Claims
- 1. 9-Aminonaphthacene derivative having the formula: ##STR15## wherein R.sup.1 and R.sup.2 are both hydrogen atoms or either one of them is a hydrogen atom and the other is hydroxy group or methoxy group; R.sup.3 is acetyl group or 1-hydroxyethyl group; R.sup.4 is a hydrogen atom; R.sup.5 is a hydrogen atom, hydroxy group, lower alkanoyloxy group or amino group; R.sup.6 is a hydrogen atom, hydroxy group or lower alkanoyloxy group; R.sup.7 is a hydrogen atom or methyl group; R is a hydrogen atom; and n is one.
- 2. A compound according to claim 1 wherein both R.sup.1 and R.sup.2 are hydrogen atoms.
- 3. A compound according to claim 1 wherein R.sup.1 is methoxy group and R.sup.2 is a hydrogen atom.
- 4. A compound according to claim 1 wherein R.sup.1 is a hydrogen atom and R.sup.2 is methoxy group.
- 5. A compound according to claim 1 wherein either R.sup.1 or R.sup.2 is a hydrogen atom and the other is hydroxy group.
- 6. A compound accroding to claim 1 wherein R.sup.3 is acetyl group.
- 7. A compound according to claim 1 wherein R.sup.3 is 1-hydroxyethyl group.
- 8. A compound according to claim 1 wherein R.sup.5 is amino group, R.sup.7 is methyl group.
- 9. A compound accroding to claim 1 wherein both R.sup.5 and R.sup.6 are hydroxy groups or acetoxy groups.
- 10. A compound according to claim 9 wherein R.sup.7 is methyl group.
- 11. A compound according to claim 9 wherein R.sup.7 is a hydrogen atom.
- 12. A compound according to claim 1 wherein R.sup.5, R.sup.6 and R.sup.7 all are hydrogen atoms.
- 13. A compound according to claim 8 wherein R.sup.6 is a hydrogen atom.
- 14. A compound according to claim 1 which is d-7.alpha.-[(2-deoxy-.beta.-D-erythro-pentapyranosyl)oxy]-9.alpha.-amino-9.beta.-acetyl-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione.
- 15. A compound according to claim 1 which is d-7.alpha.-[(2-deoxy-3,4-di-0-acetyl-.beta.-D-erythro-pentapyranosyl)oxy]-9.alpha.-amino-9.beta.-acetyl-7,8,9,10-tetrahydro-6,11-dihydroxy-5,12-naphthacenedione.
- 16. A compound according to claim 1 which is d-7.alpha.-[(2-deoxy-.beta.-D-erythro-pentapyranosyl)oxy]-9.alpha.-amino-9.beta.-acetyl-7,8,9,10-tetrahyro-6,11-dihydroxy-5,12-naphthacenedione.
- 17. A compound according to claim 1 which is a d-7.alpha.-[(2-deoxy-3,4-di-O-acetyl-.beta.-D-erythro pentapyranosyl)oxy]-9.alpha.-amino-9.beta.-acetyl-7,8,9,10-tetrahydro-6,11-dihydroxy-5-12-napthacenedione.
- 18. A pharmaceutical composition useful against P 388 Mouse Leukemia cells which comprises an effective amount of a compound of claim 1 as an active ingredient and a pharmaceutically acceptable carrier or diluent.
- 19. A method of inhibiting the growth of P 388 mouse leukemia cells in a mouse comprising administering to a mouse having P 388 mouse leukemia cells an amount of a compound of claim 1 to inhibit the growth of the P 388 mouse leukemia cells sufficiently to increase the life span of the mouse.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 57-186514 |
Oct 1982 |
JPX |
|
Parent Case Info
This is a continuation-in-part application of Ser. No. 543,967 filed on Oct. 20, 1983 now abandoned.
The present invention relates to novel aminonaphthacene derivatives and processes preparing the same. More particularly, the present invention concerns aminonaphthacene derivatives having the formula (I): ##STR2## wherein R.sup.1 and R.sup.2 are both hydrogen atoms or either one of them is a hydrogen atom and the other is hydroxy group or methoxy group; R.sup.3 is acetyl group or 1-hydroxy ethyl group; R.sup.4 is a hydrogen atom; R.sup.5 is a hydrogen atom, hydroxy group, lower alkanolyoxy group, amino group, halogen-substituted lower alkanoyl amino group, morpholino group; R.sup.6 is a hydrogen atom, hydroxy group, lower alkanoyloxy group, tetrahydropyranyloxy group; R.sup.7 is a hydrogen atom or methyl group; R is a hydrogen atom; and n is zero or one.
In the foregoing and subsequent descriptions, the term "lower alkanoyl" is intended to mean any group having C.sub.1-4 alkanoyl group. The term "halogen-substituted lower alkanoyl group" is intended to mean any group of C.sub.1-4 alkanoyl group substituted with one to three fluorine atoms, chlorine atoms, bromine atoms or iodine atoms.
Aminonaphthacene derivative having the formula (I) is analogous to anthracycline antibiotics which are familiar therapeutic chemicals for cancer clinically administered. Although "Dounomycin" and "Adoriamycin" are known as anthracycline antibiotics having strong anti-tumor activity and are clinically useful [Process Biochemistry 12-16 (1980)], they are not satisfactory yet.
The present invention provides compounds (I) which are useful as an anti-cancer chemical agents with lower toxicity and with little local irritation and are able to orally be applied.
The aminonaphthacene derivatives (I) can be administered parenterally, orally or locally to warmblooded animals and human beings in the form of conventional pharmaceutical preparations. For instance, they can be administered in the form of conventional solid pharmaceutical preparations such as tablets, capsules, powders or granules, or in the form of conventional liquid pharmaceutical preparations such as suspensions, emulsions or solutions. The daily dosage may vary depending upon the administration route and is usually between 0.1 to 100 mg/kg.
Aminonaphthacene derivative having the formula (IV) which is one of aminonaphthacene derivatives having the formula (I): ##STR3## wherein R.sup.1, R.sup.2, R.sup.4 and n are as defined above;
(A) Glucosylating a compound having the formula (II): ##STR4## wherein R.sup.1, R.sup.2 and R.sup.4 are as defined above: with a saccharide derivative having the formula (III): ##STR5## wherein R', R.sup.8, R.sup.9, R.sup.10 and n are as defined above; and X is a chlorine atom or a bromine atom; in the presence of either a soluble silver salt such as silver salt of trifluoromethane sulfonic acid, etc., or a mercuric salt such as mercuric oxide, mercuric cyanate, and mercuric bromide, etc., in a solvent of a halogenated alkyl solvent such as dichloromethane and dichloroethane, etc., an ethereal solvent such as tetrahydrofuran and diethylether, etc., or a mixture thereof;
(B) Glucosylating a compound having the formula (II) with one of compounds having the formulas (V) and (VI): ##STR6## wherein R', R.sup.8, R.sup.9 and R.sup.10 are as defined above; in the presence of an acidic catalyst such as methane sulfonic acid, p-toluene sulfonic acid, in an anhydrous organic solvent such as dimethylformamide, benzene, toluene, tetrahydrofuran and dioxane, etc.
Compound having the formula (IV) obtained according to the glycosylating reaction above is usually a mixture of two forms of compounds with respect to configuration of sugar component, i.e., (1) 1'.alpha.-combination (.alpha.-anomer) and (2) 1'.alpha.-combination (.beta.-anomer).
Stereoisomers of compound having the formula (IV) are discussed below. There are two forms of compounds in the starting compound having the formula (II) in respect to configuration of the oxygen atom at 7-position and the nitrogen atom at 9-position, i.e., cis form and trans form. For instance, compound having the formula (IV) is given in the form of a mixture of four steric isomers when the glycosylating reaction is carried out between racemate of the compound (II) in cis form and optically active compound selected from sugar derivatives having the formulas (III), (V) and (VI). Also, a mixture of two steric isomers is obtained when the glycosylating reaction is effected between optically active form of the compound (II), e.g., cis form, and the optically active sugar derivative. Isomers above can be separated from each other by means of chromatography using, for example, silica gel. Alternatively, the separation may be effected after hydrolysis discussed hereinafter.
Hydrolysis of ester group of aminonaphthacene derivatives having the formula (IV) and having ester group to obtain aminonaphthacene derivative having the formula (VII): ##STR7## wherein R.sup.1, R.sup.2, R.sup.4 and n are defined above; R.sup.11 is a hydrogen atom, hydroxy group or halogen-substituted lower alkanoylamino group; R" and R.sup.12 are a hydrogen atom or hydroxy group, respectively; R.sup.13 is a hydrogen atom, methyl group or hydroxymethyl group but R.sup.13 is not a hydrogen atom nor methyl group when both R.sup.11 and R.sup.12 are hydrogen atoms, may be carried out with inorganic bases such as sodium hydroxide, potassium carbonate, sodium hydrogen carbonate etc. or with organic bases such as triethylamine, in a solvent such as methanol, ethanol, hydrous tetrahydrofuran, hydrous acetone etc. Hydrolysis above of the compound where ester group is trifluoroacetoxy group may be effected under milder conditions than those to be applied for the other ester groups, for example, with triethylamine or sodium hydrogen carbonate in methanol or hydrous acetone. Hydrolysis of aminonaphthacene derivative having the formula (IV) above and containing trifluoroacetamido group in addition to ester group may be effected under such conditions that the trifluoroacetamido group is hardly hydrolysed, for example, with potassium carbonate, at a temperature of from - 20.degree. C. to 5.degree. C. for a period of time from 0.5 to 2 hours, resulting in aminonaphthacene derivative having the formula (VII) and having trifluoroacetamido group as well as hydroxy group.
A compound having the formula (VIII): ##STR8## wherein R", R.sup.1, R.sup.2, R.sup.12, R.sup.13 and n are defined above and R.sup.14 is a hydrogen atom, hydroxy group, amino group or halogen-substituted lower alkanoylamino group excluding trifluoroacetamido group, is prepared from an aminonaphthacene derivative having the formula (IV) and R.sup.4 is trifluoroacetyl group. When there is ester group in the molecule of the compound having the formula (IV), there are two procedures. One is that the ester group is first hydrolysed according to the above procedure before the trifluoroacetamido group is hydrolysed; and another is that both the ester group and the trifluoroacetamido group are hydrolysed at one time. In the former procedure a compound having the trifluoroacetamide group obtained from hydrolysis of the ester group is allowed to react with an inorganic base such as sodium hydroxide, potassium carbonate, etc., in a solvent such as methanol, hydrous acetone, hydrous tetrahydrofuran, etc., at a temperature of from 0.degree. C. to 10.degree. C. for from 0.5 to 20 hours, resulting in hydrolysis of the trifluoroacetamido group until a compound having the formula (VIII) is obtained. In the latter procedure, the hydrolysis is effected under the conditions above where the trifluoroacetamide group as well as the ester group are hydrolysed, until a compound having the formula (VIII) is obtained. A compound having the formula (VIII) is also obtained by hydrolysis of a compound having the formula (IV) where R.sup.4 is trifluoroacetyl group and there is no ester group in the molecule, under the same conditions as in the latter procedure above.
A compound having the formula (X): ##STR9## wherein R", R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.13 and n are as defined above, is obtained by allowing a compound having the formula (IX), one of compounds having the formula (IV): ##STR10## wherein R", R.sup.1, R.sup.2, R.sup.11, R.sup.12, R.sup.13 and n are as defined above; and R.sup.15 is a hydrogen atom, hydroxy group, amino group or halogen-substituted lower alkanoylamino group; to react with trifluoroacetic acid anhydride in a solvent such as dichloromethane, chloroform, tetrahydrofuran, etc., in the presence of a base such as triethylamine, pyridine, etc., followed by addition of a mixture of (1) methanol or hydrous methanol with (2) triethylamine or sodium hydrogen carbonate until partial trifluoroacetylation of only amino group in the molecule is selectively effected.
A reaction of a compound having the formula (XI) with a compound having the formula (XII) in a solvent such as dimethylformamide, dimethylsulfoxide, tetrahydrofuran, diglyme, etc., in the presence of tertiary amine such as triethylamine, dimethylaniline, etc., produces a compound having the formula (XIII): ##STR11## wherein R", R.sup.1, R.sup.2, R.sup.4, R.sup.12, R.sup.13 and n are as defined above; and Y is a bromine atom or an iodine atom.
A reaction of a compound having the formula (XIV) with dihydropyran in an anhydrous solvent such as toluene, acetonitrile, dimethylformamide, etc., in the presence of an acid catalyst such as p-toluenesulfonic acid; benzenesulfonic acid, produces a compound having the formula (XV): ##STR12## wherein R.sup.1, R.sup.2, R.sup.4 and n are as defined above; R.sup.16 is a hydrogen atom, amino group, or halogen-substituted lower alkanoyl amino group; and R.sup.17 is a hydrogen atom or methyl group.
Reduction of the compound having the formula (XVI) obtained according to the procedure above, until 13-oxo group is reduced, produces a compound having the formula (XVII): ##STR13## wherein R, R.sup.1, R.sup.2, R.sup.4, R.sup.5, R.sup.6, R.sup.7 and n are as defined above. The reduction may be carried out with a reducing agent which is capable of reducing oxo-group, such as a boron-containing reducing agent, e.g., sodium cyanoborohydride, lithium cyanoborohydride, or sodium borohydride, or an aluminum-containing reducing agent, e.g., lithium aluminum hydride, diisobutylaluminum hydride, sodium diethyl dihydro aluminate. Boron-containing reducing agent is preferred when ester group and amido group are present in the molecule. The reduction is carried out in such a solvent as water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixture thereof at a temperature of from -20.degree. C. to 40.degree. C., when the boron-containing reducing agent is employed. On the other hand, the reduction is carried out in a solvent such as tetrahydrofuran, dioxane, diethyl ether, etc., at a temperature of from -100.degree. C. to -20.degree. C., when the aluminum-temperature containing reducing agent is employed.
Compound (A) having the formula (XVII) and having an amido linkage in the molecule is obtained by reduction of oxo group of the corresponding compound having the formula (XVI) in the manner mentioned above. Alternatively, the compound (A) above is obtained by amidation of a compound having the formula (XVII) and having amino group, until the amino group is converted into amido group. On the other hand, a compound having the formula (XVII) and having amino group in the molecule may also be obtained by hydrolysis of a compound having the formula (XVII) and having trifluoroacetamido group in the molecule.
A compound having the formula (II) wherein both R.sup.1 and R.sup.2 are hydrogen atoms, which is the starting compound of the present invention, is prepared according to processes disclosed in EPC Publication No. 72259 published on Feb. 16, 1983. A compound wherein either R.sup.1 or R.sup.2 is a hydrogen atom and the other is methoxy group or hydroxy group, which is new, is prepared according to the reaction scheme mentioned below: ##STR14## wherein R.sup.17 is as defined above; R.sup.18 is lower alkyl group or halogenated lower alkyl group (C.sub.1-3 alkyl group); R.sup.19 and R.sup.20 are both methyl groups or ethyl groups or, when taken together represent an ethylene group; and hydroxy or methoxy group in the formulas (3), (4), (5), (6), (7), (7'), (8), (8'), (9), (9') locates at 1- or 4-position.
As illustrated above, compound (1) is allowed to react with derivative of phthalic anhydride (2) in the presence of a Lewis acid such as aluminum chloride to obtain a compound (3). Conversion of phenolic hydroxy group of the compound (3) into methoxy group as in the compound (4) is made by use of a compound such as dimethylsulfate. Treatment of the compound (4) with a compound such as aluminum chloride provides a compound (5). Protection of the ketone group of the compound (5) is made by the manner familiar to the skilled to obtain a compound (6) which is then allowed to react with a halogenating agent such as N-bromo succinic acid amide to produce a compound (7) wherein R.sup.17 =CH.sub.3. Hydrolysis of the compound (7) with an acid such as hydrochloric acid produces a compound (8) where R.sup.17 is methyl group, and, if necessary, the methyl group is converted into a hydrogen atom by use of a compound such as aluminum chloride. Treatment of the compound (7 ) with a compound such as aluminum chloride gives a compound (7') where R.sup.17 is a hydrogen atom. Hydrolysis of the compound (7') with an acid such as hydrochloric acid gives the compound (8') where R.sup.17 is a hydrogen atom. If necessary, acylation of the compound (8) or (8') gives a compound (9) or (9'), respectively.
Compound (3) produced from a reaction between compounds (1) and (2) has two positional isomers depending on position of the hydroxy group. Compounds (4), (5), (6), (7), (7), (8), (8'), (9) and (9') also have the same isomers. It is possible to separate these isomers from each other by chromatography or others in any of the compounds (3)-(9) and (9'), but preferably in compound (5) or (7), more preferably in compound (5) by fractional crystallization.
Optically active forms of the compounds (8) and (9) are obtained as in the same scheme above when optically active form of the compound (1) is used. Racemic and optically active compound (1) are obtained in accordance with the procedure described in EPC Publication No. 72259 published on Feb. 16, 1983. A compound having the formula (II) wherein both R.sup.1 and R.sup.2 are hydrogen atoms is also obtained as in the same procedure as above.
Aminonaphthacene derivative having the formula (I) of the present invention consists of a sugar component and an aglycone component. The steric configuration of the compound (I) is as follows.
Preferable sugar component of the compound (I) is 2,6-dideoxy-L and D-lyxo-hexopyranose derivative, 3-amino-2,3,6-trideoxy-L and D-lyxo-hexopyranose derivative, 2,6-dideoxy-L and D-arabino-hexopyranose derivative, 2,3,6-trideoxy-L and D-erythro-hexopyranose derivative, 2,3,6-trideoxy-L and D-galacto-hexopyranose derivative, 2-deoxy-L and D-arabino-hexopyranose derivative, 3-amino-2,3,6-trideoxy-L and D-arabino-hexopyranose derivative, 3-amino-2,3,4,6-tetradeoxy-L and D-threo-hexopyranose derivative, 2-deoxy-L and D-erythro-pentapyranose derivative, 2-deoxy-L and D-threo-pentapyranose derivative, tetrahydropyranyl, and tetrahydrofuranyl.
The sugar component forms 1'.alpha.- or 1'.beta.-combination with the aglycone component.
The aglycone component is illustrated by planar structural formulas wherein there are asymmetric carbon atoms at 7- and 9-positions, and, in some cases, at 13-position, too. The present compound includes all steric isomers based on these asymmetric carbon atoms. Stereo-configuration of the aglycone component, preferable from a view point of an anti-tumor activity, is that the oxygen atom at 7-position and the nitrogen atom at 9-position define cis-coordination, more preferably, stereoconfiguration at 9-position of aglycone is the same as that of 2-position of l-isomer of a compound (1) in the scheme above where R.sup.18 is methyl group.
The preparation of pharmaceutical compositions can be carried out by a conventional method, for example, the aminonaphthacene derivatives (I), they may be mixed with carriers, diluents, lubricants, fillers and/or binders such as lactose, sucrose, calcium, phosphate, starch, talcum, casein, magnesium stearate, methyl cellulose, polyglycols, tragacanth and the like, sometimes together with stabilizers and emulsifying agents. The resulting mixture may be processed in a usual manner to tablets, capsules, pills, ampoules and the like.
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Date |
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|
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|
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Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 72259 |
Feb 1983 |
EPX |
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| Entry |
| Iwamoto, Tetrahedron Letters, No. 36, pp. 3891-3894, 1968. |
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Continuation in Parts (1)
|
Number |
Date |
Country |
| Parent |
543967 |
Oct 1983 |
|
Patent Grant
4673668
