JPH05163293A - Anthracycline-macrolide complex - Google Patents

Abstract

PURPOSE:To obtain the subject new complex effective to lung cancer with few side effects by using a macrolide-based antibiotic as drug carrier to direct anthracycline-based carcinostatic antibiotics toward the lung. CONSTITUTION:The objective complex of formula I [R<1> is H or CH2OR<9> (R<9> is of formula II); R<2> is O=, HO, etc.; R<3> is H, COC2H5, etc.; R<4> is CH3 or C2H5; R<5> is H or of formula III (R<11> is H or COCH3; R<12> is H, COC3H7, etc.); R<6> is H, OH< etc.; R<7> is NH2, NHCOCF3, etc.; R<8> is H or of formula IV]. It is recommended that this complex be obtained by a process wherein the 7- aldehydemethyl group of the 2-oxo-oxacyclohexadeca-11,13-diene ring of a macrolide antibiotic is oxidized into 7-carboxymethyl group; whereas, the amino group of daunosamine, an anthracycline-based carcinostatic antibiotic, is protected in advance; then, an ester linkage is formed between the 8- hydroxyacetyl group of 5,12-naphthacenedione and the above-mentioned 7- carboxymethyl group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel anthracycline-macrolide complex in which an anthracycline anticancer drug is directed to the lung by using a macrolide antibiotic as a drug delivery carrier.

[0002]

2. Description of the Related Art Anthracycline anticancer antibiotics such as adriamycin are currently one of the most widely used anticancer agents. However, while the antibiotics of this system have clear efficacy clinically, they have drawbacks in side effects, and therefore, many derivatives have been synthesized so far for the purpose of alleviating side effects. For example, THP-adriamycin developed by one of the present inventors has antitumor activity comparable to that of adriamycin, while toxicity is reduced and side effects are mild (Shigeru Tsukakoshi: Problems in developing anticancer drug derivatives, cancer. And chemotherapy 15 (8), 2
173-2178 (1988)).

Considering such circumstances, it is known that the anthracycline anticancer antibiotics are the drugs that most require the application of drug delivery technology aiming at organ orientation, including the purpose of reducing side effects. Has been. For example, it is ineffective in lung cancer, but this is due to poor directionality to the lungs, and if the drug becomes concentrated in the lungs, it will also be effective in lung cancers, and at the same time, due to the reduction of the required dose. It can be expected to reduce side effects.

It is already well known that macrolide antibiotics have a strong affinity for specific organs, especially the lungs. That is, macrolide antibiotics are generally excellent in tissue migration and exhibit good migration to the lung as well as quinolone antibacterial agents (Development of Pharmaceuticals Vol. 4 (published by Hirokawa Shoten) 332-33).
Page 5 (1991)).

[0005]

In view of the above-mentioned situation of the prior art, the present inventor has taken up the aim of directing anthracycline anticancer antibiotics to the lung as a problem to be solved, and as a means for solving this problem, lung migration The present invention has been completed by attempting to use a good macrolide antibiotic as a transport carrier.

The present invention will be described below. The substance of the present invention is
Formula (I) below

[0007]

[Chemical 7]

Is indicated by The aglycone skeleton of the macrolide antibiotic, which is the carrier moiety in the substance of the present invention, is a 16-membered ring, that is, 2-oxooxacyclohexadeca-11,13-diene, and Micaminoze is 1
It is essential as a sugar linked to the 6-position of the 6-membered ring. The basic skeleton of an anthracycline anticancer antibiotic as a drug moiety is 5,12-naphthacenedione, and daunosamine is essential as a sugar linked to the 10-position of the naphthacenedione. The bond between the carrier moiety and the drug moiety is made by the ester bond between the carboxylic acid derivative of the macrolide antibiotic and the anthracycline anticancer antibiotic.

In the formula (I), R ¹ represents H or CH ₂ OR ⁹ , provided that R ⁹ represents a sugar represented by the following formula (II).

[0010]

[Chemical 8]

R ² is O =, HO, CH ₃ COO, C ₂ H
₅ COO or R ¹⁰ O (wherein R ¹⁰ represents the following formula (III)).

[0012]

[Chemical 9]

R ³ represents H, COCH ₃ or COC ₂ H ₅ . R ⁴ represents CH ₃ or C ₂ H ₅ . R ⁵ represents H or Micarases represented by the following formula (IV),

[0014]

[Chemical 10]

However, in the formula (IV), R ¹¹ is H or COC.
Represents H ₃ , and R ¹² represents H, COCH ₃ , COC ₂ H
₅ , COC ₃ H ₇ or COCH ₂ CH (CH ₃ ) ₂ is represented. R ⁶ represents H, OH or OCH ₃ . R ⁷ is NH
₂ , NHCOCF ₃ or

[0016]

[Chemical 11]

Represents R ⁸ represents H or the following formula (V).

[0018]

[Chemical 12]

Examples of macrolide antibiotics as carrier moieties include josamycin, leucomycin, midecamycin, kitasamycin, rokitamycin, spiramycin, tylosin and their ester derivatives and acid salts.

Examples of anthracycline anticancer antibiotics as drug moieties include daunorubicin, doxorubicin (adrimycin), pirarubicin (THP-adriamycin), epirubicin and acid salts thereof.

In the production of the substance of the present invention, a macrolide antibiotic and an anthracycline antitumor antibiotic can be appropriately reacted according to the chemical structural formulas of the combined substances. It is done like. That is, the 7-aldehydemethyl group of the 2-oxooxacyclohexadeca-11,13-diene ring of the macrolide antibiotic is oxidized to a 7-carboxymethyl group, while the amino acid of daunosamine of the anthracycline anticancer drug is After pre-protecting the group, an ester bond is formed between the 8-hydroxyacetyl group of 5,12-naphthacenedione and the 7-carboxymethyl group.

[0022]

The substance (I) of the present invention is expected to act effectively on lung cancer. In other words, anthracycline anti-cancer antibiotics, which have been effective in vitro in the past but did not show remarkable efficacy in lung cancer in vivo, are now concentrated in lung cancer tissues, and as a result, It will be effective.

[0023]

The present invention will be described in more detail with reference to the following examples.

[0024]

Example 1

[Chemical 13]

Starting compound 1 600.0 mg (1.035
mmol) in 15 times the amount of chloroform 9.00 ml, cooled at 0 ° C. and equimolar triethylamine 144.
3 μl was added. Next, 3.00 ml of 5-fold anhydrous trifluoroacetic acid was added at 0 ° C., and the mixture was stirred for 3.5 hours. After confirming the completion of the reaction by thin layer chromatography (TLC) (chloroform: methanol = 5: 1), 5.00 ml of methanol was added under ice cooling, and the mixture was concentrated under reduced pressure until it became a syrup. The concentrated residue was dissolved in 290 ml of methanol, 6.42 ml of a 10-fold molar 10% potassium carbonate solution was added under ice cooling, and the mixture was stirred for 1.5 hours. After confirming the completion of the reaction by TLC (chloroform: methanol = 5: 1), the reaction system was concentrated under reduced pressure to about 150 ml, 500 ml of water was added, and liquid separation extraction was performed with chloroform (80 ml × 3). The organic layer was concentrated under reduced pressure and the concentrated residue was purified by silica gel chromatography (Daisogel, 33 g, ethyl acetate) to give 560.0 mg of dark red crystals of the title compound 2 (AD-N-TFA).
(Yield 84.6%) was obtained.

Compound 2: [α] _D ³⁴ + 290.4 ° (c 1.50
, MeOH) ¹ H-NMR (CD ₃ OD, 270MHz): δ 1.28 (s, H-6 ^' ) 1.78 (dd, H-2'a) 2.05 ~ 2.19 (m, H-2 ^' b, H-8a ) 2.35 (d, H-8b) 2.80, 2.99 (ABq, H-10a, H-10b) 3.67 (t like, H-4 ^' ) 3.96 (s, OMe) 4.14 ~ 4.35 (m, H-3 ^' , H-5 ^' ) 4.74 (s, H-14) 5.01 (dull d, H-7) 5.40 (d like, H-1 ^' ) 7.43 (dd, H-3) 7.65 ~ 7.77 (m, H-1, H-2)

[0027]

[Chemical 14]

Starting compound 3 612.2 mg (0.739)
4mmol) in 42.9ml of dioxane and 18.4ml of water, 100.3mg of sodium chlorite (1.109mmo)
l) and sulfamic acid 107.7 mg (1.109 mmol)
Was added and reacted at room temperature for 15 minutes. The reaction system was extracted with saturated saline and chloroform, concentrated under reduced pressure, and the concentrated residue was subjected to silica gel chromatography (Daisogel, 30
g, chloroform: methanol = 10: 1),
510.5 mg (yield 82.0%) of a white foam solid of the title compound 4 (18-COOH-josamycin) was obtained.

[0029]

[Chemical 15]

Compound 4 365.0 mg (0.4325 mm
10 times the amount of anhydrous tetrahydrofuran (THF)
The mixture was dissolved in 3.65 ml, 1.5 times mol of triethylamine (90.5 μl) and 1.05 times mol of α-naphthalenecarbonyl chloride (68.4 μl) were added, and the mixture was stirred for 1 hour.
276.6 mg of an equimolar amount of Compound 2 with respect to Compound 4,
What was dissolved in 2.77 ml of anhydrous THF in an amount 10 times that of compound 2 was added to the reaction system of compound 4, and 2 times the molar amount of 4 was added.
-Dimethylaminopyridine 105.7 mg and anhydrous benzene 3.65 ml were added and reacted for 3 hours. After confirming the completion of the reaction by TLC (chloroform: methanol = 10: 1), 10 ml of water was added, and the mixture was separated and extracted with ethyl acetate (20 ml × 4). Furthermore, 10 ml of acetic acid water (pH 3) and ethyl acetate 2
The organic layer was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (Daisogel, 12 g, ethyl acetate, acidic acetic acid (pH 3)) to elute unreacted compound 2 and the like. (Chloroform: methanol = 1
Elute with 5: 1), purify and purify the title compound 5 (18-
40.8 mg (yield 8.3%) of dark red crystals of (AD-N-TFA) -josamycin) were obtained.

Compound 5: [α] _D ³¹ + 76.3 ° (c0.80, C
HCl ₃ ) ¹ H-NMR (CDCl ₃ , 270MHz): δ 0.97 (d) 1.03 (d) 1.10 (s, (CH ₃ of 3 ^'' ) 1.14 (d) 1.24〜1.35 (m) 1.75〜1.90 (m ) 2.14 (s, COCH ₃ ) 2.16,2.29 (ABq, H-8 ^''' ) 2.50 (s, NMe ₂ ) 3.00,3.45 (ABq, H-10 ^''' ) 3.22 ~ 3.45 (m) 3.56 (s , OMe of 4) 3.60 ~ 3.69 (m) 4.00 (d) 4.09 (s, OMe of 4 ^''' ) 4.42 (s, H-14 ^''' ) 4.40 ~ 4.52 (m) 4.63 (d) 4.97 ~ 5.11 (m) 5.17 (d) 5.31 (dd, H-7 `` <sup>''</sup> ) 5.53 (dd, H-1 `` ^'' ) 5.58 ~ 5.85 (m, H-12, 13) 6.07 (dd, H-10 ) 6.54 ~ 6.70 (m, H-11, NH) 7.40 (d, H-3 ^''' ) 7.79 (t, H-2 ^''' ) 8.06 (d, H-1 ^''' )

[0031]

Example 2

[0032]

[Chemical 16]

Starting Compound 3 7.03 g (8.48 mmo)
141 ml of an anhydrous methylene chloride solution of 1) was poured into an anhydrous methylene chloride solution of 6.10 g (14.4 mmol) of Dess-Martin reagent at room temperature and stirred for 1.5 hours. To the reaction system, 35.1 ml of ether and a saturated NaHCO ₃ —Na ₂ S ₂ O ₃ (1: 7) aqueous solution were added, and after separation and extraction, the organic layer was saturated aqueous sodium hydrogen carbonate, and then
The extract was washed with saturated saline and concentrated under reduced pressure. The concentrated residue was purified by silica gel chromatography (Daisogel, 350 g, chloroform: acetone = 7: 2) to give the title compound 6
White crystals of (carbomycin B) 5.00 g (yield 7
1.3%) was obtained.

[0034]

[Chemical 17]

Compound 6 (1.45 g, 1.76 mmol) was dissolved in THF (14.5 ml), 2N HCl (14.5 ml) was added, and the mixture was reacted at room temperature for 30 minutes. The reaction system was adjusted to pH 8 with saturated aqueous sodium hydrogen carbonate, extracted with chloroform, and washed with saturated brine. The organic layer was concentrated under reduced pressure, and the concentrated residue was purified by silica gel chromatography (Daisogel, 50 g, chloroform: methanol = 5: 1) to give the title compound 7
As a result, 991.0 mg (yield 94.1%) of a white foam-like solid of (demicalosyl carbomycin) was obtained.

[0036]

[Chemical 18]

Compound 7 531.0 mg (0.89 mmol)
Was dissolved in 37 ml of dioxane and 16 ml of water, 120.7 mg (1.34 mmol) of sodium chlorite and 130.1 mg (1.34 mmol) of sulfamic acid were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After completion of the reaction, saturated saline was added and extracted with chloroform. The organic layer was concentrated under reduced pressure, and the residue was subjected to silica gel chromatography (Dasigel, 28 g,
Purified with chloroform: methanol = 2: 1), 418.7 mg (0.68) of the title compound 8 as a white foamy solid.
mmol) (yield 77%).

[0038]

[Chemical 19]

Compound 8 385.0 mg (0.6273 mm
ol) in 10 volumes of anhydrous THF (3.85 ml),
131.2 μl of 1.5 times the molar amount of triethylamine and 1.
05 times mol of α-naphthalene carbonyl chloride 9
After adding 9.3 μl and stirring for 40 minutes, 3.85 ml of anhydrous benzene was added. Next, 401.2 mg of Compound 2 in an equimolar amount to Compound 8 was dissolved in 10 times the amount of anhydrous THF to Compound 2 was added to the reaction system of Compound 8, and 2-fold molar amount of 4-dimethylamino was added. Pyridine 153.3
mg was added and reacted for 3.5 hours. After confirming the completion of the reaction by TLC (chloroform: methanol = 5: 1), 10 ml of water was added and chloroform (50 ml, 10 ml ×).
It was extracted in 4). The concentrated residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Daisogel, 39 mg, ethyl acetate) to elute unreacted compound 2 and the like, and then (n-butanol: ethanol: chloroform: H).
₂ O = 4: 4: 2: 3) and further purified by silica gel chromatography (Kieselgel forflush, 25 g, chloroform: methanol = 5: 1) to give the title compound 9 (18- (AD-N 78.5 mg (yield 10.1%) of dark red crystals of -TFA-DMC) were obtained.

Compound 9: [α] _D ³⁴ + 55.4 ° (cl.OO, C
HCl ₃ ) ¹ H-NMR (CDCl ₃ , 270MHz): δ 1.06 〜 1.35 (m) 2.13 (s, COCH ₃ ) 2.53 (s × 2, N Me ₂ ) 2.65 〜 3.40 (m) 3.41 〜 3.75 (m) 3.56 (s, OMe) 3.58 (s, OMe) 4.09 (s, OMe) 4.35 ~ 4.45 (m, H-14 ^'' ) 4.55 (d, H-1 ^' ) 4.80 ~ 4.94 (m) 5.50 ~ 5.40 (m ) 5.55 (dd, H-7 ^'' ) 6.00 ~ 6.43 (m, H-10,12,13) 6.65 ~ 6.78 (m, NH) 7.40 (d, H-1 ^'' ) 7.78 (t, H-2 ^'' ) 8.04 (d, H-3 ^'' )

[0041]

Example 3

[0042]

[Chemical 20]

5.0 g of raw material compound 10 (tylosin)
(5.46 mmol) dioxane 350 ml and water 150 ml
1.23 g of sodium chlorite (1
3.64 mmol) and sulfamic acid 1.38 (14.1)
(9 mmol) was added, and the mixture was stirred as it was at room temperature for 20 minutes. After completion of the reaction, saturated saline was added and extracted with chloroform.
The organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography (Daisogel, 255 g, chloroform: methanol = 2: 1) to give 3.73 g (4.00 mmol) of the title compound 11 as a white foam solid (yield 74%). ) Got.

[0044]

[Chemical 21]

Compound 11 2.7279 g (2.926)
6 mmol) was dissolved in 27.3 ml of 10 times anhydrous THF,
1.5-fold molar triethylamine 0.589 ml and 1.0
5-molar α-naphthalene carbonyl chloride 0.4
After adding 46 ml and stirring for 20 minutes, anhydrous benzene 2
7.3 ml was added. Next, a solution obtained by dissolving 1.8716 g of Compound 2 in an equimolar amount to Compound 11 in 10 times the amount of anhydrous THF to Compound 2 was added to the reaction system of Compound 11, and 2-fold molar amount of 4-dimethylamino was added. Pyridine 715.1
mg was added and reacted for 5.5 hours. After confirming the completion of the reaction by TLC (chloroform: methanol = 10: 1), 50 ml of water was added, and the mixture was extracted with chloroform (100 ml × 4). The concentrated residue obtained by concentration under reduced pressure was purified by silica gel chromatography (Fujigel, 145 g, ethyl acetate) to elute unreacted compound 2 and the like.
Elution with (chloroform: acetone = 1: 1), purification, and dark-red crystals of the title compound 12 (20- (AD-N-TFA) -tylosin) 517.7 mg (yield 17.8).
%) Was obtained.

Compound 12: [α] _D ³⁴ + 52.2 ° (c 1.OO
, CHCl ₃ ) ¹ H-NMR (CDCl ₃ , 270 MHz): δ 0.94 (t, H-17) 1.00 (d) 1.10 to 1.40 (m) 2.05 (dd) 2.31 (dd) 2.64 (s, NMe ₂ ) 2.90 ~ 3.17 (m) 3.48 (s, OMe) 3.61 (s, OMe) 3.76 (s) 4.09 (s, OMe) 4.15 ~ 4.38 (m) 4.44-4.64 (m) 4.47 (s, H-14 `` ^'' ) 5.10 (dd, H-1 ^'' ) 5.30 (m) 5.53 (dd, H-1 ^''''' ) 5.84 ~ 6.00 (m, H-13) 6.15 ~ 6.39 (m, H-10) 6.74 ( d, NH) 7.35 (m, H-12) 7.40 (d, H-3 ^''''' ) 7.78 (t, H-2 ^''''' ) 8.03 (d, H-1 ^''''' )

[Chemical formula 22]

Claims (4)

[Claims] 1. An anthracycline-macrolide complex represented by the following formula (I). [Chemical 1] [Wherein R ¹ represents H or CH ₂ OR ⁹ (wherein R ⁹ represents the following formula (II)), and R ² represents O =, HO, CH ₃ COO, C ₂ H ₅ COO or R ¹⁰ O (wherein R ¹⁰ represents the following formula (III)), and R ³ represents H, COCH ₃ or COC ₂ H ₅ , R ⁴ represents CH ₃ or C ₂ H ₅ , R ⁵ is H or the following formula (IV) (However, R ¹¹ represents H or COCH ₃ , R ¹² represents H,
COCH ₃ , COC ₂ H ₅ , COC ₃ H ₇ or COCH ₂
CH (CH ₃ ) ₂ ), R ⁶ represents H, OH or OCH ₃ , and R ⁷ is NH ₂ , NHCOCF ₃ or R ⁸ is H or the following formula (V): Represents] 2. R ¹ is H, R ² is HO, and R ³ is COCH.
₃ , R ⁴ is CH ₃ , R ⁵ is the formula (IV) (provided that R ¹¹ is H,
R ¹² is COCH ₂ CH (CH ₃ ) ₂ ), R ⁶ is OCH ₃ ,
The anthracycline-macrolide complex according to claim 1, wherein R ⁷ is NHCOCF ₃ and R ⁸ is H. 3. R ¹ is H, R ² is O =, and R ³ is COCH.
The anthracycline-macrolide complex according to claim 1, wherein ₃ , R ⁴ is CH ₃ , R ⁵ is H, R ⁶ is OCH ₃ , R ⁷ is NHCOCF ₃ and R ⁸ is H. 4. R ¹ is CH ₂ OR ⁹ (wherein R ⁹ is formula (II)), R ² is O =, R ³ is H, R ⁴ is C ₂ H ₅ , R
The anthracycline-macrolide complex according to claim 1, wherein ⁵ is the formula (IV) (wherein R ¹¹ is H, R ¹² is H), R ⁶ is OCH ₃ , R ⁷ is NHCOCF ₃ and R ⁸ is H. ..