CA1137874A - Anthraquinone compounds as anti-cancer agents - Google Patents
Anthraquinone compounds as anti-cancer agentsInfo
- Publication number
- CA1137874A CA1137874A CA000283844A CA283844A CA1137874A CA 1137874 A CA1137874 A CA 1137874A CA 000283844 A CA000283844 A CA 000283844A CA 283844 A CA283844 A CA 283844A CA 1137874 A CA1137874 A CA 1137874A
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- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09B—ORGANIC DYES OR CLOSELY-RELATED COMPOUNDS FOR PRODUCING DYES, e.g. PIGMENTS; MORDANTS; LAKES
- C09B1/00—Dyes with anthracene nucleus not condensed with any other ring
- C09B1/16—Amino-anthraquinones
- C09B1/20—Preparation from starting materials already containing the anthracene nucleus
- C09B1/26—Dyes with amino groups substituted by hydrocarbon radicals
- C09B1/28—Dyes with amino groups substituted by hydrocarbon radicals substituted by alkyl, aralkyl or cyclo alkyl groups
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
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- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A composition of a pharmaceutically acceptable salt of an anthraquinone compound of the formula
A composition of a pharmaceutically acceptable salt of an anthraquinone compound of the formula
Description
BRIEF SUMMARY OF THE INVENTION
... .
This invention relates to processes of ameliorating cancer diseases in mamma~s such as leukemia. The essential active ingredient, utilized in the processes în an effective amount, is a pharmaceutically acceptable salt of an anthraquinone compound of the formula O NS-R-N~-~O~
O NH-R-N~-RO~
where R is alkylene having 1-4 carbons, wherein the active ingredient is present at between about 0.1 and about 400 milli-grams per milliliter of carrier.
DETAILED DESCRIPTION
.
This invention relates to a pharmaceutical composition and the use thereof and more particularly to a pharmaceutical anthraquinone composition and to a process for its administration.
The compound of the above formula wherein R is ethyl has shown presumptive activity against leukemia in mice used as standard test animals. Each of the compounds of the above formula, and their pharmaceutically acceptable salts, would be expected to show activity against a broad range of cancer diseases, and especially blood cancer diseases such as leukemia, in standard test animals and in humans at doses below substantially toxic levels.
The inventive composition is an anthraquinone composition of the above formula or pharmaceutically acceptable salts thereof dispersed in a pharmaceutically acceptable carrier. The anthraquinone compounds can be prepared according to the methods disclosed in United States Patent 4,051,155 issued Sept. 27, 1~77.
1~ 3~B~a~
The pharmaceutically acceptable salts lnclude the acid salts, for example, those of hydrochloric, citric, succinic, maleic, tartaric, acet~c, and like ac~ds. Of the acid ~alts, the acetate and hydrochloride are preferred. Such salts are pharmaceutically acceptable in the sense of having no ~ubstan-t~ally different activity or toxicity compared to the base.
The modes contemplated for carrying out the invention include pharmaceutical compositions and processes of administra- ¦
tion thereof.
10Solutions of the principal active ingredient as a free base or salt can be prepared in water or in water suitably mixed with, for example, surfactants. The preferred compound, where R
is ethyl in the above formula, is slightly soluble in water. It can, for example, be converted to a partial acetate having a pH in aqueous solution of about 7.4 which, on analysis, shows about 1-1/2 acetic acid residues/anthraquinone nucleus. A diacetate may also be produced having a pB in aqueous solution of about 6.2. The diacetate is soluble in water to the extent of about 400 mg/
milliliter of water. The base or various salts may be made more soluble by the addition of surfactants such as hydroxypropyl-cellulose to the composition. Dispersions can also be prepared in glycerol, liquîd polyethylene glycols, and mi~tures thereof and in oils. Vnder ordinary conditions of`storage and use, ~hese prepara-tions ~ontain a preservative to prevent the growth of microoganisms.
The pharmaceutical compositions can be in forms suitable for injectable use, which forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous prepara tion of sterile injectable solutions or dispersions In all cases the form ~ust be sterile and must be fluid to the extent that easy syrinqabil;ty exists. It must be stable under the oonditions of manufacture and storage and must be preserved against _he contami-.
~,' ~''' ~ ' .
~7 ~
nating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various anti-bacterial and antifungal agents~ for example, parabens, chloro-butanol, benzoalcohol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferably to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorp-tion of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporat-ing the principal active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingre-dients enumerated above, as required, followed by filtered steri-lization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingre-dients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
The powders can also be sterilized by use of a gas, for example, ethylene oxide and subsequently incorporating, with the required 1~37~ ~ ~
additional ingredients and in the proper particle size, into the basic powder for later reconstitution with the desired suspending liquid which, of course, itself must be sterile.
As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings, anti-bacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharma-ceutical ac~ive substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, its use in the present compositions is contemplated within the scope of the invention.
Supplementary active ingredients can also be incorpor-ated into the inventive compositions.
It is especially advantageous to formulate inventive compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specifica-tion and claims herein refers ~G physically discreet units suited as unitary dosages for the animal and human subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification, these being features of the present invention.
The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condi-tion and its severity; particular form of the active ingredient and the route of administration. A daily dose of from about 1 to about 100 mg/kg, given singly or in divided doses of up to 5 times a day embraces the effective range for the treatment of most con-ditions for which the compound is effective and substantially non-toxic. For a 75 kg subject, this translates into between about 75 and about 7500 mg/day. If the dosage is divided, for example, into 3 individual dosages, these will range from about 25 to about 2500 mg of the active ingredient. The preferred range is from about 2 to about 50 mg/kg of body weight/day with about 2 to about 30 mg/kg/day being more preferred.
The principal active ingredient is compounded for con-venient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for exam-ple, contain the principal active ingredient in amounts ranging from about 0.1 to about 400 mg, with from about 1 to about 30 mg being preferred. Expressed in proportions, the active ingredient 20 is generally present in from about 0.1 to about 400 mg/ml of carrier.
In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Regression and palliation of cancers are attained, for example, using intraperitoneal administration. A single intra-venous dosage or repeated daily dosages can be administered~ Daily dosages up to about 5 or 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to aid regression and palliation of the leukemia or the 3~l37,~1L
,.
like, in the absence of excessive deleterious side effects of a cytotoxic nature to the hosts harboring the cancerO In the fol-lowing data using mice and the base of the above ~ormula where R is ethylene, it can be seen-that some toxicity exists at about 50 mg/kg and that increasing toxicity occurs from 50 to about 100 m~/kg. Nevertheless, daily dosa~es up to about 100 mg/kg are within the preferred range/ especially when aclministered on different regimens and ~or various of the anthraquinone compounds and salts within the scope of the present inventio~9 10As used herein, cancer is meant blood malignancies such as leukemia, as well as other solid and non solid malignancies such as the melancarcinomas, lung carcinomas and mammary tumors.
By regression and pallation is meant arresting or retarding the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence o treatment. In many oE the gollowing examples, mice are used as standard test animals to show the efective and toxic levels of the novel compositions.
It is within the scope of the present invention, however, to treat i higher mammals including humans with the novel composition to aid in the amelioration and regression of cancer diseases. From the test data with lower mammals it would be expe-cted that the novel compositions are so effecti~e below substantially toxic levels~
The following examples set ~orth the manner a~d process of making and using the inventive compositions. They also include test data showing the effectiveness of the present compositions in treating leukemia~like tumors in standard test animals.
Example 1 - Preparation of Base .
121 grams of para leuco quini~arine, or 2,3-dihydro-1,4-dihydroxy anthraquinone, were charged with 300 cc of ethyl alcohol solvent into a 1 liter Elask. The mixture was ayitated to form a uniform slurry, and to the slurry was charged 124 grams oE N-amino---6~
~, .
~13~7l5!~g~
ethylethanolamine. The resulting mixture was agitated at room temperature for one hour, heated to 75-80C and held at that temperature for six hours. While the temperature was maintained at 75-80C, the mixture was aerated until the leuco product was oxidized as indicated by the product being completely in solution.
The solution was cooled to 10C, filtered, washed with ethyl alcohol and dried under vacuum. The yield was 138 grams.
Other bases within the scope of this invention can be made with N-aminoethylethanolamine replaced by N-aminomethylmeth-anolamine, N-aminopropylpropanolamine or N-aminobutylbutanolamine.
~xample 2 - Preparation of Salts Any of the bases of Example 1 can be neutralized with an acid such as acetic or hydrochloric acid to form a salt. An excess of dilute aqueous acetic acid is added to the dried compound of Example 1 (derived from N-aminoethylethanolamine) The mixture is heated to about 50C and held there for about 2 hours. An excess of chloroform is added and after phase separation, the organic phase is discarded. The salt is then vacuum dried.
Example 3 - Preparation of Injectable Composition _ Ten grams of the acetate salt of Example 2 are dissolved in one liter of saline solution creating a solution with 10 mg/ml of active ingredient. A five ml dose of this composition thus provides 50 mg of active ingredient.
Solutions can be prepared of the various bases and salts of the invention with most standard pharmaceutically-acceptable solvents. Particularly with the free bases, a surfactant such as hydroxypropylcellulose improves solubility.
Example 4 - Preparation of Powder Composition Ten grams of the free base of Example 1, prepared using N-aminoethylethanolamine is dispersed in l9a grams of glycerine.
A one gram dose of this powder thus provides 50 mg of active in-gredient.
1~.3~87~
Powders may be prepared with most standard pharmaceuti-cally-acceptable dispersion agents. The powder may then be combined with other agents as desired and encapsulated by conventional ;~techniques.
~; Exampl~ 5 Six male mice of strain CDF~L were injected on day 0 intraperitoneally with 106 cells of L-1210 lymphoid leukemia.
; Beginning on day 1 and daily for a total of 9 days, each mouse was treated by an intraperitoneal injection of 250 mg/kg of body 10 weight of the compound of Example 1 in a carrier of hydroxypropyl-¢ ***
cellulose sold as Rluccel. After five days two of the six had survived. The mean survival time was 6.5 days for the test animals, 9.9 days for the controls.
Exampsles 6-11 The test of Example S was repeated for groups of six mice and a group of controls at the doses indicated in Table 1.
The means survival times are indicated in Table 1. The test was discontinued after 30 days.
Table :L - Lymphoid Leukemia ~L-1210) Dose mg/kg Survival 'Mean Apparent 20 Example Body Weight at 5 days Survival TimeCures**
250 2/6 6.5 6 125 4/6 6.8 7 62.5 5/6 21~8 2 Control__ o 9.9 8* 95~0 6~6 7.3 9* 62.5 6/6 11.3 10* 42.0 6/6 11.3 11~ 28.0 6/6 18.3 2 Control 0 8.4 *Mouse strain BD~l.
**Mice surviving until end of test.
*** Trade Mark -s , ~
1~ ~7~74 It appears from these tests that dosages of 62.5 mg/kg of body weight and over begin to show some toxicity to mice under this test regime. Suhstantially improved survival times compared to the controls ~innoculated only) is found in dosages from about 28 to about 62.5 mg/kg of body weight.
E~ample 12 Six male mice, strain CDFl, were innoculated with P388 lymphocytic leukemia applied intraperitoneally at 106 cells in ascitic fluid. Beginning the first day after innoculation and then daily for nine days, the compound of Example 1 was applied at a close level of 128 mg/kg of body weight in saline solution with ~Tween-80n. Four of six mice survived after five days and the median survival time for the six mice was 5.9 days.
Examples 13-29 Example 12 was repeated with groups of six mice at dif-ferent dosage levels with the results shown in Table 2. This test was discontinued after 30 days.
Table 2 - Lymphocytic Leukemia (P388~
Dose mg/kg Survival Mean Apparent 20 Example Body Weight at 5 daysSurvival Time Cures 12 128 4/6 5.9 13 64 6/6 6.4 14 32 6/6 8.8 16.0 ~/6 29.7 3 16 800 6/6 29.9 17 4.0 6/6 29.7 3 Control 0 10 8 . . _ ~ , * Trade Mark _9_ 1~ 37~7~
Table 2 - Lymphocytic Leukemia (P388) (Continued) 18 128 6/6 6.4 19 64 4/6 6.3 32 6~6 7.8 21 16.0 6/6 10.1 22 8.0 6/6 21.0 %
23 4.0 6/6 2g.7 3 Control 0 11.0 . . _ 24 128 2/6 5.0 10 25 64 6/6 6.2 26 32 5/6 8.0 27 16.0 6/6 28.8 2 28 8.0 6/6 23.0 29 4.0 6/6 19.8 Control 0 _ _ 10.8 NOTE: The "%" figure in this and subsequent tables indicates that the only surviving animals were adjudged upon autopsy to be "no-takes" for the tumor.
These tests show substantial activity in the 4.0-16.0 mg/kg body weight range. At a dosage of 32.0 mg/kg and especially 64.0 mg/kg, the toxicity of the drug appears to overtake the bene ficial effects.
Example 30 Ten more male mice, strain BDFl, were innoculated intra-peritoneally with an unspecified level of the homogenate of tumor B-16 meloncarcinoma. Beginning the first day after innoculation and every second day thereafter, the mice were treated with intraperi-toneal injections of 128 mg/kg of body weight of the compound of Example 1 in saline solution with "Tween-80". Injections occurred intraperitoneally on survivors on days 3, 5, 7, 9, 11, 13, 15 and 17. The median survival time was 5.2 days compared to 21.3 days for the control. Evaluation ended on the 60th day.
~3r,~ ot~
Examples 31-47 Example 30 was repeated a~ dosage levels shown in Table 3 with the results indicated in Table 3.
Table 3 - Melancarcinoma (B-16) Dose mg/kg Survival Mean Apparent ExampleBody Weightat 5 daysSurvival Time Cures ... .. _ _ 30128 3/10 5.2 3164.0 8/10 6.1 3232.0 10/10 10.8 33,16.0 10/10 59.8 8 1034 8.0 10/10 59.8 6 354.0 10/10 59O8 6 Control 0 21.3 _ 36 128 4/10 5.4 37 64.0 8/10 7.1 38 32.0 10/10 11.1 .
39 16.0 10/10 51.0 tumored survi-vors only 8.0 10/10 60.0 10 41 4.0 10/10 43.0 %
Control 0 25 2 . . . _ _ . _ _ . . .
20 42 128 10/10 9.3 43 64.0 8/10 16.8 44 32.0 10/10 37.0 45 16.0 10/10 34.0 46 8.010/10 36.0 47 4.010/10 32.0 Control 0 18.8 _ _ _ ... .. _ ~ 3~
Table 3 - Melancarcinoma (B-16) (continued) Dose mg/kg Survival Mean Apparent _ample Body Weight at 5 days Survival Time Cures 48** 128 7.0 49** 64.0 12.0 50** 32.0 31.0 51** 16.0 31.0 52** 8.0 26.3 53** 4.0 27.0 Control 0 30.3 *The serum of example 30-41 was diluted 10:1 before innoculation in Examples 42-53. Also the surfactant Tween-80 was omitted.
**In examples 48-53, the injections were on days 1, 3, 5,7, 9, 11, 13, 15 and 17.
Example 54 Six male mice, strain CDFl, were innoculated intraperi-toneally with 105 cells of L-1210 lymphoid leukemia~ Reginning on the first day a~ter innoculation and daily for a total of nine days, the mice were innoculated with intraperitoneal injections of 128 mg/kg of body weight of the compound of Example 1 in saline.
Five of the six mice survived to the fifth day and the median sur-vival time was 6.1 days. The test was terminated after 30 days.
Examples 55-77 -Example 54 was repeated at the dosa~e levels indicated in Table 4. In examples 62-69 the injections were subcutaneous.
In examples 70-77 the compound was given orally.
Table 4 - Lymphoid Leukemia (L-1210) Dose mg/kg Survival ~ean Apparent Example Body Weight at 5 days Survival Time Cures 54 _ 128 5/6 6.1 64.0 6/6 7.8 56 32.0 6/6 11.0 57 16.0 6/6 15.3 58 8.0 6/6 16.0 ~3'~7~
Table 4 - Lymphoid Leukemia (L-1210) (Continued) Dose mg/kg Survival Mean Apparent Example sody Weight at 5 days Survival Time Cures 59 4.0 6/6 12.8 3
... .
This invention relates to processes of ameliorating cancer diseases in mamma~s such as leukemia. The essential active ingredient, utilized in the processes în an effective amount, is a pharmaceutically acceptable salt of an anthraquinone compound of the formula O NS-R-N~-~O~
O NH-R-N~-RO~
where R is alkylene having 1-4 carbons, wherein the active ingredient is present at between about 0.1 and about 400 milli-grams per milliliter of carrier.
DETAILED DESCRIPTION
.
This invention relates to a pharmaceutical composition and the use thereof and more particularly to a pharmaceutical anthraquinone composition and to a process for its administration.
The compound of the above formula wherein R is ethyl has shown presumptive activity against leukemia in mice used as standard test animals. Each of the compounds of the above formula, and their pharmaceutically acceptable salts, would be expected to show activity against a broad range of cancer diseases, and especially blood cancer diseases such as leukemia, in standard test animals and in humans at doses below substantially toxic levels.
The inventive composition is an anthraquinone composition of the above formula or pharmaceutically acceptable salts thereof dispersed in a pharmaceutically acceptable carrier. The anthraquinone compounds can be prepared according to the methods disclosed in United States Patent 4,051,155 issued Sept. 27, 1~77.
1~ 3~B~a~
The pharmaceutically acceptable salts lnclude the acid salts, for example, those of hydrochloric, citric, succinic, maleic, tartaric, acet~c, and like ac~ds. Of the acid ~alts, the acetate and hydrochloride are preferred. Such salts are pharmaceutically acceptable in the sense of having no ~ubstan-t~ally different activity or toxicity compared to the base.
The modes contemplated for carrying out the invention include pharmaceutical compositions and processes of administra- ¦
tion thereof.
10Solutions of the principal active ingredient as a free base or salt can be prepared in water or in water suitably mixed with, for example, surfactants. The preferred compound, where R
is ethyl in the above formula, is slightly soluble in water. It can, for example, be converted to a partial acetate having a pH in aqueous solution of about 7.4 which, on analysis, shows about 1-1/2 acetic acid residues/anthraquinone nucleus. A diacetate may also be produced having a pB in aqueous solution of about 6.2. The diacetate is soluble in water to the extent of about 400 mg/
milliliter of water. The base or various salts may be made more soluble by the addition of surfactants such as hydroxypropyl-cellulose to the composition. Dispersions can also be prepared in glycerol, liquîd polyethylene glycols, and mi~tures thereof and in oils. Vnder ordinary conditions of`storage and use, ~hese prepara-tions ~ontain a preservative to prevent the growth of microoganisms.
The pharmaceutical compositions can be in forms suitable for injectable use, which forms include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous prepara tion of sterile injectable solutions or dispersions In all cases the form ~ust be sterile and must be fluid to the extent that easy syrinqabil;ty exists. It must be stable under the oonditions of manufacture and storage and must be preserved against _he contami-.
~,' ~''' ~ ' .
~7 ~
nating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. The prevention of the action of microorganisms can be brought about by various anti-bacterial and antifungal agents~ for example, parabens, chloro-butanol, benzoalcohol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferably to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorp-tion of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
Sterile injectable solutions are prepared by incorporat-ing the principal active ingredient or ingredients in the required amount in the appropriate solvent with various of the other ingre-dients enumerated above, as required, followed by filtered steri-lization. Generally, dispersions are prepared by incorporating the various sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingre-dients from those enumerated above.
In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
The powders can also be sterilized by use of a gas, for example, ethylene oxide and subsequently incorporating, with the required 1~37~ ~ ~
additional ingredients and in the proper particle size, into the basic powder for later reconstitution with the desired suspending liquid which, of course, itself must be sterile.
As used herein, "pharmaceutically acceptable carrier"
includes any and all solvents, dispersion media, coatings, anti-bacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharma-ceutical ac~ive substances is well known in the art. Except insofar as any conventional media or agent is incompatable with the active ingredient, its use in the present compositions is contemplated within the scope of the invention.
Supplementary active ingredients can also be incorpor-ated into the inventive compositions.
It is especially advantageous to formulate inventive compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used in the specifica-tion and claims herein refers ~G physically discreet units suited as unitary dosages for the animal and human subjects to be treated, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specifications for the novel dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active material and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active material for the treatment of disease in living subjects having a diseased condition in which bodily health is impaired as disclosed in detail in this specification, these being features of the present invention.
The dosage of the principal active ingredient for the treatment of the indicated conditions depends upon the age, weight and condition of the subject being treated; the particular condi-tion and its severity; particular form of the active ingredient and the route of administration. A daily dose of from about 1 to about 100 mg/kg, given singly or in divided doses of up to 5 times a day embraces the effective range for the treatment of most con-ditions for which the compound is effective and substantially non-toxic. For a 75 kg subject, this translates into between about 75 and about 7500 mg/day. If the dosage is divided, for example, into 3 individual dosages, these will range from about 25 to about 2500 mg of the active ingredient. The preferred range is from about 2 to about 50 mg/kg of body weight/day with about 2 to about 30 mg/kg/day being more preferred.
The principal active ingredient is compounded for con-venient and effective administration in effective amounts with a suitable pharmaceutically-acceptable carrier in dosage unit form as hereinbefore disclosed. A unit dosage form can, for exam-ple, contain the principal active ingredient in amounts ranging from about 0.1 to about 400 mg, with from about 1 to about 30 mg being preferred. Expressed in proportions, the active ingredient 20 is generally present in from about 0.1 to about 400 mg/ml of carrier.
In the case of compositions containing supplementary active ingredients, the dosages are determined by reference to the usual dose and manner of administration of the said ingredients.
Regression and palliation of cancers are attained, for example, using intraperitoneal administration. A single intra-venous dosage or repeated daily dosages can be administered~ Daily dosages up to about 5 or 10 days are often sufficient. It is also possible to dispense one daily dosage or one dose on alternate or less frequent days. As can be seen from the dosage regimens, the amount of principal active ingredient administered is a sufficient amount to aid regression and palliation of the leukemia or the 3~l37,~1L
,.
like, in the absence of excessive deleterious side effects of a cytotoxic nature to the hosts harboring the cancerO In the fol-lowing data using mice and the base of the above ~ormula where R is ethylene, it can be seen-that some toxicity exists at about 50 mg/kg and that increasing toxicity occurs from 50 to about 100 m~/kg. Nevertheless, daily dosa~es up to about 100 mg/kg are within the preferred range/ especially when aclministered on different regimens and ~or various of the anthraquinone compounds and salts within the scope of the present inventio~9 10As used herein, cancer is meant blood malignancies such as leukemia, as well as other solid and non solid malignancies such as the melancarcinomas, lung carcinomas and mammary tumors.
By regression and pallation is meant arresting or retarding the growth of the tumor or other manifestation of the disease compared to the course of the disease in the absence o treatment. In many oE the gollowing examples, mice are used as standard test animals to show the efective and toxic levels of the novel compositions.
It is within the scope of the present invention, however, to treat i higher mammals including humans with the novel composition to aid in the amelioration and regression of cancer diseases. From the test data with lower mammals it would be expe-cted that the novel compositions are so effecti~e below substantially toxic levels~
The following examples set ~orth the manner a~d process of making and using the inventive compositions. They also include test data showing the effectiveness of the present compositions in treating leukemia~like tumors in standard test animals.
Example 1 - Preparation of Base .
121 grams of para leuco quini~arine, or 2,3-dihydro-1,4-dihydroxy anthraquinone, were charged with 300 cc of ethyl alcohol solvent into a 1 liter Elask. The mixture was ayitated to form a uniform slurry, and to the slurry was charged 124 grams oE N-amino---6~
~, .
~13~7l5!~g~
ethylethanolamine. The resulting mixture was agitated at room temperature for one hour, heated to 75-80C and held at that temperature for six hours. While the temperature was maintained at 75-80C, the mixture was aerated until the leuco product was oxidized as indicated by the product being completely in solution.
The solution was cooled to 10C, filtered, washed with ethyl alcohol and dried under vacuum. The yield was 138 grams.
Other bases within the scope of this invention can be made with N-aminoethylethanolamine replaced by N-aminomethylmeth-anolamine, N-aminopropylpropanolamine or N-aminobutylbutanolamine.
~xample 2 - Preparation of Salts Any of the bases of Example 1 can be neutralized with an acid such as acetic or hydrochloric acid to form a salt. An excess of dilute aqueous acetic acid is added to the dried compound of Example 1 (derived from N-aminoethylethanolamine) The mixture is heated to about 50C and held there for about 2 hours. An excess of chloroform is added and after phase separation, the organic phase is discarded. The salt is then vacuum dried.
Example 3 - Preparation of Injectable Composition _ Ten grams of the acetate salt of Example 2 are dissolved in one liter of saline solution creating a solution with 10 mg/ml of active ingredient. A five ml dose of this composition thus provides 50 mg of active ingredient.
Solutions can be prepared of the various bases and salts of the invention with most standard pharmaceutically-acceptable solvents. Particularly with the free bases, a surfactant such as hydroxypropylcellulose improves solubility.
Example 4 - Preparation of Powder Composition Ten grams of the free base of Example 1, prepared using N-aminoethylethanolamine is dispersed in l9a grams of glycerine.
A one gram dose of this powder thus provides 50 mg of active in-gredient.
1~.3~87~
Powders may be prepared with most standard pharmaceuti-cally-acceptable dispersion agents. The powder may then be combined with other agents as desired and encapsulated by conventional ;~techniques.
~; Exampl~ 5 Six male mice of strain CDF~L were injected on day 0 intraperitoneally with 106 cells of L-1210 lymphoid leukemia.
; Beginning on day 1 and daily for a total of 9 days, each mouse was treated by an intraperitoneal injection of 250 mg/kg of body 10 weight of the compound of Example 1 in a carrier of hydroxypropyl-¢ ***
cellulose sold as Rluccel. After five days two of the six had survived. The mean survival time was 6.5 days for the test animals, 9.9 days for the controls.
Exampsles 6-11 The test of Example S was repeated for groups of six mice and a group of controls at the doses indicated in Table 1.
The means survival times are indicated in Table 1. The test was discontinued after 30 days.
Table :L - Lymphoid Leukemia ~L-1210) Dose mg/kg Survival 'Mean Apparent 20 Example Body Weight at 5 days Survival TimeCures**
250 2/6 6.5 6 125 4/6 6.8 7 62.5 5/6 21~8 2 Control__ o 9.9 8* 95~0 6~6 7.3 9* 62.5 6/6 11.3 10* 42.0 6/6 11.3 11~ 28.0 6/6 18.3 2 Control 0 8.4 *Mouse strain BD~l.
**Mice surviving until end of test.
*** Trade Mark -s , ~
1~ ~7~74 It appears from these tests that dosages of 62.5 mg/kg of body weight and over begin to show some toxicity to mice under this test regime. Suhstantially improved survival times compared to the controls ~innoculated only) is found in dosages from about 28 to about 62.5 mg/kg of body weight.
E~ample 12 Six male mice, strain CDFl, were innoculated with P388 lymphocytic leukemia applied intraperitoneally at 106 cells in ascitic fluid. Beginning the first day after innoculation and then daily for nine days, the compound of Example 1 was applied at a close level of 128 mg/kg of body weight in saline solution with ~Tween-80n. Four of six mice survived after five days and the median survival time for the six mice was 5.9 days.
Examples 13-29 Example 12 was repeated with groups of six mice at dif-ferent dosage levels with the results shown in Table 2. This test was discontinued after 30 days.
Table 2 - Lymphocytic Leukemia (P388~
Dose mg/kg Survival Mean Apparent 20 Example Body Weight at 5 daysSurvival Time Cures 12 128 4/6 5.9 13 64 6/6 6.4 14 32 6/6 8.8 16.0 ~/6 29.7 3 16 800 6/6 29.9 17 4.0 6/6 29.7 3 Control 0 10 8 . . _ ~ , * Trade Mark _9_ 1~ 37~7~
Table 2 - Lymphocytic Leukemia (P388) (Continued) 18 128 6/6 6.4 19 64 4/6 6.3 32 6~6 7.8 21 16.0 6/6 10.1 22 8.0 6/6 21.0 %
23 4.0 6/6 2g.7 3 Control 0 11.0 . . _ 24 128 2/6 5.0 10 25 64 6/6 6.2 26 32 5/6 8.0 27 16.0 6/6 28.8 2 28 8.0 6/6 23.0 29 4.0 6/6 19.8 Control 0 _ _ 10.8 NOTE: The "%" figure in this and subsequent tables indicates that the only surviving animals were adjudged upon autopsy to be "no-takes" for the tumor.
These tests show substantial activity in the 4.0-16.0 mg/kg body weight range. At a dosage of 32.0 mg/kg and especially 64.0 mg/kg, the toxicity of the drug appears to overtake the bene ficial effects.
Example 30 Ten more male mice, strain BDFl, were innoculated intra-peritoneally with an unspecified level of the homogenate of tumor B-16 meloncarcinoma. Beginning the first day after innoculation and every second day thereafter, the mice were treated with intraperi-toneal injections of 128 mg/kg of body weight of the compound of Example 1 in saline solution with "Tween-80". Injections occurred intraperitoneally on survivors on days 3, 5, 7, 9, 11, 13, 15 and 17. The median survival time was 5.2 days compared to 21.3 days for the control. Evaluation ended on the 60th day.
~3r,~ ot~
Examples 31-47 Example 30 was repeated a~ dosage levels shown in Table 3 with the results indicated in Table 3.
Table 3 - Melancarcinoma (B-16) Dose mg/kg Survival Mean Apparent ExampleBody Weightat 5 daysSurvival Time Cures ... .. _ _ 30128 3/10 5.2 3164.0 8/10 6.1 3232.0 10/10 10.8 33,16.0 10/10 59.8 8 1034 8.0 10/10 59.8 6 354.0 10/10 59O8 6 Control 0 21.3 _ 36 128 4/10 5.4 37 64.0 8/10 7.1 38 32.0 10/10 11.1 .
39 16.0 10/10 51.0 tumored survi-vors only 8.0 10/10 60.0 10 41 4.0 10/10 43.0 %
Control 0 25 2 . . . _ _ . _ _ . . .
20 42 128 10/10 9.3 43 64.0 8/10 16.8 44 32.0 10/10 37.0 45 16.0 10/10 34.0 46 8.010/10 36.0 47 4.010/10 32.0 Control 0 18.8 _ _ _ ... .. _ ~ 3~
Table 3 - Melancarcinoma (B-16) (continued) Dose mg/kg Survival Mean Apparent _ample Body Weight at 5 days Survival Time Cures 48** 128 7.0 49** 64.0 12.0 50** 32.0 31.0 51** 16.0 31.0 52** 8.0 26.3 53** 4.0 27.0 Control 0 30.3 *The serum of example 30-41 was diluted 10:1 before innoculation in Examples 42-53. Also the surfactant Tween-80 was omitted.
**In examples 48-53, the injections were on days 1, 3, 5,7, 9, 11, 13, 15 and 17.
Example 54 Six male mice, strain CDFl, were innoculated intraperi-toneally with 105 cells of L-1210 lymphoid leukemia~ Reginning on the first day a~ter innoculation and daily for a total of nine days, the mice were innoculated with intraperitoneal injections of 128 mg/kg of body weight of the compound of Example 1 in saline.
Five of the six mice survived to the fifth day and the median sur-vival time was 6.1 days. The test was terminated after 30 days.
Examples 55-77 -Example 54 was repeated at the dosa~e levels indicated in Table 4. In examples 62-69 the injections were subcutaneous.
In examples 70-77 the compound was given orally.
Table 4 - Lymphoid Leukemia (L-1210) Dose mg/kg Survival ~ean Apparent Example Body Weight at 5 days Survival Time Cures 54 _ 128 5/6 6.1 64.0 6/6 7.8 56 32.0 6/6 11.0 57 16.0 6/6 15.3 58 8.0 6/6 16.0 ~3'~7~
Table 4 - Lymphoid Leukemia (L-1210) (Continued) Dose mg/kg Survival Mean Apparent Example sody Weight at 5 days Survival Time Cures 59 4.0 6/6 12.8 3
2.0 6/6 12.7 61 1.0 6/6 11.3 62 SC 128 6/6 10.3 3 63 64.0 6/6 11.8 64 32.0 6/6 11.8 16.0 6/6 10.4 66 8.0 6/6 8.4 67 4.0 6/6 8.3 3 68 2.0 6/6 8.4 69 1.0 6/6 8.2 70 Oral 512 6/6 8.1 71 256 6/6 9.0 72 128 6/6 8.8 73 64.0 6/6 8.8 74 32.0 6/6 8.4 16.0 6/6 8.4 76 8.0 6/6 9.2 77 4.0 6/6 9.2 Control 0 8.0 ~ . . . _ _ . . _ _ . . .
When given intraperitoneally, the compound showed substantialy activity at dosages of 16.0 and 8.0 mg/kg of body weight. More limited activity was seen in this particular test series when the same or higher dosages were injected subcutaneously or were intro-duced by oral administration.
Example 78 Ten male mice, strain BDFl, were innoculated with Lewis lung carcinoma homogenate at unspecified dosage intravenously.
Beginning on the first day after innoculation and for a total of ~ 3~
nine days, the mice were treated with 32 mg of the compound of Example 1 per kg of body weight. After five days all 10 mice survived. The median survi~al time was 8.2 days.
Examples 79-89 Example 78 was repeated at the dosage levels shown in Table 5. In Examples 84-89, tumor fragments rather than tumor homogenate were used for innoculation. These tests were discon tinued after 60 days.
Table 5 - Lewis Lung Carcinoma .
Dose mg/kgSurvival Mean ~pparent Example Body Weightat 5 daysSurvival TimeCures 78 32.0 10/10 8.2 79 16.0 10/10 18.0 8.0 10/10 32.0 %
81 4.0 10/10 23.3 %
~2 2.0 10/10 25.0 %
83 1.0 10/10 22.8 Control 0 22.7 84 32.0 10/10 8.4 2085 16.0 10/10 11.0 86 8.0 10/10 28.0 ~87 4.0 10/10 27.0 88 2.0 10/10 39.0 ~9 1.0 10/10 50.3*
Control 0 24.0 For this tumor, the effect was appreciably over the dosage range of 2.0-8.0 mg/kg although the results are not as drama~ic as for other tumors. The high value in Example 89 is somewhat inconsistent with the toxicity pattern based on body weight change, which peaks at a dosage of 2.0 mg/kg.
d ~L
Example _ Six female mice, strain CDFl, were innoculated intraperi-toneally with 106 cells of P388 lymphocrytic leukemia. On the the first day after innoculation and on days 5 and 9 for a total of three days, the mice were treated with 512 mg/kg of body weight of the compound of Example 1 in saline solution with "Tween-80" surfac-tant. Tests were discontinued after 30 days. The median survival time was 2.1 days.
Examples 91-102 Example 90 was repeated at the dosage levels indicated in Table 6 with the results indicated.
Table 6 - Female Mice Dose mg/kg Survival Mean Apparent Example Body Weight at 5 days Survival Time Cures _ 90* 512 0/6 2.1 91* 256 0/6 2.7 92* 128 2/6 5.0 93* 64.0 5/6 7.8 94* 32.0 6/6 29.7 95* 16.0 6/6 26.0 20 Control 0 _ 11.1 96** 64.0 4/6 6.3 97** 32.0 6/6 8.7 98** 16.0 6/6 34.9 4 99** 8.0 6/6 28.0 100** 4.0 6/6 22.3 101** 2.0 6/6 24.0 102** 1.0 5/6 17.9 Control 0 10.5 *Example 90-95 involved injection on days 1, 5 and 9 only.
**Examples 96-102 and their control were continued to the thirty-fifth day. Injections were daily for nine days.
-15~
7~7~
These tests show substantial activity, particularly at dosages of about 16.0 mg/kg.
Example 103 Ten male mice, strain BDFl, were innoculated with an the same unspecified amount of B16 melanocarcinoma tumor homogenate - as in Examples 30-41, diluted 1:10 as in Examples 42-53, intra-peritoneally. Beginning on the first day after innoculation, and every other day thereafter for a total of nine injections, the mice were injected with ]25 mg/kg of body weight of the compound of Example 1 in saline solution with hydroxypropylcell~lose, sold as Kluccel. All ten mice survived after 5 days. The median survival time was 8.4 days. The test was discontinued after sixty days.
Example 104-107 Example 103 was repeated at the doses indicated in Table 7.
Table 7 Dose mg/kg Survival Mean Apparent Example Body Weight at 5 days Survival Time Cures 103 125 10/10 8.4 104 62.5 10/10 16.0 2 105 31.2 10/10 49.0 2 106 16.6 10/10 43.3 2 107 8.3 1~/10 42.8 Control 0 18.7 In these tests, substantial results were shown over the dosage range of 8.3-31.2 mg/kg. These results further support the activity against melancarcinoma shown in Examples 30-53.
Example 108 Ten male mice, strain CDFl, were innoculated with a dilute homogenate of Colon 26 tumor (National Cancer Institute identi~ication C6). They were then injected with 125 mg/kg of body weight of the compound of Example 1 in hydroxypropylcellulose solution, sold as 1~.3~fB~
Kluccel, on days 1, 5 and 9 after innoculation. This evaluationwas continued for 70 days. All ten mice survived the fifth day and the medium survival time was 27.0 days compared to 26.5 for the controls.
Examples 109-1_2 Example 108 was repeated at the dosages shown in Table 8.
Table_8 - Tumor C6 Dose mg/kg Survival Median Apparent Example Body Weight at_5 days Survival Time Cures 108 125 10/10 27.0 109 35.2 10/10 32.0 110 31.2 10/10 29.0 111 16.6 10/10 29.0 112 ~.3 10/10 33.8 Control 0 26.5 These tests show some effectiveness against this partic-ular tumor. A lesser degree of toxicity was found at the 125 mg/kg level compared to some of the other Examples.
Example 113 Ten male mice, strain CD8Fl, were innoculated with CD8F
mammary tumor homogenate between about 500 and 1000 mg in size, subcutaneously. On days 1, 8, 15 and 22 after innoculation, the mice were treated with an injection of 125 mg/kg of body weight of the compound of Example 1 in hydroxypropylcellulose (Kluccel) intraperitoneally. Eight of ten mice survived the fifth day.
After 36 days, the mice were killed and the mean tumor weight was determined to be 630 mg.
~3~7~
Examples 114-117 Example 113 was repeated at the dosages shown in Table 8.
Table 8 - Mammary Tumor CD8F1 - Tumor Weight Dose mg/kgSurvival Mean Tumor Example Body Weightat 5 days Weight (mg~
114 62.5 9/10 989 115 31.2 10/10 423 116 16.6 10/10 1354 117 8.3 35/35 37 Control 0 1665 These results indicate substantial inhibition of tumor growth at many levels and apparent decreases in tumor sizes in some instances.
When given intraperitoneally, the compound showed substantialy activity at dosages of 16.0 and 8.0 mg/kg of body weight. More limited activity was seen in this particular test series when the same or higher dosages were injected subcutaneously or were intro-duced by oral administration.
Example 78 Ten male mice, strain BDFl, were innoculated with Lewis lung carcinoma homogenate at unspecified dosage intravenously.
Beginning on the first day after innoculation and for a total of ~ 3~
nine days, the mice were treated with 32 mg of the compound of Example 1 per kg of body weight. After five days all 10 mice survived. The median survi~al time was 8.2 days.
Examples 79-89 Example 78 was repeated at the dosage levels shown in Table 5. In Examples 84-89, tumor fragments rather than tumor homogenate were used for innoculation. These tests were discon tinued after 60 days.
Table 5 - Lewis Lung Carcinoma .
Dose mg/kgSurvival Mean ~pparent Example Body Weightat 5 daysSurvival TimeCures 78 32.0 10/10 8.2 79 16.0 10/10 18.0 8.0 10/10 32.0 %
81 4.0 10/10 23.3 %
~2 2.0 10/10 25.0 %
83 1.0 10/10 22.8 Control 0 22.7 84 32.0 10/10 8.4 2085 16.0 10/10 11.0 86 8.0 10/10 28.0 ~87 4.0 10/10 27.0 88 2.0 10/10 39.0 ~9 1.0 10/10 50.3*
Control 0 24.0 For this tumor, the effect was appreciably over the dosage range of 2.0-8.0 mg/kg although the results are not as drama~ic as for other tumors. The high value in Example 89 is somewhat inconsistent with the toxicity pattern based on body weight change, which peaks at a dosage of 2.0 mg/kg.
d ~L
Example _ Six female mice, strain CDFl, were innoculated intraperi-toneally with 106 cells of P388 lymphocrytic leukemia. On the the first day after innoculation and on days 5 and 9 for a total of three days, the mice were treated with 512 mg/kg of body weight of the compound of Example 1 in saline solution with "Tween-80" surfac-tant. Tests were discontinued after 30 days. The median survival time was 2.1 days.
Examples 91-102 Example 90 was repeated at the dosage levels indicated in Table 6 with the results indicated.
Table 6 - Female Mice Dose mg/kg Survival Mean Apparent Example Body Weight at 5 days Survival Time Cures _ 90* 512 0/6 2.1 91* 256 0/6 2.7 92* 128 2/6 5.0 93* 64.0 5/6 7.8 94* 32.0 6/6 29.7 95* 16.0 6/6 26.0 20 Control 0 _ 11.1 96** 64.0 4/6 6.3 97** 32.0 6/6 8.7 98** 16.0 6/6 34.9 4 99** 8.0 6/6 28.0 100** 4.0 6/6 22.3 101** 2.0 6/6 24.0 102** 1.0 5/6 17.9 Control 0 10.5 *Example 90-95 involved injection on days 1, 5 and 9 only.
**Examples 96-102 and their control were continued to the thirty-fifth day. Injections were daily for nine days.
-15~
7~7~
These tests show substantial activity, particularly at dosages of about 16.0 mg/kg.
Example 103 Ten male mice, strain BDFl, were innoculated with an the same unspecified amount of B16 melanocarcinoma tumor homogenate - as in Examples 30-41, diluted 1:10 as in Examples 42-53, intra-peritoneally. Beginning on the first day after innoculation, and every other day thereafter for a total of nine injections, the mice were injected with ]25 mg/kg of body weight of the compound of Example 1 in saline solution with hydroxypropylcell~lose, sold as Kluccel. All ten mice survived after 5 days. The median survival time was 8.4 days. The test was discontinued after sixty days.
Example 104-107 Example 103 was repeated at the doses indicated in Table 7.
Table 7 Dose mg/kg Survival Mean Apparent Example Body Weight at 5 days Survival Time Cures 103 125 10/10 8.4 104 62.5 10/10 16.0 2 105 31.2 10/10 49.0 2 106 16.6 10/10 43.3 2 107 8.3 1~/10 42.8 Control 0 18.7 In these tests, substantial results were shown over the dosage range of 8.3-31.2 mg/kg. These results further support the activity against melancarcinoma shown in Examples 30-53.
Example 108 Ten male mice, strain CDFl, were innoculated with a dilute homogenate of Colon 26 tumor (National Cancer Institute identi~ication C6). They were then injected with 125 mg/kg of body weight of the compound of Example 1 in hydroxypropylcellulose solution, sold as 1~.3~fB~
Kluccel, on days 1, 5 and 9 after innoculation. This evaluationwas continued for 70 days. All ten mice survived the fifth day and the medium survival time was 27.0 days compared to 26.5 for the controls.
Examples 109-1_2 Example 108 was repeated at the dosages shown in Table 8.
Table_8 - Tumor C6 Dose mg/kg Survival Median Apparent Example Body Weight at_5 days Survival Time Cures 108 125 10/10 27.0 109 35.2 10/10 32.0 110 31.2 10/10 29.0 111 16.6 10/10 29.0 112 ~.3 10/10 33.8 Control 0 26.5 These tests show some effectiveness against this partic-ular tumor. A lesser degree of toxicity was found at the 125 mg/kg level compared to some of the other Examples.
Example 113 Ten male mice, strain CD8Fl, were innoculated with CD8F
mammary tumor homogenate between about 500 and 1000 mg in size, subcutaneously. On days 1, 8, 15 and 22 after innoculation, the mice were treated with an injection of 125 mg/kg of body weight of the compound of Example 1 in hydroxypropylcellulose (Kluccel) intraperitoneally. Eight of ten mice survived the fifth day.
After 36 days, the mice were killed and the mean tumor weight was determined to be 630 mg.
~3~7~
Examples 114-117 Example 113 was repeated at the dosages shown in Table 8.
Table 8 - Mammary Tumor CD8F1 - Tumor Weight Dose mg/kgSurvival Mean Tumor Example Body Weightat 5 days Weight (mg~
114 62.5 9/10 989 115 31.2 10/10 423 116 16.6 10/10 1354 117 8.3 35/35 37 Control 0 1665 These results indicate substantial inhibition of tumor growth at many levels and apparent decreases in tumor sizes in some instances.
Claims (5)
1. A composition for aiding regression or palliation of cancer in mammals which comprises as active ingredient a pharmaceutically acceptable salt of an anthraquinone compound of the formula where R is alkylene having 1-4 carbons, in a pharmaceutically acceptable carrier, wherein the active ingredient is present at between about 0.1 and about 400 milligrams per milliliter of carrier.
2. The composition of Claim 1 where R is ethylene.
3. The composition of Claim 1 or 2 wherein the active ingredient is an acetate salt.
4. The composition of Claim 1 or 2 wherein the active ingredient is the diacetate of said anthraquinone compound.
5. The composition of Claim 1 or 2 wherein the active ingredient is the partial acetate showing about 1-1/2 acetic acid residues/anthraquinone nucleus.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81803777A | 1977-07-22 | 1977-07-22 | |
| US818,037 | 1977-07-22 |
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| Publication Number | Publication Date |
|---|---|
| CA1137874A true CA1137874A (en) | 1982-12-21 |
Family
ID=25224487
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000283844A Expired CA1137874A (en) | 1977-07-22 | 1977-08-02 | Anthraquinone compounds as anti-cancer agents |
Country Status (5)
| Country | Link |
|---|---|
| CA (1) | CA1137874A (en) |
| CH (1) | CH642053A5 (en) |
| FI (1) | FI772593A (en) |
| NL (1) | NL7709434A (en) |
| NO (1) | NO143793C (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102241598B (en) * | 2011-05-24 | 2014-07-09 | 福州大学 | Monohydroxy emodin dioctyl quaternary ammonium salt with anticancer activity |
-
1977
- 1977-08-02 CA CA000283844A patent/CA1137874A/en not_active Expired
- 1977-08-26 NL NL7709434A patent/NL7709434A/en not_active Application Discontinuation
- 1977-09-01 NO NO773030A patent/NO143793C/en unknown
- 1977-09-01 FI FI772593A patent/FI772593A/en not_active Application Discontinuation
-
1978
- 1978-07-21 CH CH793278A patent/CH642053A5/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CH642053A5 (en) | 1984-03-30 |
| NO773030L (en) | 1979-01-23 |
| NO143793C (en) | 1981-04-15 |
| NL7709434A (en) | 1979-01-24 |
| NO143793B (en) | 1981-01-05 |
| FI772593A (en) | 1979-01-23 |
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