman, 30 ml of 4N hydrochloric acid and 300 ml of acetone was allowed to stand at room temperature for 1 hour. diluted with water, the precipitated product was filtered off, washed with water to remove acid and dried. The crude product was crystallized from methanol.

IH was prepared according to the above example. Table III also describes the chromene derivatives whose physical constants and yields are reported there.

HU 204 043 Β

Nr. , R Position R Position Yield: % Op 1 H-NMR CDCl 3 First methyl 8 phenyl 7 78.4 147-148 1.50 (s, 6H), 2.24 (s, 3H), 2.70 (s, 2H), 4.68 (s, 2H), 6.54-7.78 (m, 7H), δ , 20 (s, 1H) Second methyl 5 2-methylphenyl 2 87.7 172-173 1.46 (s, 6H), 2.28 (s, 3H), 2.64 (s, 3H), 2.70 (s, 2H), 4.68 (s, 2H), 6.42-7.94 (m, 6H), 8.14 (s, 1H) Third H phenyl 7 87.6 155-156 1.46 (s, 6H), 2.67 (s, 2H), 4.60 (s, 2H), 6.40-7.84 (m, 8H), 8.20 (s, 1H) 4th H 2-chloro-phenyl 7 83.7 171-172 1.48 (s, 6H), 2.70 (s, 2H), 4.68 (s, 2H), 6.47-8.44 (m, 7H). 8.90 (s, 1H) 5th H 4-methylphenyl 7 78.5 191-192 1.46 (s, 6H), 2.36 (s, 3H), 2.67 (s, 2H), 4.60 (s, 2H), 6.32-7.45 (m, 7H), 8.07 (s, 1H) 6th methyl 8 4-methyl-phenyl 7 90.5 171-172 1.50 (s, 6H), 2.24 (s 3H), 2.36 (s, 3H), 2.78 (s, 2H), 4.70 (s, 2H), 6.56-7.80 (m, 6H), 8.17 (s, 1H) 7th methoxy 6 phenyl 7 76.9 154 1.48 (s, 6H), 2.67 (s, 2H), 3.94 (s, 3H), 4.68 (s, 2H), 6.50-7.62 (m, 7H), δ, 66 (s, 1H) 8th methoxy 6 2-bromophenyl 7 75.3 174-175 1.32 (s, 6H), 2.68 (s, 2H), 3.90 (s, 3H), 4.67 (s, 2H), 6.30-8.28 (m, 6H) 9th methoxy 7 phenyl 6 68.1 93-94 1.46 (s, 6H), 2.67 (s, 2H), 3.96 (s, 3H), 4.57 (s, 2H), 7.10-7.57 (m, 7H), δ , 69 (s, 1H) 10th methoxy 7 2-methylphenyl 6 82.9 158-159 1.50 (s, 6H), 2.35 (s, 3H), 2.67 (s, 2H), 3.92 (s, 3H),

4.60 (s, 2H), 6.43-8.07 (m, 6H), 8.62 (s, 1H)

Nr. R Position R Position Yield: % Op.'C 1 H-NMR CDCl 3 First methyl 8 phenyl 7 88.5 124-125 1.36 (s, 3H), 1.48 (s, 3H), 1.84 (dd, 1H), 2.14 (dd, 1H), 2.16 (s, 3H), 4.57 (s, 2H), 4.80 (dd, 1H), 6.48-7.54 (m, 7H), 8.28 (s, 1H) Second methyl 5 2-methylphenyl 2 92.5 148-149 1.40 (s, 3H), 1.44 (s, 3H), 1.48 (dd, 1H), 2.10 (dd, 1H), 2.28 (s, 3H), 2.46 (s, 3H), 4.60 (s, 2H), 4.86 (dd, 1H), 6.28-8.00 (m, 6H), δ , 16 (s, 1H) Third H phenyl 7 82.2 134-135 1.34 (s, 3H), 1.42 (s, 3H), 1.86 (dd, 1H), 2.56 (dd, 1H), -4.54 (s, 2H), 6.44-7.56 (m, 8H), 8.22 (s, 1H) 4th H 2-chlorophenyl 7 86.0 155-156 1.34 (s, 3H), 1.48 (s, 3H), 1.84 (dd, 1H), 2.18 (dd, 1H), 4.58 (s, 2H), 4.80 (dd, 1H), 6.42-8.48 (m, 7H), 9.00 (s, 1H) 5th H 4-methylphenyl 7 96.1 115-116 1.42 (s, 3H), 1.46 (s, 3H), 1.51 (dd, 1H), 2.10 (dd, 1H), 2.38 (s, 3H), 4.57 (s, 2H), 4.86 (dd, 1H), 6.30-8.00 (m, 7H), 8.17 (s, 1H) 6th methyl 8 4-methylphenyl 7 88.8 71-72 1.30 (s, 3H), 1.46 (s, 3H), 1.76 (dd, 1H), 2.04 (dd, 1H), 2.10 (s, 3H), 2.32 (s, 3H), 4.56 (s, 2H), 6.44-7.48 (m, 6H), 9.4 (s, 1H)

HU 204043 Β

Nr. R Position R ' Position Yield: % Op. * C 1 H-NMR CDCl 3 7. methoxy 6 phenyl 7 882 143-1¼ 1.34 (s, 3H), 1.46 (s, 3H), 1.8 (dd, 1H), 2.16 (dd, 1H), 3.90 (s, 3H), 4.62 (s, 2H), 4.80 (dd, 1H), 6.38-7.60 (m, 7H), 8.90 (s, 1H) 8. Tnetoxi 6 2-bromophenyl 7 873 117-118 1.34 (s, 3H), 1.46 (s, 3H), 1.8 (dd, 1H), 2.14 (dd, 1H), 3.86 (s, 3H), 4.60 (s, 2H), 4.82 (dd, 1H), 6.40-832 (m, 6H) 9. methoxy phenyl 6 97.3 126-127 1.35 (s, 3H), 1. ¼ (s, 3H), 1.85 (dd, 1H), 2.18 (dd, 1H), 3.92 (s, 3H), 4.62 (s, 2H), 4.80 (dd, 1H), 7.12-7.62 (m, 7H), 9.00 (s, 1H) 10. methoxy 7 2-methyl-phenyl 6 962 115-116 1.32 (s, 3H), 1.45 (s, 3H), 1.82 (dd, 1H), 2.12 (dd, 1H), 2.32 (s, 3H), 3.86 (s, 3H), 4.54 (s, 3H), 4.72 (dd, 1H), 6.32-8.00 (m, 6H), 8.71 (s, 1H)

ΙΠ. Spreadsheet

% phenyl

1. methyl

2. methyl

H

H

H

2-methylphenyl 2-phenyl

2-chlorophenyl

6. methyl

7. methoxy

8. methoxy

9. methoxy

10. methoxy

11. methyl

12. methyl

4-methylfeml 7

4-methyl-phenyl 7-phenyl 7

2-Bromophenyl 7 Phenyl 6

2-methylphenyl 6 phenyl 7

2,6-Diethylphenyl 7

13. methoxy 6 2,6-diethylphenyl 7

14. methoxy

2-methyl-6-ethyl-7-phenyl

63.4 77-78 1.46 (s, 6H), 2.20 (s, 3H), 436 (s, 2H), 530 (d, 1H),

6.74 (d, 1H), 6.24-7.56 (m, 7H), 8.26 (s, 1H)

91.2 109-110 1.44 (s, 6H), 2.28 (s, 3H), 2.30 (s, 3H), 4.60 (s, 2H),

4.54 (d, 1H), 6.44 (d, 1H), 6.36-8.00 (m, 6H), 8.18 (s, 1H) 873 104-105 1.46 (s, 6H) ), 4.60 (s, 2H), 5.54 (d, 1H), 6.30 (d, 1H),

6.46-7.60 (m, 8H), 8.24 (s, 1H)

86.8 96-97 1.46 (s, 6H), 4.60 (s, 2H), 530 (dd, 1H), 6.27 (dd, 1H),

6.40-8.46 (m, 7H), 9.00 (s, 1H)

98.0 110-111 1.45 (s, 6H), 2.23 (s, 3H), 437 (s, 2H), 5.51 (d, 1H),

6.27 (d, 1H), 6.42 (d, 1H), 7.02-7.20 (m, 3H), 8.00 (d, 1H), 8.17 (s, 1H)

87.7 91-92 1.46 (s, 6H), 2.20 (s, 3H), 2.36 (s, 3H), 4.60 (s, 2H), 636 (d, 1H), 6 , 84 (d, 1H), 6.28-7.46 (m, 6H), 8.26 (s, 1H)

89.2 77-78 1.44 (s, 6H), 3.92 (s, 3H), 4.64 (s, 2H), 5.53 (d, 1H),

6.26 (d, 1H), 6.50-7.60 (m, 7H), 8.94 (s, 1H)

892 92-93 1.34 (s, 6H), 3.84 (s, 3H), 4.60 (s, 2H), 5.54 (d, 1H),

6.24 (d, 1H), 6.36-8.38 (m, 6H)

1.45 (s, 6H), 3.92 (s, 3H), 4.60 (s, 2H), 5.52 (d, 1H),

6.24 (d, 1H), 6.46-7.63 (m, 7H), 9.00 (s, 1H)

95.0 101-102 1.43 (s, 6H), 2.32 (s, 3H), 3.84 (s, 3H), 4.55 (s, 2H),

5.48 (d, 1H), 6.18 (d, 1H), 6.40-8.02 (m, 6H), 8.70 (s, 1H)

94.2 120-121 1.46 (s, 6H), 2.30 (s, 3H), 4.66 (s, 2H), 532 (d, 1H),

6.42 (d, 1H), 6.34-7.58 (m, 7 aromatic protons) 8.12 (s, 1H)

89.4 112-113 1.16 (t, 6H), 1.42 (s, 6H), 2.32 (s, 3H), 236 (q, 4H),

4.68 (s, 2H), 534 (d, 1H), 6.40 (d, 1H), 6.34-7.30 (m, 5 aromatic protons), 7.70 (s, 1H)

86.7 110-111 l, 18 (t, 6H), 1.48 (s, 6H), 2.58 (q.H), 3.82 (s, 3H),

4.68 (s, 2H), 534 (d, 1H). 6.22 (d, 1H), 6.40-7.28 (m, 5 aromatic protons), 8.20 (s, 1H)

74.8 80-81 1.16 (t, 3H), 1.46 (s, 6H), 2.22 (s, 3H), 236 (q, 2H),

3.80 (s, 3H), 4.70 (s, 2H), 5.52 (d, 1H), 6.21 (d, 1H), 6.42-7.32 (rn, 5 aromatic protons) 8.20 (s, 1H)

HU 204043 Β

Nr. R Position R ¹ Position Yield Op. 'C' Η NMR CDCb%

15th methoxy 7 2,6-diethyl-phenyl 6 96.8 134-135 16th H 2-methyl-6-ethyl- phenyl 7 97.2 111-112 17th H 2,6-diethyl-phenyl 7 94.5 98-99 18th methyl 8 2-methylphenyl 7 86.7 123-124

1.18 (t, 6H), 1.43 (s, 6H), 2.56 (q, 4H), 3.83 (s, 3H),

4.64 (s, 2H), 5.48 (d, 1H), 6.20 (d, 1H), 6.40-7.22 (m, 5 aromatic protons), 8.23 (s, 1H)

1.16 (t, 3H), 1.44 (s, 6H), 2.23 (s, 3H), 2.55 (q, 2H),

4.67 (s, 2H), 5.54 (d, 1H), 6.30 (d, 1H), 6.46-7.18 (m, 6 aromatic protons), 7.79 (s, 1H).

1.18 (t, 6H), 1.44 (s, 6H), 2.57 (q, 4H), 4.69 (s, 2H),

5.52 (d, 1H), 6.30 (d, 1H), 6.46-7.28 (m, 6 aromatic protons), 7.7 (s, 1H)

1.44 (s, 6H), 2.18 (s, 3H), 2.24 (s, 3H), 4.60 (s, 2H),

5.51 (d, 1H), 6.23 (d, 1H), 6.28-7.16 (m, 6 aromatic protons), 8.80 (s, 1H)

Chromium derivatives of the general formula (TV) are substances with valuable physiological properties which, according to the Writhing pharmacological test, effectively eliminate the induced pain.

More specifically, following the method of Handershot and Forsaith, Handershot, L. C., Forsaith, J., J. Pharmacol. Exp. Ther., 725, 237 (1959)], treated with 18-22 g of male OF1 strain orally (p.o.) in a volume of 0.1 m] / 10 g. After 30 minutes, mice were injected with 0.2 ml of 0.05% p-phenylquinone (FLUKA) intraperitoneally, and for 20 minutes, the animals were counted for typical abdominal contractions (stimulation of the peritoneal pain sensing re20 receptors). as a result.

The compounds of the present invention may be formulated into compositions for direct use in medicine after the addition of physiologically inactive or preferred excipients, carriers, diluents and other excipients by known methods of pharmaceutical manufacture. The drug may be in the form of a tablet, dragee, capsule or similar oral dosage form.

ARC. Table: Analgesic Effect of New Compounds on Phenylquinone Writhing Assay

example number number of experimental animals dose mg / kg po % inhibition ED mg / kg po 6 50 22 8 6 25 - - 6 10 - 6 50 - - 11 6 25 - - • 6 10 - - 6 50 0 12 6 25 - - 6 10 - - 6 50 58 1 6 25 14 50 6 10 - 6 50 95 13 6 25 62 29 6 10 30 6 50 82 16 6 25 67 29 6 10 14 6 50 56 17 6 25 33 -50 6 10 - 6 50 58 15 6 25 14 -50 6 10

HU 204043 Β

example number number of experimental animals dose mg / kg po % inhibition EDjo mgfcg po 6 50 96 18 6 25 39 28 6 10 10 6 50 53 14 6 25 28 ~ 50 - 6 10 - 6 50 85 7 6 25 37 22 6 10 20

As in IV. Table 3 shows that some substances have an analgesic effect in the order of Codein.

Claims (2)

A process for the preparation of a compound of the formula: wherein R is (C1-C4) -alkyl, (C1-C4) -alkoxy, hydrogen, R 1 is a C 6 -C 10 homoaromatic group which may be optionally substituted on the ring by halogen to form chromene slags, wherein R 1 is as defined above, wherein R 1 is as defined above. , X is a halogen compound in a polar protic or bipolar aprotic solvent in the presence of alkali hydroxides, alkali carbonates as bases, alkali iodides as catalysts at 50-120 ° C, and the resulting compound (Π) The chromanone slag compound of the formula wherein R and R 1 are as defined above is reduced with the complex metal hydride, alcohols, ethers at the boiling point of the solvents, and the resulting chromanol derivative (ΙΠ) is dehydrated. 2. A process for the preparation of a biologically active composition of formula IV, wherein R and R 1 are as defined above, wherein the chromene derivative of formula IV, wherein R and R 1 are as defined above, is conventionally used in the pharmaceutical art. mixed with the additives and excipients used and formulated as an analgesic.