CN1281561C - Compound with base skeleton of 1,6-methylene-[10]-annulene and use thereof - Google Patents

Abstract

The present invention relates to a compound with the basic skeleton of 1, 6-methylene-10-annulene, which has the structural formula, wherein * represents single-bond or double-bond, R<1>=H, -OR', -CHO, -COOH, -CO2Me, -CO2CH2CH3, -P(O)(OCH2CH3)2, -OCOCH(OH)CH3, -OCOCH2CH2COOH, (disclosed in the formula)-OCOCH(NH2)R<3> or OCOC(OH)CH(NHCOR<4>)C6H5; R<2>=OR', -OCH2OCH3, =O, -CHO, -COCH3, -COOH, -CO2CH3, -CO2CH2CH3, -OCOCH3, -OCOCH2CH3, (disclosed in the formula) or (disclosed in the formula), n=0 to 2, R'=C1 to C10 alkyl or cycloalkyl, C1 to C10 saturated or unsaturated acyl and C2 to C10 alkenyl, R<3>=-H, -CH3, -CH2OH, -CH(OH)CH3, -CH2C6H5, -CH2C6H5OH, -CH2CH(CH3)2, -CH(CH3)2, CHCH3(CH2CH3)2 and -CH2-CONH2 or -CH2CH2CONH2 -CH2OH, R<4>=-C6H5, C1 to C5 alkyl, and -C(CH3)=CHCH3 or -CH=CHC6H5. The compound has inhibitory activity effect on tumor cells, and can be used for being developed into novel antitumor medicine for treating lung cancer, mammary cancer and liver cancer or leukemia.

Description

A compound with 1,6-methylene-[10]-annulene basic skeleton and its use

technical field

This patent relates to a compound with a basic skeleton of 1,6-methylene-[10]-annulene and its use. These compounds were efficiently synthesized using fluorosulfonyl fluoride-induced carbocation rearrangement reactions. This class of compounds has been shown to have anticancer activity and is an antitumor compound.

Background technique

In order to discover and develop new drugs, the search for natural or non-natural compounds with special biological activity and unique chemical structure has always been the goal pursued by chemists, biologists and drug manufacturers. To this end, natural product chemists are tirelessly and constantly changing methods to find novel natural compounds with special biological activities and unique chemical structures from the biological world; medicinal chemists and synthetic chemists tirelessly design and synthesize compounds based on the knowledge that humans have acquired. new molecules. Obviously, discovering compounds with unique and novel chemical structures is the basis for finding new drugs.

According to some basic principles of drug design, chemical synthesis and investigation of some molecules with unique and novel structures is one of the important ways to find new drugs. It is known that many bioactive molecules contain the basic skeleton of naphthalene, and there are 142 kinds of drugs with naphthalene skeleton by searching the MDLComprehensive Medicinal Chemistry database. The uses relate to enzyme inhibitors, anti-tumor, anti-fungal and so on.

ALRESTATIN (enzyme inhibitor) AMONAFIDE (anti-tumor) ALRESTATIN (anti-fungal)

According to the similarity in chemical structure and physicochemical properties, 1,6-methylene-[10]-annulene can be regarded as the equivalent of naphthalene compounds. However, through literature search, it is known that since American professor Vogel synthesized such molecules in 1964, only their physical and chemical properties have been investigated, and there is almost no research on their biological properties, and even less research on their analogs. Among numerous natural products, only Spiniferin-1 (see Tetra.Lett.1975(45), 3727; J . Amer. Chem. Soc. 1980(102), 4274). In order to understand the biological properties of compounds with 1,6-methylene-[10]-annulene basic skeleton, we have synthesized the dihydro product of Spiniferin-1 (CN 02145067.6, Chem.Commun.2003 (7) 838) , biological activity investigation found that it has a certain anti-tumor activity (CN 03115527.8). In view of the instability of the chemical properties of natural spiniferin-1 and its dihydrogen product, we also designed and synthesized a steroid molecule with the basic skeleton of furo-1,6-methylene-[10]-annulene (CN 02145067.6) , the latter also exhibits desired antitumor activity (CN 03115525.1).

In order to further explore the biological properties of compounds with 1,6-methylene-[10]-annulene basic skeleton, we designed a more easily synthesized 1,6-methylene-[10]-annulene basic skeleton Biological tests show that they have stronger antitumor activity than the furo-1,6-methylene-[10]-annulene compounds that we have synthesized. The patent of this invention involves the design and synthesis, biological activity and potential use of these new molecules.

Contents of the invention

The purpose of the present invention is to provide a new type of anti-tumor compound with the basic skeleton of polyhydro 1,6-methylene-[10]-annulene.

Another object of the present invention is to provide a use of the above-mentioned antitumor compound.

A class of compounds with polyhydrogen 1,6-methylene-[10]-annulene basic skeleton has the following structural formula:

或

n＝0-2，R’＝C1-10的烷基或环烷基、C1-C10饱和的或不饱和的酰基、以及C2-C10的烯基；R³＝-H，-CH₃，-CH₂OH，-CH(OH)CH₃，-CH₂C₆H₅，-CH₂C₆H₅OH，-CH₂CH(CH₃)₂，-CH(CH₃)₂，CHCH₃(CH₂CH₃)₂，-CH₂-CONH₂或-CH₂CH₂CONH₂；R⁴＝-C₆H₅，C1-C5的烷基，-C(CH₃)＝CHCH₃，或-CH＝CHC₆H₅，其中

为单键和R²＝O时，R¹≠-OCH₃，-OCOCH₃，-OCOC₂H₅。in Expressed as a single or double bond, R ¹ =-OR', -OCOCH(OH)CH ₃ , -OCOCH ₂ CH ₂ COOH, -OCOCH(NH ₂ )R ³ or OCOC(OH)CH(NHCOR ⁴ )C ₆ H ₅ ; R ² =OR', -OCH ₂ OCH ₃ , =O, -CHO, -COCH ₃ , -COOH, -CO ₂ CH ₃ , -CO ₂ CH ₂ CH ₃ , -OCOCH ₃ , -OCOCH ₂ CH ₃ ,,

or

n=0-2, R'=C1-10 alkyl or cycloalkyl, C1-C10 saturated or unsaturated acyl, and C2-C10 alkenyl; R ³ =-H,-CH ₃ ,- CH ₂ OH, -CH(OH)CH ₃ , -CH ₂ C ₆ H ₅ , -CH ₂ C ₆ H ₅ OH, -CH ₂ CH(CH ₃ ) ₂ , -CH(CH ₃ ) ₂ , CHCH ₃ ( CH ₂ CH ₃ ) ₂ , -CH ₂ -CONH ₂ or -CH ₂ CH ₂ CONH ₂ ; R ⁴ =-C ₆ H ₅ , C1-C5 alkyl, -C(CH ₃ )=CHCH ₃ , or - CH=CHC ₆ H ₅ , where

When it is a single bond and R ² =O, R ¹ ≠ -OCH ₃ , -OCOCH ₃ , -OCOC ₂ H ₅ .

The synthesis method of this type of compound of the present invention uses fluorosulfonyl fluoride-induced carbocation rearrangement to efficiently synthesize this type of compound (see CN 97106576.4).

The compound of the present invention has inhibitory activity on tumor cells, and may be developed into a new class of anti-tumor drugs.

Detailed ways

The following examples will help to understand the present invention, but do not limit the content of the present invention.

Synthesis of Example 1 Compound 2

Take 320mg (1mmol) of compound 1, dissolve it in 15mL of anhydrous THF, add 0.22mL (1.5mmol) of 1,5-diazabicyclo[5.4.0]undec-5-ene (1,5 - Diazabicyclo[5.4.0]undec-5-ene), after 30 min, 0.22 mL (1.5 mmol) of HCF ₂ CF ₂ OCF ₂ CF ₂ SO ₂ F was added, and the reaction was continued to stir at 0°C. After 30 min, TLC (P/E=1:1) showed that the starting material spot disappeared. Pass the reaction solution through a thick silica gel column, wash with THF (15 mL), combine the eluents, add 0.74 mL (5 mmol) triethylamine, and reflux the oil bath for reaction. The reaction stopped after 2 hours. After spin-drying, 254 mg of compound 2 was obtained by column chromatography, yield: 80%.

Compound 2: C ₂₀ H ₂₈ O ₂ (300.44)

IR (KBr): v2927, 2872, 1669, cm ^-1

¹ H-NMR (CDCl ₃ , 300MHz): δ0.32 (1H, d, J = 5Hz, 9-H), 2.48 (1H, d, J = 18Hz, cp-H), 2.85 (1H, d, J = 18Hz, cp-H), 3.27 (1H, t, J = 8Hz, 17-H), 3.36 (3H, s, 17-OMe), 5.76 (1H, d, J = 10Hz, 1-H), 7.32 (1H, d, J=10Hz, 2-H).

EIMS: m/e 300(M).

Elemental Analysis: Calculated: C: 79.96%, H: 9.39%

  Measured value: C: 79.42%, H: 9.16%

Synthesis of Example 2 Compound 3

Take 100 mg (0.33 mmol) of compound 2 and dissolve in 2.1 mL of acetic acid, add 0.42 mL of acetic anhydride, add 125 mg (0.66 mmol) of p-toluenesulfonic acid, and stir at room temperature for reaction. After 1 hour, add 5 mL of ice water to the reaction solution, stir, a light yellow solid precipitates out, filter with suction, wash the filter cake with water, extract the filtrate with dichloromethane, wash the extract with water, saturated NaHCO ₃ , and water respectively; the filter cake is washed with two Chloromethane was dissolved and washed twice with water. The extract and solution were combined, dried over anhydrous sodium sulfate, spin-dried, and column chromatographed to obtain 96 mg of compound 3 with a yield of 85%.

Compound 3: C ₂₂ H ₃₀ O ₂ (342.48)

IR (KBr): v2933, 1747, 1601cm ^-1

¹ H-NMR (CDCl ₃ , 300MHz): δ0.40(1H, m, 9-H), 0.91(3H, s, 18-Me), 2.20(3H, s, MeCO-), 2.28～2.31(2H , m, cp-H), 3.26 (1H, t, J=8Hz, 17-H), 3.35 (3H, s, 17-OMe), 5.78 (1H, s, 4-H), 5.96 (1H, d , J=6Hz, 1-H), 6.38 (1H, d, J=6Hz, 2-H).

EIMS: m/e 342(M), 300(M-Ac)

Elemental Analysis: Calculated: C: 77.16%, H: 8.83%

  Measured value: C: 76.69%, H: 9.05%

Synthesis of Example 3 Compound 5

0.5 mmol of substrate 4 was dissolved in 10 ml of anhydrous THF. 1.5eq. of 1,5-Diazabicyclo[5.4.0]undec-5-ene and 1.5eq. of HCF ₂ CF ₂ OCF ₂ CF ₂ SO ₂ F were added dropwise in an ice-water bath. After adding, react for 30 minutes. The reaction solution was filtered through a short thick silica gel column, and an equal volume of solvent was rinsed. Combine the washings and filtrates.

5eq. of triethylamine was added thereto, heated to reflux, and reacted until the TLC detected raw material point disappeared. The solvent and triethylamine were distilled off under reduced pressure. The residue was separated by column chromatography to obtain the intermediate.

Add 4.0eq. of 1,5-Diazabicyclo[5.4.0]undec-5-ene and 4.0eq. of HCF ₂ CF ₂ OCF ₂ CF ₂ SO ₂ F, and filter the reaction solution through a short and thick silica gel column. Solvent rinse. Combine the washings and filtrates. The solvent was evaporated under reduced pressure. The residue was separated by column chromatography to obtain product 5.

Compound 5 C ₂₁ H ₂₆ O ₃ (326.44)

¹ H-NMR (CDCl ₃ ): δ6.70 (1H, d, J=6.0Hz, 1-H), 6.07 (1H, d, J=6.1Hz, 2-H), 6.07 (1H, s, 4 -H), 5.87 (1H, tt, J=52.6Hz and 3.0Hz, HCF ₂ CF ₂ ), 3.41 (1H, d, J=10.4Hz, 19-Ha), 1.03 (3H, s, 18-CH ₃ ), 0.88 (1H, d, J=10.2Hz, 19-Hb)

Synthesis of Example 4 Compound 6

Add 200 mg (0.35 mmol) of compound 5 and 2 ml of anhydrous dimethylformamide into a dry 25 ml egg-shaped bottle to dissolve it. Then 16 mg (0.04 eq.) tetrakistriphenylphosphine palladium, 140 μl triethylamine and 33 μl anhydrous formic acid were added. Stir, heat up to 60°C, and react for 1 hour. The reaction liquid was cooled to room temperature, poured into water, added 1ml of 2N dilute hydrochloric acid, and extracted with ether. The organic phases were combined, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography to obtain 86 mg (91%) of 6 as a white solid.

Compound 6 C ₁₉ H ₂₄ O(268.40)

m.p.124-125℃

[α] _D ²⁰ =+159 (c0.83, CHCl ₃ )

IR(KBr): v1737(C=O), 1589cm ^-1 (C=C)

¹ H-NMR (CDCl ₃ ): δ6.72-6.59 (2H, m, 2-H and 3-H), 5.95 (2H, m, 1-H and 4-H), 3.28 (1H, d, J =10.1Hz, 19-Ha), 1.03(3H, s, 18- _CH3 ), 0.67(1H, d, J=10.0Hz, 19-Hb), 0.49(1H, m, 6-H)

EIMS: m/e 268(M), 104(100%)

Elemental analysis: calculated value. (%): C 85.03, H 9.01

  Measured value (%): C 85.20, H 9.11

Synthesis of Example 5 Compound 7

Add 200 mg (0.35 mmol) of compound 5 and 2 ml of anhydrous dimethylformamide into a dry 25 ml egg-shaped bottle to dissolve it. Then 20 mg (0.05 eq.) of tetrakistriphenylphosphine palladium, 2 ml of anhydrous methanol and 140 μl (3 eq.) of triethylamine were added. Carbon monoxide was introduced into the reaction liquid, the temperature was raised to 80° C., and the reaction was carried out for 3 hours. The reaction solution was poured into water and extracted with ether. The organic phases were combined, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography to obtain 90 mg (79%) of 7 as a white solid.

Compound 7 C ₂₁ H ₂₆ O ₃ (326.44)

m.p.172-173℃

[α] _D ²⁰ =+294 (c 0.30, CHCl ₃ )

IR(KBr): v1737 (ketone C=O), 1703cm ^-1 (ester C=O)

¹ H-NMR (CDCl ₃ ): δ7.68 (1H, d, J = 5.9Hz, 2-H), 6.57 (1H, s, 4-H), 6.14 (1H, d, J = 5.8Hz, 1 -H), 3.84 (3H, s, OCH ₃ , 3.37 (1H, d, J=9.9Hz, 19-Ha), 1.03 (3H, s, 18-CH ₃ ), 0.65 (1H, d, J=9.9 Hz, 19-Hb), 0.52 (1H, m, 6-H)

EIMS: m/e 326 (M), 311 (M-CH ₃ ), 295 (M-OCH ₃ ), 267 (100%, M-CO ₂ CH ₃ )

Elemental analysis: calculated value. (%): C 77.27, H 8.03

  Measured value (%): C 77.24, H 8.11

Example 6 Synthesis of Compound 8

Add 290 mg (0.51 mmol) of compound 5 and 2 ml of anhydrous dimethylformamide into a dry 25 ml three-necked flask to dissolve it. Then 23 mg (0.04 eq.) of palladium tetrakistriphenylphosphine, 340 µl of triethylamine and 90 µl (1.5 eq.) of diethyl phosphite were added. Under the protection of nitrogen, the temperature was raised to 60° C., and the reaction was carried out for 30 hours. The reaction solution was cooled to room temperature, poured into 2N dilute hydrochloric acid, and extracted with ether. The organic phases were combined, washed with water, washed with saturated sodium chloride, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by column chromatography to obtain 173 mg (89%, after deducting unreacted raw materials) of compound 8.

Compound 8 C ₂₃ H ₃₃ O ₄ P (404.48)

IR (Film): v1739 (ketone C=O), 1583 (C=C), 1242cm ^-1 (P=O)

¹ H-NMR (CDCl ₃ ): δ7.42 (1H, dd, J _HH = 5.9Hz and J _HP = 20.4Hz, 2-H), 6.28 (1H, d, J _HP = 7.4Hz, 4-H) , 6.09 (1H, d, J _HH = 5.1Hz, 1-H), 4.19-4.01 (4H, m, 2xOCH ₂ ), 3.34 (1H, d, J = 9.9Hz, 19-Ha), 1.33 (6H, m, 2xOCH ₂ CH ₃ ), 1.03 (3H, s, 18-CH ₃ ), 0.63 (1H, d, J=9.9Hz, 19-Hb), 0.50 (1H, m, 6-H).

EIMS: m/e 404(M), 277(100%)

Example 7 Physiological activity of compound 3

The test result of physiological activity is as shown in table 1

Table 1

The active comparison with the patented compound (CN 03115527.8) is shown in Table 2

Table 2

The test methods are shown in Table 2:

Table 2 Cell line: A-549 human lung cancer screening method: sulforhodamine B (sulforhodamineB, SRB) protein staining time: 72h Cell line: MCF-7 human breast cancer Screening method: sulforhodamine B (sulforhodamineB, SRB) protein staining time: 72h Cell line: BEL-7402 human liver cancer Screening method: sulforhodamine B (sulforhodamineB, SRB) protein staining time: 72h Cell line: P388 mouse leukemia Screening method: tetrazolium salt (microcultoretetrozolium, MTT) reduction method Action time: 48h

Claims (3)

1. one kind has 1, and the compound of 6-methylene radical-[10]-annulene basic framework has following structural formula:

R wherein ¹=-OR ' ,-OCOCH (OH) CH ₃Or-OCOCH ₂CH ₂COOH; R ²=OR ' ,-OCH ₂OCH ₃,-CHO ,-COCH ₃,-COOH ,-CO ₂CH ₃,-CO ₂CH ₂CH ₃,-OCOCH ₃,-OCOCH ₂CH ₃,, Or

N=0-2, the thiazolinyl of the alkyl of R '=C1-10, the saturated or unsaturated acyl group of C1-C10 and C2-C10.

2. as claimed in claim 1 a kind ofly have 1, the compound of 6-methylene radical-[10]-annulene basic framework, and its feature has following structural formula:

3. as claimed in claim 1 a kind ofly have 1, and the purposes of the compound of 6-methylene radical-[10]-annulene basic framework is characterized in that being used for preparation treatment lung cancer, mammary gland, cancer liver or leukemic antitumor drug.