IL37850A - 2-(p-phenylbenzyl)-oxazolines,their preparation and pharmaceutical compositions containing them - Google Patents

Description

οΓ ap present invention relates to agents and is more particularly concerned with certain oxazolines which possess a high degree of compositions to alleviate inflammation and symptoms thereof in a living animal than The agents of the present invention are preferably compounds having the Formula I and are and is hydrogen and and is chlorine and methyl the structural formula given the asterisks serve to point out the asymmetric carbon present in many of the compounds of the present for when and R2 are When two asymmetric are pairs of diastereoisomers are These together with their optically active are included within novel compounds of the present invention at Jl6 reduced the response to pleural The inflammatory action of the novel compounds was demonstrated using a modification of the Evans Pleural Effusion test Journal of Pharmacology and mental Therapeutics The potency of the most active compounds are set forth in Table The potencies were determined relative to the standard inflammatory I Potency of Oxazolines Relative to Phenylbutazone Example Potency Confidence Limits Phenylbutazone 1 1 7 12 The data was obtained using doses of 10 and 2 per TABLE II of oxazolines in the Evans pleural effusion Reduction 6 8 9 5 10 10 50 11 316 23 It an object of the present invention to provide novel compounds which have a high degree of inflammatory An additional object is the provision of compounds having activity and which produce minimal side object is to provide certain novel A still further object is to provide therapeutic compositions oontaining the same and methods for the utilization Other objects of this invention will be apparent to one skilled in the art and still other objects will become apparent In the definition of symbols in the foregoing Formula I and where they appear elsewhere throughout this terms have the following term as used herein includes straight and branched chain radicals of up to eight carbon atoms inclusive and is exemplified by such groups as tertiary and the The acids starting materials and the aminoalcohols used in the present invention are either commercially available or they can be prepared by methods well to the Method of Preparation The preparation of the may be accomplished by mixing and reacting a acid with an aminoalcohol The reaction sequence is illustrated by the wherein R R and R have the values given A general procedure for the preparation of the stirred mixture of one part of a acid one and parts of an and 500 parte of a water immiscible organic solvent such as phenyl ether and the like is refluxed in a system containing a water trap for a period of from about four hours to about four days during which period the water formed during the reaction is separated in the After the theoretical amount of water has the hot reaction mixture is filtered and the oxazoline is isolated from the filtrate by a suitable When at least one of the substituents in the of the oxazoline ring is the product separates from the cooled filtrate as a crystalline When one or both substituents in the are the product is usually a low melting solid which is isolated by concentration of the filtrate and distillation in vacuo of the residue to give the oxazoline which crystallizes on Optically active oxazolines are readily prepared as described hereinabove by using optically active aminoalcohols as starting Examples 8 and 9 Table III were prepared using optically active oxazolines can also be prepared by cyclization of acetamides in a dehydrating medium as described The acetamides which are usually crystalline solids are prepared by reacting coh ls in a suitable following examples are given by way of illustration and are not Example 1 z line A solution of of acid and of in 600 of xylene was refluxed overnight using a trap during which time the theoretical amount of water The reaction mixture was filtered while hot and the filtrate was cooled to room The white crystals which formed on standing were separated by filtration and washed with water on the filter until the filtrate was of neutral lization of the solid from xylene gave product which melted at Calculated for Found 2 A solution of of acid and of lamine in of xylene was refluxed 12 hours using a The hot reaction mixture was filtered and the product which separated from the cooled filtrate was collected and washed with water until the washings were The white crystalline product was recrystallized from to give 6 of product which melted at Calculated for Pound Example h ine Using the procedure of Example acid and were reacted together in refluxing xylene to give oxazoline in Calculated for Found Example 4 oxazoline Using the procedure of Example phenylacetic acid and were reacted together in refluxing xylene to give a yield of which melted at Calculated for Found Example 5 Using the procedure of Example acid and are reacted together in refluxing xylene to give Examples Examples were prepared using the procedure of Example The physical data are summarized in Table TABLE III Analysis C H N ample R Found Found Found 6 CH3 CHs H 7 CH3 H H H H H H 98 CHa H H H 10 H H H 11 H H H 12 CH3 CHs CH3 H 15 H CHs H 14 OH CHs CHs H 15 OH CHs H 16 CHs H H 17 CHs CHs H 18 CHs CHs H Example 19 in the procedure of Example there is substituted acid an equivalent amount of the followingi and there are obtained and Formulation and Administration present invention also contemplates novel compositions containing the compounds of the invention as active In forming the novel compositions of this the active ingredient is incorporated in a suitable a pharmaceutical Suitable pharmaceutical carriers which are useful in formulating the compositions of this invention include magnesium malt and the Liquid compositions are also within the purview of this invention and suitable liquid pharmaceutical carriers include ethyl propylene glucose syrup and the Although small quantities of the active materials of the present invention are effective when minor therapy is involved or in cases of administration to subjects having a relatively low body unit dosages are fifty or one hundred milligrams Fifty to 100 milligrams appear to be optimum per unit while usual broader ranges appear to be to 300 milligrams per unit The following are examples of compositions formed in accordance with this Capsules Capsules of of active ingredient per capsule are Typical Blend for Encapsulation Per Active ingredient Lactose Magnesium stearate Total capsule formulations preferably contain a higher dosage of active ingredient and are as ingredients 100 per Capsule Active ingredient 100 Lactose Starch 99 Magnesium stearate each uniformly blend the selected ingredient and magnesium stearate and encapsulate the Tablets A typical formulation for a tablet containing of active ingredient per tablet The formulation may be used for other strengths of active ingredient by adjustment of weight of dicalcium Per Active ingredient Milo starch Corn starch Lactose Calcium stearate Total Uniformly blend the active milo starch and the corn This blend is granulated using water as a granulating The wet granules are passed through an eight mesh screen and dried at l0 to l60 degrees Fahrenheit The dried granules are passed through a number ten mesh screen and blended with the proper amount of calcium stearate and this blend is then converted into tablets on a suitable tablet 100 Tablet Per Active ingredient Lactose phosphate Starch Milo starch Calcium stearate Total Uniformly blend the active dicalcium starch and This blend is granulated with water and the wet mass is passed through a number eight mesh The wet granules are dried at ΐ degrees Fahrenheit The dried granules are passed through a number ten mesh These dried granules are blended with the proper weight of calcium stearate and the lubricated granules are then converted into tablets on a suitable tablet press Various and equivalents will be apparent to one skilled in the art and may be made in the and procedures of the present invention without departing from the spirit or scope and it is therefore to be understood that the invention is to be limited only by the scope of the appended insufficientOCRQuality

Claims (1)

1. AHR-210 eip What we claim is: — 1 - A compound selected from 2-(p-phenylbenzyl )oxazolines having the formula: wherein; 1 R and R are each selected from the group consisting of hydrogen, lower-alkyl and hydroxylower-alkyl, 3 R is selected from the group consisting of hydrogen and lower-alkyl, and R4 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and trifluoromethyl . - 2 - A compound as defined in Claim 1 which is 2-(p-phenylbenzyl) 4-hydroxymethyl- -methyloxazoline. - 3 - A compound as defined in Claim 1 which is 2-(p-phenylbenzyl) -methyloxazo1ine . - H — A compound as defined in Claim 1 which is 2-(p-phenylbenzyl) 4,4-dimethyloxazoline . - 5 - A compound as defined in Claim 1 which is 2-£p-phenyl-(a- methyl)benzyl]- , Ij-dimethyloxazoline . AHR-210-CIP - 6 - A compound as defined in Claim 1 which is 2-[p-phenyl-(a-methyl)benzyl]- -methyloxyazoline. - 7 - A process for the preparation of 2-(p-phenylbenzyl) oxazolines having the formula: \ wherein; R1 and R2 are each selected from the group consisting of hydrogen, lower-alkyl and hydroxylower-alk 1, R3 is selected from the group consisting of hydrogen and lower-alkyl, and R4 is selected from the group consisting of hydrogen, fluorine, chlorine, bromine and trifluoromethyl, which comprises mixing and reacting together a p-phenyl-phenylacetic acid of the formula: wherein R and R are as defined above with an aminoalcohol of the formula: -HaN-CRXR2-CBfeOH wherein R1 and R2 are as defined above in a procedure so as to eliminate two molecules of water and form the oxazoline ring. AHR-210-CIP if - 8 - A process as defined in Claim 7 wherein the reaction is ^carried out .in a water immiscible solvent. - 9 - A process as defined in Claim 8 wherein the reaction is carried out at the reflux temperature of the water immiscible solvent . - 10 - other than A method of alleviating inflammation in a living animaV humans 'which comprises administering to said animal an effective amount of a compound selected from the group consisting of anti¬ inflammatory active oxazolines having the formula: wherein; R1 and R2 are each selected from the group consisting of hydrogen, lower-alkyl and hydroxy lower-alkyl, R3 is selected from the group consisting of hydrogen and lower-alkyl , and R4 is selected from the group consisting of hydrogen, fluorine, bromine, chlorine and trifluoromethyl . - 11 - A method as defined in claim 10, wherein the active anti¬ inflammatory agent is administered together with a pharmaceuti¬ cally acceptable carrier and in amounts of about 50 to 300 milligrams . AHR-210-CIP - 12 - aJhe method of Claim 11 wherein the active anti- inflammatory agent is 2-(p-phenylbenzyl) - -hydroxymethyl- -methyl oxazoline . - 15 - - The method of claim 11 wherein the active anti- inflammatory agent is 2-(p-phenylbenzyl)- -methyloxazoline . - 14 - The method of Claim 11 wherein the active agent is 2-( p-phenylbenzyl)-4, -dimethyloxazoline . - 15 - Hie method of Claim 11 wherein the active agent is 2-[p-phenyl-(a-methylbenzyl]- , 4-dimethyloxazoline . - 16 - The method of Claim 11 wherein the active agent is 2-[p-phenyl- (a-me thyl) benzyl ]-4-methyloxazol ine . - 17 - A therapeutic composition suitable for the alleviation of inflammation comprising ( 1) an effective amount of about 50 to 00 milligrams of an anti- inflammatory active compound selected from the group consisting of oxazolines having the formula : wherein; R1 and R2 are each selected from the group consisting of lower-alkyl and hydroxy lower-alkyl, Rs is selected from the group consisting of hydrogen and AHR-210-CIP R is selected from the group of hydrogen, fluorine, bromine, chlorine and trifluoromethyl, and (2) a pharmaceutically acceptable carrier therefor. - 18 - A -composition as defined in claim 17 wherein the active anti-inflammatory agent is 2-( p-phenylbenzyl)-4-hydroxymethyl-4-methyloxazoline . - 19 - A composition as defined in Claim 17 wherein the active anti-inflammatory agent is 2-(p-phenylbenzyl) -4-methyloxazoline. - 20 - A composition as defined in Claim 17 wherein the active anti-inflammatory agent is 2-(p-phenylbenzyl) -4 , 4-dimethyl-oxazoline. - 21 - A composition as defined in Claim 17 wherein the active anti-inflammatory agent is 2-[p-phenyl-(a-raethyl)benzyl]- 4, 4-dimethyloxazoline . - 22 - A composition as defined in claim 17, wherein the active anti-inflammatory agent is 2-[p-phenyl-(a-methyl)benzyl]-4-methyloxazoline . For the Applicants DR. RtlKKOLD COHtTAND PARTNERS,