Method for producing derivatives of azulene

专利摘要:
New azulene derivatives of the general formula …<CHEM>… where: R<1> is a lower alkyl group, a group of the general formula …<CHEM>… or a benzyl group, R<5>, R<6> and R<7> each representing H or a lower alkyl group and n being 1 or 2;… R<2> and R<3> each represents H or a lower alkyl group;… R<4> is H or an alkoxy group;… and X is Na or Al(OH)2 are stable to light and heat and are useful as anti-ulcerative and anti-inflammatory agents. …<??>The azulene derivatives may be prepared by reacting a compound of the formula …<CHEM>… wherein R<1>, R<2>, R<3> and R<4> are as defined above with a sulfonating agent and converting the resulting sulfonic acid to its sodium or aluminium salt.
公开号:SU1311618A3
申请号:SU3785251
申请日:1984-08-23
公开日:1987-05-15
发明作者:Такасе Кахей；Ясунами Масафуми；Томияма Цуеси；Томияма Акира；Янагисава Такаси
申请人:Котобуки Сейяку Ко.,Лтд (Фирма)；
IPC主号:

专利说明:

one
The invention relates to a process for the preparation of new azulene derivatives of the general formula
(I)
where R is lower alkyl, benzyl or group
-CH- (SND
/

R
R
four
where Ry-R is hydrogen or lower alkyl; or 2;
hydrogen or lower: alkyl; hydrogen or lower alkoxy group;
 X is sodium or A1 (OH), which exhibit anti-ulcer and anti-inflammatory activity and can be used in medicine.
The purpose of the invention is to develop a method for obtaining new derivatives of azulene, which have a higher and more stable anti-inflammatory and anti-spinal activity.
Example 1. 1-Metsh1azulen-3-sodium sulfonate.
Stage I. 1 Methyl-3-carboxymethyl-azulene (B).
The solution of oxazulene (A) 6 g, propionic aldehyde 5,22. g and morpholine 7.84 g in 120 ml of ethyl alcohol is heated to reflux for 4 hours. The mixture is cooled and the organic solvent is distilled off under reduced pressure. The residue is extracted with benzene, and the organics
Compounds 2-32 were prepared, the organic layer was washed with water and dried. After benzene has been distilled off, the residue is subjected to a subsequent sulfonation procedure according to chromatography on a CI-UIH-column of III from the corresponding starting materials.
Example 2. Sodium sodium 3-ethylaselenesulfonate (compound 2) is prepared.
5.9 g (98.5%) of the product are obtained in about analogy to example 1 using n-butyraldehyde instead of propionic O aldehyde in stage I (mp. 28-30 ° C), IR spectrum, 1630; 1425; 1,400;
.1220; 850.
H-NMR (CDC1: 2.58 (3N, s. Me), 55 EXAMPLE 3. 3-Ethyl-7-isopropyl- 3.92 (3N, s, OMe); 7.28 (1H , dd, J sodium azulenesulfonate (compound 3)
was prepared according to the procedure of Example 1, using a 5-isopropyl-substituted oxazulen derivative as a source of carbon, using benzene as eluent.
solid form after removal of the solvent, so pl. 69-7l c.
IR spectrum, 2950; 1690; 1450; 1440; 1421; 1202; 1027; 774; 746.
9.6 „9.6, Н-5); 7.37 (1H, dd., 6, 9.6, H-7); 7.67 (1H, dd,, 6, 9.6, H-6); 8.14 (1H, s, H-2); 8.24 (1H,
20
-thirty
35
40 16182
dd, 6, 1.4, H - 4); 9.49 (1H, dd,, 6, 1.4, H-8).
Stage II, 1-Methylazulene (C). 5.91 g of compound B are dissolved in 5 to 60 ml of phosphoric acid and the mixture is heated at C90 ° C) for 15 minutes in a water bath. After cooling, the mixture is poured into 300 ml of ice water and extracted with n-hexane. The organic layer is separated, washed with water, dried over anhydrous sodium sulfate and fractionated by chromatography on KO7 silica gel using benzene as eluant. 5 3.72 g (90.1%) of the title compound are obtained.
IR spectrum, sm: 3012; 2930; 1577; 1455; 1396; 947; 880
 H-NMR (CDClg): 2.58 (3N, s. Me),
3., 92 (ZN, s, OMe); 7.28 (1H, dd, J 9.6, 9.6, H-5); 7.37 (1H, dd,, 6, 9.6, H-7); 7.67 (1H, dd,, 6, 9.6, H - 6), 8.14 (1H, s, H-2); 8.24 (1H, 2 dd, 6, 1.4, H-4); 9.49 (1H, dd,, 6, 1.4, H-8).
Stage III. Sodium 3-methylaselenesulfonate (Compound 1).
10 ml of acetic anhydride is added to 1.0 g of 1-methylazulene while cooling with ice water, 3.4 g of sulfonic acid is added dropwise and the reaction mixture is stirred for 4 hours at. Then the reaction mixture is alkalinized to pH 8-9 with 40% solution, sodium hydroxide. The resulting solid is collected and dried. The product is recrystallized from 95% ethanol.
1.1 g of the expected compound are obtained, m.p. ZZ-ZV S.
IR mpektr, cm: 1630; 1420; 1220; 750
Compounds 2-32 are prepared using the sulfonation procedure according to diy III from the corresponding end products.
313
product instead of oxaoulene (A) and n-butyraldehyde instead of propionaldehyde. The sulfonation is carried out according to the method at stage III of Example 1 (mp 85-88 ° C).

1650; 1640; 1565;
IR spectrum, cm 1418; 1180; 1050.
H-NMR (DMSO): 1.30 (3N, t, 4, CHj); 1.33 (6H, d,, 6, (CH) -);
3.00 (2H, apt., 4, CHj); 3.50 (1H, sept.,, 6, -CH-CCH,)); 4.10 (1H, brs,); 7.20 (2H, d,, H-7), 7.90 (1H, s, H-2); 8.23 (1H, d, L 10, H-4); 9.17 (1H, s, H-8).



PRI me R 4. H-Ethyl-6-isopropyl-15 210-2 15 C (decomp.). sodium azulenesulfonate (compound 4), IR spectrum, mp. 55-58 0.
..
1640; 1580, 1410.
3400; 2940; 2850;
1580; .1420; 1,400; 1200; 1090; 1020; . 960; 880; 750; 740,670.
Example 12. 3-Methyl-7-isopropyl 10, H-4).
EXAMPLE 5 Sodium 3- (l -Rj S-D, dimethyl-4-hexene) -azule sulfonate (compound 5) is prepared according to the procedure of Example 1, using d, l-.
IR spectrum, cm 1190; 1060.
H-NMR (DMSO): 1.27 (3N, t, 4, 20 sodium pilazule sulfonate - (compound, CH3); 1.30 (6H, d, 6, (CHj) -); 12), t .pl. 91-93 ° C. 2.96 (1H, sept.,, 6, isopropyl); IR Spectrum, 3450; 2950; 1640; 3.02 (2H, q, 4, CHj); 7.17 (2H, 1250; 1070; 1010; 790. d, H-5.7); 7.70 (1H, s, H-2); EXAMPLE 13 3-n-Butylazulene-8.20 (1H, d,, H-8) 8.90 (1H, d, 25 sodium sulfate) (compound 13);
m.p. 215-220 C (decomp.).
IR Spectrum, 3450; 2900; 1570; 1390; 1190.
PRI me R 14. 3-n-Pentylazulen-30 sodium sulfonate (compound 14),
citronellal instead of propionic al- so pl. 217-220 s (decomp.). degida (mp. 78-8G). IR spectrum, cm H 3450, 2900; 1570;
IR Spectrum, 1630; 1560; 1420; 1390; 1190 1400; 1190; 1120; 1050; 750.p im im 15. 7-Isopropyl-3-np r.i mep 6. S-Methyl-2-ethylazapropylalensulfonate sodium (compound sodium sulfonate (compound 6) nenie 15), m.p. . 138-143 ° C. prepared according to the procedure of Example 1, using 3- (1-pyrrolidinyl) -2-pentene instead of propionaldehyde and morphololine in stage I (mp. 280-283 ° C)
IR spectrum, 1640; 1560; 1420; 1190; 1040; 740.
 ,,., „. r n IR spectrum, cm-: 3450; 2950; 1640;
Example7. 3- (1 -S-1, 5-Dime-1575 1465
tyl-4-hexene) -sodium azulene sulfonate, (
(compound 7) was prepared according to the method of Example 17. 7-Production 1-3-n-pen example 1, using d-citronellal instead of propionaldehyde in stage I (mp. 78-81 ° C). .
IR spectrum, cm-: 1630; 1560; 1420; 2860; 1620; 1580; 1470; 1440; 1380 .: 1400; 1190; 1120; 1050; 750. 1190; 1060.
EXAMPLE 8 3- (G-E-1, 5-Dime-EXAMPLE 18. 7-Isopro-1-3- (1-TSP-4 -hexene) -sodium sodium sulfonate (compound 8 ) receive according to the method of example 1, using 1-citron.allal instead of propionaldehyde in stage I (so pl. 78-81 O.
IR Spectrum, 3450; 2950; 1630; 1575; 1470; 1415; 1390; 1220; 1050; 930.
40 Example16. 7-Isobutyl-3-n-butylazulenesulfonate sodium (compound 16): so pl. 150-T52 ° C.
sodium tilazulenesulfonate (compound 17), m.p. 168-170;
IR spectrum, cm: 3400; 2950; 2930;
IR Spectrum, 1630; 1560; 1420; 1,400; 1190; 1120; 1050; 750
R, S-1 -5-dimethyl-4-hexene) -azulene sulfonate sodium (compound 18), m.p. PZ-Pb S.
IR Spectrum, 3450, 2950; 1640; 1380; 1240; 1180.
PRI me R 19. 7-Isopropyl-3- (1 - R-I, 5-dimethyl-4-hexene) -azulensut pl.: SE-PO C. IR spectrum, cm 1220; 1050.
PRI me R 9. 3- (G-5-G, 5-Dimethyl-4-hexene) -7-isopropylylenesulfonate sodium (compound 9), mp; 108-1 10 seconds
IR spectrum, cm: 1630; 1560; 1420; 1220; 1050.
Example 10. 3- (1-R-1, 5-dimethyl-4-hexene) -7-isopropylazulene sodium sulfonate (compound 10),
1630; 1560; 1420;
m.p .: SE-PO S. IR spectrum, cm 1220; 1050.
Example 11. Sodium 3-propylazulenesulfonate (compound 11), m.p.
210-2 15 C (decomp.). IR spectrum
210-2 15 C (decomp.). IR spectrum
3400; 2940; 2850;
1580; .1420; 1,400; 1200; 1090; 1020; . 960; 880; 750; 740,670.
Example 12. S-Methyl-7-isopropylase sulphonate sodium - (compound 12), m.p. 91-93 ° C. IR Spectrum, 3450; 2950; 1640; 1250; 1070; 1010; 790. PRI me R 13. 3-n-Butylazulene-ultsnat sodium (compound 13);
 sodium propylalenesulfonate (compound 15), m.p. 138-143 ° C.
IR Spectrum, 3450; 2950; 1630; 1575; 1470; 1415; 1390; 1220; 1050; 930.
40 Example16. 7-Isobutyl-3-n-butylazulenesulfonate sodium (compound 16): so pl. 150-T52 ° C.
 PRI me R 17. 7-Propsh1-3-n-pen-
sodium tilazulenesulfonate (compound 17), m.p. 168-170;
IR spectrum, cm: 3400; 2950; 2930;
 PRI me R 18. 7-Isopropsh-3- (1 -
R, S-1 -5-dimethyl-4-hexene) -azulene sulfonate sodium (compound 18), m.p. PZ-Pb S.
IR Spectrum, 3450, 2950; 1640; 1380; 1240; 1180.
PRI me R 19. 7-Isopropyl-3- (1 - R-I, 5-dimethyl-4 -hexene) -azylene 5 .131
sodium lonate (compound 19), m.p. P4 117 ° C.
IR spectrum, cm: 3450; 2950; 1640; 1380; 1240; 1180.
Example 20. 7-Isopropyl-3- (1-S-t, 3-dimethyl-4-hexene) sodium azulenesulphonate (compound 20), mp. 115-118 C.
IR spectrum, cm: 3450; 2950; 1640; 1380; 1240; 1180.
EXAMPLE 21 7-Isopropyl-3-benzyl-nesulfonate sulfonate sodium (compound 21), m.p. (different).
IR spectrum, cm: 3450; 2950; 1640; 1560; 1530; 1460; 1420.
Example 22-. Sodium 4-methoxy-3-methyl-azulenesulfonate (compound 22) m.p. 186-188 ° C (decomp.).
IR Spectrum, 3400; 1600; 1570; 1460; 1370; 1270.
Note 23. 4-Methoxy-3-ethyl-azulenesulfonate sodium (compound 23), m.p. .
IR Spectrum, 3400; 2950; 1600; 1570; 1540; 1450; 1370; 1270.
EXAMPLE 24 Sodium 4-Metoxn-3-ethylpylazulenesulfonate (compound 24), m.p. 108-110 C.
IR spectrum, cm: 3450; 2910; 2850; 1600; 1570, 1530.
Example 25 4-Methoxy-3-butyl-azulenesulfonate sodium (compound 25), mp. 188-190 ° C (decomp.).
IR Spectrum, 3450; 2950; 1600; 1570; 1530; 1460.
, Example 26, .4-Methoxy-3-sodium-pentalenesulfonate sulfonate (compound 26), m.p. 189-193 C (decomp.).
IR spectrum: 3450; 2950; 1600; 1560; 1530; 1450.
Example 27. 4-Methoxy-3-sodium hexyl silzenesulfonate (compound 27), m.p. 225-228 C (decomp.} ..
JK-spectrum, cm-: 3450 | 2900; 1650; 1560; 1520; 1460.
Example 28. 7-Isopropyl-4-methoxy-3-methylaselenesulfonate sodium (compound 28), mp. 95-97 C.
IR spectrum, cm-: 3450; 2950; 1650;
1540; 1280; 1180. I
Example 29. 7-Isopropyl-4-methoxy-3-ethylaselenesulfonate sodium (compound 29), mp. 108-110 C.
IR spectrum, cm-: 3450; 2950; 1650; 1540; 1260; 1180.
Example 30. 7-Isopropyl-4-methoxy-3-propylazulene sulfoate sodium (compound 30), mp. 188-190 ° c7
6186
IR spectrum, cm: 3450; 2950; 1640; S60; 1530.
PRI me R 31. 7-Isopropyl-4-methoxy-3-buty. Sodium pazulene sulfonate (compound 31), mp. 166-168 0.
IR Spectrum, 3450; 2950; 1640; 1560; 1530; 147P.
Example 32. 7-Isopropyl-4-methoxy-3-pentylazulenesulfonate sodium (compound 32), mp. 123-125 ° C.
 IR spectrum, cm: 3450; 2950; 1650; 1520; 1260; 1010.
PRI me R 33. Aluminum salt-3-methylaselenesulfonic acid (compound 33).
5 g of sodium 3-methylenesulfonate are dissolved in water. After filtering off the precipitate, 2.73 g of AlCl in 40 ml of water are added to this solution and stirred for 30 minutes at room temperature. The reaction mixture is adjusted to pH 4-4.5 with the addition of 10% NaOH. The resulting precipitates are collected by filtration, washed with water and dried (mp. Above 250 ° C).
IR Spectrum, 3400; 1630; 1580; 1395; 1140; 1040; 740. A1 content 13.96%. Compounds 34-36 are prepared according to the method of Example 33 from the corresponding sodium sulfonate derivatives.
Example 34. Aluminum salt of 3-ethylaselenesulfonic acid (compound 34), so pl. more than 250 C. 5 IR spectrum, .- 3400; 2950; 1580; 1,400; 1150; 1050; 750. A1 content 13.00%. PRI me R 35. Aluminum salt of 7-isopropyl-3-methylalensulfonic acid (compound 35), mp. over 250 C. IR spectrum, 3400; 2950; 1420; 1150; 1040.
The content of A1 is 9.46%. I
45 EXAMPLE 36 Aluminum salt of 7-isopropyl-3-ethylaselenesulfonic acid (compound 36), m.p. over 250 C.
IR spectrum, cm-: 3400; 2950; 1580; 1420; 1390; 1150. 50 Al content 10,58%.
The proposed compounds are characterized by increased resistance to light and heat, and some of these compounds possess anti-gastric and anti-gastritic activity 55 and are useful for therapeutic use.
Biological activity versus sodium guanyazulen-3-sulfonate
713116188
(gene) as a standard pre-bovine serum as substrate
 pepsin.
Pharmacological data 1. The activity is expressed as a percentage. The antiseptic activity of the compound inhibition to the control.
The scientific research institute was determined in vitro according to the known 5th value (no inhibitor added),
method using albumin presented in table 1.
Table 1
Note. LDgg - doses that provide
50% inhibition.
Pharmacological data 2. Imposition of ligature of animals killed
and removed the stomach. Induced
For the determination of anti-ulcer zoo, erosion was measured by the area and exposure of the compounds in vitro in rats or by the link index (V, 1.). The Shay data were starved and, under conditions of percentage inhibition of mild anesthesia, ligations (see Table 2) were applied relative to the contour on the pylorus. A drug of the mean value as given above was administered orally. 16 hours later, the same equation.
Control value - Experimental value
9, 1311618
. Continuation of table 2
100 100 100 100 100
9.8 63.4 75.6 75.6 66.3
Table3
MethodI
administered
Orally 1000 (833.3 - 1200) 1200 (983.6 - 146.4) Intraperitoneally 165 (136.4 - 199.8) 180 (153.8 - 210.6) Intravenous130 153 (111.7 - 209.6 )
Note. Confidence interval 95%.
 t
 The stability of compound 3 is presently being applied clinically in comparison with the guai-30 practice (see table 4). sodium azulenesulfonate, which
Table4
Storage 40 ° С, 60 ° С, 70 ° С, 80 ° С, 96 h 192 h 240 h 288 h
Guayazulenesulfonate sodium 100 51.3 9.3 1.5
Connection 3 100 100 100 100
Note. The data are expressed as the% residue of the original compound after storage under the specified conditions.
The proposed compounds can be administered to animals and humans orally, parenterally or rectally in the form of JQ active ingredients in a conventional unit.
Continuation of table 2
100 100 100
42.0 38.0 58.7
The acute toxicity of Compound 3 was determined using Lichfnold and Wilcoxon techniques on SD rats.
The value of LDjf (mU / kg) for the compound is given in Table 3.

权利要求:
Claims (1)
[1]
up to 60 mg when taken three times a day for an adult Patient. Invention Formula
The method of obtaining derivatives, azulene General formula
SOjX
ъ
a dosage composition consisting of an inert pharmaceutical carrier and one effective active ingredient dosage unit, such as tablets,
zeros, capsules, suspensions, etc. One RI is an effective dosage where R is lower alkyl, benzyl, or a unit of the proposed compounds from group 2
Lena of the general formula
SOjX
ъ
,,
-CH- (CHJ
I
.R / 6
R
R-R - have the indicated values, are reacted with sulfuric acid
acid in acetic anhydride at 0 ° C, followed by treatment with lyluch- where Ry-Rj is hydrogen or lower alkyl; 5 th sulfonic acid sodium hydroxide
, ti 1 or 2;
 - hydrogen or lower alkyl;
R is hydrogen or lower alkoxy;
ten
and selecting the desired product or converting the resulting sodium salt to aluminum by treating it with an aqueous solution of aluminum chloride.
X is sodium or
different azulene general formula
Cts
R-R - have the indicated values, are reacted with sulfuric acid
and selecting the desired product or converting the resulting sodium salt to aluminum by treating it with an aqueous solution of aluminum chloride.
Priority on the basis of: 24.08.83 - according to the values of the radicals of the compounds obtained according to examples 1-11;
01/28/84 - by the values of the radicals of the compounds obtained in Examples 12-36.
Editor L.Pcholinsk
Compiled by T.Vlasova
Tehred L. Oliynps Corrector A. Ilyin
Order 1906/58 Circulation 372 Subscription
VNIIPI USSR State Committee
for inventions and discoveries 113035, Moscow, Zh-35, Raushsk nab., 4/5
Production and printing company, Uzhgorod, st. Design, 4.

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法律状态:
2005-05-10| REG| Reference to a code of a succession state|Ref country code: RU Ref legal event code: MM4A Effective date: 20030824 |

优先权:

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申请号 | 申请日 | 专利标题

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JP15318783A|JPH0149259B2|1983-08-24|1983-08-24|

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JP59014028A|JPH0547536B2|1984-01-28|1984-01-28|

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