CA2053246A1 - Amonafide salts - Google Patents
Amonafide saltsInfo
- Publication number
- CA2053246A1 CA2053246A1 CA002053246A CA2053246A CA2053246A1 CA 2053246 A1 CA2053246 A1 CA 2053246A1 CA 002053246 A CA002053246 A CA 002053246A CA 2053246 A CA2053246 A CA 2053246A CA 2053246 A1 CA2053246 A1 CA 2053246A1
- Authority
- CA
- Canada
- Prior art keywords
- amonafide
- salts
- preparation
- monohydrochloride
- tablets
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- UPALIKSFLSVKIS-UHFFFAOYSA-N 5-amino-2-[2-(dimethylamino)ethyl]benzo[de]isoquinoline-1,3-dione Chemical class NC1=CC(C(N(CCN(C)C)C2=O)=O)=C3C2=CC=CC3=C1 UPALIKSFLSVKIS-UHFFFAOYSA-N 0.000 title claims abstract description 22
- 229960004701 amonafide Drugs 0.000 claims abstract description 19
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 238000002360 preparation method Methods 0.000 claims description 9
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Substances CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 5
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
- 238000000034 method Methods 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 abstract description 3
- 239000000243 solution Substances 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000012141 concentrate Substances 0.000 description 3
- 239000007903 gelatin capsule Substances 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002730 additional effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000010425 asbestos Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 230000000622 irritating effect Effects 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- VJZLQIPZNBPASX-OJJGEMKLSA-L prednisolone sodium phosphate Chemical compound [Na+].[Na+].O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)COP([O-])([O-])=O)[C@@H]4[C@@H]3CCC2=C1 VJZLQIPZNBPASX-OJJGEMKLSA-L 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229910052895 riebeckite Inorganic materials 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 239000008215 water for injection Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
- C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
- C07D221/04—Ortho- or peri-condensed ring systems
- C07D221/06—Ring systems of three rings
- C07D221/14—Aza-phenalenes, e.g. 1,8-naphthalimide
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Emulsifying, Dispersing, Foam-Producing Or Wetting Agents (AREA)
Abstract
- 7 - O.Z. 0480/01066 Knoll AG
Amonafide salts Abstract of the disclosure The monohydrochloride and the monomethane-sulfonate of amonafide are described. The salts have good pharmaceutical properties besides their antitumor action.
Amonafide salts Abstract of the disclosure The monohydrochloride and the monomethane-sulfonate of amonafide are described. The salts have good pharmaceutical properties besides their antitumor action.
Description
~32~5 Knoll A&O.Z. 0480/01066 Amonafide salts Description The present invention relates to novel salts of amonafide.
Amonafide (Eur. J. Med. Chem. Chim. Ther. 16, 207 (1981)) is a substance which has antitumor action. It exists in the form of very fine needle-like yellow crystals which are reminiscent of asbestos and are very difficult to process to oral forms or injection solutions.
Attempts to react amonafide with acids such as hydrochloric acid or methanesulfonic acid result in salts which, because of their strongly acidic properties, are unsuitable for the preparation of pharmaceutical forms.
The reason for this is that the salts elicit irritant effects because of their strongly acidic nature. An addi-tional factor is that they are incompatible with many pharmaceutical auxiliaries required for preparing cap-sules.
It has now been found that although certain salts of amonafide do not have the abovementioned adverse properties, they do not differ from amonafide in terms of the antitumor action.
The invention relates to salts of amonafide of the formula ,~, 3 IH2--CH2_7--CH3 O~N~O H X-~NH 2 in which X is a Cl or CH3-SO3- ion.
stable in the dark, and in solid form they can easily be metered, are free-flowing, readily compressible and only moderately hygroscopic and easy to dry. They have the further advantage that they are compatible with gelatin so that they can easily be proc:essed to soft and hard gelatin capsules. The latter particularly applies to the monohydrochloride.
The salts are prepared by reacting amonafide with the calculated amount of acid. The salt formation preferably takes place in alcoholic solution.
Examples 1 and 2 show the preparation of the novel salts:
3 g of amonafide were dissolved under reflux in 60 ml of virtually anhydrous ethanol. Subsequently 1 ml of 35~ strength hydrochloric acid was added dropwise while shaking vigorously. After cooling, the resulting crystals were filtered off and washed with 10 ml of anhydrous ethanol. 3.1 g (93%) of amonafide monohydro-chloride were obtained (C16H18ClN3O2), melting point = 290C.
Example 2 3.4 g (85%) of amonafide monomethanesulfonate, melting point = 255C, are obtained in analogy to Example 1 by reaction with 0.8 ml of methanesulfonic acid.
The following examples show the good pharmaceuti-cal processability of the novel salts:
_ 3 _ ~ 3 f~ ~ $
Example A
Preparation of amonafide tablets Amonafide HCl 288.4 mg D-mannitol 40.6 mg Polyvinylpyrroldone [sic] 13.0 mg Nicrocrystalline cellulose 20.0 mg Sodium carboxymethylstarch 10.0 mg Highly disperse silica 2.0 mg Talc 4.0 mg Magnesium ~tearate 2.0 mg 380.0 mg Granules were obtained by granulation of active substance and mannitol with the aid of polyvinylpyrroli-done and, after mixing with the other substances men-tioned, were readily converted into tablets in conven-tional tablet presses. Used as tableting tool were 11 mm round punches. The tablet disintegration time was 9 min.
The polyvinylpyrrolidone used had the viscosity of 20 mPa-sec in a 20% strength aqueous solution at 25C.
Example B
Preparation of film-coated $ablets Tablets from Example A were coated with a coating of the following composition until the weight gain per 25 tablet core was found to be about 20 - 30 mg:
Hydroxypropylmethylcellulo~e 0.064 kg Polyethylene glycol with the average molecular weight 8000 0.040 kg Talc 0.080 kg Titanium dioxide 0.020 kg Sodium lauryl sulfate 0.002 kg Ethanol 0.794 kg Example C
Preparation of enteric tablets Tablets from Example A were coated with a coating of the following composition until the weight gain per 5 tablet core was found to be about 40 - 50 mg.
Hydroxypropylmethylcellulose phthalate 0.1620 kg Dibutyl phthalate 0.0324 kg Acetone 0.8826 kg Isopropanol 0.8826 kg Coloring pigment 0.0404 kg Example D
Preparation of an injection solution as concentrate Amonafide-HCl 564.3 mg Water for injection ad 10 ml The solution was sterilized by filtration, dispensed into 10 ml brown glass ampoules and autoclaved.
Example E
Preparation of amonafide injection concentrate as lyophi-lisate Amonafide-2HC1 2.992 kg NaOH, 5 m 1.998 kg Water for in~ection ad 20.000 kg The solution was sterilized by filtration and subsequently dispensed in 2 ml portions into vials of glass type I (brown glass) and freeze-dried. The pH of the reconstituted solution was 5.5 ~ 0.5, the osmolarity was about 1,000 mosmolJkg and the residual moisture was about 1~.
The amonafide was in the form of the 2~ d~
monohydrochloride in the concentrate.
Example F
Preparation of soft gelatin capsules Amonafide HCl 28.2 g Silicone oil ad lOO.O g The homogeneous suspended composition was dis-pensed into soft gelatin capsules of size 16 minims.
Amonafide (Eur. J. Med. Chem. Chim. Ther. 16, 207 (1981)) is a substance which has antitumor action. It exists in the form of very fine needle-like yellow crystals which are reminiscent of asbestos and are very difficult to process to oral forms or injection solutions.
Attempts to react amonafide with acids such as hydrochloric acid or methanesulfonic acid result in salts which, because of their strongly acidic properties, are unsuitable for the preparation of pharmaceutical forms.
The reason for this is that the salts elicit irritant effects because of their strongly acidic nature. An addi-tional factor is that they are incompatible with many pharmaceutical auxiliaries required for preparing cap-sules.
It has now been found that although certain salts of amonafide do not have the abovementioned adverse properties, they do not differ from amonafide in terms of the antitumor action.
The invention relates to salts of amonafide of the formula ,~, 3 IH2--CH2_7--CH3 O~N~O H X-~NH 2 in which X is a Cl or CH3-SO3- ion.
stable in the dark, and in solid form they can easily be metered, are free-flowing, readily compressible and only moderately hygroscopic and easy to dry. They have the further advantage that they are compatible with gelatin so that they can easily be proc:essed to soft and hard gelatin capsules. The latter particularly applies to the monohydrochloride.
The salts are prepared by reacting amonafide with the calculated amount of acid. The salt formation preferably takes place in alcoholic solution.
Examples 1 and 2 show the preparation of the novel salts:
3 g of amonafide were dissolved under reflux in 60 ml of virtually anhydrous ethanol. Subsequently 1 ml of 35~ strength hydrochloric acid was added dropwise while shaking vigorously. After cooling, the resulting crystals were filtered off and washed with 10 ml of anhydrous ethanol. 3.1 g (93%) of amonafide monohydro-chloride were obtained (C16H18ClN3O2), melting point = 290C.
Example 2 3.4 g (85%) of amonafide monomethanesulfonate, melting point = 255C, are obtained in analogy to Example 1 by reaction with 0.8 ml of methanesulfonic acid.
The following examples show the good pharmaceuti-cal processability of the novel salts:
_ 3 _ ~ 3 f~ ~ $
Example A
Preparation of amonafide tablets Amonafide HCl 288.4 mg D-mannitol 40.6 mg Polyvinylpyrroldone [sic] 13.0 mg Nicrocrystalline cellulose 20.0 mg Sodium carboxymethylstarch 10.0 mg Highly disperse silica 2.0 mg Talc 4.0 mg Magnesium ~tearate 2.0 mg 380.0 mg Granules were obtained by granulation of active substance and mannitol with the aid of polyvinylpyrroli-done and, after mixing with the other substances men-tioned, were readily converted into tablets in conven-tional tablet presses. Used as tableting tool were 11 mm round punches. The tablet disintegration time was 9 min.
The polyvinylpyrrolidone used had the viscosity of 20 mPa-sec in a 20% strength aqueous solution at 25C.
Example B
Preparation of film-coated $ablets Tablets from Example A were coated with a coating of the following composition until the weight gain per 25 tablet core was found to be about 20 - 30 mg:
Hydroxypropylmethylcellulo~e 0.064 kg Polyethylene glycol with the average molecular weight 8000 0.040 kg Talc 0.080 kg Titanium dioxide 0.020 kg Sodium lauryl sulfate 0.002 kg Ethanol 0.794 kg Example C
Preparation of enteric tablets Tablets from Example A were coated with a coating of the following composition until the weight gain per 5 tablet core was found to be about 40 - 50 mg.
Hydroxypropylmethylcellulose phthalate 0.1620 kg Dibutyl phthalate 0.0324 kg Acetone 0.8826 kg Isopropanol 0.8826 kg Coloring pigment 0.0404 kg Example D
Preparation of an injection solution as concentrate Amonafide-HCl 564.3 mg Water for injection ad 10 ml The solution was sterilized by filtration, dispensed into 10 ml brown glass ampoules and autoclaved.
Example E
Preparation of amonafide injection concentrate as lyophi-lisate Amonafide-2HC1 2.992 kg NaOH, 5 m 1.998 kg Water for in~ection ad 20.000 kg The solution was sterilized by filtration and subsequently dispensed in 2 ml portions into vials of glass type I (brown glass) and freeze-dried. The pH of the reconstituted solution was 5.5 ~ 0.5, the osmolarity was about 1,000 mosmolJkg and the residual moisture was about 1~.
The amonafide was in the form of the 2~ d~
monohydrochloride in the concentrate.
Example F
Preparation of soft gelatin capsules Amonafide HCl 28.2 g Silicone oil ad lOO.O g The homogeneous suspended composition was dis-pensed into soft gelatin capsules of size 16 minims.
Claims (3)
Patent Claims
1. A salt of amonafide of the formula X-in which X- is a C1- or CH3-SO3- ion.
2. Amonafide monohydrochloride.
3. A process for the preparation of the salts as claimed in claim 1, which comprises reacting amonafide with the calculated amount of hydrochloric or mono-methanesulfonic acid.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3922771.5 | 1989-07-11 | ||
| DE3922771A DE3922771A1 (en) | 1989-07-11 | 1989-07-11 | Amonafide SALTS |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2053246A1 true CA2053246A1 (en) | 1991-01-12 |
Family
ID=6384737
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002053246A Abandoned CA2053246A1 (en) | 1989-07-11 | 1990-07-06 | Amonafide salts |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0482043B1 (en) |
| JP (1) | JPH04506956A (en) |
| AT (1) | ATE112269T1 (en) |
| CA (1) | CA2053246A1 (en) |
| DE (2) | DE3922771A1 (en) |
| ES (1) | ES2061052T3 (en) |
| HU (1) | HU211744A9 (en) |
| WO (1) | WO1991000857A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6693198B2 (en) * | 2002-04-22 | 2004-02-17 | Xanthus Life Sciences, Inc. | Amonafide salts |
| US20040082788A1 (en) * | 2002-07-08 | 2004-04-29 | Chemgenex Therapeutics, Inc. | Naphthalimide synthesis including amonafide synthesis and pharmaceutical preparations thereof |
| ES2338193B8 (en) * | 2008-02-25 | 2011-07-19 | Centro Atlantico Del Medicamento, S.A. | NEW SALTS OF AMONAFIDE. |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2423547A1 (en) * | 1974-05-15 | 1975-12-04 | Hoechst Ag | Basic dyes of 4-amino 1,8-naphthalimide series - for dyeing natural fibres and synthetic fibres contg. acid gps. |
| ES459497A1 (en) * | 1977-06-04 | 1978-04-16 | Made Labor Sa | N(Aminoalkyl)-naphthalimides and their derivatives |
| EP0125439B1 (en) * | 1983-04-01 | 1990-01-24 | Warner-Lambert Company | 3,6-disubstituted-1,8-naphthalimides and methods for their production and use |
-
1989
- 1989-07-11 DE DE3922771A patent/DE3922771A1/en not_active Withdrawn
-
1990
- 1990-07-06 CA CA002053246A patent/CA2053246A1/en not_active Abandoned
- 1990-07-06 EP EP90910683A patent/EP0482043B1/en not_active Expired - Lifetime
- 1990-07-06 JP JP2509969A patent/JPH04506956A/en active Pending
- 1990-07-06 AT AT90910683T patent/ATE112269T1/en not_active IP Right Cessation
- 1990-07-06 WO PCT/EP1990/001088 patent/WO1991000857A1/en active IP Right Grant
- 1990-07-06 ES ES90910683T patent/ES2061052T3/en not_active Expired - Lifetime
- 1990-07-06 DE DE59007354T patent/DE59007354D1/en not_active Expired - Fee Related
-
1995
- 1995-06-30 HU HU95P/P00709P patent/HU211744A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU211744A9 (en) | 1995-12-28 |
| ATE112269T1 (en) | 1994-10-15 |
| ES2061052T3 (en) | 1994-12-01 |
| WO1991000857A1 (en) | 1991-01-24 |
| JPH04506956A (en) | 1992-12-03 |
| DE59007354D1 (en) | 1994-11-03 |
| EP0482043B1 (en) | 1994-09-28 |
| EP0482043A1 (en) | 1992-04-29 |
| DE3922771A1 (en) | 1991-01-24 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |