DE2151799A1 - 2- (p-Phenylbenzyl) oxazolines and processes for their preparation - Google Patents

Description

DR. E. WIEGAND DIPL-ING. W. NIEMANN 2151799 DR. M. KÖHLER DIPL-ING. C. GERNHARDT MÖNCHEN HAMBURG TELEPHONE: 55547 «8000 MÖNCH EN 15, TELEGRAMS: KARPATENT NUSSBAUMSTRASSE 10

18 »October 1971 W 40 719/71

A. H. Robins Company, Incorporated, Richmond, Virginia (V.St.A.)

2- (p-Phenylbenzyl) oxazolines and processes for their preparation

The invention relates to anti-inflammatory (anti-inflammatory) agents; more particularly relates to certain 2 ~ (p-3? henylb <? nzyl) OXR. · Zoline, which have a high anti-inflammatory activity, a process for their preparation, to drive these oxazolines therapeutic preparations contained as an active ingredient and an Ver · to Verv7endung of these compounds and preparations for relieving inflammation and the symptoms thereof in a living animal body.

In the case of the fiiitiinflansnatorischen means IV, it is preferably about compounds of the general Γοΐ-: · \ ^ι .1

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where mean:

1 2

R and R

Hydrogen, lower alkyl and hydroxy lower alkyl, Hydrogen and lower alkyl and hydrogen, fluorine, bromine, chlorine and trifluoromethyl,

In the structural formula entered above, the asterisks (*) the asymmetric carbon atoms that are found in many according to the invention Connections are present, for example when R "and

R are different. If there are two asymmetric centers, pairs of diastereoisomers are possible. These diastereoisomers as well as their optically active forms, fall within the scope of the present invention.

The new compounds according to the invention reduce in one dose of 316 mg / kg (p.o.) the susceptibility to pleurisy. The anti-inflammatory effect of the new compounds korn using a modification of Evans Bluo-Carrageenan Pleural Effusion Tests (L.F. Sancilio, "Journal of Pharmacology and Experimental Therapeutics ", J.68, pages 199-204 (1969)) be demonstrated. The potency of the most active Compounds "is given in the following table Ϊ. The effectiveness sgr ade were anti-inflammatory towards phenylbutazone, deia Standard means, determined,

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Table I Degree of effectiveness of the oxazolines in relation to phenylbutazone *

Example efficiency level 95% reliability ^ -

border

Plieny Ibu t a ζ on

12 13

The data are obtained using doses of 50, 10 and 2 mg / kg p.o.

Table II

Activity of the oxazolines in the six-hour Evans Blue Crrra geenr.n pleural effusion test.

example

1 0.56 until 1 , 38 0.9 0.61 until 5 , 28 1.9 0.9 until 2 , 3 1.5 3.8 4.1 until 5 , 24 4.3

10 11 15

dose % Reduction in rog / ko; p, o. 316 37.8 316 32.4 316 49.2 50 31.8 10 13.4 50 OT O
-J J., υ 10 11.9 50 37.5 316 23 316 38

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Accordingly, the aim of the present invention is to develop new compounds with a high level of anti-inflammatory (anti-inflammatory) activity, as well as those compounds with a indicate anti-inflammatory activity that has minimal negative side effects demonstrate. Another object of the invention is to provide certain new 2- (p-phenylbenzyl) oxazolines. Another object of the invention is the production of therapeutic preparations which contain the new compounds, and the provision of procedures for their use. Other objects of the invention will be apparent to those skilled in the art and are evident from the following description.

The symbols in the above general formula I have the following there and in the remainder of the description in which they appear Meanings:

The term "lower alkyl" as used herein includes straight chain and branched chain radicals of up to and including 8 carbon atoms and examples of such radicals are methyl, ethyl, propyl, isopropyl, But3> -1, tert-butyl, amyl, hexyl, octyl and like that.

In the £> -Pkenylpbenylessigsäure-AuS "used according to the invention" gang materials and the amino alcohols are either to commercial products or they can be manufactured according to known processes will.

The production of 2- (p-phenylbenzyl) oxazoline!) (The formula l) can be carried out in such a way that a p-Pheiiylphe -

209817/1666 _eAD original

nyl acetic acid (formula II) with an amino alcohol (formula III) mixes and implements. The reaction that occurs is explained by the following equation:

CHGOOH + H ₂ NCR ¹ R ² CH ₂ OH III

wherein R,. R, R and R have the meanings given above.

A general process for the preparation of 2- (p-phenylbenzyl) -oxazolines (of formula I) is the following:

A stirred mixture of 1 part of a p-phenylphenylacetic acid (Formula II), 1 1/10 part of an amino alcohol (Formula III) and 500 parts of a water-immiscible organic solvent, such as benzene, toluene, xylene, tetralin, phenyl ether and the like are used in a system containing a water trap refluxed for about four hours to about four days, during which time that formed during the reaction Water is separated in the case. After the theoretical amount of water has separated out, the hot reaction

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mixture is filtered and the oxazoline (formula I) is isolated from the filtrate by a suitable method. If at least one of the substituents on the 4-position of the oxazoline ring is hydroxymethyl, the product will separate from the cooled one .Filtrate in the form of a well-defined crystalline material. If one or both substituents in the 4-position are lower alkyl radicals are, the product is usually a low-melting solid, which is obtained by concentrating the filtrate and The residue is isolated by distillation in vacuo to form of the oxazoline, which crystallizes out when left to stand.

The optically active oxazolines are easily prepared using optically active amino alcohols as described above as starting materials. Examples 8 and 9 in Table HI were performed using optically active amino alcohols manufactured. The oxazolines can also be dehydrated by cyclization of α- (p-phenylphenyl) -N-substituted acetamides Medium (dehydrating medium) as described above, prepared. The acetamides, which are usually good represent defined crystalline solids are obtained by reacting p-phenylphenylacetyl halides with amino alcohols prepared in a suitable solvent.

The following examples are intended to explain the invention in more detail. but without restricting them to this »

example 1

2- (g-Pheny! Benzene) -4 ~ hydroxYmethy_l-4-methy ₎ loxr2oline

A solution of 32.0 g (0.15 Hol) p-phenylphenylacetic acid and

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17.5 g (0.17 mol) of 2-amino-2-methyl-1,3-propanediol in 600 ml Xylene was isolated using a Dean-Stark trap overnight heated under reflux, during which time the theoretical amount of water separated out. The reaction mixture was .Filtered in the hot state and the filtrate was heated to the maximum temperature cooled down. The white crystals that formed on standing were separated by filtration and with Washed water on the filter until the filtrate was neutral pH. After recrystallization of the solid from Xylene gave 25 g (59.5%) of product, mp 116-118 ° C.

Analysis

for C ₁₈ H ₁₉ KO ₂ : Calculated: C 76.84; II 6.81; N 4.98

Found: 77.14; 6.77; 4.91.

Example 2

2- (p _t ~ Phenylbenzy_3.) - 4 _i 4-bis-hydroxyme1; hvloxazolin

A solution of 5.1 g (0.025 mol) of p-pheny! Phenylacetic acid and 4.0 g (0.033 mol) tris (hydroxymethyl) methylamine in 300 ml >] ylol was Ιε-ng for 12 hours using a Dean-Stark trap heated to reflux. The hot reaction mixture was filtered and that which separated out from the cooled filtrate Product was collected and washed with water until the washing water neutral \; aren. The white crystalline product turned off Acctone / nthanol recrystallized and 6 g (81%) of product were obtained, 160-161 ° C.

Arialysis

for C ₁₈ II ₁₉ NO ₃ : calc .: C 72.70; H 6.44; W 4.71

Found: 72.66; 6.44; 4.73. 209817/1666

Example 3

Following the procedure of Example 1, p-phenyl phenylacetic acid was obtained and 2-amino-2-methyl-1-propanol reacted with one another in refluxing xylene to form 2- (biphenyl-4-ylmethyl) -4,4-dimethyloxazoline (F, 54-56 ° C) in 87.7% yield.

analysis

for C _lg H NO: calc .: C 81.47; H 7.22; H 5.22

Found: 81.31; 7.22 5.31.

Example 4

Following the procedure of Example 1, p- (4-fluorophen3? "L) -phenylacetic acid and 2-amino-2-methyl-1,3-propanediol were reacted with one another in refluxing xylene to form 2- (4 -fluorobiphenyl- 4 ~ ylmethyl) -4-hydroxymethyi-4-met.hyI- k oxazoline in a yield of 48.4%, which had a melting point of 105 to 107 ⁰ C, "

analysis

for ^C ₁₈ ^H ₁₈ ^NO 2 ^F: Calculated: C 72.22; H 6.06; N 4.68

Found: 72.07; 6.08; 4.74.

Example 5

2 · - (g-Pheny ^ lb <2nzy_ 1) oxazo lin

Following the procedure of Example 1, p-Phenylphenylessig-

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acid and 2-aminoethanol in refluxing xylene with one another converted to form 2- (biphenyl-4-ylmethyl) ~ oxazoline.

Examples 6-18

Examples 6-18 were prepared following the procedure of the example. The physical data are in the table below III summarized.

Table III

R '

ο— '

■ R

analysis

at
game R ¹ R ² R ³ R ⁴ F. (cp.)
in OC /
mm Hg C.
ber.
& sL H
ber.
found N
ber. 6th CH ₃ CH ₃ H p-F 59-61 76.30
76.12 6.40
6.43 4.94
4.61 7th CH ₃ H H H 53-55 81.24
81.20 6.82
6.83 5.57
5.55 8 ¹ CII ₃ II H H 52-54.5 81.24
80.86 6.81
6.87 5.57
5.42 9 ² CII ₃ H H H 81.24
81.06 6.82
6.91 5.57
5.08 10 C ₂ H ₅ H H K 36-38 81.47
80.78 7.22
7.25 5.28
5.27 11 (CH ₃ ) ₂ CH II H II (160-2 / 0.01) 81.17
81.04 7.57
7.57 5.26
5.04

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analysis

at
game R ¹ R ² E ³ R ⁴ F. (cp.)
in ⁰ C /
mm Hg C.
ber.
found H
ber.
found N
ber.
found 12th CH ₃ CH ₃ CH ₃ H 55-57 81.39
81.48 7.59
7.22 4.61
5.28 13th CH ₃ H CH ₃ H (140-5 / 0.05) 81.48
80.38 7.22
7.24 5.28
5.12 14th CH ₂ OH CH ₃ CH ₃ H 67-69 72.82
73.53 7.39
7.03 4.46
4.47 15th CH "0H CH ₃ H m-Cl 113-115 68.46
68.17 5.74
5.79 4.43
4.55 16 CH ₃ H H p-F (124-6 / 0.1) 76.30
75.81 6.40
6.21 4.94
4.78 17th CH ₃ CH ₃ H IQ-F 4.93
5.05 18th
1 . _ CH ₃ CH ₃ H m-Cl 4.67
4.53

d-isomer made using d-2-amino-l-pro panol.

6-isomer made using £ ~ 2-amino ~ 1 ~ propanol.

Example 19

When in the procedure of Example 1, the p-Phen} ^'r lpheny acetic acid is replaced by an equivalent amount of the following acids!:

p- (3-Tr if luorme thy lphe'nyl) phenylacetic acid, ρ- (3-] 3romphenyl) pheny! acetic acid and
ρ- (4 ~ bromopheiiyl phenylacetic acid,

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then you get:

2- [p- (3-trifluoromethylphenyl) benzoyl] -4-hydroxymethyl-4-methyloxazoline,

2- [p- (3 ~ bromophenyl) benzyl] -4-hydroxymethyl ~ 4-methyloxazoline and 2- [p- (4-bromophenyl) benzyl] -4-hydrox} methyl-4-methyloxazoline.

Formulation and administration

The present invention also relates to new preparations containing the compounds according to the invention as active constituents. In the production of the new preparations according to the invention, the active ingredient is incorporated into a suitable carrier, for example a pharmaceutical carrier. Examples of suitable pharmaceutical carriers which can be used for formulating the preparations according to the invention are starch, gelatin, glucose, magnesium carbonate, lactose, salt and the like. Liquid formulations also fall within the scope of the present invention and examples of suitable liquid pharmaceutical carriers are ethyl alcohol, ^'r glycol, glycerine prop3 the like, and Glykosesyrup.

Although small amounts of the active materials of the invention are effective when it comes to minor therapy or in FäE ^ n the administration to patients or animals wit a relatively low body weight, the Do is ~ Sizing units 50 or 100 mg. 50 to lOOrag seems the best to be per Dosierimgseinheit while usually wider Ranges from 50 to 300 mg per dosage unit include.

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* 12 -

The following examples are intended to prepare preparations according to the invention explain.

1. Capsules

Capsules containing 50 mg and 100 mg of active ingredient were made.

Typical mix for encapsulation mg per capsule

Active ingredient 50.0

) Lactose 251.7

Magnitude 129.0

Magnesium stearate 4.3

total 435.0 mg.

Other capsule formulations preferably contain a higher dosage of active ingredient, such as the following:

Ingredients 100 mg per capsule

Active ingredient lactose
I strength

Magnes iums tearat

In either case, the selected active ingredient is included Lactose, starch and magnesium stearate mixed and evenly mixed the mixture was encapsulated.

100 , 0 231 , 5 99 , 2 4th all in all 435 , 0.

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2. Tablets

A typical formulation for a tablet containing 50.0 mg of active ingredient per tablet is as follows: The formulation can be used for other strengths of active ingredient by adjusting the weight of Dicalciumphos-.phat.

mg per tablet

Active ingredient 50.0

Mileage 20.0

Corn starch (paste) 38.0

Lactose 90.0 calcium stearate 2.0

total 200.0 mg.

The active ingredient, lactose, milo starch and corn starch are mixed together thoroughly. This mixture is granulated using water as a granulating medium. The wet granules are passed through a 2.35 ^µm (δ mesh) sieve and dried overnight at 60 to 71 C (140-160 F). The dried granules are passed through a 1.97 mm (10 mesh) screen and mixed with the correct amount of calcium stearate and this mixture is then converted into tablets in a suitable tablet press.

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100 mg tablet

Ingredients mg per tablet

Active ingredient 100.0

Lactose 190.0

Dicalcium phosphate 172.2

Strength 54.0

Milo strength 21.6

Calcium steaxate 2.2

total 540.0 mg.

The active ingredient, lactose, dicalcium phosphate, di & starch and milo starch are evenly mixed together. This mixture is granulated with water and the moist mass is passed through a sieve with a mesh size of 2.35 ¹ ^ (8 mesh). The wet granules are dried overnight at 60-71 C (140-160 F). The dried granules are passed through a 1.97 mm (10 mesh) screen. The dried granules are mixed with the correct weight of calcium stearate and the lubricated granules are then converted into tablets with a suitable tablet press.

As is readily apparent to the person skilled in the art, the inventive egg Compounds, Preparations, Processes and Driving to use them in a wide variety of ways can be modified and altered without departing from the scope of the present invention.

BATH ORIGINAL 209817/1666

Claims (1)

- 15 claims 2- (p-Phenylbenzyl) oxazoline, 'gfekennzeich.net by the general formula .1 V7orin mean: 1 2
R and R each hydrogen, lower alkyl and hydroxy lower alkyl, 3
R is hydrogen and lower alkyl and 4th
R hydrogen, fluorine ^ bromine, chlorine and trifluoromethyl. 2. A compound according to claim 1, characterized by the formula 2 · (p-Phcnylbenzyl) -4-hydroxymethyl-4-methylox »zoline. 3. Compound according to claim 1, characterized by the formula 2 (p-phenylbenzyl) -4-metbyloxazoline. 4. A compound according to claim 1, characterized by the formula 2 · (p-Phonylberizy 1) -4,4-diraethylox ^ zo lin. 5. Compound ii;: c'i Anspi-uch 1, characterized by the formula 2- [p ~ I ³ henyl (a «methyl) benzyl] -4,4-dimethyloxazoline. 6. A compound according to claim 1, characterized by the formula 2- [p-phen) "l- (a-raethyl) benzyl] -4-mGthyloxazoline. 209817 / 1BB6 7. Process for the preparation of the 2- (p-PhenyIbenzy1) oxazolines the general formula: R " , N- CH-C Ό— ' -R where mean: 1 2 R and R jev; partly hydrogen, lower alkyl and Hydroxynledr-ig- alkyl,
3 R is hydrogen and lower alkyl and 4th
R hydrogen, fluorine, chlorine, bromine and trifluoromethyl, characterized in that one p-pheny! phenylacetic acid the formula in which R and R have the meanings given above, with an amino alcohol of the formula JLL 1 2 in the R and R 'the above rn; _; .ef-; eber; on Bedcutuiigcn "bccitzerij mitej / aandor mixes and with the elimination of: .i zxjei l." olc-: ülo? .i VJasser and under jjiläung des Cow.zol in ringes laitciiiiaiiucr υ.ΐϊ-sets .. 209817/1666 BATH ORIGINAL 8. The method according to claim .7, characterized in that the reaction in a water-immiscible solvent is carried out. . 9. The method according to claim 8, characterized in that the reaction at the reflux temperature of the V / water is not miscible solvent is carried out. 10. Therapeutic preparation suitable for alleviating inflammation, characterized in that it contains (1) an effective amount of about 50 to about 300 mg of an anti-inflammatory compound selected from the group ^; the oxazolines of the general formula wor5.n mean: R ¹ and R each are lower alkyl and Ilydroxy-lower alkyl, R is hydrogen and R ⁴ hydrogen, fluorine, bromine, chlorine and trifluoromethy: and
(II) a pharmaceutically acceptable carrier therefor. 209817/1666 • 11 «preparation according to claim 10, characterized in that " It contains 2 ~ (p-phenyl ~ benzyl) -4-hydroxymethyl-4-methyloxazoline as an active anti-inflammatory agent. 12. Preparation according to claim] 0, characterized in that 'Use it as an * active anti-inflammatory agent 2- (p-Pbenylbenzyl) ~ 4-metbyloxazoline contains. 13; Preparation according to claim 10, characterized in that it as an active anti-inflammatory agent 2- (p-phenyl ~ benzyl) -4,4-dimethyloxazoline. 1 ** · preparation according to claim] 0, characterized in that it as an active anti-inflammatory agent 2 ~ ([p-phenyl · ' (a ~ methyl) benzyl] ~ 4j4-dimethyloxazoline contains. 15 · Preparation according to claim K), characterized in that it contains 2- [p-phenyl-- as active anti-inflammatory agent * (a ~ methyl) benzyl] ~ 4-methyloxazoline contains. 209817 / -1666