JPS58180462A - Optically active alkyloxynaphthacene derivative - Google Patents

Abstract

NEW MATERIAL:The optically active compound of formula I (A is alkylene which may have one or more lower alkyl substituent groups; R<1> and R<2> are H, lower alkyl, lower hydroxyalkyl, or lower aminoalkyl) and its acid addition salt. EXAMPLE:7 (S)-( 2-Aminoethyl )oxy-9 (S)-acetyl-6,9,11-trihydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-d ione. USE:Carcinostatic agent. PROCESS:The compound of formula I can be prepared by reacting the 9-acetyl- 6,7,9,11-tetrahydroxy-5,7,8,9,10,12-hexahydronaphthacene-5,12-dione with the alcohol derivative of formula II or its active ester derivative under proper condensation reaction condition.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a novel optically active alkyloxynaphthacene derivative and a method for producing the same.

More specifically, 7=furkyl oxyre j, 7. 9, 10. /2-Hexahydronaphthacene derivatives and acid addition salts thereof.

[In the formula, 5 means a proper alkylene group having 7 or more lower alkyl 1f substituents, and R1 and R2 are four or different hydrogen atoms.

It means a lower alkyl group, a lower hydroxyrealkyl group or a lower aminoalkyl group. ] Inorganic acids and organic acids are used as acids for acid addition. Any acid can be selected as long as it does not adversely affect the human body.

Here, the meanings of terms representing substituents used in this specification will be mentioned.

"Lower alkyl group" refers to a straight-chain alkyl group with 7 to 7 carbon atoms, specifically a methyl group, an ethyl group, an n-propyl group, an isopropyl group, an n-butylene group. group, isobutyl group, t-butyl group, etc.

"Alkylene group" refers to a linear alkylene having 2 or more carbon atoms, and more specifically, -(OH2)rn-(m=-~
g) It is shown by the formula: The "alkylenete 1" can be substituted with 7 or more lower alkyl groups. The "lower hydroxylalkyl group" and the "lower aminoalkyl group" are each represented by the general formula (I). It means a lower alkyl group substituted with a Dorochile group or an amino group at a position other than the carbon adjacent to the nitrogen atom.

Compound Fi represented by the general formula [1] is extremely effective as an anticancer agent. Adriamycin (hereinafter abbreviated as ADH) and daunomycin (hereinafter abbreviated as DMO) currently used clinically have strong efficacy, but they also have strong side effects, typified by fatal cardiac bulking. . Furthermore, it is difficult to separate and purify these anthracycline antibiotics during production. For these reasons, ADH-? Research into new analogues of DMO through chemical modification or total synthesis has been actively conducted, particularly research into analogues in which the sugar moiety has been changed in a certain way. However, to date, there have been no reports of homologues of 7th acycline in which the sugar moiety is converted to a substituent other than sugar and which exhibits a strong anticancer effect.

For example, Journal of Medicinal Chemistry, Volume 2.2, Issue 9. ! According to page 9.26, the 7-0-β-alanine ester of daunomycin has shown only borderline efficacy against P311r leukemia in animal experiments using mice.

Compound [1] according to the present invention stimulates tumor cells at P3 to 706
In a survival test of intraperitoneally transplanted mice (medication was administered on the 7th and 7th day of the month, closing the day of migration at θ8), the following significant effects were shown. In other words, ADR is /the same humiliated child/■μ
While the life extension rate (engineering LS) (3) of section 93 was shown in No. 93,? -7 cetyl-2-β-dimethylaminoethyloxy-A, ? , //-trihydrochyle 5
,7. G,? , 10. /,2-hexahydronaphthacene-s,i,2-dione showed a life extension rate (LSS) of 7.2θ in the jθqAy cast lid. The present invention provides an anticancer agent having a strong action obtained by introducing an easily available aminoalkyloxy group into the 7-position of an anthracycline aglycon as a substituent.

Is the compound CI according to the present invention a known stock? -7 Sechiru 1. ,7,9. //-) Rehydroxy S, 7.
To,? , /θ, 7.2 to hexahydronaphthacene-5,
/2-dione and the following general formula (II) [wherein A, R1, and R2 have the same meanings as above. ] (G) It can be easily synthesized by reacting the alcohol derivative shown in (g) or its active ester derivative under appropriate condensation reaction conditions.

The stereoisomers of the compound (1) according to the present invention include the following formulas [d], [IV] and (V) [layer].
[Lv) (V) [In the formula, A, R1, R"ij: have the same meanings as above.] However, in addition to (1), this application covers all of these isomers and It also includes mixtures of all stereoisomers in any combination in any proportion.

Hereinafter, a part of the compound group according to the present invention will be mentioned more specifically as follows: 07(S)-(,2-7minoethyl)oxy-? (S)
-acetyl-b,? , //-trihydrhydroΔ-2
7, g, 9. /θ, 7.2-hexahydronaphthacene-
j, /--dione 7(8'l-<2-methylaminoethyl)oxy-9(
8)-7 cetyl b, 9. //-trihydroxy-,!
t, 7. g, 9. /θ, /2-hexahydronaphthacene-j, /,! -Dione 7(S)-(2-dimethylaminoethyl)oxy-?
(S)-7 Cetyl 4.9. //-1 rihydroxyj
, 7, 9. /θ, /, 2-hexahydronaphthacene-j
, Hatodione 7(S)-(J-dimethylamylablevir)oxy-9
(S)-7 Cetyl 6.9. //-1-dihydroxy-
3,7,g,9. /θ, pigeon hexahydronaphthacene-
,s,/,2-dione 7(S)-(,2-diethylaminoethyl)oxy-9(+3)-7cetyl 4.9. /
/-trihydroxy-3,7,g,? , /θ, 7.2-
Hexahydronaphthane-5. /2-dione 7(S) (,2-hydroxyethyl)aminoethyl)oxy-? (S)-Acetyl-6, Ri.

//-trihydroxy-3,7,g, 9. /θ.

/2-hexahydronaphthacene-5,/2-dione 7(El)-<2-(cordimethylaminoethyl)aminoethyl)oxy-? (S)-7 Sechiru 6゜9, /
/-trihydroxy-j, 7. and,? .

/θ, 7.2-hexahyizlonaphthacene-S, /-one sion Next, the present invention will be explained in more detail with reference to Examples.
The present invention is not limited only to the following examples.

Example/Teracetyl-Otsu, 7,9. //-tetrahydroxy=
5.7. 9. /θ,/--hexahydronaphthacene-5,/:l-dione (7) (/, θy) is dissolved in trifluoroacetic acid (5Jttl). 11 dimethylaminoethanol (p to 7, 2) was dropped at θ~S′C under the phoneme air flow, Sθ~s s ”
2-dimethylaminoethanol (,2,1I31) was reacted for 9 hours at the same processing temperature. Excess trifluoric acid M was distilled off under reduced pressure (performed azeotropically with a 2nd mixed solvent three times.
1) and chloroform (/θθd). The organic layer is further extracted with -2 to 3 times with 111Il hydrochloric acid <SOFutori1). Combine the hydrochloric acid aqueous layers and adjust the pH to θ with caustic soda water at 5-70°C. Extract the organic matter with chloroform (,2θθ1), wash with water (/θθ1), dry (mirabilite), remove the solvent, and purify the resulting crude product with silica gel chromatography (chloroform/methanol-9/1) to obtain 7-3β-dimethyl. aminoethyloxy-teracetyl-4,9,//-trihydroxy-3,7,g,
/θ, 7.2-hexahydro (δ ) naphthacene-,! ;, /: orange crystal of 2-dione (I[I
p, 2&! ~, ℃ to 2F, TR (Nujol) νf
fi 1; , Bθθ~3 sweat, /7/θ, /A30, /
! ;90, NMR(0IIX]ff13) δ; /,
7g ~2. Og(/H,m)1.2. JJ(AH,s
)1.2. <j/(JH,s), -0/~J, &(5H
, m), 3.7-41. θ(JH, m), y, gg −
s, 6g (/H,'be), 7.63-7.93 (2
H, m), ni, /do~gsg(,2H,m),/,2.
4t ~/I1. θ (/H, m, D20 disappearance),
Mass spectrometry (by field desorption mass spectrometry. The same applies hereinafter); lIVθ (M/)
+) was obtained. 7-β-dimethylaminoethyloxy-teracetyl-A, in which the 7°-terdihydroxy groups are trans-isomers with each other as a result of the above procedure, ? , //-trihydroxy3.7. G,? ,/θ,7.2-hexahydronaphthacene-j,/,2-dione red-orange crystals (mp 23
! ; ~2110"C1IR(Nujol) ν(yg
(1; 3〃〜Ω〃, /7.X), /12), /K
gθ, NMR (OrOM3) δ:/, 5'? (/H,s
.

D20 disappearance), 2.33 (Otsu H,s) 1.2.3g
(3■1, s), θ~jJ (2H, m)1.
2. ! ;g −,2,7(,2H,t ),3.0(/
H,s), (/H,t), 7.62-7.9.2 (j
H, m), /~g,'l (JH, m), /-2,
-2! ~/J-g (/H, m, D20 disappearance), mass spectrometry; mass θ (M/)) was also obtained.

Example: Optical rotation [α] 萱+g/, 110 (0-θ.80HOQ3
) optically active 9(S)-acetyl-B, 7,9. ///
-tetrahydroxy-5,7,9. /θ.

/2-hexahydronaphthacene-3,/,2-dione (
θ. %3)) in the same molar ratio as in Example/, post-treatment was carried out to obtain an optical rotation [α1 +, v, 3° (C = θ, 8aHcM
3) optically active 7-β-dimethylaminoethyloxy-9(8)-acetyl-6,de.

//-trihydroxy-J, 7. G,? .

/θ, 7.2-hexahydronaphthacene-5°7.2-
Zeon's red-orange crystal (mp?θ~23℃, engineering R (Nujo
l)' 360t9~33t90,ryxy,
7w, ms) LI′:rn was obtained.

Example 3? -7 Sechi J Ray Otsu, 7,9. //-tetrahydroxy-5,7,? , /θ, /, 2-hexahydronaphthacene-j, /, 2-dione (θ, t?) and --diethylaminoethanol were reacted in the same molar ratio as in Example /, and 7-β-diethylamino Ethyloxy-deacetyl-6,9,//-trihydroxy-7,
9,,/θ,/,2-hexahydronaphthacene-5,
/, 2-dione orange crystal (mp, 234-45-J,
,! to, IR (Nujol) νz 1: 31-0
0 to 3100, /711/6°B1/9θ, NMR(O
DOM3) δ:/, θ(AH, t), 8~ko. θ(/
H, d) 1.2. ．． 2~. 2. to (7H, nn) 1.2
．． 4'(JH, 1it),! ,? 7 (/H, θ), 3°, 15 (/H, s), 3° (s H+ t ), 11
．． 9~. S, / (/H, bs), 7.63-7.
9 (,2H, m), za, 2~ni, ri (,2H, m)
, mass spectrometry;
)νctn”; /7/,!r, /AX), 1
m, N111R(GIX3M,) J; /, 0(
A H,t ), /, 5'-z2. / (/H,
a) 1.2. X (3H,e)1.2. ．． 25~j
, 7 (7H, m), 3°θ (/H, s), JJ (/
H,s), 3゜7(,2H,t), gu, 汀～9/(/
H, t), 7°7~7°ta (,2H.

m), g, /3-, &(,2H,m), mass spectrometry;
&67 M+) was obtained.

(//) Example y Soacetyl-1,,7,? , //-tetrahydrohydo! ;,7. G,? , /θ, /, 2-hexahydronaphthacene-j, /, 2-dione (θ, s W ) and 3-dimethylamino-7-propanol were reacted in the same molar ratio as in Example /, and 7 -T-dimethylaminopropyloxy-deacetyl-6,? , //-trihydroxy3.7. G,? , /θ, /,! -hexahydronaphthacene-! , 7.2-dione red-orange A (mp, 2119
~2! ;/℃, IR(Nujol) ν(7B,
31-00~x〃, /7/,,! ;、 /Otsu30.
/39θ, NMR (OIXIIM3)δ; /, 63~
．． 2. /(+H,m)1.2. ．． 2 (6H, s), 2.
35 (3H, s), L2~. 2Jj (, Otsu H, m
), 3°θ(/H+s), J,/J(/H,8)
,JJ(,21(,t),G,NiJ=!;,0.2
(/H, bs), 7.7-7.9 (,!H,m),
, 3 to 1'i' (2H*m), mass spectrometry;
'13'1(M+/)'') and 7,9-trans form (
mpJj -ff ”C1IP, (NujOl) ν(
7B*/7/J, /A3θ, /9θ quality analysis; gujgu (M+/)) was obtained.

(/, 2) Example j Deacetyl-6,7,? , //-tetrahydroxy-3,7. lr,? , /θ, /, 2-hexahydronaphthacene-j, /, 2-dione (θ, s y ) and N-methylethanolamine were reacted in the same molar ratio as in Example /, and 7-β- Methylaminoethyloxy-deacetyl-6,9,//-trihydroxy-j, 7° and 9
．． /θ, 7.2-hexahydronaphthacene-5,/2-
Reddish brown crystals of dione (mp, 259~.2A2℃, IR
(Nujol) l'g''; 3u) 0~3300.
/700, /6x1/Taku θ, NMR (anon3)
a ; /, g ~, 2. / (/H, cl)1.2.
．． 2~j,? (7H, m)1.2. tI(JH,s),
3.0(/H,s), 3.73-(/H,s), 3.9
(,2H,t),g,? ~j,%(/H,be)
,7.7~7.9 (,2H,m),to,2~to,1
．． 2H, m), mass spectrometry: 1A2A (M+/ )+)
and 7,9 trans isomer (■/S6 Rin~/total 'C1IR (Nujol) νcm + 3
'100-3000, /7z.

Claims (1)

Claims: General formula [wherein A means an alkylene group which may have 7 or more lower alkyl substituents, 11. R2 is 4- or differently a hydrogen atom. A novel optically active alkyloxynaphthacene derivative represented by ◇, which means a lower alkyl group, a lower hydroxyalkyl group, or a lower aminoalkyl group, and an acid addition salt thereof.