CA1201065A - 1-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1h, 3h)-diones and 1-(3-nitrophenyl)quinazoline-2,4(1h, 3h)-diones as cutaneous medicaments - Google Patents
1-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1h, 3h)-diones and 1-(3-nitrophenyl)quinazoline-2,4(1h, 3h)-diones as cutaneous medicamentsInfo
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- 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
1-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1H, 3H)-diones and 1-(3-nitrophenyl)quinazoline-2,4(1H, 3H)-diones as cutaneous medicaments A B S T R A C T
Medicament for combating inflammatory and/or painful processes in human and non-human animals suitable for cutaneous administration containing a compound of the general formula
Medicament for combating inflammatory and/or painful processes in human and non-human animals suitable for cutaneous administration containing a compound of the general formula
Description
\
The present invention relates to cutaneous medi.caments containing certain known quinazoline compounds.
The pharmaceutical use of compounds of the following general formula (I) and their preparation have already been disclosed in DE-OS (German Published Specification) 2,459,060 and DE-OS (German Published Specification) 2,459,090. Pharmacological efEects were demonstrated by intraperitoneal or oral administra-tion of the substances to rodents. Oral administration of the substances is associated, in many cases, with considerable side effects, such as nausea or tachyphylaxis.
The present invention now provides medicaments suitable for cutaneous administration containing an inert cutaneous pharmaceutical carrier and a compound of the general formula o N-R
y ~ N ~ ~ tI) ~N02 in which R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a halogenoalkyl, propargyl or cyclopropylmethyl group, a halogeno-alkyl group having 1 to 3 carbon atoms, a trihalogenoalkyl group having 1 to 3 carbon atoms, an acetoxyethyl group, a hydroxyalkylgroup having 2 or 3 carbon atoms, an alkoxyalkyl group having 2 ~4~
,; -- 1 --I
gfi~
to 4 carbon atoms or a vinyloxyethyl, hydroxyethoxyethyl, carboxymethyl, ethoxycarbonylmethyl, 2,3-epoxypropyl, diethyl-aminoethyl, 4-methylpiperazinoethyl, benzyl, phenethyl or cinnamyl group, X represents oxygen or sulphur and Y represents nitrogen or a CH group, in particular medicaments which serve to treat inflammatory and/or painful processes.
The alkyl group or alkyl part of the aralkyl group of R preferably has 1 to 4 carbon atoms, and the alkenyl or alkynyl groups of R preferably have 2 to 4 carbon atoms.
- la -,~ ,~
Surprisingly, it has been found that compounds of the general formula (I), in an appropriate form, have strong anti-inflammatory effects on topical use without inducing the side effects described above.
The cutaneous medicament of the present invention are distinguished by having to be in a form which perrnits topical administration.
The present invention further relates to a pharma-ceutical composition containing as an active ingredient a 1û compound of formula (I) in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent;
the said solid liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous administration.
In addition the invention relates to a rnethod of combatin9 inflammatory and/or painful processes in human and non-human animals which comprises administering cutaneously to the animals an active compound of formula (I) either alone or in admixture with a diluent or in the form of a cutaneous medicament of the invention.
Cutaneous administration in the sense of the present invention is to be understood to include topical use in general and the use or application on mucous membranes except the mucous membrane of the mouth.
The pharmaceutical composition according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols) 7 lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents or powders.
The pharmaceutical formulations can contain the active compound or compounds alongside the customary excipients, such as (a) fillers and extenders5 for example starches, lactose, sucrose, glucose, mannitol and silica, -b~
(b) binders, for example carboxymethylcellulose, alginates, gelatin and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) solution retarders, for example paraffin and (e) adsorption accelerators, for example quaternary ammonium compounds~ (f) wetting agents, for example cetyl alcohol and glycerol monostearate, (g) ad-sorbants, -For example kaolin and bentonite and (h) lubri-cants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols, or mixtures of the substances listed under (a) to (h).
The formulations can also be of such composition that they release the active compound or compounds only in a delayed manner~ examples of embedding compounds which can be used being polymeric substances and waxes.
; 15 The diluents to be used in pharmaceutical composit-ions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures af these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the abovementioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolvin9 agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl-formamide, oils, especially cotton seed oil, maize germ oil, olive oil and sesame oil, glycerol, glycerol-formal, tetra-hydrofurfuryl alcohol, polyethylene glycols and fatty acid 1û esters of sorbitan or mixtures of these substances.
The following are particularly preferably used according to the invention for the preparation of solutions, suspensions or emulsions of the substances which are to be administered cutaneously: dimethyl sulphoxide, dimethyl-formamide, dimethylacetamide, lutrol, cremophor, castor oil,groundnut oil, N-methylpyrrolidone, etofenamate and methyl-salicylate.
Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl alcohol or pro-pylene glycol, surface-active agents (for example ethoxylated isostearyl alcohols, polyoxyethylene sorbite esters and sorbitane esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
The formulation forms mentioned can also contain coloured agents and colourants, preservatives and additives which improve the odour, for example peppermint oil and eucalyptus oil.
The pharmaceutical compositions according to the invention generally contain from 0.1 to 99.5O usually from 0.5 to 95O of the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the ?i$5 invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
The abovementioned pharmaceutical formulations are prepared in the customary manner according to known methods, for example by mixing the active compound or com-pounds with the excipient or excipients.
This invention further provides a method of com-bating (including prevention, relief and cure of) the abOvementioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
In general it has proved advantageous both in human medicine and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of from 0.1 to 100, preferably 0.5 to 10 mg/kg of body weight per day, optionally in the form of several individual administrations, to achieve effective results. An individual administration preferably contains the active compound or compounds according to the invention in amounts of O.l to 70, in especially 0.1 to 2.0 mg/kg of body weight. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal sub~ject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the abovemen-tioned minimum dosage rate~ whilst other cases -the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
Preferred compounds of formula (I) for cutaneous administration according to the present invention are those in which Y and X have the meanings given above, and R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a halogenoalkyl, propargyl or cyclopropyl-methyl group, a halogenoalkyl group having 1 to 3 carbonatoms, a trihalogenoalkyl group having 1 to 3 carbon atoms, an acetoxyethyl group, a hydroxyalkyl group having 2 or 3 carbon atoms, an alkoxyalkyl group having 2 to 4 carbon atoms, or a vinyloxyethyl, hydroxyethoxyethylg carboxymethyl, ethoxycarbonylmethyl, 2,3-epoxypropyl, diethylaminoethyl, 4-methylpiperazinoethyl, benzyl, phenethyl or cinnamyl group.
Particularly preferred compounds of formula (I), used according to the present invention are:
Compound (1): 1-(3-nitrophenyl)-3-ethylquinazoline-2,4(1H, 3H)-dione Compound (2): 1-(3-nitrophenyl)-3-(2-fluoroethyl)-quin-azoline-2,4(1H, 3H)-dione Compound (3): 1-(3-nitrophenyl)-3-ethylpyrido[2,3-d]pyrim-idine-2~4(1H~ 3H)-dione.
The inhibitory effect of the test substances on oedema after topical use was found with the aid of the oedema of rat paw induced by kaolin.
The experiments were carried out with male rats (strain: Bor: WISW (SPF-Cpb; weight: 150-220 9). One hour before induction of the oedema (0.1 ml of kaolin suspension subplantar per animal), the substance dissolved in the particular solvent was applied to the dorsal skin of the animals, which had been shaved on the previous day, and gently massaged in; a sacond animal group was treated with pure solvent without the substance as a control.
Q~5 The volumes of the paws were measured by the method of F. Kemper and G. Ameln, Z. ges. exp. Med. 131, 407 (1959), in which the difference of the volume of the paws five hours after induction oF oedema and the normal volume of the paws gives the volume of oedema.
As an example, the ED50 for compound (l) was initially determined after cutaneous administration in dimethyl sulphoxide. It was found that it was possible to obtain the same antiphlogistic effect by cutaneous administration of 0.3 mg/kg of compound (l) in dimethyl sulphoxide as after oral administration of 0.3 mg/kg.
In continuation of the investigations, the same amounts Gf compound (l) (0.3 mg/kg in each case) in various solvents were administered cutaneously. According to thiS, dimethyl sulphoxide, dimethylformamide, dimethyl-acetamide, methylsalicylate and, preferably, N-methyl-pyrrolidone are particularly suitable, in respect of the antiphlO9istic effect, as solvents for cutaneous admini-stration of compound (l) (Table l).
Table l Antiphlogistic effect of compound (l).
0.3 mg/kg, mode of administration: cutaneously, I rat, n - 5 (n - number of rats) Solvent O inhibition of kaolin oedema 25 Dimethyl sulphoxide 48.3 Dimethylformamide 35.0 Dimethylacetamide 50.5 Lutrol 18.3 Cremophor 14.2 30 Castor oil 14.2 Groundnut oil 16.7 N-methylpyrrolidone 63.2 Methylsalicylate 77.1 (methylsalicylate alone 39.4) -s The other compounds of the general formula I can also be used cutaneously in the same manner (Table 2).
Table 2 Inhibition of kaolin oedema after cutaneous administration of solutions of the test compounds in dimethyl sulphoxide mg/kg ~ inhibitionED Kaolin Compound (cutan- of kaolin50 oedema eously) oedema(mg/l<g) p.o.
(l) 0.3 48.3 0.3
The present invention relates to cutaneous medi.caments containing certain known quinazoline compounds.
The pharmaceutical use of compounds of the following general formula (I) and their preparation have already been disclosed in DE-OS (German Published Specification) 2,459,060 and DE-OS (German Published Specification) 2,459,090. Pharmacological efEects were demonstrated by intraperitoneal or oral administra-tion of the substances to rodents. Oral administration of the substances is associated, in many cases, with considerable side effects, such as nausea or tachyphylaxis.
The present invention now provides medicaments suitable for cutaneous administration containing an inert cutaneous pharmaceutical carrier and a compound of the general formula o N-R
y ~ N ~ ~ tI) ~N02 in which R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a halogenoalkyl, propargyl or cyclopropylmethyl group, a halogeno-alkyl group having 1 to 3 carbon atoms, a trihalogenoalkyl group having 1 to 3 carbon atoms, an acetoxyethyl group, a hydroxyalkylgroup having 2 or 3 carbon atoms, an alkoxyalkyl group having 2 ~4~
,; -- 1 --I
gfi~
to 4 carbon atoms or a vinyloxyethyl, hydroxyethoxyethyl, carboxymethyl, ethoxycarbonylmethyl, 2,3-epoxypropyl, diethyl-aminoethyl, 4-methylpiperazinoethyl, benzyl, phenethyl or cinnamyl group, X represents oxygen or sulphur and Y represents nitrogen or a CH group, in particular medicaments which serve to treat inflammatory and/or painful processes.
The alkyl group or alkyl part of the aralkyl group of R preferably has 1 to 4 carbon atoms, and the alkenyl or alkynyl groups of R preferably have 2 to 4 carbon atoms.
- la -,~ ,~
Surprisingly, it has been found that compounds of the general formula (I), in an appropriate form, have strong anti-inflammatory effects on topical use without inducing the side effects described above.
The cutaneous medicament of the present invention are distinguished by having to be in a form which perrnits topical administration.
The present invention further relates to a pharma-ceutical composition containing as an active ingredient a 1û compound of formula (I) in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent;
the said solid liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous administration.
In addition the invention relates to a rnethod of combatin9 inflammatory and/or painful processes in human and non-human animals which comprises administering cutaneously to the animals an active compound of formula (I) either alone or in admixture with a diluent or in the form of a cutaneous medicament of the invention.
Cutaneous administration in the sense of the present invention is to be understood to include topical use in general and the use or application on mucous membranes except the mucous membrane of the mouth.
The pharmaceutical composition according to the invention may, for example, take the form of ointments, gels, pastes, creams, sprays (including aerosols) 7 lotions, suspensions, solutions and emulsions of the active ingredient in aqueous or non-aqueous diluents or powders.
The pharmaceutical formulations can contain the active compound or compounds alongside the customary excipients, such as (a) fillers and extenders5 for example starches, lactose, sucrose, glucose, mannitol and silica, -b~
(b) binders, for example carboxymethylcellulose, alginates, gelatin and polyvinylpyrrolidone, (c) humectants, for example glycerol, (d) solution retarders, for example paraffin and (e) adsorption accelerators, for example quaternary ammonium compounds~ (f) wetting agents, for example cetyl alcohol and glycerol monostearate, (g) ad-sorbants, -For example kaolin and bentonite and (h) lubri-cants, for example talc, calcium stearate and magnesium stearate and solid polyethylene glycols, or mixtures of the substances listed under (a) to (h).
The formulations can also be of such composition that they release the active compound or compounds only in a delayed manner~ examples of embedding compounds which can be used being polymeric substances and waxes.
; 15 The diluents to be used in pharmaceutical composit-ions adapted to be formed into suppositories can, for example, be the usual water-soluble diluents, such as polyethylene glycols and fats (e.g. cocoa oil and high esters (e.g.
C14-alcohol with C16-fatty acid)) or mixtures af these diluents.
The pharmaceutical compositions which are ointments, pastes, creams and gels can, for example, contain the usual diluents, e.g. animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures of these substances.
The pharmaceutical compositions which are powders and sprays can, for example, contain the usual diluents, e.g. lactose, talc, silicic acid, aluminium hydroxide, calcium silicate, and polyamide powder or mixtures of these substances. Aerosol sprays can, for example, contain the usual propellants, e.g. chlorofluorohydrocarbons.
The pharmaceutical compositions which are solutions and emulsions can, for example, contain the customary diluents (with, of course, the abovementioned exclusion of solvents having a molecular weight below 200 except in the presence of a surface-active agent), such as solvents, dissolvin9 agents and emulsifiers; specific examples of such diluents are water, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl-formamide, oils, especially cotton seed oil, maize germ oil, olive oil and sesame oil, glycerol, glycerol-formal, tetra-hydrofurfuryl alcohol, polyethylene glycols and fatty acid 1û esters of sorbitan or mixtures of these substances.
The following are particularly preferably used according to the invention for the preparation of solutions, suspensions or emulsions of the substances which are to be administered cutaneously: dimethyl sulphoxide, dimethyl-formamide, dimethylacetamide, lutrol, cremophor, castor oil,groundnut oil, N-methylpyrrolidone, etofenamate and methyl-salicylate.
Suspensions can contain, in addition to the active compound or compounds, the customary excipients, such as liquid diluents, for example water, ethyl alcohol or pro-pylene glycol, surface-active agents (for example ethoxylated isostearyl alcohols, polyoxyethylene sorbite esters and sorbitane esters), microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances.
The formulation forms mentioned can also contain coloured agents and colourants, preservatives and additives which improve the odour, for example peppermint oil and eucalyptus oil.
The pharmaceutical compositions according to the invention generally contain from 0.1 to 99.5O usually from 0.5 to 95O of the active ingredient by weight of the total composition.
In addition to a compound of the invention, the pharmaceutical compositions and medicaments according to the ?i$5 invention can also contain other pharmaceutically active compounds. They may also contain a plurality of compounds of the invention.
The abovementioned pharmaceutical formulations are prepared in the customary manner according to known methods, for example by mixing the active compound or com-pounds with the excipient or excipients.
This invention further provides a method of com-bating (including prevention, relief and cure of) the abOvementioned diseases in human and non-human animals, which comprises administering to the animals a compound of the invention alone or in admixture with a diluent or in the form of a medicament according to the invention.
In general it has proved advantageous both in human medicine and in veterinary medicine to administer the active compound or compounds according to the invention in total amounts of from 0.1 to 100, preferably 0.5 to 10 mg/kg of body weight per day, optionally in the form of several individual administrations, to achieve effective results. An individual administration preferably contains the active compound or compounds according to the invention in amounts of O.l to 70, in especially 0.1 to 2.0 mg/kg of body weight. Nevertheless, it can at times be necessary to deviate from those dosage rates, and in particular to do so as a function of the nature and body weight of the human or animal sub~ject to be treated, the individual reaction of this subject to the treatment, the type of formulation in which the active ingredient is administered and the mode in which the administration is carried out, and the point in the progress of the disease or interval at which it is to be administered. Thus it may in some case suffice to use less than the abovemen-tioned minimum dosage rate~ whilst other cases -the upper limit mentioned must be exceeded to achieve the desired results. Where larger amounts are administered it can be advisable to divide these into several individual administrations over the course of the day.
Preferred compounds of formula (I) for cutaneous administration according to the present invention are those in which Y and X have the meanings given above, and R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a halogenoalkyl, propargyl or cyclopropyl-methyl group, a halogenoalkyl group having 1 to 3 carbonatoms, a trihalogenoalkyl group having 1 to 3 carbon atoms, an acetoxyethyl group, a hydroxyalkyl group having 2 or 3 carbon atoms, an alkoxyalkyl group having 2 to 4 carbon atoms, or a vinyloxyethyl, hydroxyethoxyethylg carboxymethyl, ethoxycarbonylmethyl, 2,3-epoxypropyl, diethylaminoethyl, 4-methylpiperazinoethyl, benzyl, phenethyl or cinnamyl group.
Particularly preferred compounds of formula (I), used according to the present invention are:
Compound (1): 1-(3-nitrophenyl)-3-ethylquinazoline-2,4(1H, 3H)-dione Compound (2): 1-(3-nitrophenyl)-3-(2-fluoroethyl)-quin-azoline-2,4(1H, 3H)-dione Compound (3): 1-(3-nitrophenyl)-3-ethylpyrido[2,3-d]pyrim-idine-2~4(1H~ 3H)-dione.
The inhibitory effect of the test substances on oedema after topical use was found with the aid of the oedema of rat paw induced by kaolin.
The experiments were carried out with male rats (strain: Bor: WISW (SPF-Cpb; weight: 150-220 9). One hour before induction of the oedema (0.1 ml of kaolin suspension subplantar per animal), the substance dissolved in the particular solvent was applied to the dorsal skin of the animals, which had been shaved on the previous day, and gently massaged in; a sacond animal group was treated with pure solvent without the substance as a control.
Q~5 The volumes of the paws were measured by the method of F. Kemper and G. Ameln, Z. ges. exp. Med. 131, 407 (1959), in which the difference of the volume of the paws five hours after induction oF oedema and the normal volume of the paws gives the volume of oedema.
As an example, the ED50 for compound (l) was initially determined after cutaneous administration in dimethyl sulphoxide. It was found that it was possible to obtain the same antiphlogistic effect by cutaneous administration of 0.3 mg/kg of compound (l) in dimethyl sulphoxide as after oral administration of 0.3 mg/kg.
In continuation of the investigations, the same amounts Gf compound (l) (0.3 mg/kg in each case) in various solvents were administered cutaneously. According to thiS, dimethyl sulphoxide, dimethylformamide, dimethyl-acetamide, methylsalicylate and, preferably, N-methyl-pyrrolidone are particularly suitable, in respect of the antiphlO9istic effect, as solvents for cutaneous admini-stration of compound (l) (Table l).
Table l Antiphlogistic effect of compound (l).
0.3 mg/kg, mode of administration: cutaneously, I rat, n - 5 (n - number of rats) Solvent O inhibition of kaolin oedema 25 Dimethyl sulphoxide 48.3 Dimethylformamide 35.0 Dimethylacetamide 50.5 Lutrol 18.3 Cremophor 14.2 30 Castor oil 14.2 Groundnut oil 16.7 N-methylpyrrolidone 63.2 Methylsalicylate 77.1 (methylsalicylate alone 39.4) -s The other compounds of the general formula I can also be used cutaneously in the same manner (Table 2).
Table 2 Inhibition of kaolin oedema after cutaneous administration of solutions of the test compounds in dimethyl sulphoxide mg/kg ~ inhibitionED Kaolin Compound (cutan- of kaolin50 oedema eously) oedema(mg/l<g) p.o.
(l) 0.3 48.3 0.3
(2) 0.3 56.0 0.2
(3) 0.3 79.8 0.1 The advantage according to the invention of cutaneous compared to oral use consists in that pharma-cologically valuable effects of the substance are retained 10 due to the selection of this particular mode of adminis-tration, whilst undesired side effects can be avoided, that is to say the compounds according to the general for-mula (I) can only be pharmaceutically utilised at all by cutaneous use in suitable solvents.
1'he avoidance of side effects by cutaneous administration of compound (l) is described in the following Examples.
Example A
Both oral and also intramuscular administration 20 of compound (l) led to severe emetic symptoms in the dog at and above a dose as little as about O.l mg/kg. This emetic effect in the dog did not occur even on cutaneous administration of 5 mg/kg of the substance.
Example B
Compound (l) induced pronounced tachyphylaxis, after only three to four days, on oral administration for several days to rats. This loss of activity of the substance ,investigated was completely avoided by cutaneous administ ration. Even after 6 days of continuous topical pre-treatment of the rats with the substance (0.3 mg/kg/day) dissolved in dimethyl sulphoxide, compound (1) still showed its unambiguous inhibitory effect on oedema.
Thus it was surprising that the compounds of the general formula (I), in a suitable form, have strong anti-inflam~atory effects on topical use, and without inducing -the side effects described above and illustrated in the foregoing Examples A and B.
1'he avoidance of side effects by cutaneous administration of compound (l) is described in the following Examples.
Example A
Both oral and also intramuscular administration 20 of compound (l) led to severe emetic symptoms in the dog at and above a dose as little as about O.l mg/kg. This emetic effect in the dog did not occur even on cutaneous administration of 5 mg/kg of the substance.
Example B
Compound (l) induced pronounced tachyphylaxis, after only three to four days, on oral administration for several days to rats. This loss of activity of the substance ,investigated was completely avoided by cutaneous administ ration. Even after 6 days of continuous topical pre-treatment of the rats with the substance (0.3 mg/kg/day) dissolved in dimethyl sulphoxide, compound (1) still showed its unambiguous inhibitory effect on oedema.
Thus it was surprising that the compounds of the general formula (I), in a suitable form, have strong anti-inflam~atory effects on topical use, and without inducing -the side effects described above and illustrated in the foregoing Examples A and B.
Claims (10)
PROPERTY OR PRIVELEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A medicament composition adapted for cutaneous administration containing an anti-inflammatory effective amount of a compound of formula (I) in which R represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, an alkenyl group having 3 to 5 carbon atoms, a halogenoalkyl, propargyl or cyclopropylmethyl group, a halogenoalkyl group having 1 to 3 carbon atoms, a trihalogenoalkyl group having 1 to 3 carbon atoms, an acetoxyethyl group, a hydroxyalkyl group having 2 or 3 carbon atoms, an alkoxyalkyl group having 2 to 4 carbon atoms or a vinyloxyethyl, hydroxyethoxyethyl, carboxymethyl, ethoxycarbonylmethyl, 2,3-epoxy-propyl, diethylaminoethyl, 4-methylpiperazinoethyl, benzyl, phenethyl or cinnamyl group, X denotes oxygen or sulphur and Y denotes nitrogen or CH and an inert cutaneous pharmaceutical carrier.
2. A medicament according to claim 1, containing a compound of formula (I) in which Y has the same meanings as in claim 1, X denotes oxygen, and R represents an alkyl group having 1 to 4 carbon atoms, a mono-halogenoalkyl group having 1 to 3 carbon atoms or a trihalogenoalkyl group having 1 to 3 carbon atoms.
3. A medicament according to claim 1, in which the compound of formula (I) is 1-(3-nitrophenyl)-3-ethylquinazoline-2,4(1H, 3H)-dione, 1-(3-nitrophenyl)-3-(2-fluoroethyl)-quinazoline-2,4(1H, 3H)-dione, or 1-(3-nitrophenyl)-3-ethylpyrido[2,3-d]pyrimidine-2,4(1H, 3H)-dione.
4. A medicament according to any of claims 1 to 3, in the form of a suppository.
5. A pharmaceutical composition containing as an active ingredient a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; the said solid, liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous adminis-tration.
6. A pharmaceutical composition containing as an active ingredient a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; the said solid, liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous admins-tration, the composition being in the form of a gel; paste; spray; suspension;
solution or emulsion of the active ingredient in an aqueous or non-aqueous diluent; or a powder.
solution or emulsion of the active ingredient in an aqueous or non-aqueous diluent; or a powder.
7. A pharmaceutical composition containing as an active ingredient a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; in the form of an ointment, cream or lotion.
8. A pharmaceutical composition containing as an active ingredient from 0.5 to 95% by weight of a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; the said solid, liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous administration.
9. A pharmaceutical composition containing as an active ingredient from 0.5 to 95% by weight of a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; the said solid, liquid or liquefied gaseous diluent being a diluent appropriate only to pharmaceutical compositions for cutaneous administration, the composition being in the form of a gel; paste;
spray; suspension; solution or emulsion of the active ingredient in an aqueous or non-aqueous diluent; or a powder.
spray; suspension; solution or emulsion of the active ingredient in an aqueous or non-aqueous diluent; or a powder.
10. A pharmaceutical composition containing as an active ingredient from 0.5 to 95% by weight of a compound as defined in any one of claims 1 to 3 in admixture with a solid or liquefied gaseous diluent or in admixture with a liquid diluent other than a solvent of a molecular weight less than 200 except in the presence of a surface-active agent; in the form of an ointment, cream or lotion.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP3150271.7 | 1981-12-18 | ||
| DE19813150271 DE3150271A1 (en) | 1981-12-18 | 1981-12-18 | 1- (3-NITROPHENYL) PYRIDO (2.3-D) PYRIMIDINE-2.4 (1H, 3H) -DIONE AND 1- (3-NITROPHENYL) CHINAZOLINE-2.4 (1H, 3H) -DIONE AS A CUTANE MEDICINAL PRODUCT |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1201065A true CA1201065A (en) | 1986-02-25 |
Family
ID=6149136
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000417905A Expired CA1201065A (en) | 1981-12-18 | 1982-12-16 | 1-(3-nitrophenyl)pyrido[2,3-d]pyrimidine-2,4(1h, 3h)-diones and 1-(3-nitrophenyl)quinazoline-2,4(1h, 3h)-diones as cutaneous medicaments |
Country Status (11)
| Country | Link |
|---|---|
| EP (1) | EP0082385B1 (en) |
| JP (1) | JPS58110518A (en) |
| AT (1) | ATE21032T1 (en) |
| AU (1) | AU9144682A (en) |
| CA (1) | CA1201065A (en) |
| DE (2) | DE3150271A1 (en) |
| FI (1) | FI824330L (en) |
| GR (1) | GR78419B (en) |
| NO (1) | NO824044L (en) |
| PT (1) | PT75957B (en) |
| ZA (1) | ZA829268B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CA2366998A1 (en) * | 1999-03-19 | 2000-09-28 | Mingshu Li | Quinazoline formulations and therapeutic use thereof |
| US7064114B2 (en) | 1999-03-19 | 2006-06-20 | Parker Hughes Institute | Gel-microemulsion formulations |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4016166A (en) * | 1973-12-14 | 1977-04-05 | Hisamitsu Pharmaceutical Co., Inc. | 1-Nitrophenylquinazoline-2,4(1H,3H)-diones |
| JPS5649917B2 (en) * | 1973-12-18 | 1981-11-25 | ||
| DE3172006D1 (en) * | 1980-05-22 | 1985-10-03 | Masayuki Ishikawa | Novel quinazoline-dione compounds, process for production thereof and pharmaceutical use thereof |
-
1981
- 1981-12-18 DE DE19813150271 patent/DE3150271A1/en not_active Withdrawn
-
1982
- 1982-12-02 NO NO824044A patent/NO824044L/en unknown
- 1982-12-04 DE DE8282111233T patent/DE3272381D1/en not_active Expired
- 1982-12-04 AT AT82111233T patent/ATE21032T1/en not_active IP Right Cessation
- 1982-12-04 EP EP82111233A patent/EP0082385B1/en not_active Expired
- 1982-12-09 PT PT75957A patent/PT75957B/en unknown
- 1982-12-13 AU AU91446/82A patent/AU9144682A/en not_active Abandoned
- 1982-12-14 JP JP57217921A patent/JPS58110518A/en active Pending
- 1982-12-16 CA CA000417905A patent/CA1201065A/en not_active Expired
- 1982-12-16 GR GR70099A patent/GR78419B/el unknown
- 1982-12-16 FI FI824330A patent/FI824330L/en not_active Application Discontinuation
- 1982-12-17 ZA ZA829268A patent/ZA829268B/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| DE3272381D1 (en) | 1986-09-04 |
| FI824330L (en) | 1983-06-19 |
| EP0082385A1 (en) | 1983-06-29 |
| GR78419B (en) | 1984-09-27 |
| JPS58110518A (en) | 1983-07-01 |
| DE3150271A1 (en) | 1983-06-30 |
| ZA829268B (en) | 1983-10-26 |
| EP0082385B1 (en) | 1986-07-30 |
| FI824330A0 (en) | 1982-12-16 |
| PT75957B (en) | 1985-10-04 |
| NO824044L (en) | 1983-06-20 |
| PT75957A (en) | 1983-01-01 |
| ATE21032T1 (en) | 1986-08-15 |
| AU9144682A (en) | 1983-06-23 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |