GB1604085A - Pharmaceutical preparations containing 1,2,4-triazine derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 604 085

e 1 ( 21) Application No 33941/80 ( 22) Filed 16 May 1978 0 ( 62) Divided out of No 1604083 ( 31) Convention Application No 797676 ( 32) Filed 17 May 1977 ( 31) Convention Application No 897803 ( 32) Filed 19 April 1978 in ( 33) United States of America (US) ( 44) Complete Specification published 2 Dec 1981 ( 51) INT CL 3 A 61 K 31/53 ( 52) Index at acceptance A 5 B 180 381 38 Y 420 42 Y 542 54 Y 586 58 Y 650 65 Y H ( 72) Inventors JAMES MICHAEL GULLO WILLIAM PAUL HEILMAN ROBERT JOHN WAYNER and ROBERT EUGENE MOSER ( 54) IMPROVEMENTS IN OR RELATING TO PHARMACEUTICAL PREPARATIONS CONTAINING 1,2,4-TRIAZINE DERIVATIVES ( 71) We, DIAMOND SHAMROCK CORPORATION, of 1100 Superior Avenue, Cleveland, Ohio 44114, United States of America, a corporation organised and existing under the laws of the State of Delaware, United States of America, do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be 5

particularly described in and by the following statement:-

The present invention relates to compositions containing 1,2,4-triazine compounds and, more particularly, certain substituted triazines which exhibit pharmaceutical utility in warm-blooded animals.

Our copending Application 19869/78 (Specification No 1,604,083, discloses 10 and claims novel substituted 1,2,4-triazine compounds, various classes of pharmacologically-active preparations in dosage unit form based upon such compounds and methods of promoting various pharmaceutical effects in nonhuman animals by the administration of the appropriate compounds or compositions based upon them The substituted 1,2,4-triazine compounds, 15 pharmaceutical compositions containing them and such compositions having various pharmacological activities and methods of use of such compounds and compositions disclosed in our aforesaid application comprise compounds of the formula:

R 3 N N R 20 R R wherein:

R 1 represents a hydrazino, N'-(C C 4-alkyl)-hydrazino or NH-NH-N-C-R 4 group, where R 4 is a C,-C 8-alkyl, C 2-C 8-alkenyl, halo-(C,-Cs-alkyl), halo-(C 2 25 2 C 8-alkenyl), C 6-C,0-cycloalkyl or 25 -CH-NHZ Rs 2 1,604,085 2 group, Rs being a hydrogen atom or a C C 4-alkyl or benzyl group and Z being a hydrogen atom or a benzyloxy-carbonyl group, or R 1 represents a hydroxy-(C 1 C 4-alkyl)-amino, N (C,-C 2 alkyl) N (hydroxy C,-C 4 alkyl) amino, C 1-C,0-alkoxy, C 6-CW 0-aryloxy, C 3-C 6cycloalkoxy, phenylalkoxy, allyloxy, halophenoxy, C,-C 4-alkylphenoxy, C,C 4 5 alkoxyphenoxy, C,-C,0-alkylthio, C 3-C 6-cycloalkylthio, C 1-C 4alkylsulphinyl, C,-C 4-alkylsulphonyl, phenyl-(C, C 4-alkyl)-thio, cis-dimethylpyrrolidyl or pyridyl group; R 2 represents a hydrogen atom or a C,-C 4-alkyl, C 3-C 6-cycloalkyl, adamantyl, furyl, thienyl, benzofuryl, indolyl, pyridyl, halothienyl or phenyl group 10 or a phenyl group substituted with at least one substituent selected from halogen, C,-C,-alkyl, halo-(C, Ca-alkyl), C,-C,-alkoxy, acetamido, benzyloxy, diphenylmethyl, morpholino, methylenedioxy and nitro substituents; and R 3 represents a hydrogen atom or a C,-C 6-alkyl, pyridyl, furyl or phenyl group or a phenyl group substituted with at least one substituent selected from 15 halogen, C,-C -alkyl, C 1-C 8-alkoxy, methylenedioxy and acetamido substituents; subject to the provisos that; (i) when R 2 is a hydrogen atom, R 3 is also a hydrogen atom; (ii) when R, is a phenylalkylthio, alkoxy, alkylthio, cycloalkylthio 20 cycloalkoxy or phenylalkoxy group, R 2 and R 3 are not selected from halophenyl, C,-C -alkylphenyl and C,-C 3-alkoxyphenyl groups; (ill) when R, is a dimethylpyrolidyl, hydroxyalkylamino or N (C,-C 2 alkyl) N (hydroxy C,-C 4 alkyl) amino group, R 2 and R 3 are not both halophenyl, both C,-C 3-alkylphenyl or both C,-C 3-alkoxyphenyl groups: 25 (iv) when R, is a hydrazino, alkylthio, methoxy or ethoxy group, R 2 is other than a phenyl group and R 2 and R 3 are not both methyl groups; (v) when R, is a hydrazino or N'-(C C 4-alkyl)-hydrazino group, R 2 is other than a C,-C 4-alkyl group; and (vi) when R, is an alkoxy group, R 2 is other than a pyridyl group; and the 30 pharmaceutically-acceptable salts thereof.

This application discloses matter divided out of the aforesaid application and

Claims (4)

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 35 previously been prepared and suggested for use in various applications and our 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 incorporated in the compositions on which the present invention is based 40 According to the present invention, a pharmaceutical preparation in dosage unit form is provided, comprising, per dosage unit, an amount within the range from I to 300 milligrams of at least one compound of the formula: COH wherein: 45 R represents a C,-C 4-alkyl, phenyl or halo-(C, C 4-alkyl)phenyl group; 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 a central nervous system effect in a non-human animal, which comprises administering thereto a 50 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 of the present invention, for instance, to alter solubility properties or augment bioavailability The criteria for selecting and 55 methods for preparing salts 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 60 those salts capable of being formed with the basic triazine compounds without materially altering the chemical structure or pharmacological properties of the parent triazine compounds. The active compounds present in the compositions of the present invention may possess anti-inflammatory, anti-pyretic, analgesic and antihypertensive effects, as well as central nervous system (e g, hypnotic, sedative, antidepressant, 5 muscle relaxant, spasmolytic and tranquilizing) 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 regimen and mode of administration, as well as the mammalian species involved 10 The compositions are pharmaceutical preparations in dosage unit form, comprising per dosage unit from I 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, the preparations are formulated for oral administration 15 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 intended route of administration and conventional pharmaceutical practices For example, for 20 oral administration in the form of tablets or capsules, the active compound of 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 preselected active compounds in combination with suitable non-toxic solvents, flavourings, colouring 25 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 appropriate solutes to provide isotonicity, may be employed Other adjuvants and dosage forms will be apparent 30 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 responses, generally range from 1 to 300 mg/kg/day in laboratory mice based upon 35 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 responsiveness of the particular animal species under consideration 40 The compounds used in compositions of the invention exhibit relatively low toxicities and the LD 50 (lethal dose to 50 percent of mice treated intraperitoneally) generally is greater than 300 mg/kg. The following compound was prepared using the synthesis procedures elaborated in the aforesaid copending application 45 Example 3-hydroxy-5-phenyl 1,2,4-triazine m p -2350-2370 C While the invention as been described and illustrated with reference to certain preferred embodiments thereof, those skilled in the art will appreciate that various changes, modifications, and substitutions can be made therein For 50 example, effective dosages other than the preferred ranges set forth hereinabove may be applicable as a consequence of variations in the responsivess of the mammal treated, severity of observed conditions, dosage-related adverse effects, if any, observed and analogous considerations Likewise, the specific pharmacological responses observed may vary depending upon the particular 55 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 variations or differences in results are contempated in accordance with the present invention 60 WHAT WE CLAIM IS:1 A pharmaceutical preparation in dosage unit form, for administration to obtain a central nervous system effect, comprising, per dosage unit, an amount within the range from 1 to 300 milligrams of at least one compound of the formula:

1,604,085 NN R N OH wherein:

R represents a C,-C 4-alkyl, phenyl or halo-(C,-C 4-alkyl)phenyl group: or at least one pharmaceutically-acceptable acid addition salt of a compound of the formula: and a pharmaceutical carrier 5

2 A composition according to claim 1, substantially as hereinbefore described.

3 A method of promoting a central nervous system effect in a non-human animal, which comprises administering thereto a therapeuticallysufficient amount of at least one composition according to claim I or 2.

4 A method as claimed in claim 3, wherein the therapeutically-sufficient 10 amount ranges from 1 to 300 mg/Kg/day.

A method as claimed in claim 4, 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, 53/54 High Holborn, London, WC 1 V 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.

1,604,085