US3817994A - Substituted (phenyl) (2-oxazolidinyl) and (phenyl) (2-tetrahydrooxazinyl) ketones and lower alkanols - Google Patents

Abstract

2-Aroyloxazolidine, 2-aroyltetrahydrooxazines and 2-( Alpha aralkanol)-oxazolidine derivatives possessing central nervous system depressant activity are prepared by condensing substituted phenyl glyoxals with 1-amino-2-alcohols or 1-amino-3-alcohols to form a ketone and subsequently alkylating the product to the tertiary alcohol.

Description

United States Patent v V [191 Teller et al.

[ June 18, 1974 SUBSTITUTED (PHENYL) (Z-OXAZOLIDINYL) AND (PHENYL) (2-TETRAHYDROOXAZINYL) KETONES AND LOWER ALKANOLS Inventors: Daniel M. Teller, Devon; Charles J. Guinosso, Abington; Stanley C. Bell, Penn Valley; George H. Douglas, Paoli, all of Pa.

Assignee: American Home Products Corporation, New York, NY.

Filed: Dec. 3, 197i Appl. No.: 204,715

US. Cl. 260/244 R, 260/307 F, 260/999 Int. Cl C07d 85/26 Field of Search 260/307 F, 244 R [56] References Cited UNITED STATES PATENTS 3,674,802 7/1972 Franz 2 60/307 F Primary ExaminerRaymond V. Rush [57] ABSTRACT 11 Claims, No Drawings SUBSTITUTED (PHENYL) (2-OXAZOLIDINYL) AND (PHENYL) (Z-TETRAHYDROOXAZINYL) KETONFS AND LOWER ALKANOLS BACKGROUND OE THE INVENTION The condensation reaction of simple aldehydes and ketones with I-amino-Z-alcohols is known to produce oxazolidine derivatives (Bergmann, Chem. Rev.,

53,309-352 (1953). The reaction proceeds according to the equation:

| R 0- OH NHR g b 1 11-0111 15 R R; R HCH-R \O I which, when alkylated yields an a-aralkanol of the structure:

0H illalkyl in which n is one of the integers 0 and l.

The compounds of this invention are biologically ac- 5 tive in that they are central nervous system depressants. In addition to the central nervous system depressant activity of the compounds in general, certain specific compounds exhibit anti-inflammatory activity and/or inhibition of blood platelet aggregation or adhesiveness.

DETAILED DESCRIPTION OF THE INVENTION In accordance with this invention there is provided a group of chemical compounds characterized by the structural formula:

in which R is a member of the group consisting of -I-I, -Cl.

. T -0Hs R is a member, of the group consisting of H and R is a member of the group consisting of l-l andphenyl;

R is a member of the group consisting of H and lower alkyl;

R if a member of the group consisting of H and lower alkyl;

R is a member of the group consisting of -low.er alkyl of l to 6 carbon atoms, aryl 6-10 carbon atoms, aralkyl of 7-10 carbon atoms and arylsulfonyl of 6-10 carbon atoms;

n is one of the integers and 0 and l; and

A is a be th sreyasq sstmsaf O OH II and i l lower alkyl The ketones of this invention are prepared by the reaction f a 99mm f h mq az,

t e 2 1t9tb9 f mu a;

in which the groups RR and n are defined above, at a temperature between from about room temperature to about C. in an inert solvent system for a time from about 10 minutes to about 3 hours. The reaction rate may be increased by use of a strong acid catalyst 0 such as p-toluenesulfonic acid if desired.

The tertiary alcohols of this invention are prepared by the reaction of the ketones prepared by the method outlined in the preceding paragraph having the structural formula:

' v R1 o N-CH -os 01111 n 5 with an alkylating agent such as the Grignard reagents,

methyl magnesium bromide and butyl magnesium bromide.

The compounds in which A is the carbonyl group are preferred over the corresponding tertiary alcohol for economic reasons in that they are prepared in fewer steps requiring less supervision of manufacturing personnel and equipment. However, the tertiary alcohol derivatives provide a unique functional group which may be readily utilized to tailor the compounds for special applications without any appreciable loss of activity.

The compounds of this invention are central nervous system depressants. As such, they are administered orally or intraperitoneally as the amine orin the form of pharmaceutically acceptable salts, with or without a physiologically acceptable carrier. The addition salts may be prepared by known techniques and include the hydrochloride, hydrobromide, sulfate, nitrate and phosphate salts.

The depressant activity of the compounds disclosed and claimed herein was established by the oral and intraperitoneal administration to three mice weighing from 14 to 24 grams at each of the dosage levels 400, 127, 40, 12.7, 4.0 and 1.27 milligrams per kilogram body weight. The mice were then observed for at least two hours during which time, signs of general stimulation (i.e. increased spontaneous motor activity, hyperactivity on tactile stimulation, etc.), general depression (i.e. decreased motor activity, decreased respiration, etc.) and autonomic activity (i.e. ptosis, mydriasis, etc.) were noted. Each of the claimed compounds were active in the dosage range at or below about 127 milligrams per kilogram body weight, to about l.27 milligrams per kilogram. Within the range of activity, each of the compounds of this invention induced depressant activity evidenced by decreased motor activity and respiration.

ln addition to the activity of the compounds as central nervous system depressants, certain members of the compound genus disclosed herein inhibit blood platelet aggregation or adhesiveness. As such, those compounds are useful anti-thrombotic agents for the inhibition of the arteriosclerotic process which begins in a thrombus formation via blood platelet aggregation or clotting.

The compounds which have been found to possess CNS depressant activity and the ability to prevent blood platelet aggregation are those of the formula:

R is hydrogen;

R is selected from the group consisting of -H and R is selected from the group consisting of CH;;,

phenyl, benzyl, p-tolylsulfonyl; and

n is one of the integers 0 and 1.

Both in vitro and in vivo activity as inhibitors of blood platelet aggregation was evaluated. The in vitro studies were made on platelet rich plasma obtained from normal fasted malerats. Adenosine diphosphate was added to the platelet rich plasma in an amount predetermined to maximize platelet aggregation. A curve of per cent light transmission at 610 millimicrons was plotted for a seven minute period. 5 The compounds being tested are incorporated in identical formulations and the concentration effecting a 50 per cent inhibition of the adenosine diphosphate activity was determined by comparison with the standard curve. The compounds of this invention inhibited blood platelet aggregation at concentrations as low as about 0.03 millimolar while increased activity occurred with increased concentration.

The in vivo testing of the anti-thrombotic compounds was performed on male rats administered with adenosine diphosphate. The compounds of this invention generally demonstrated significant inhibition in dosages as low as 50 milligrams per kilogram body weight. The compound of Example 8, infra, was exceptional in that it exhibited marked activity at a concentration as low as 25 milligrams per kilogram body weight when orally administered and slight activity at 20 milligram per kilogram body weight.

In addition to central nervous system depressant activity and its anti-thrombotic function, the compound (3 ,4-dimethyl-5-phenyl-2-oxazolidinyl) pmethoxyphenyl ketone is a very effective antiinflammatory agent. Furthermore, the alcohol, a-methyl-a,3-diphenyl-2-oxazolidinemethanol, exhibits central nervous system depressant activity and acts as an anti-inflammatory agent as well. Likewise, the compound (3-benzyltetrahydro-2H-l,3-oxazin-2-yl) (pchlorophenyl) ketone is a central nervous system depressant, inhibits blood platelet aggregation and serves as an anti-inflammatory agent.

The anti-inflammatory activity of the compounds possessing that activity was illustrated by acceleration of the reaction of albumin (serum albumin, Fraction V) with 5,5'-di-thiobis-2-nitrobenzoic acid to produce 5- thio-2-nitrobenzoic acid in the presence of the novel anti-inflammatory agents when compared to the reaction rate in the absence of the agents. In detail, solutions were prepared by dissolving 3 milliliters of 4.1 per cent serum albumin (Fraction V), 0.2 milliliters of 2 millimolar 5,5'-dithiobis-2-nitrobenzoic acid and varying concentrations of the compound being tested (3,4- dimethyl-5-phenyl-2-oxazolidinyl) p-methoxyphenyl ketone, (a-methyl-a,3-diphenyl-2-oxazolidinylmethanol), and (3-benzyltetrahydro-2H-l ,3-oxazin- 2-yl) (p-chlorophenyl) ketone in 3 milliliter samples containing 0.1 molar potassium phosphate buffer to obtain a pH of 7.4. Tests in the range from 1.0 millimolar to a minimum of 0.3 millimolar concentration of test compound were studied by incubation of the 3 milliliter samples at 30C. while colorimetrically (absorbance at 412 millimicrons) following the reaction rate at 10 minute intervals for 40 minutes. The test results obtained demonstrated that the compounds were effective inhibitors.

The indicated in vitro anti-inflammatory activity was confirmed by in vivo studies in which over 40 per cent inhibition of experimentally induced edema in the hind paw of male rats weighing from 120-160 grams was observed. In practice, from 1.0 to milligrams of the compound being tested per kilogram body weight of the rat was administered orally to six rats with a six rat control being administered aqueous vehicle with no active compound. Sixty minutes after drug administration, edema was induced by injection of 0.05 milliliters of 1 per cent carrageenin solution in saline into the subplantar tissue of the rats right hind paw. The paw volume was immediately volumetrically determined with a plethysmograph and again 3 hourslater. The mean volume swelling for the control group was determined and compared to the test group. Swelling inhibition of 23 per cent or more is considered to be indicative of an active compound. The alcohol amethyl-a-,3 diphenyl- 2-oxazolidirie-methanol exhibited a 43 per cent inhibition while the ketone, (3,4-dimethy1-5-pheny1-2- oxazolidinyl) p-methoxyphenyl ketone inhibited inflammation by 46 per cent and (3-benzyltetrahydro- 2H-1,3-oxazin-2-yl) (p-chlorophenyl) ketone was similarly active.

The following preparative procedures for producing the compounds of this invention are presented for purpose of illustration and are not to be construed as the limiting factors on the proper scope of the disclosed invention. It is recognized that those of average skill in the art, when apprized of the invention herein disclosed will contemplate and be placed in possession of applicants contribution to the extent of its true scope.

In the examples, all temperatures are indegrees Centigrade; all infra-red analysis is expressed in microns (u) whereas the ultra-violet maxima is expressed in millimicrons (mu); the nuclear magnetic resonance (NMR) data is presented as parts per million (ppm); TLC represents thin layer chromotography; and (d) means decomposes.

EXAMPLE 1 (p-Chlorophenyl) (3-methyl-2-oxazolidinyl) ketone A solution of p-chlorophenylglyoxal, hydrate (10.0 g., 0.054 mole), N-methylethanolamine (4.44 g., 0.059 mole), and p-toluenesulfonic acid monohydrate (0.10

g.) in benzene (400 ml.) is refluxed for 2 hours using EXAMPLE 2 (3-Methyl-2-oxazolidinyl)phenyl Ketone Using the conditions described in Example 1, but substituting phenylglyoxal, hydrate for pchlorophenylglyoxal, hydrate gives the title compound;

b.p. 112/0.2 mm; A,,,,,," 5.88; A 245 my. (6 5,750); NMR has methyl singlet at 2.37 ppm and singlet at 4.98 ppm.

Calcd. for C,,H, NO C, 69.17; H, 6.81; N, 7.33. Found: C, 69.22; H, 7.08; N, 7.68.

- EXAMPLE 3 (p-Chloropheny1)(3,4-dimethyl-5-phenyl-2- I oxazolidinyl) ketone Using the conditions described in Example 1, but substituting l-ephedrine for N-methylethanolamine gives the title compound m.p. 89; A 5.90 11.; lt 256 mp. 6 15,300); NMR has methyl doublet centered at 0.69 ppm, methyl singlet at 2.45 ppm and singlet at 4.81 ppm.

Calcd. for C,,H,,C1N0,; C, 68.50: H, 5.70; N, 4.44;

Found: C, 68.60; H, 5.76; N, 4.72; Cl, 11.44.

EXAMPLE 4 EXAMPLE 5 Phenyl (3-phenyl-2-oxazolidinyl)ketone Using the conditions described in Example 1 but substituting phenylglyoxal, hydrate for pchlorophenylglyoxal, hydrate and N- phenylethanolamine for N-methylethanolamine gives the title compound; m.p. 13l133; A,,,,,,,"'.5.94 ,u.; A 2.46 my. (6 26,200); NMR has singlet at 6.05 PP Calcd for C H, NO C, 75.87; H, 5.97; N, 5.53. Found: C, 75.92; H, 6.22; N, 5.51.

EXAMPLE 6 (3,4 Dimethyl-5-phenyl-2-oxazolidinyl)phenylketone Using the conditions described in Example '1 but substituting l-ephedrine for N-methylethanolamine and phenylglyoxal, hydrate for p-chlorophenylgloyoxal, hy drate gives the title compound; m.p. 8488, )t,,',,,,'" 5.88 ,u.; h f' 247 my. (2 1 1,700); NMR has methyl singlet at 2.41 ppm and singlet at 4.90 ppm.

Calcd for C,,,H ,NO C, 76.84; H, 6.81; N, 4.98. Found: C, 76.96; H, 7.03; N, 5.24.

EXAMPLE 7 (3 ,4-Dimethy1-5-phenyl-2-oxazolidinyl ptolyl)ketone Using the conditions described in Example 1, but

substituting p-tolylglyoxal, hydrate for pchlorophenylglyoxal, hydrate and l-ephedrine for N- methylethanolamine gives the title compound; mp. 92- 95; A 5.92 t; )t 257 my. (6 15,400; NMR has methyl singlet at 2.36 ppm and singlet at 4.82

Calcd for C H NO C, 77.26; H, 7.17; N, 4.74.

Found: C, 77.53; H, 7.56; N, 4.69.

EXAMPLE 8 (p-Anisoyl )(3,4-dimethyl-5-phenyl-2- oxazo1idiny1)ketone A solution of 10.0 g. of p-methoxyphenyl glyoxal (0.055 moles), 9.60 g. of l-ephedrine hemihydrate (0.055 moles) and 100 mg. of p-toluenesulfonic acid in 50 ml. of benzene was refluxed for 2 hours using a Dean-Stark receiver to remove water. The solution was cooled to room temperature, washed with aqueous sodium bicarbonate, brine dried over anhydrous sodium sulfate and stripped in vacuo. Crystallization of the residu'e from isopropanol gave 8.70 g. of colorless solid, m.p. 89-93C, homogeneous on TLC; A 5.92 1.; k f 283 mp. (e 16,400); NMR displayed a methyl singlet at 2.39 ppm, methoxyl singlet at 3.78 ppm and a singlet at 4.87 ppm.

Calcd for C H NO C, 73.29; H, 6.80; N, 4.50.

Found: C, 73.21; H, 6.72; N, 4.47.

EXAMPLE 9 (p-Anisoyl 3,4-dimethyl-5-phenyl-2- oxazolidinyl)ketone Using the conditions described in Example 1, but substituting p-anisoylglyoxal, hydrate for pchlorophenylglyoxal, hydrate and d-pseudoephedrine for N-methylethanolamine gives the title compound;

m.p. 68.72"; )t 5.98 [.L; A 283 my (6 16,1- NMR has methyl singlet at 2.37 ppm, methoxyl singlet at 3.80 ppm and singlet at 4.88 ppm.

Calcd for C H NO C, 73.29: H, 6.80; N, 4.50.

Found: C, 73.53; H, 7.05; N, 4.58.

EXAMPLE l0 EXAMPLE 1 1 2-Benzoyl-3-(p-tolylsulfonyl) oxazolidine A solution of phenylglyoxal, hydrate (5.0 g., 0.033 moles), N-tolylsulfonamidoethanolamine (7.8 g., 0.036 moles), and p-toluenesulfonic acid monohydrate in benzene (200 ml.) is refluxed for 1.5 hours using a Dean-Stark receiver to remove water. After cooling to room temperature the mixture is washed with 5 percent aqueous sodium hydroxide, saturated aqueous sodium bicarbonate, brine dried over anhydrous sodium sulfate and stripped in vacuo. The gummy residue is columned on Florex using 100 percent benzene as eluant to give 0.85 g. of colorless solid after recrystallization from methanol; m.p. l08l 5.89, 7.39, 8.59 ,u.; A 240 mp. (6 16,400); NMR 1 proton singlet at 6.57 ppm.

Calcd for C, H NSO,: C, 61.63; H, 5.17; N, 4.23; S,

9.67. Found: C, 61.67; H, 5.32; N, 4.08; 8, 10.08.

EXAMPLE 12 a-Methyl-a-3diphenyl-Z-oxazolidincmethanol To a slurry of phenyl (3-phenyl-2- oxozolidinyl)ketone (10.0 g., 0.04 mole) in ether (1,000 ml) under nitrogen is added at room temperature over 10 minutes a solution of methyl magnesium bromide (70 ml of -3 M solution in ether) in ether (500 ml). The mixture is refluxed for 2.5 hours, poured onto 5 ice, and the layers separated. The aqueous layer is extracted with ether and the extracts combined with the organic layer. The organic layer is washed with saturated aqueous sodium bicarbonate, brine, dried over anhydrous sodium sulfate and stripped in vacuo. The residue is crystallized from hexane giving 6.80 g. of colorless solid, m.p. 8082; A 2.92 p. and no carbonyl absorption, lt 246 my. (6 11,400); NMR has methyl singlet at 1.64 ppm.

Anal. Calcd for C, H, NO C, 75.81; H, 7.11; N,

5.20. Found: C, 75.89; H, 7.28; N, 5.11.

EXAMPLE l3 (3-Benzyltetrahydro-2H- 1 ,3-oxazin-2-yl)(pchlorophenyl) ketone Following the procedure of Example 1, with the exception that 3-benzylaminopropan-l-ol was substituted for N-methylethanolamine, afforded the title compound; m.p. 5559C; A I 5.88 11.; A 257 mu (6 14,100); NMR singlet at 5.20 ppm.

Elemental Analysis: C H ClNO I Calculated: C, 68.46; H, 5.74; N, 4.43; C1, 1 1.23 Found: C, 68.03; H, 5.49; N, 4.86; C], 11.50. What is claimed is:

l. A compound of the fomiula:

R R5 0 sLJm CH;;, phenyl, benzyl, p-tolylsulfonyl; and

R is a member selected from the group consisting of a

Claims (10)

1. 2. The compound of claim 1 which is (p-chlorophenyl) (3-methyl-2-oxazolidinyl) ketone.
2. 3. The compound of claim 1 which is (3-methyl-2-oxazolidinyl) phenyl ketone.
3. 4. The compound of claim 1 which is (p-chlorophenyl) (3,4-dimethyl-5-phenyl-2-oxazolidinyl) ketone.
4. 5. The compound of claim 1 which is phenyl (3-phenyl-2-oxazolidinyl) ketone.
5. 6. The compound of claim 1 which is (3,4-dimethyl-5-phenyl-2-oxazolidinyl) phenyl ketone.
6. 7. The compound of claim 1 which is (3,4-dimethyl-5-phenyl-2-oxazolidinyl)(p-methoxyphenyl) ketone.
7. 8. The compound of claim 1 which is (2,6-dichlorophenyl) (3,4-dimethyl-5-phenyl-2-oxazolidinyl) ketone.
8. 9. The compound of claim 1 which is (phenyl)(3-p-tolylsulfonyl-2-oxazolidinyl) ketone.
9. 10. The compound of claim 1 which is (3-benzyltetrahydro-2H-1,3-oxazin-2-yl)(p-chlorophenyl) ketone.
10. 11. The compound which is (3,4-dimethyl-5-phenyl-2-oxazolidinyl)(p-tolyl) ketone.