Claims
- 1. New quinolinediones of formula ##STR18## R.sup.3 is hydrogen, trifluoromethyl, phenyl or C.sub.1 -C.sub.3 alkyl, X is methylene optionally substituted by one or two C.sub.1 -C.sub.3 alkyl and
- R.sub.1 "' is hydrogen, C.sub.1 -C.sub.3 alkyl optionally substituted by phenyl, fluorophenyl, chlorophenyl or bromophenyl, by carboxy or by C.sub.2 -C.sub.4 alkoxycarboxyl, C.sub.4 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.5 alkenyl or C.sub.3 -C.sub.5 alkynyl, a C.sub.2 -C.sub.3 alkyl substituted in the 2- or 3- position by hydroxy, alkoxy or alkylmercapto, in which the alkoxy or alkymercapto substituent may in each case contain 1 to 3 carbon atoms, or tetrahydrofurfuryl and R.sub.4 is C.sub.1 -C.sub.5 alkyl or R.sub.1 "' is C.sub.1 -C.sub.3 alkyl optionally substituted by phenyl, fluorophenyl, chlorophenyl or bromophenyl, by carboxy or by C.sub.2 -C.sub.4 alkoxycarboxyl, C.sub.4 -C.sub.6 alkyl, C.sub.3 -C.sub.6 cycloalkyl, C.sub.3 -C.sub.5 alkenyl or C.sub.3 -C.sub.5 alkynyl, a C.sub.2 -C.sub.3 alkyl substituted in the 2- or 3- position by hydroxy, alkoxy or alkylmercapto, in which the alkoxy or alkylmercapto substituent may in each case contain 1 to 3 carbon atoms, or tetrahydrofurfuryl and R.sub.4 is hydrogen.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 3808136 |
Mar 1988 |
DEX |
|
Parent Case Info
This is a Continuation-In-Part of application Ser. No. 322,602 filed on Mar. 13, 1989 now abandoned.
Quinolin-2,5-diones have already been described in the literature without any mention whatever of their pharmacological properties (see Arch. Pharm. 308, 588-594 (1975), J. Het. Chem. 22, 1503-1509 (1985), J. Org. Chem. 33, 1089-1092 (1968), Eur. J. Med. Chem. 14, 499-506 (1979), Chem. Ber. 103, 2403-2410 (1970), C. A. 67, 99689, Bull. Soc. Chim. Belge 88. 671-676 (1979), J. Org. Chem. 46, 3719-3721 (1981), Tetrahedron Letters 1965, 2441-2444, Tetrahedron Letters 1967, 2563-2566 and J. Chem. Soc., Perkin Trans. 1 1984, 287-290).
Japanese laid-open specification 76/32568 also describes, inter alia, 5-(3-amino-2-hydroxy-propoxy)-3,4-dihydrocarbostyrile derivatives substituted in the one- position by an ethyl or allyl group, although the 1-ethyl- and 1-allyl5-oxo-hexahydro-carbostyriles necessary for preparing them are not described explicitly.
It has now been found that the quinolin-2,5-diones of formula ##STR2## and, if they contain an optically active carbon atom, optically active antipodes thereof, have valuable pharmacological properties, particularly an analgesic, antipyretic and/or antiphlogistic effect.
In formula I above:
A and B each represent a hydrogen atom or together represent a carbon-carbon bond,
R.sup.1 represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms optionally substituted by a phenyl, fluorophenyl, chlorophenyl or bromophenyl group, by a carboxy group or by an alkoxycarbonyl group with a total of 2 to 4 carbon atoms, an alkyl group with 4 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an alkenyl or alkynyl group with 3 to 5 carbon atoms, an alkyl group with 2 or 3 carbon atoms substituted in the 2-or 3-position by a hydroxy, alkoxy or alkylmercapto group, wherein the alkoxy or alkylmercapto substituent may contain from 1 to 3 carbon atoms, a phenyl group optionally substituted by a halogen atom or by an alkyl or alkoxy group with 1 to 3 carbon atoms in the alkyl part, or a tetrahydrofurfuryl group;
R.sup.2 represents a hydrogen atom or an alkyl group with 1 to 3 carbon atoms,
R.sup.3 represents a hydrogen atom, a trifluoromethyl, phenyl or alkyl group with I to 3 carbon atoms or
R.sup.2 and R.sup.3 together represent an n-alkylene group with 3 to 5 carbon atoms; and
X represents a methylene group optionally substituted by one or two alkyl groups each having 1 to 3 carbon atoms.
The quinolin-2,5-diones which are new are those wherein if A and B together represent another carbon-carbon bond,
R.sup.2 represents an alkyl group with 1 to 3 carbon atoms and R.sup.1, R.sup.3 and X are defined as hereinbefore or
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom and the methyl and ethyl groups, and R.sup.2, R.sup.3 and X are defined as hereinbefore or, if A and B each represents a hydrogen atom,
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom, the methyl group and the benzyl group, and R.sup.2, R.sup.3 and X are defined as hereinbefore or
R.sup.2 represents an alkyl group with 2 or 3 carbon atoms and R.sup.1, R.sup.3 and X are defined as hereinbefore.
The present invention thus relates to the new pharmaceutical compositions containing a compound of formula I which are suitable for controlling pain, fever and inflammation and for controlling cold symptoms, the new quinolin-2,5-diones of formula I above and processes for the preparation thereof.
As examples of definitions of the groups R.sup.1, R.sup.2, R.sup.3 and X mentioned hereinbefore:
R.sup.1 may represent a hydrogen atom, a methyl, ethyl, n-propyl isopropyl, n-butyl, isobutyl, n-pentyl, n-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, allyl, n-but-2-enyl, n-but-3-enyl, n-pent-2-enyl, n-pent-3-enyl, propargyl, n-but-2-ynyl, n-but-3-ynyl, n-pent-2-ynyl, n-pent-3ynyl, 2-methyl-n-but-2-enyl, benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, 1-phenylethyl, 2-phenylethyl, 3-phenylpropyl, 2-(chlorophenyl)-ethyl, carboxymethyl, 1-carboxy-ethyl, 2-carboxyethyl, 1-carboxy-n-propyl, 2-carboxy-n-propyl, 3-carboxy-propyl, methoxycarbonylmethyl, 1-ethoxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, 3-ethoxycarbonyl-n-propyl, 2-hydroxyethyl, 2-hydroxy-n-propyl, 2-hydroxy-1-methyl-ethyl, 2-methoxy-ethyl, 3-ethoxy-n-propyl, 2-n-propoxy-1-methyl-ethyl, 2-methylmercapto-ethyl, 2-ethylmercapto-n-propyl, 2-isopropylmercapto-1-methylethyl, 3-methyl-mercapto-n-propyl, phenyl, fluorophenyl, chlorophenyl, bromophenyl, hydroxyphenyl, methylphenyl, ethylphenyl, isopropylphenyl, methoxyphenyl, ethoxyphenyl, n-propoxy-phenyl or tetrahydrofurfuryl group,
R.sup.2 may represent a hydrogen atom, a methyl, ethyl, n-propyl or isopropyl group,
R.sup.3 may represent a hydrogen atom, a methyl, ethyl, n-propyl, isopropyl, trifluoromethyl or phenyl group or
R.sup.2 and R.sup.3 may together represent the n-propylene, n-butylene or n-pentylene group and
X may represent a methylene, methyl-methylene, dimethylmethylene, methyl-ethyl-methylene, diethyl- methylene or n-propyl-methylene group.
The following compounds, which are covered by the scope of this invention but not described explicitly in the Examples, will now be mentioned by way of example:
However, preferred compounds of general formula I mentioned hereinbefore are those wherein
A and B each represent a hydrogen atom or together represent another carbon-carbon bond,
R.sup.1 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms, an ethyl group substituted in the 2-position by a hydroxy, methoxy, methylmercapto or phenyl group, a phenyl group optionally substituted by a fluorine, chlorine or bromine atom or by a methyl or methoxy group, a cyclohexyl, 3-methoxy- propyl, allyl, propargyl, carboxymethyl, methoxy- carbonylmethyl, benzyl, chlorobenzyl or tetrahydro- furfuryl group,
R.sup.2 represents a hydrogen atom or a methyl group,
R.sup.3 represents a hydrogen atom, a methyl, ethyl, trifluoromethyl or phenyl group or
R.sup.2 and R.sup.3 together represent an n-propylene or n-butylene group and
X represents a methylene, methyl-methylene or dimethylmethylene group, whilst the new quinolin-2,5-diones are those wherein, if A and B together represent another carbon-carbon bond,
R.sup.2 represents a methyl group and R.sup.1, R.sup.3 and X are defined as hereinbefore or
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom and the methyl and ethyl groups, and R.sup.2, R.sup.3 and X are defined as hereinbefore or, if A and B each represent a hydrogen atom,
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom, the methyl group, ethyl group, allyl group and benzyl group, and R.sup.2, R.sup.3 and X are defined as hereinbefore.
Particularly preferred compounds of formula I mentioned hereinbefore are those wherein
A and B each represent a hydrogen atom or together represent another carbon-carbon bond,
R.sup.1 represents a hydrogen atom, an alkyl group with 1 to 4 carbon atoms or an ethyl group substituted in the 2-position by a hydroxy, methoxy or methyl- mercapto group,
R.sup.2 represents a hydrogen atom or a methyl group and R.sup.3 represents a hydrogen atom or
R.sup.2 represents a hydrogen atom and R.sup.3 represents a methyl or ethyl group and
X represents a methylene group, whilst the new quinolin-2,5-diones are those wherein, when A and B together represent another carbon- carbon bond,
R.sup.2 represents a methyl group and
R.sup.3 represents a hydrogen atom and
R.sup.1 and X are defined as hereinbefore or
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom, the methyl and ethyl groups, and R.sup.2, R.sup.3 and X are defined as hereinbefore or, if A and B each represent a hydrogen atom and
R.sup.1 has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom, the methyl and ethyl groups, and R.sup.2, R.sup.3 and X are defined as hereinbefore.
The above-mentioned new quinolin-2,5-diones are obtained according to the invention by the following processes:
a) reaction of a compound of formula ##STR3## wherein
A, B, R.sup.2, R.sup.3 and X are as hereinbefore defined, with an amine of formula ##STR4## wherein
R.sup.1 is defined as hereinbefore.
The reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxan, methylene chloride or benzene or in an excess of the amine of formula III used as solvent, conveniently at temperatures of between -30.degree. and 180.degree. C., but preferably at temperatures between 15.degree. and 50.degree. C. The reaction may, however, also be carried out without a solvent.
b) Reaction of a compound of formula ##STR5## (wherein
A, B, R.sup.2, R.sup.3 and X are defined as hereinbefore and
Z.sup.1 represents a nucleophilic leaving group such as a hydroxy group, an alkoxy group with 1 to 3 carbon atoms or a halogen atom) with an amine of formula ##STR6## wherein
R.sup.1 is defined as hereinbefore.
The reaction is preferably carried out in a solvent such as methanol, ethanol, isopropanol, tetrahydrofuran, dioxan, methylene chloride or benzene or in an excess of the amine of formula III used as solvent, conveniently at temperatures of between -30.degree. and 200.degree. C., but preferably at temperatures of between 140.degree. and 180.degree. C. The reaction may, however, also be carried out without a solvent.
c) In order to prepare compounds of formula I wherein R.sup.2 represents a hydrogen atom:
Decarboxylation of a compound of formula ##STR7## wherein
A, B, R.sup.1, R.sup.3 and X are defined as hereinbefore.
The decarboxylation is preferably carried out in a high-boiling solvent such as quinoline, collidine, dimethylsulphoxide, diphenyl, tetralin, decalin, o-dichlorobenzene, ethylene glycol or 2-n-butoxy- ethanol and optionally in the presence of a reaction accelerator such as copper powder at elevated temperatures, e.g. at temperatures above 80.degree. C., but preferably at temperatures between 100.degree. and 200.degree. C. The reaction may, however, also be carried out without a solvent.
However, it is particularly advantageous to perform the reaction by preparing a compound of general formula V in the reaction mixture, for example by heating a corresponding ester such as the methyl, ethyl or isopropyl ester in a suitable solvent such as dimethylsulphoxide in the presence of an alkali metal halide, preferably lithium chloride or sodium chloride, and in the presence of water. The quantity of water required is conveniently 2 to 6 times the equimolar amount, preferably 3 to 4 times the equimolar amount, based on the ester used.
A compound of formula V used may also be prepared in the reaction mixture.
d) In order to prepare compounds of formula I wherein R.sup.1 has the meanings given hereinbefore with the exception of a hydrogen atom:
reaction of a compound of formula ##STR8## wherein
A, B, R.sup.2, R.sup.3 and X are defined as hereinbefore, with a compound of formula
R.sup.1 ' has the meanings given for R.sup.1 hereinbefore with the exception of the hydrogen atom and Y represents a nucleophilic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonyloxy group, e.g. a methane- sulphonyloxy or p-toluenesulphonyloxy group, or Y together with a beta-hydrogen atom of an alkyl group with 2 to 6 carbon atoms of the group R.sup.1 ' represents an oxygen atom.
The alkylation is carried out in a suitable solvent such as methanol, ethanol, diethylether, acetone, methylene chloride, tetrahydrofuran, dioxan, dimethyl- formamide or dimethylsulphoxide, but preferably in an aprotic solvent such as acetone, dimethylformamide or dimethylsulphoxide, in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, sodium hydride or potassium hydroxide with a suitable alkylating agent such as methyl iodide, dimethyl sulphate, ethyl bromide, diethyl sulphate, benzyl chloride, n-propyl bromide, isopropyl bromide, 2-hydroxy-ethyl bromide, ethylene oxide or n-propylen- 2,3-oxide at temperatures of between 0.degree. and 100.degree. C., but preferably at temperatures of between 10.degree. and 50.degree. C.
e) In order to prepare compounds of formula I wherein A and B each represent a hydrogen atom:
reaction of an enaminoketone of formula ##STR9## wherein R.sup.1 and X are defined as hereinbefore, with a compound of formula ##STR10## wherein
R.sup.2 and R.sup.3 are as hereinbefore defined and Z.sup.2 represents a nucleophilic leaving group such as a hydroxy group, an alkoxy group with 1 to 3 carbon atoms or a halogen atom.
The reaction is conveniently carried out in a high boiling solvent such as tetralin, decalin, diphenyl or o-dichlorobenzene, but preferably without a solvent at elevated temperatures, e.g. at temperatures between 100.degree. and 250.degree. C., but preferably at temperatures between 120.degree. and 180.degree. C. However, it is particularly advantageous to carry out the reaction in a pressurised vessel.
As already mentioned hereinbefore, the new compounds may occur in the form of their enantiomers, mixtures of enantiomers or racemates or, if they contain 2 asymmetric carbon atoms, in the form of their diastereoisomers or mixtures of diastereoisomers.
Thus, the compounds of general formula I which contain only one optically active centre may be resolved into their optical antipodes by methods known per se (see Allinger N. L. and Eliel W. L. in "Topics in Stereochemistry", Vol. 6, Wiley Inter- science, 1971), e.g. by recrystallisation from an optically active solvent.
Moreover, the compounds of general formula I obtained having 2 asymmetric carbon atoms may be separated into their diastereoisomers on the basis of their physico-chemical differences using methods known per se, e.g. chromatography and/or fractional crystallisation. A pair of enantiomers thus obtained can then be resolved into the optical antipodes thereof, as described above.
The compounds of formulae II to IX used as starting materials are obtained by methods known from the literature.
Thus, a compound of formula II or IV is obtained by reacting a corresponding cyclohexan-1,3-dione with a corresponding carboxylic acid derivative, a compound of formula V which may be new is obtained by reacting a corresponding 2-amino-methylene-cyclohexan- 1,3-dione with a cyanoacetate and subsequent saponification or by reacting a corresponding cyclohexan-1,3-dione with an alkoxymethylenecyanoacetate and subsequent saponification and a compound of formula VI is obtained by cyclisation of a corresponding 1-amino- cyclohexen-3-one with a corresponding alpha, beta- unsaturated carboxylic acid derivative.
A stereoselective starting compound of formula V which contains only one optically active centre in the 4-position can be prepared analogously to the method described by Enders et al. in Tetrahedron Letters 28, 3795-3798 (1987). In order to do this, for example (S)-1-amino-2-methoxymethyl-pyrrolidine is converted with dimedon or cyclohexan-1,3-dione into the corresponding (S)-hydrazone derivative which is then reacted, after metallisation, e.g. with n-butyllithium at -78.degree. C., with a corresponding benzylidene-malonate. The resulting (S--R)-2-[(2-bis(alkoxycarbonyl)-1-phenyl)-ethyl]-3-[(2-methoxymethyl)-pyrrolidine-1-yl]-en-amino-cyclohexan-3-one is cyclised to form the corresponding quinolinedione, which is converted by acidic reduction, e.g. with zinc/glacial acetic acid, and simultaneous saponification into the desired compound of formula V, which is not isolated.
A further aspect of the present invention is the new quinolinediones of formula ##STR11## wherein
R.sup.3 and X are as hereinbefore defined, and R.sup.1 " represents a hydrogen atom, an alkyl group with 1 to 3 carbon atoms optionally substituted by a phenyl, fluorophenyl, chlorophenyl or bromophenyl group, by a carboxy group or by an alkoxycarboxyl group with 2 to 4 carbon atoms in all, an alkyl group with 4 to 6 carbon atoms, a cycloalkyl group with 3 to 6 carbon atoms, an alkenyl or alkynyl group with 3 to 5 carbon atoms, an alkyl group with 2 or 3 carbon atoms substituted in the 2- or 3-position by a hydroxy, alkoxy or alkylmercapto group, in which the alkoxy or alkylmercapto or alkylmercapto substituent may in each case contain 1 to 3 carbon atoms, or a tetrahydrofurfuryl group and R.sup.4 represents an alkyl group with 1 to 5 carbon atoms, or
R.sup.1 " has the meanings given for R.sup.1 " above with the exception of a hydrogen atom and R.sup.4 represents a hydrogen atom which can be converted directly or after conversion into the corresponding carboxylic acid into a corresponding compound of formula I in which R.sup.1 ", R.sup.3 and X are as hereinbefore defined.
According to the invention the new compounds are obtained by reaction of a cyclohexan -1,3-dione of formula ##STR12## in which X is as defined hereinbefore, with a cyanoacetate of formula ##STR13## wherein
U1represents a hydrogen atom and U.sup.2 together with the hydrogen atom of the neighbouring CH group represents a group of formula ##STR14## or
U1 together with the hydrogen atom of the neighbouring CH group represents a group of formula ##STR15## where
R.sup.3 is as hereinbefore defined and each R.sup.5, which can be identical or different represents an alkyl group with 1 to 5 carbon atoms; reaction of the resulting tetrahydrocumarinone of formula ##STR16## wherein
R.sup.3 and X are as hereinbefore defined and R.sup.5 is as defined above, with an amine of formula ##STR17## wherein
R.sup.1 " is as defined above and, if desired, subsequent hydrolysis of an ester so obtained.
The cyclisation reaction is preferably effected in a solvent such as dimethylformamide, dimethylsulphoxide, dioxan or chloroform, optionally in the presence of a base such as sodium ethoxide, potassium hydroxide, potassium tertbutoxide or sodium hydride, at temperatures between -20.degree. and +50.degree. C., but preferably at ambient temperature.
The subsequent reaction with an amine of formula III is expediently effected in a solvent such as ethanol, dimethylformamide, dimethylsulphoxide, dioxan, chloroform or also in the amine of formula III itself as solvent, at temperatures between 0.degree. and 50.degree. C., preferably at ambient temperature.
The subsequent hydrolysis, whereby a product of formula V or X is obtained, is preferably effected in an aqueous solvent such as ethanol/water, dioxan/water or water, and preferably in the presence of an acid such as hydrochloric or sulphuric acid or in the presence of a base such as sodium hydroxide or potassium hydroxide at elevated temperatures, preferably at the boiling temperature of the reaction mixture.
A compound of formula Ia can particularly advantageously be obtained as characterised in claim 18 from a compound of formula X thus obtained, according to the process c) as described previously.
As already mentioned hereinbefore, the compounds of general formula I have valuable pharmacological properties, particularly antipyretic, analgesic and/or antiphlogistic properties.
For example, the following compounds:
1. The effect on the pain of inflammation in rats was tested using the method of RANDALL and SELITTO (Arch. int. Pharmacodyn. 111, 409 (1957)). The test substances were administered to male rats weighing between 100 and 130 g as a trituration in 1% methylcellulose (1.0 ml/100 g of animal) 90 or 135 minutes after subcutaneous administration of yeast by oesophageal tube. From the pain threshold measured 90 or 45 minutes after administration of the various doses, the ED.sup.50 was determined by linear regression analysis as the dosage which raised the pain threshold by 50%. The following
Table contains the results obtained:
2. The effect on heat-induced pain in mice was investigated using the method of CHEN and BECKMAN (Science 113, 631 (1951). Male mice with an average weight of 20 g were given the test substances as a trituration in 1% methylcellulose (0.1 ml/10 g of animal by oesophageal tube. From the lengthening of the individual reaction time observed after various doses, the ED.sup.100 was calculated by linear regression analysis as the dosage which doubled the reaction time.
The Table which follows contains the results obtained:______________________________________SUBSTANCE ED.sup.100 mg/kg______________________________________A 71B 155C 99D 98E 135F 109G 59H 101I 70______________________________________
3. The effect on mechanically induced pain was investigated by the tail clamp method according to HAFFNER (Dtch. med. Wschr. 54, 731 (1929). Male mice weighing between 19 and 24 g were given the test substances as a trituration in 1% methyl- cellulose (0.1 ml/10 g of animal) by oescophageal tube. At intervals of 30 minutes, the number of mice which no longer reacted to the putting on of the clamp was determined after the treatment.
An ED.sup.50 was calculated by probit analysis from the percentage of animals which showed no pain-reaction after various doses.
The following Table contains the results obtained:______________________________________Substance ED.sup.50 mg/kg______________________________________A 80B 100C 129D 129E 102F 86G 26H 50I 55______________________________________
4. The effect on body temperature was investigated on normothermic rats weighing between 120 and 140 g. The test substances were administered by oesophageal tube as a trituration in 1% methylcellulose (1.0 ml/100 g of animal). From the lowering of rectal temperature observed after various dosages, the ED.sup.-1.5.degree. C. was calculated by linear regression analysis as the dosage which lowered the body temperature by 1.5.degree. C.
The following Table shows the results obtained:______________________________________Substance ED.sup.-1.5.degree. C. mg/kg______________________________________A 29B 35C 26D 25E 34F 36G 11H 36I 22______________________________________
5. The acute toxicity was determined in mice or rats of both sexes with an average weight of 20 g. The test substances were administered by oesophageal tube as a trituration in 1% methylcellulose (0.2 ml/10 g of animal). Wherever possible the LD50 was calculated according to LITCHFIELD and WILCOXON (J. Pharmacol. exp. Therap. 96, 99 (1949)) from the percentage of animals which died within 14 days after receiving various doses.
The following Table shows the results obtained:______________________________________ LD.sup.50 mg/kgSubstance Mouse Rat______________________________________A 767 489B 1220 659C 985 748D -- 1370E 825F 296 396G -- --H -- --I -- --______________________________________
The pharmacological properties found show that the compounds of general formula I are analgesics/anti- pyretics of the same type as aminophenazone. They are therefore suitable for combatting pain such as headache, toothache, menstrual pain, neuralgia, migraine, post-operative and post-traumatic pain, and also for combatting fever and inflammation or cold symptoms. The compounds of general formula I, optionally combined with other active substances, may be formulated with one or more inert carriers and/or diluents, e.g. with water, corn starch, potato starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, hard fat, carboxymethylcellulose or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suppositories, suspensions and solutions. The single dose in adults is 25-1200 mg, conveniently 50-600 mg, but preferably 100 to 300 mg.
Foreign Referenced Citations (1)
| Number |
Date |
Country |
| 76104787 |
Mar 1976 |
JPX |
Non-Patent Literature Citations (3)
| Entry |
| Mosti et al., J. Heterocyclic Chem. 22 1503 (1985). |
| Pettit et al., J. Org. Chem 33(3) 1968, pp. 1089-1092. |
| Ruangsiyanand et al., Chem. Ber. 103 2403-2410 (1970). |
Continuation in Parts (1)
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Number |
Date |
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| Parent |
322602 |
Mar 1989 |
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Patent Grant
5068334
