CA1306681C - Antioxidant metallo-organic treatment of inflammation - Google Patents
Antioxidant metallo-organic treatment of inflammationInfo
- Publication number
- CA1306681C CA1306681C CA000537099A CA537099A CA1306681C CA 1306681 C CA1306681 C CA 1306681C CA 000537099 A CA000537099 A CA 000537099A CA 537099 A CA537099 A CA 537099A CA 1306681 C CA1306681 C CA 1306681C
- Authority
- CA
- Canada
- Prior art keywords
- complex
- cobalt
- bis
- metallo
- ethylenediimine
- 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.)
- Expired - Lifetime
Links
Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/555—Heterocyclic compounds containing heavy metals, e.g. hemin, hematin, melarsoprol
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic System
- C07F15/06—Cobalt compounds
- C07F15/065—Cobalt compounds without a metal-carbon linkage
Abstract
ABSTRACT OF THE DISCLOSURE
A method of treating an inflammatory condition in a mammalian subject, particularly arthritis, comprising the steps of administering an effective and nontoxic dose for an inflammation ameliorating period to the subject of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal of the complex is selected from the group which consists of cobalt and iron.
A method of treating an inflammatory condition in a mammalian subject, particularly arthritis, comprising the steps of administering an effective and nontoxic dose for an inflammation ameliorating period to the subject of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal of the complex is selected from the group which consists of cobalt and iron.
Description
~3~66~1~
ANTIOXIDANT METALLO~ORGANIC TREATMENT OF INFLAMMATION
Field of the Invention Our present invention relates to a method of treatment of mammalian subjects for inflammatory conditions and, more particularly, arthritis and like active-oxygen or superoxide based conditions.
Background of the Invention It has been recognized for some time that inflammation in mammalian species can be traced at least in part to active oxygen species, including superoxide, and radicals associated therewith at the inflammatory site. Considerable r~search has been undertaken to measure and detect oxygen radicals, to establish the mechanisms whereby enzymes such as superoxide dismutase is effective in countering oxygen radical toxicity and even in the development and use of copper amine oxidases in preventing tissue damage and even in promoting damaged-tissue recovery.
However, the compounds which have been developed heretofore for active-oxygen or superoxide antagonism and destruction n Vivo have not proved as effective as desired or were characterized by side reactions or could not be made in commercially significant quantities at reasonable cost.
Ob~ects of the Invention It is, therefore, the principal ob~ect of our invention to provide an improved m~thod of treatment of mammalian subjects ~h ~66~
for inflammatory conditions whereby the aforedescribed drawbacks are obviated.
Another object of our invention is to provide an improved method of treating a mammalian subject for a condition resultiny from active oxygen or superoxide toxicity which may result in acute or chronic inflammation or any other disorder.
Still another object is to provide a method of treatm~nt which is nontoxic and has no measurable side-effects but which is particularly effective in the treatment of arthritic conditions cr the lika.
Summary of the Invention These objects and others which will become apparent hereinafter are attained, in accordance with the present invention in a method of treating active-oxygen and superoxide associated inflammator~ conditions in mammalian subjects which comprises administering an eEfective and nontoxic dose for an inflammation ameliorating period to the subject of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal of the complex is selected from the group which consists of cobalt and iron.
Preferably the method is used in the treatment of acute or chronic arthritis in a dosage of 0.1 to 250 mg/kg of body weight, but in all cases at most 50% of the LD50 value of the compound, when the complex is administered orally as is pre~erred. However the complex or a combination of the complexes can be administered subcutaneously or even topically in a suitable vehicle, e.g. physiological saline in the case of s.c. administration an~ dimethylsulfoxide (DMSO) in the case of a topical administration, although ointments, salves or like ~3~66~1 conventional vehicles may be employed.
For oral administration, the complex or mixture of complexes may be prepared in suitable dosage forms. For example it may be prepared a5 dragees, as capsules, as tablets, as an elixir or other oral dosage form.
The dose may he administered one to six times daily, depending upon the severity of the inflammatory condition, preferably under medical supervision so that the dosage can be reduced or the number of daily administrations limited as the inflammatory condition subsides.
The compounds of the invention may also have prophylactic properties in preventing the spread of arthritic inflammation and has been found to be effective in reducing the sevPrity of the actual condition which develops in subjects who are prone to such inflammatory states. The compounds may also be effective in preventing postischemic heart damage and for geriatric applications other than as antiarthritics.
We have found that the anti-inflammatory effect is exceptionally pronounced with low-toxicity metallo-organic complexes selected from the group which consists of:
[Co~2,3,g,10-tetra~low~r-alkyl}-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}Cl2~Cl, a 1,1-dimethylfexrocenium or other alkyl ferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenediimine complex, and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca--1(17),2,11,13,15-pentaene}C12]Cl H20.
In the case of the ferrocenium derivatives, we have discovered that the key to the effect is the ferrocenium ion, so that any physiologically compatible or pharmaceutically ~3~6~
effective salt thereof can be employed. Furthermore, the methyl groups arQ important only in the sense that two methylene structures -CH2- moieties are attached to the ferrocenium moiety. The methyls can thus be substituted by Cl to C5 -alkyl, alkenyl or alkoxyO Best results are obtained with 1,1-dimethylferrocenium salts.
In the case of the (Co{2,3,9,10-tetra{lower-alkyl}-1,4,8,-11-tetraazacyclotetradeca-1,3,8,10-tetraene}C12)Cl, we have ~ound that the lower alkyl can be Cl to C6-alkyl but that best results are obtained when the tCo~2,3,9,10-tetra{lower--alkyl}-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}C12) Cl is Co{2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca--1,3,8,10-tetraene)C12)Cl.
Preferably the cobalt(III)-bis(acetyl or propio acetone)-e~thylenediimine complex is a cobalt(III)-bis(acetylacetone)--ethylenediimine complex, and more specifically the [Co(bis~acetylacetone}-ethylenediimine)(NH3)2]+ Cl-.
We have found that the complexes specifically identified above can be used together with hitherto-known anti-inflammator-ies with propionic acid side chains, especially indomethacine to further alleviate the suffering of arthritic inflammation.
Preparation o~ the Compounds [Co(Tim)C12]Cl - Compound 8) Tim = 2,3,9,10 tetramethyl 1,4,8,11-tetraazcyclotetradeca--1,3,3,10-tetraene.
The procedure of Bush et al ~Inorg. Chem., 1972, 11, 2893) ; was employed to prepare [Co(Tim~C12]PF6.
A saturated solution of tetramethylammonium chloride in 68~
acetone was added slowly to a saturated solution of [Co(Tim)C12]PF6 in acetone until the solution became cloudy. Cooling afforded light green crystals of compound 8.
Anal. Calcd. for C14H24N4CoC13: C, 40.63; H, 5.8;
N, 13:54. Found: C, 40.57; H, 5.67; N, 13.15.
l,l-Dimethylferrocenium Salts (PF6- Cl-~
- 4~ 1_4-~ -- Compound 19) The procedure of Wahl et al. (J. Phys. Chem., 1975, 79, 2049-52) was employed.
A solution of dimethylferrocene (0.65 g. 3 mmol) in concentrated sulfuric acid (8 ml) was stirred at room temp. for 10 min. and then poured into 60 ml. of cold, dist. water. The insoluble material was removed by ~iltration, the deep-blue ; filtrate treated with 0.82 g (5 mmol) of ammonium hexafluorophosphate, stirred for 1/2 hr. and cooled. The separated solid (compound 19) was collected, washed with ethyl ether and dried under vacuum for two days.
Anal. Calcd. for C12H~4FePF6: C, 40.14; H, 3.93.
Found: C, 39.98; H, 4.23.
Cobalt(III~ Bis(acetylacetone)-ethylenediimine Complex ~Compound 23) [C(BAE)(NH3)2]cl ~his complex was prepared by a modification of the procedure described by G. Costa et al., J. Organometal. Chem., 966, 6, 1~1 - 187.
. 5 _ ~3~66~3~
Bis(acetylacetone)-ethylenediimine (BAE, 2.24 g, 10 mmol) was dissolved in methanol (100 ml) and treated with cobalt chloride hexahydrate (2.38 g, 10 mmol). The brown solution was stirred at room temperature for 1 1/2 days in order to allow oxidation of the cobalt (no precipitate formed), treated with 7 ml of conc. ag. ammonia solution, and then heated under reflux for 2 hrs. The yellow-brown solid that separated upon standing was recrystd. from ethanol/water (compound 23).
Anal. Calcd. for C12H242N4C~l C, 41.09; H, 6.90. Found: C, 40.81: ~, 7.00.
[Co(CR)C12]Cl H20 (Compound 39~
CR= 2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]
heptadeca-1(17),2,11,13,15-pentaene The Co(II) complex, [Co(CR)C12], was prepared and oxidized by the procedure described by Poon et al. for the analogous perchlorate (J. Chem. Soc. Dalton, 1977, 1247-1251).
The complex ~compound 39) was recrystallized from acetone.
Anal. Calcd. for : C16H240N4CoC13: C, 42035; H, 5.33; N, 12.35; Cl, 23.45. Found: C, 41.35; H, 5.69; N, 12.07; Cl, 23.64.
In vivo_Inflammatory Studies The drugs used are prspared just before performing the ex-periment. Drugs are dissolved at a concentration of 10 2M (or 2 x 10 2M or 4 x 10 2M) in pyrogen free sterile saline. The dissolved drug is then filtered through a sterile and ~3~66B~
pyrogen-free 0.2 micron filter (acrodisc, Gelman).
Procedure 8-12 CD-l female mice (Charles river), age 2-5 months are numbered, weighed and distrihuted to 2-3 cages, 3-4 mice in each cage. 0.2 ml of pyrogen-free saline or drug are injected subcutaneously in a randomized order.
Thirty minutes after injecting the drugs or the saline, tha right paw of each mouse is injected with 25 microliters of 1% carrageenin (vi6carin type, Marine Colloids) in pyrogen-free saline or with 5 microliters (0.227 U) of xanthineoxidase (Sigma).
1.5 hr to 2 hrs after injecting the inflammatory stimulus to the right paw, both paws of the animal are amputated at the knee joint and weighed. The uninjected left paw serves as an internal control for the degree oE swelling of the right paw in each animal.
In some experiments the surface temperature of the right and left paws were recorded also before the amputation was performed.
Calculations The difference in mg between the weight of the right and left paw in control animals (injected with saline) rapresents lOO~o Of the acute inflammatory response. Concomitantly, the difference between paws of the drug treated animals is calculated and compared to control.
TAB~E 1: Effect of several pruducts on carrageenin paw oedema in mice measured by paw weight.
13~66~1 Paw Wei~ht Product No.of total route of average % % inhib-expts. mice admin. mg/kg activity ition-saline - - *S.CO - 100% 0 23 4 14 *S.C. 2563.1% 36.9%
8 4 15 *S.C. 29.873.2% 26.8%
39 5 18 *S.C. 35.764.7% 35.3%
19 1 ~ *S.C. 23.588.2% 11.8%
19 3 11 *S.C. 58.954 % 46 %
*subcutaneously TABLE 2: Effect o~ several products on xanthine oxidase paw oedema measured by temperature reduction Product No.of total route of average % % inhib-expts. mice admin. mg/kg activity ition-saline ~ - *S.C. -100 % 0 23 2 6 *S.C. 22.731 % 69 %
8 3 10 *S.C. 25.133.2% 66.8%
19 1 4 *S.C. ~6.869.5% 30.5%
19 3 12 *S.C. 91.549.6% 50.4%
-*subcutaneously ~ \
~3C~6~
TABLE 3: LD50 and ED50 of various drugs on xanthine oxidase and carrageenin paw oedema in mice stimulus :xanthine carrageenin oxidase measurement :temp. _weight mg_ DrugLD50 ED50 ED50 mq/kq _ mq/kq m~/k~
23 75 <38 25 19 >>875 93 65 8 172 ~24 not determined Orally_and S.C.Administerable Com~ositions Example 1 The composition o~ tablets is as ~ollows:
, active ingredient (one or more of compounds 8, }9, 23~or 39) 25~0 mg.
corn starch 97.0 mg.
polyvinyl pyrrolidone 175.0 mg~
magnesium stearate 3.0 mg.
300.0 mg.
The active ingredient and th~ corn starch are wetted by an _ g _ 1~3066Bl aqueous polyvinyl pyrrolidone solution of approx. 15% w/v/, followed by granulation, and drying of the wet granules at about 40-45C. The dried granulate is thoroughly mixed with magnesium stearate, and the mixture so obtained is further processed by a tabl~t machine, equipped with an appropriate pressing tool, to give tablets of 300 mg. weight containing 25 mg. of active ingredient. One manufacturing lot includes 1000 tablets.
Example 2 Dragees of the following composition are preparedo active ingredient (one or more of compounds 8, 19, 23 or 39) 50.0 mg.
lactose 94.0 mg.
polyvinyl pyrrolidone 154.0 mg.
magnesium stearate 2.0 mg.
300 mg.
Granulate~ are preparPd according to Example 1, and from them dragee kernels of 150 mg. weight are pressed. The dragee kernels are coated with a layer containing sugar and talc followed by coloring with an approved food colorant and polishing with bees wax.
Ex~amplP 3 25 mg. of active ingredient (one or more of compounds 8, 19, 23 or 39) are dissolved in 1000 ml. of distilled water. The solution is filled into 500 ampoules. In this way ampoules containing 2 ml. of a solution containing 25 mg./ml. of active "~
~3~6~
agent each are obtained. The contents of an ampoule are injected subcutaneously.
Example_4 Gelatin capsules of the following composition are prepared:
active ingredient (one or more of compounds 8, 19, 23 or 39~ 25.0 mg.
maize starch 122.0 mg.
colloidal silica 3.0 mq.
150.0 mg.
The ingredients are homogenized, and the homogenate is filled into hard gelatine capsules. 1000 capsules of 150 mg.
~filling) weight each, containing 25.0 mg. of active ingredient per capsule, make a lot~
i6~
The formulae of some of the compounds referred to in the specification are the following:
~8) / CH2 Cl ~ CO ~
l Cl 1 3~ C1 CH2 ~CH2 CH
#19) ~ 3 ~ Lc~ IPP6 ~, .
~l3 #23) 3 \ CH3 ~
~ C - N / I ~ ~ > ~ Cl :~ / \ NH3 ~
:: ~ H3C CH2 _~ CH2 CH3 ~3q;~66~
L H3C ¦ ~ 3 :
:: :
~: :
` :
ANTIOXIDANT METALLO~ORGANIC TREATMENT OF INFLAMMATION
Field of the Invention Our present invention relates to a method of treatment of mammalian subjects for inflammatory conditions and, more particularly, arthritis and like active-oxygen or superoxide based conditions.
Background of the Invention It has been recognized for some time that inflammation in mammalian species can be traced at least in part to active oxygen species, including superoxide, and radicals associated therewith at the inflammatory site. Considerable r~search has been undertaken to measure and detect oxygen radicals, to establish the mechanisms whereby enzymes such as superoxide dismutase is effective in countering oxygen radical toxicity and even in the development and use of copper amine oxidases in preventing tissue damage and even in promoting damaged-tissue recovery.
However, the compounds which have been developed heretofore for active-oxygen or superoxide antagonism and destruction n Vivo have not proved as effective as desired or were characterized by side reactions or could not be made in commercially significant quantities at reasonable cost.
Ob~ects of the Invention It is, therefore, the principal ob~ect of our invention to provide an improved m~thod of treatment of mammalian subjects ~h ~66~
for inflammatory conditions whereby the aforedescribed drawbacks are obviated.
Another object of our invention is to provide an improved method of treating a mammalian subject for a condition resultiny from active oxygen or superoxide toxicity which may result in acute or chronic inflammation or any other disorder.
Still another object is to provide a method of treatm~nt which is nontoxic and has no measurable side-effects but which is particularly effective in the treatment of arthritic conditions cr the lika.
Summary of the Invention These objects and others which will become apparent hereinafter are attained, in accordance with the present invention in a method of treating active-oxygen and superoxide associated inflammator~ conditions in mammalian subjects which comprises administering an eEfective and nontoxic dose for an inflammation ameliorating period to the subject of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal of the complex is selected from the group which consists of cobalt and iron.
Preferably the method is used in the treatment of acute or chronic arthritis in a dosage of 0.1 to 250 mg/kg of body weight, but in all cases at most 50% of the LD50 value of the compound, when the complex is administered orally as is pre~erred. However the complex or a combination of the complexes can be administered subcutaneously or even topically in a suitable vehicle, e.g. physiological saline in the case of s.c. administration an~ dimethylsulfoxide (DMSO) in the case of a topical administration, although ointments, salves or like ~3~66~1 conventional vehicles may be employed.
For oral administration, the complex or mixture of complexes may be prepared in suitable dosage forms. For example it may be prepared a5 dragees, as capsules, as tablets, as an elixir or other oral dosage form.
The dose may he administered one to six times daily, depending upon the severity of the inflammatory condition, preferably under medical supervision so that the dosage can be reduced or the number of daily administrations limited as the inflammatory condition subsides.
The compounds of the invention may also have prophylactic properties in preventing the spread of arthritic inflammation and has been found to be effective in reducing the sevPrity of the actual condition which develops in subjects who are prone to such inflammatory states. The compounds may also be effective in preventing postischemic heart damage and for geriatric applications other than as antiarthritics.
We have found that the anti-inflammatory effect is exceptionally pronounced with low-toxicity metallo-organic complexes selected from the group which consists of:
[Co~2,3,g,10-tetra~low~r-alkyl}-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}Cl2~Cl, a 1,1-dimethylfexrocenium or other alkyl ferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenediimine complex, and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]heptadeca--1(17),2,11,13,15-pentaene}C12]Cl H20.
In the case of the ferrocenium derivatives, we have discovered that the key to the effect is the ferrocenium ion, so that any physiologically compatible or pharmaceutically ~3~6~
effective salt thereof can be employed. Furthermore, the methyl groups arQ important only in the sense that two methylene structures -CH2- moieties are attached to the ferrocenium moiety. The methyls can thus be substituted by Cl to C5 -alkyl, alkenyl or alkoxyO Best results are obtained with 1,1-dimethylferrocenium salts.
In the case of the (Co{2,3,9,10-tetra{lower-alkyl}-1,4,8,-11-tetraazacyclotetradeca-1,3,8,10-tetraene}C12)Cl, we have ~ound that the lower alkyl can be Cl to C6-alkyl but that best results are obtained when the tCo~2,3,9,10-tetra{lower--alkyl}-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}C12) Cl is Co{2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca--1,3,8,10-tetraene)C12)Cl.
Preferably the cobalt(III)-bis(acetyl or propio acetone)-e~thylenediimine complex is a cobalt(III)-bis(acetylacetone)--ethylenediimine complex, and more specifically the [Co(bis~acetylacetone}-ethylenediimine)(NH3)2]+ Cl-.
We have found that the complexes specifically identified above can be used together with hitherto-known anti-inflammator-ies with propionic acid side chains, especially indomethacine to further alleviate the suffering of arthritic inflammation.
Preparation o~ the Compounds [Co(Tim)C12]Cl - Compound 8) Tim = 2,3,9,10 tetramethyl 1,4,8,11-tetraazcyclotetradeca--1,3,3,10-tetraene.
The procedure of Bush et al ~Inorg. Chem., 1972, 11, 2893) ; was employed to prepare [Co(Tim~C12]PF6.
A saturated solution of tetramethylammonium chloride in 68~
acetone was added slowly to a saturated solution of [Co(Tim)C12]PF6 in acetone until the solution became cloudy. Cooling afforded light green crystals of compound 8.
Anal. Calcd. for C14H24N4CoC13: C, 40.63; H, 5.8;
N, 13:54. Found: C, 40.57; H, 5.67; N, 13.15.
l,l-Dimethylferrocenium Salts (PF6- Cl-~
- 4~ 1_4-~ -- Compound 19) The procedure of Wahl et al. (J. Phys. Chem., 1975, 79, 2049-52) was employed.
A solution of dimethylferrocene (0.65 g. 3 mmol) in concentrated sulfuric acid (8 ml) was stirred at room temp. for 10 min. and then poured into 60 ml. of cold, dist. water. The insoluble material was removed by ~iltration, the deep-blue ; filtrate treated with 0.82 g (5 mmol) of ammonium hexafluorophosphate, stirred for 1/2 hr. and cooled. The separated solid (compound 19) was collected, washed with ethyl ether and dried under vacuum for two days.
Anal. Calcd. for C12H~4FePF6: C, 40.14; H, 3.93.
Found: C, 39.98; H, 4.23.
Cobalt(III~ Bis(acetylacetone)-ethylenediimine Complex ~Compound 23) [C(BAE)(NH3)2]cl ~his complex was prepared by a modification of the procedure described by G. Costa et al., J. Organometal. Chem., 966, 6, 1~1 - 187.
. 5 _ ~3~66~3~
Bis(acetylacetone)-ethylenediimine (BAE, 2.24 g, 10 mmol) was dissolved in methanol (100 ml) and treated with cobalt chloride hexahydrate (2.38 g, 10 mmol). The brown solution was stirred at room temperature for 1 1/2 days in order to allow oxidation of the cobalt (no precipitate formed), treated with 7 ml of conc. ag. ammonia solution, and then heated under reflux for 2 hrs. The yellow-brown solid that separated upon standing was recrystd. from ethanol/water (compound 23).
Anal. Calcd. for C12H242N4C~l C, 41.09; H, 6.90. Found: C, 40.81: ~, 7.00.
[Co(CR)C12]Cl H20 (Compound 39~
CR= 2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]
heptadeca-1(17),2,11,13,15-pentaene The Co(II) complex, [Co(CR)C12], was prepared and oxidized by the procedure described by Poon et al. for the analogous perchlorate (J. Chem. Soc. Dalton, 1977, 1247-1251).
The complex ~compound 39) was recrystallized from acetone.
Anal. Calcd. for : C16H240N4CoC13: C, 42035; H, 5.33; N, 12.35; Cl, 23.45. Found: C, 41.35; H, 5.69; N, 12.07; Cl, 23.64.
In vivo_Inflammatory Studies The drugs used are prspared just before performing the ex-periment. Drugs are dissolved at a concentration of 10 2M (or 2 x 10 2M or 4 x 10 2M) in pyrogen free sterile saline. The dissolved drug is then filtered through a sterile and ~3~66B~
pyrogen-free 0.2 micron filter (acrodisc, Gelman).
Procedure 8-12 CD-l female mice (Charles river), age 2-5 months are numbered, weighed and distrihuted to 2-3 cages, 3-4 mice in each cage. 0.2 ml of pyrogen-free saline or drug are injected subcutaneously in a randomized order.
Thirty minutes after injecting the drugs or the saline, tha right paw of each mouse is injected with 25 microliters of 1% carrageenin (vi6carin type, Marine Colloids) in pyrogen-free saline or with 5 microliters (0.227 U) of xanthineoxidase (Sigma).
1.5 hr to 2 hrs after injecting the inflammatory stimulus to the right paw, both paws of the animal are amputated at the knee joint and weighed. The uninjected left paw serves as an internal control for the degree oE swelling of the right paw in each animal.
In some experiments the surface temperature of the right and left paws were recorded also before the amputation was performed.
Calculations The difference in mg between the weight of the right and left paw in control animals (injected with saline) rapresents lOO~o Of the acute inflammatory response. Concomitantly, the difference between paws of the drug treated animals is calculated and compared to control.
TAB~E 1: Effect of several pruducts on carrageenin paw oedema in mice measured by paw weight.
13~66~1 Paw Wei~ht Product No.of total route of average % % inhib-expts. mice admin. mg/kg activity ition-saline - - *S.CO - 100% 0 23 4 14 *S.C. 2563.1% 36.9%
8 4 15 *S.C. 29.873.2% 26.8%
39 5 18 *S.C. 35.764.7% 35.3%
19 1 ~ *S.C. 23.588.2% 11.8%
19 3 11 *S.C. 58.954 % 46 %
*subcutaneously TABLE 2: Effect o~ several products on xanthine oxidase paw oedema measured by temperature reduction Product No.of total route of average % % inhib-expts. mice admin. mg/kg activity ition-saline ~ - *S.C. -100 % 0 23 2 6 *S.C. 22.731 % 69 %
8 3 10 *S.C. 25.133.2% 66.8%
19 1 4 *S.C. ~6.869.5% 30.5%
19 3 12 *S.C. 91.549.6% 50.4%
-*subcutaneously ~ \
~3C~6~
TABLE 3: LD50 and ED50 of various drugs on xanthine oxidase and carrageenin paw oedema in mice stimulus :xanthine carrageenin oxidase measurement :temp. _weight mg_ DrugLD50 ED50 ED50 mq/kq _ mq/kq m~/k~
23 75 <38 25 19 >>875 93 65 8 172 ~24 not determined Orally_and S.C.Administerable Com~ositions Example 1 The composition o~ tablets is as ~ollows:
, active ingredient (one or more of compounds 8, }9, 23~or 39) 25~0 mg.
corn starch 97.0 mg.
polyvinyl pyrrolidone 175.0 mg~
magnesium stearate 3.0 mg.
300.0 mg.
The active ingredient and th~ corn starch are wetted by an _ g _ 1~3066Bl aqueous polyvinyl pyrrolidone solution of approx. 15% w/v/, followed by granulation, and drying of the wet granules at about 40-45C. The dried granulate is thoroughly mixed with magnesium stearate, and the mixture so obtained is further processed by a tabl~t machine, equipped with an appropriate pressing tool, to give tablets of 300 mg. weight containing 25 mg. of active ingredient. One manufacturing lot includes 1000 tablets.
Example 2 Dragees of the following composition are preparedo active ingredient (one or more of compounds 8, 19, 23 or 39) 50.0 mg.
lactose 94.0 mg.
polyvinyl pyrrolidone 154.0 mg.
magnesium stearate 2.0 mg.
300 mg.
Granulate~ are preparPd according to Example 1, and from them dragee kernels of 150 mg. weight are pressed. The dragee kernels are coated with a layer containing sugar and talc followed by coloring with an approved food colorant and polishing with bees wax.
Ex~amplP 3 25 mg. of active ingredient (one or more of compounds 8, 19, 23 or 39) are dissolved in 1000 ml. of distilled water. The solution is filled into 500 ampoules. In this way ampoules containing 2 ml. of a solution containing 25 mg./ml. of active "~
~3~6~
agent each are obtained. The contents of an ampoule are injected subcutaneously.
Example_4 Gelatin capsules of the following composition are prepared:
active ingredient (one or more of compounds 8, 19, 23 or 39~ 25.0 mg.
maize starch 122.0 mg.
colloidal silica 3.0 mq.
150.0 mg.
The ingredients are homogenized, and the homogenate is filled into hard gelatine capsules. 1000 capsules of 150 mg.
~filling) weight each, containing 25.0 mg. of active ingredient per capsule, make a lot~
i6~
The formulae of some of the compounds referred to in the specification are the following:
~8) / CH2 Cl ~ CO ~
l Cl 1 3~ C1 CH2 ~CH2 CH
#19) ~ 3 ~ Lc~ IPP6 ~, .
~l3 #23) 3 \ CH3 ~
~ C - N / I ~ ~ > ~ Cl :~ / \ NH3 ~
:: ~ H3C CH2 _~ CH2 CH3 ~3q;~66~
L H3C ¦ ~ 3 :
:: :
~: :
` :
Claims (20)
1. Use of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal of said complex is selected from the group which consist of cobalt and iron, for treating an inflammatory condition in a mammalian subject.
2. Use as defined in claim 1 wherein said metallo-organic complex is selected from the group which consists of:
[Co{2,3,9,10-tetra{lower-alky}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene}Cl2]Cl, a 1,1-dimethylferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenedi-imine complex and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]-heeptadeca-1(17),2,11,13,15.pentaene}C12]Cl?H2O.
[Co{2,3,9,10-tetra{lower-alky}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene}Cl2]Cl, a 1,1-dimethylferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenedi-imine complex and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]-heeptadeca-1(17),2,11,13,15.pentaene}C12]Cl?H2O.
3. Use as defined in claim 2 wherein said 1,1-di-methylferrocium salt is 1,1- dimethylferrocenium hexa-fluorophosphate.
4. Use as defined in claim 2 wherein said [Co-{2,3,9,10-tetra{lower-alkyl}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene}Cl2]Cl is [Co{2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}Cl2]Cl.
5. Use as defined in claim 2 wherein said cobalt (III)-bis(acetyl or propio acetone)-ethylenediimine complex is cobalt(III)-bis(acetylacetone)-ethylenediimine complex.
6. Use as defined in claim 2 wherein said cobalt-(III)-bis(acetylacetone)-ethylenediimine complex is [CO(bis{acetylacetone}-ethylenediimine)(NH3)2]Cl.
7. Use as defined in claim 2 wherein said inflam-matory condition is arthritis.
8. Use as defined in claim 7 wherein said inflam-matory condition is acute arthritis.
9. Use as defined in claim 2 wherein said metallo-organic complex is in combination with a pharma-ceutically effective amount of indomethacin.
10. Use as defined in claim 2 wherein said metallo-organic complex is in an oral dosage form.
11. Use as defined in claim 2 wherein said metallo-organic complex is in a topical form.
12. Use of at least one metallo-organic complex capable of in vivo superoxide anti-oxidant effects and wherein the metal. of said complex is selected from the group which consists of cobalt and iron, in the prepara-tion of a medicine for treating an inflammatory condition in a mammalian subject.
13. Use as defined in claim 12 wherein said metallo-organic complex is selected from the group which consists of:
[Co{2,3,9,10-tetra{lower-alkyl}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene}Cl2]Cl, a 1,1-dimethylferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenedi-imine complex and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]-heptadeca-1(17),2,11,13,15-pentaene}Cl2]Cl?H2O.
[Co{2,3,9,10-tetra{lower-alkyl}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene}Cl2]Cl, a 1,1-dimethylferrocenium salt, a cobalt(III)-bis(acetyl or propio acetone)-ethylenedi-imine complex and [Co{2,12-dimethyl-3,7,11,17-tetraazabicyclo[11.3.1]-heptadeca-1(17),2,11,13,15-pentaene}Cl2]Cl?H2O.
14. Use as defined in claim 13 wherein said 1,1-dimethylferrocium salt is 1,1-dimethylferrocenium hexa-fluorophosphate.
15. Use as defined in claim 13 wherein said [Co-(2,3,9,10-tetra{lower-alkyl}-1,4,8,11-tetraazacyclo-tetradeca-1,3,8,10-tetraene Cl2]Cl is [Co{2,3,9,10-tetramethyl-1,4,8,11-tetraazacyclotetradeca-1,3,8,10-tetraene}Cl2]Cl.
16. Use as defined in claim 13 wherein said cobalt (III)-bis(acetyl or propio acetone)-ethylenediimine complex is cobalt(III)-bis(acetylacetone)-ethylenediimine complex.
17. Use as defined in claim 13 wherein said cobalt-(III)-bis(acetylacetone)-ethylenediimine complex is [CO(bis{acetylacetone}-ethylenediimine)(NH3)2]Cl.
18. Use as defined in claim 13 wherein said metallo-organic complex is in combination with a pharma-ceutically effective amount of indomethacin.
19. Use as defined in claim 12 wherein said medi-cine is in an oral dosage
20. Use as defined in claim 12 wherein said medi-cine is in a topical form.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US86280486A | 1986-05-13 | 1986-05-13 | |
| US862,804 | 1986-05-13 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1306681C true CA1306681C (en) | 1992-08-25 |
Family
ID=25339401
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000537099A Expired - Lifetime CA1306681C (en) | 1986-05-13 | 1987-05-12 | Antioxidant metallo-organic treatment of inflammation |
Country Status (7)
| Country | Link |
|---|---|
| AT (1) | AT397036B (en) |
| CA (1) | CA1306681C (en) |
| DE (1) | DE3715525C2 (en) |
| FR (1) | FR2598616B1 (en) |
| GB (2) | GB2190836B (en) |
| IL (1) | IL82376A (en) |
| IT (1) | IT1221920B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5049557A (en) * | 1986-05-13 | 1991-09-17 | Chai-Tech Corporation | Metallo-organic salt compounds and pharmaceutical uses thereof |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB841710A (en) * | 1957-08-12 | 1960-07-20 | Ici Ltd | Pharmaceutical compositions comprising ferrocene derivatives |
| US3420865A (en) * | 1966-05-12 | 1969-01-07 | Colgate Palmolive Co | Novel carbocyclic ferrocenes |
| DE2527158A1 (en) * | 1975-06-18 | 1976-12-23 | Herz Eberhard | MEDICINAL PRODUCTS FOR THE TREATMENT OF INFECTIOUS DISEASES AND INFLAMMATION IN HUMAN AND VETERINAL MEDICINE THAT CANNOT BE DETECTED BY MICROORGANISMS |
| CA1218600A (en) * | 1982-12-06 | 1987-03-03 | Gerald L. Maurer | Methods and compositions for treating inflammation or arthritis |
| DE3404443A1 (en) * | 1984-02-08 | 1985-08-08 | Hartmut Prof. Dr. 1000 Berlin Köpf | METALLICENIUM SALTS AND THEIR USE AS CYTOSTATICA IN CANCER FIGHTING |
-
1987
- 1987-04-30 IL IL82376A patent/IL82376A/en not_active IP Right Cessation
- 1987-05-05 FR FR878706682A patent/FR2598616B1/en not_active Expired - Fee Related
- 1987-05-07 AT AT0115287A patent/AT397036B/en not_active IP Right Cessation
- 1987-05-09 DE DE3715525A patent/DE3715525C2/en not_active Expired - Fee Related
- 1987-05-11 GB GB8711051A patent/GB2190836B/en not_active Expired - Lifetime
- 1987-05-12 IT IT20473/87A patent/IT1221920B/en active
- 1987-05-12 CA CA000537099A patent/CA1306681C/en not_active Expired - Lifetime
-
1990
- 1990-02-27 GB GB909004351A patent/GB9004351D0/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| GB2190836B (en) | 1990-12-05 |
| FR2598616B1 (en) | 1991-01-18 |
| GB2190836A (en) | 1987-12-02 |
| IT1221920B (en) | 1990-08-23 |
| FR2598616A1 (en) | 1987-11-20 |
| ATA115287A (en) | 1993-06-15 |
| IT8720473A0 (en) | 1987-05-12 |
| DE3715525A1 (en) | 1988-02-11 |
| GB9004351D0 (en) | 1990-04-25 |
| GB8711051D0 (en) | 1987-06-17 |
| IL82376A (en) | 1991-06-10 |
| DE3715525C2 (en) | 1998-09-17 |
| AT397036B (en) | 1994-01-25 |
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