no claim is made herein to any compound, composition or method which is
claimed in the aforesaid application.
Substituted 1,2,4-triazine compounds having various substituents have previously been prepared and suggested for use in various applications and our 35 aforesaid application refers to many previous publications in this connection.
These prior publications include disclosures of methods of synthesis of 1, 2,4triazines, which can also be used in appropriate ways to make the compounds included in compositions on which the present invention is based.
According to the present invention, a pharmaceutical preparation in dosage 40 unit form is provided, comprising, per dosage unit, an amount within the range from 1 to 300 milligrams of at least one compound of the formula:
R 3 R 2 wherein:
R, represents a hydrazino, N' (C,-C 4-alkyl)-hydrazino or 45 0 II -NH-NH C-R 4 group, where R 4 is a C,-C 8-alkyl, C C 8-alkenyl, halo-(C,-C 8-alkyl), halo-(C 2C 8)-alkenyl, C 6-C,0-cycloalkyl or -CH-NH 2 I R 5 group, Rs being a hydrogen atom or a C 1-C 4-alkyl or benzyl group, or an N 50 aminocarbobenzyloxy derivative thereof; or 1,604,084 R 1 represents a hydroxy-(C,-C 4-alkyl)-amino, N-(C,-C 2 alkyl) N(hydroxy C,-C 4 alkyl) amino, C,-C,0-alkoxy, phenoxy, C,-C 4alkylphenoxy, C C 4-alkoxyphenoxy, C,-C,0-alkylthio or phenyl-(C, 4-alkyl) thio group; R 2 represents a hydrogen atom or a C,-C 4-alkyl, C 3-C,-cycloalkyl, naphthyl, 5 furyl, adamantyl, thienyl, benzofuryl, indolyl, pyridyl or phenyl group or a phenyl group substituted with at least one substituent selected from a halogen atom or a C,-C 4-alkyl, halo-(C,-C 5)-alkyl, C,-C-alkoxy, acetamido, methylenedioxy, morpholino or nitro group; and R 3 represents a hydrogen atom or a C,-C,-alkyl, phenyl or pyridyl group or a 10 phenyl group substituted with at least one substituent selected from halogen, C,C 4-alkyl, C,-C 6-alkoxy and acetamido substituents; subject to the provisos that:
(i) when R 2 is a hydrogen atom, R 3 is also a hydrogen atom and (ii) when R, is a hydroxyalkylamino or X-R 6 group (wherein X=O or S and R, is a C,-C 8-alkyl, C 7-C 8-aralkyl, C 3-C-cycloalkyl or C 4-C 8cycloalkyl-alkyl 15 group), R 2 and R 3 are not both halophenyl, both C,-C 3-alkylphenyl or both C,C 3-alkoxy-phenyl groups; or at least one pharmaceutically-acceptable acid addition salt of a compound of the formula; and a pharmaceutical carrier.
The present invention also consists in a method of promoting an antiinflammatory effect in a non-human animal, which comprises administering 20 thereto a therapeutically-sufficient amount of a composition as just defined above.
Where necessary or desirable, the pharmaceutically or physiologically acceptable inorganic and organic acid addition salts of certain of the compounds may be employed in the compositions, for instance, to alter solubility properties or augment bioavailability The criteria for selecting and methods for preparing salts 25 suitable for administration are well known to those skilled in the art.
Representative of acids for reaction with the sufficiently basic triazine compounds to form acceptable acid addition salts include hydrochloric, hydrobromic, hydroiodic, nitric, phosphoric, sulphuric, tartaric and citric The expression "pharmaceutically acceptable" as used herein is intended to include those salts 30 capable of being formed with the basic triazine compounds without materially altering the chemical structure or pharmacological properties of the parent triazine compounds Additionally, compounds utilizable in compositions of the invention and containing amino acid residues, i e, an a-amino acyl group, may be obtained as their hydrate salt form, such as mono or di-hydrobromide or 35 hydrochloride hydrate and such compounds constitute particularly advantageous water-soluble 1,2,4-triazine derivatives utilizable in the compositions of the invention.
The synthesis methods described in the aforesaid application and applicable to the preparation of compounds for use in the compositions disclosed herein, in 40 certain instances, result in the preparation of mixtures of triazine isomers, e g, 5,6position isomers which can be separated by employing conventional crystallization or chromatographic techniques.
The active compounds utilizable in the compositions of the present invention may possess anti-pyretic, analgesic, antihypertensive and central nervous system 45 (e.g hypnotic, sedative, antidepressant, muscle relaxant, spasmolytic and tranquilizing) effects, as well as anti-inflammatory effects Of course, it will be appreciated that the specific response elicited upon administration of the compositions of the present invention to an animal species will vary depending upon the specific structure of the administered compound, the unit dose, dosage 50 regimen and mode of administration, as well as the mammalian species involved.
The compositions are pharmaceutical preparations in dosage unit form, comprising per dosage unit from 1 to 300 milligrams of at least one active compound, together with a pharmaceutical carrier Such preparations are preferably administered in an amount of 25 to 200 mg/Kg/day and, most preferably, 55 the preparations are formulated for oral administration.
In accordance with the present invention, the active compounds may be administered alone or in combination with each other, as compositions in which the active compound or compounds is/are in admixture with pharmaceutical diluents, carriers, excipients or adjuvants suitably selected with respect to the 60 intended route of administration and conventional pharmaceutical practices For example, for oral administration in the form of tablets or capsules, the active compound or compounds may be combined with conventional excipients, such as starch, lactose, sucrose, cellulose, talc, magnesium stearate, acacia and stearic acid Likewise, appropriate elixirs or suspensions may be formulated with 65 1,604084 preselected active compounds in combination with suitable non-toxic solvents, flavourings, colouring agents, suspending agents and emulsifiers Similarly, injectable dosage unit forms may be made up for intravenous, intramuscular or subcutaneous administration and, for such parenteral administration, suitable sterile aqueous or nonaqueous solutions or suspensions, optionally containing 5 appropriate solutes to provide isotonicity, may be employed Other adjuvants and dosage forms will be apparent to those skilled in the art.
Compositions of the invention may be administered to warm-blooded animals, i.e, mammals, including, for instance, mice, rats, guinea pigs, dogs and other domesticated animals, or humans Dosages sufficient to elicit the aboveindicated 10 responses generally range from I to 300 mg/kg/day in laboratory mice based upon body weight, and preferably, from 25 to 200 mg/kg/day The foregoing dosages are normally administered in three or four divided doses, depending upon the desired dosage regimen Of course, the actual effective dosage to be administered will vary depending upon the specific compound involved as well as the age, weight and 15 responsiveness of the particular animal species under consideration.
The compounds used in compositions of the invention exhibit relatively low toxicities and the L Dso (lethal dose to 50 percent of mice treated intraperitoneally) generally is greater than 300 mg/kg.
In order that the invention may be readily understood, the following Examples 20 are given of compounds which can be used in compositions according to this invention.
EXAMPLE I Preparation of 3-Methylthio-5-phenyl-1,2,4-triazine Into, a 1000 ml flask equipped with a magnetic stirrer, heating mantle and 25 condenser, S-methylthiosemicarbazide hydrogen iodide ( 170 1 g, 0 73 m), 430 ml ethanol, phenylglyoxal ( 95 6 g, 0 72 m) and pyridine ( 59 2 g, 0 75 m) were introduced The contents were heated under reflux for 2 hours and the ethanol was recovered under vacuum The resulting material was extracted with hexane to yield 3 methylthio 5 phenyl 1,2,4 triazine ( 109 7 g-74 9 %), m p99 0-100 C 30 Analysis calculated for C^He N 3 S (percent): C, 59 09; H, 4 46; N, 20 67 Found (percent): C, 59 58; H, 4 65; N, 20 91 To minimize formation of the 6-phenyl isomer and further optimize yield of the desired cyclic material, phenylglyoxal hydrate can be utilized in lieu of phenyl 35 glyoxal in the foregoing synthesis.
EXAMPLE 2 Preparation of 3-Methoxy-5-phenyl- 11,2,4-triazine Into a 2000 ml flask equipped with a magnetic stirrer and condenser, methanol ( 1100 ml) and sodium ( 7 4 g, 0 32 g Jatm) were introduced After the sodium had reacted, 3 methylthio 5 phenyl 1,2,4 triazine ( 61 0 g, 0 3 m) was added and 40 the contents were warmed to 40 C with a hot water-bath After dissolution of the foregoing, the bath was removed and the contents were allowed to stir at room temperature for 18 hours Then CO 2 gas was passed into the flask for 30 minutes.
The precipitated material was filtered off and discarded The filtrate was evaporated under vacuum The remaining material was extracted with chloroform 45 and the chloroform solution was evaporated under vacuum The remaining material was then extracted with hexane From the hexane solution, 53 5 g ( 95 3 %n yield) of 3 methoxy 5 phenyl 1,2,4 triazine, m p 73 -74 C was obtained.
Analysis calculated for Co H 9 N 30 (percent): C, 64 16; H, 4 85; N, 22 45 Found (percent): C, 63 72; H, 4 90; N, 22 44 50 EXAMPLE 3 Preparation of 3-Hydrazino-5-phenyl-l,2,4-triazine Into a 500 ml flask equipped with a magnetic stirrer, heating mantle and condenser, 3 methoxy 5 phenyl 1,2,4 triazine ( 37 4 g, 0 2 m), 100 ml of tetrahydrofuran, 95 % hydrazine ( 7 4 g, 0 22 m) and 20 ml of absolute methanol 55 were introduced The contents were heated under reflux for 3 5 hours and then poured into cold water The precipitated material was filtered off, waterwashed.
air-dried and crystallized from 250 ml of methanol 18 0 g ( 480 % yield) of 3 hydrazino 5 phenyl 1,2,4 triazine, m p 144 0-146 C was obtained.
1.604 084 Analysis calculated for C Hg N 5 (percent): C, 57 74; H,4 85; N, 37 41 Found(percent): C, 57 34; H, 4 87; N, 37 17 EXAMPLE 4 Preparation of 3-Hydrazino-5-t-butyl-1,2,4-triazine Into a 250 ml flask equipped with a magnetic stirrer, heating mantle and 5 condenser, 3 methylthio 5 t butyl 1,2,4 triazine ( 18 3 g, 0 1 m), 100 ml of tetrahydrofuran, 95 % hydrazine ( 3 9 g, 0 11 m) and 10 ml of absolute methanol were introduced The contents were heated under reflux for 7 5 hours, cooled and the solvents were removed under vacuum The resulting material was crystallized from 7 5 litres of hexane14 1 g ( 84 3 % yield) of 3hydrazino5 t butyl 10 1,2,4 triazine, m p 117 -118 C was obtained.
Analysis calculated for C 7 H,3 Ns (percent): C, 50 28; H, 7 84; N, 41 89 Found(percent): C, 49 88: H, 7 73; N, 41 46 EXAMPLE 5 Preparation of 3-Methylthio-5,6-dimethyl-l,2,4-triazine 15 Into a suitably equipped 2000 ml flask, S-methylthiosemicarbazide hydrogen iodide ( 222 4 g, 0 954 m) and 700 ml of ethanol were introduced, which were heated to 60 C A mixture of diacetyl ( 82 1 g, 0 954 m) and pyridine ( 75 9 g, 0 96 m) was added to the flask over 15 minutes The contents were heated under reflux for 2 hours and the ethanol was distilled off About 1200 ml of water was added to the 20 flask and the resulting mixture was extracted with chloroform.
The chloroform was evaporated under vacuum and the resulting oil was placed in a 200 ml flask for vacuum distillation 105 5 g ( 71 2 % yield) of 3 methylthio 5,6 dimethyl 1,2,4 triazine, b p 100 -102 C at 0 1 mm Hg, was obtained.
Analysis calculated for C 5 Hg N 3 S (percent): C, 46 42; H, 5 84; N, 27 07 25 Found(percent): C, 47 03; H, 6 12; N, 26 18 The following compounds were prepared using the synthesis procedures elaborated in the aforesaid copending application.
EXAMPLE 6 3 ethoxy 5 phenyl 1,2,4 traizine m p 48 -49 C 30 EXAMPLE 7 3 methoxy 5 ( 2 'naphthyl) 1,2,4 triazine m p130 -131 C.
EXAMPLE 8 3 methoxy 5,6 dimethyl 1,2,4 triazine, b p 55 -57 C at 0 05 mm.
EXAMPLE 9 35 3 hydrazino 5,6 dimethyl 1,2,4 triazine, m p 126 0-127 C.
EXAMPLE 10 3 methoxy 5,6 di( 2 'pyridyl) 1,2,4 triazine, m p 132 -133 C.
EXAMPLE 11 3 methoxy 5 ( 1 'naphthyl) 1,2,4 triazine, m p76 0-77 C 40 EXAMPLE 12 3 methoxy 5 ( 2 'naphthyl) 1,2,4 triazine, m p130 -131 C.
EXAMPLE 13 3 methoxy 5,6 diphenyl 1,2,4 triazine, m p78 -79 C.
EXAMPLE 14 45 3 ethoxy 5,6 diphenyl 1,2,4 triazine, m p 73 0-74 C.
EXAMPLE 15 3 methylthio 5 ( 1 'naphthyl) 1,2,4 triazine, m p116 5 118 C.
EXAMPLE 16 3 methoxy 5 phenyl 6 methyl 1,2,4 triazine, m p72 0-74 C 50 1.604084 - -_S O oz EXAMPLE 17 3 N nonylthio 5 phenyl 1,2,4 triazine, m p47 -49 C.
Pharmacological Activity Studies conducted with some of the above compounds utilizable in the compositions of the present invention, by the methods detailed in the aforesaid 5 copending application, gave the following results.
A Anti-inflammatory Assay-Carrageenin Assay Compound Example No Dose (mg/Kg) % Reduction of Oedema 7 200 7 10 11 200 22 B Analgesic Assay-Phenylquinone Writhing Assay (% Control) Compound 1 5 Example No Dose (mg/Kg) 15 min 30 min 60 min 7 100 20 10 10 15 11 100 10 11 50 10 11 30 10 100 10 20 While the invention has been described and illustrated with reference to 20 certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein For example, effective dosages other than the preferred range set forth hereinabove may be applicable as a consequence of variations in the responsiveness of the mammal treated, severity of observed conditions, dosage-related adverse effects, if 25 any, observed and analogous considerations Likewise, the specific pharmacological responses observed may vary depending upon the particular active compound selected or whether different active compounds are used in combination, in the presence of suitable pharmaceutical carriers, as well as the type of formulation and mode of administration employed and such expected 30 variations or differences in results are contemplated in accordance with the present invention.
Subject to the Foregoing Disclaimer, WHAT WE CLAIM IS:1 A pharmaceutical preparation in dosage unit form, for administration to 35 obtain an anti-inflammatory effect, comprising, per dosage unit, an amount within the range from I to 300 milligrams of at least one compound of the formula:
R 3 o'N 1 R wherein:
R, represents a hydrazino, N' (C 1 C 4-alkyl)-hydrazino or 40 O II -NH-NH-C-R 4 group, where R 4 is a C 1-C 8-alkyl, C 2-C 8-alkenyl, halo-(C C 8-alkyl), halo-(C 2C 8)-alkenyl, C C,0-cycloalkyl or -CH-NH 2 R, 4 5 group R being a hydrogen atom or a C 1-C 4-alkyl or benzyl group, or an N 45 aminocarbobenzyloxy derivative thereof; or 1 6 C M fl R R 1 represents a hydroxy-(C, C 4-alkyl)-amino, N (C 1-C 2 alkyl) N(hydroxy C C 4 alkyl)-amino, C 1-C,0-alkoxy, phenoxy, C 1-C 4alkylphenoxy, C,-C 4-alkoxyphenoxy, C,-C,0-alkylthio or phenyl-(C,-C 4alkyl)thio group; R 2 represents a hydrogen atom or a C,-C 4-alkyl, C 3-C 6-cycloalkyl, naphthyl, 5 furyl, adamantyl, thienyl, benzofuryl, indolyl, pyridyl or phenyl group or a phenyl group substituted with at least one substituent selected from a halogen atom or a C,-C 4-alkyl, halo-(C, C 6)-alkyl, C 1-C 6-alkoxy, acetamido, methylenedioxy, morpholino or nitro group; and IQ R 3 represents a hydrogen atom or a C,-C 6-alkyl, phenyl or pyridyl group or a 10 phenyl group substituted with at least one substituent selected from halogen, C,C 4-alkyl, C,-C 6-alkoxy and acetamido substituents; subject to the provisos that:
(i) when R 2 is a hydrogen atom, R 3 is also a hydrogen atom and (ii) when R, is a hydroxyalkylamino or X-R 6 group (wherein X=O or S and R 6 is a C 1-C 8-alkyl, C 7-C 8-aralkyl, C 3-C 8-cycloalkyl or C 4 C 8cycloalkyl-alkyl 15 group), R 2 and R 3 are not both halophenyl, both C,-C 3-alkylphenyl or both C 1C 3-alkoxy-phenyl groups; or at least one pharmaceutically-acceptable acid addition salt of a compound of the formula; and a pharmaceutical carrier.
2 A pharmaceutical preparation in dosage unit form as claimed in claim 1, formulated for oral administration 20 3 A pharmaceutical preparation in dosage unit form as claimed in claim I or 2, wherein the one or more compounds are selected from 3 hydrazino 5 phenyl 1,2,4 triazine, 3 methoxy 5 phenyl 1,2,4 triazine, 3 hydrazino 5,6 dimethyl 1,2,4 triazine, 3 methoxy 5,6 diphenyl 1,2,4 triazine, 3 hydrazino 5 t butyl 1,2,4 triazine, 3 methylthio 5 25 phenyl 1,2,4 triazine, 3 methoxy 5 ( 2 'naphthyl) 1,2,4 triazine, 3 methylthio 5 ( 3 ',4 'dimethoxyphenyl) 1,2,4 triazine, 3 methoxy 5 ( 3 ',4 'dimethoxy phenyl) 1,2,4 triazine, 3 ethoxy 5 phenyl 1,2,4 triazine, 3 methylthio 5,6 dimethyl 1,2,4 triazine, 3 methoxy 516 dimethyl 1,2,4 triazine, 3 methoxy 5,6 di( 2 'pyridyl) 1,2,4 triazine, 30 3 ethoxy 5,6 diphenyl 1,2,4 triazine, 3 methoxy 5 phenyl 6 methyl 1,2,4 triazine, 3 N nonylthio 5 phenyl 1,2,4 triazine, 3 methoxy 5 ( 2 'naphthyl) 1,2,4 triazine, 3methoxy 5 ( 1 'naphthyl) 1,2,4 triazine and 3 methylthio 5 ( 1 'naphthyl) 1,2,4 triazine.
4 A pharmaceutical preparation according to any of claims I to 3, 35 substantially as hereinbefore described.
A method of promoting an anti-inflammatory effect in a non-human animal, which comprises administering thereto a therapeutically-sufficient amount of a preparation according to any preceding claim.
6 A method as claimed in claim 5, wherein the therapeutically-sufficient 40 amount ranges from I to 300 mg/Kg/day.
7 A method as claimed in claim 6, wherein the therapeutically-sufficient amount ranges from 25 to 200 mg/Kg/day.
POLLAK, MERCER & TENCH, Chartered Patent Agents, Eastcheap House, Central Approach, Letchworth, Hertfordshire SG 6 3 DS and High Holborn House, 52/54, High Holborn, London WCIV 6 RY.
Agents for the Applicants.
Printed for Her Majesty's Stationery Office, by the Courier Press, Leamington Spa, 1981 Published by The Patent Office, 25 Southampton Buildings, London WC 2 A l AY, from which copies may be obtained.
1,604,084