US3911132A - Treating lipidemia with 1-tertiary-butyl-3-aryl-2,1-benzisoxazolines and compositions therefor - Google Patents

Treating lipidemia with 1-tertiary-butyl-3-aryl-2,1-benzisoxazolines and compositions therefor Download PDF

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US3911132A
US3911132A US445268A US44526874A US3911132A US 3911132 A US3911132 A US 3911132A US 445268 A US445268 A US 445268A US 44526874 A US44526874 A US 44526874A US 3911132 A US3911132 A US 3911132A
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phenyl
tertiary
butyl
hutyl
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Robert V Coombs
Goetz E Hardtmann
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Sandoz AG
Sandoz Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/20—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings condensed with carbocyclic rings or ring systems

Definitions

  • R and R are independently hydrogen. halo ulkyl.
  • the preserrt Invention IHVOlVCS the dlscovery that w and Y are independently hydrogen.
  • halo ofalomie Cenflm y y y l l-bllnllsoxilllllncs weight of from [8 to 80 lower alkvl of l to 4 ear- Phllrmucologlclll p p P Y- f hon atoms lower alkoxy of l to 4 earhon atoms or has been found that these compounds possess hypollplfl m-L dQmiC prope e m ng them p y suimhlk for
  • the compounds of formula I may he prepared in acmclrporutmn Phllrmwicuncul p cordanee with the two sle 1 procedure disclosed in U5v According lo U11 IH H H. ll ypo p Qflcfl 1S Pat. No. 354 I
  • Step 1 1 H J' H R LBuOH/HBF 0 0 Br, (H NO R Y C Y ll Ill Step 2 CH" CH:
  • the preparation of compounds 111 by the reaction of Step I may be carried out at temperatures in the range of from C. to bllC.. preferably C. to 35C.. and conveniently at about room temperature.
  • a strong inorganic acid adapted to form a crystalline quaternary salt is required. Acids of this type are known. and inelude by way of illustration. tetratluoroboric acid and perchloric acid.
  • the reaction is carried out in the presence of an organic solvent which is inert and adapted to dissolving the reactants and product compound of Formula lll. Suitable solvents are known and available. and include by way of illustration. the nitrated hydro carbons. e.g.. nitromethane.
  • the resulting reaction product of Formula lll may be isolated from the reaction of Step 1 by working up by conventional techniques.
  • the preparation of compounds l involving the reduction of compound lll is desirably effected with a suitable borohydride as the reducing agent. More desirably, an alkali metal borohydride such as sodium borohydride. followed by working up in a manner conventional for borohydride reductions.
  • the reduction may be carried out at temperatures in the range of 0C. to t-il)(.. preferably between l5C. to C.
  • the reaction is carried out in an organic solvent of known type. preferably a lower alkanol such as methanol or ethanol. preferably ethanol.
  • the reaction products of Formula I may be isolated from the reaction mixture of Step 2 by working up by conventional techniques.
  • the compounds of structural Formula l are useful because they possess pharmacological activity in animals.
  • the compounds are useful as hypolipi delnic agents. as evidenced. for example. by lowering cholesterol and triglyceride blood serum levels in tests on a group of white rats which are given typically l5I5U milligrams per kilogram of body weight per diem of the compound orally. for 6 days. followed by extraction with isopropanol of serum or plasma after ancsthetiIing the rates with sodium hexobarbital. and then noting the cholesterol and triglyceride contents as compared to those of a control group.
  • the cholesterol and triglyceride contents are determined by the methods described by Lofland. H.B.. Anal. Biochem.
  • the compounds may be administered orally or parenterally. preferably orally. and in admixture with comentional pharmaceutical carriers.
  • the dosage administered may vary depending upon known variables such as the particular compound employed and the severity of the condition being treated. In general, satisfactory results are obtained when administered at a daily dosage of from about 2 milligrams to about 250 milligrams per kilogram of animal body weight, preferably givcn orally and in divided doses. 2 to 4 times a day. or in sustained release form.
  • the total daily dosage is from about 140 milligrams to about l.5(l(l milligrams of the compound. and dosage forms suitable for internal administration comprise from about to 750 milligrams of the compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
  • the compounds of structural formula 1 may be administered orally in such forms as tablets. dispersible powders. granules. capsules. syrups and elixirs; and parenterally as solutions, suspensions, dispersions. emulsions, and the like. eg, a sterile injectable solution such as an aqueous suspension.
  • These pharmaceutical preparations may contain 0.5 percent up to about 90 percent of the active ingredient in combination with the carrier or adjuvant. more usually between 3 percent and percent by weight.
  • Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. and such compositions may contain one or more conventional adjuvants. such as sweetening agents. flavoring agents, coloring agents and pre serving agents.
  • Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients. e.g.. inert diluents such as calcium phosphate. calcium sulphate dihydrate, lactose and talc. granulating and disintegrating agents, e.g., starch and alginic acid. binding agents. e.g.. starch. gelatin, polyvinyl pyrrolidone and acacia. and lubricating agents, cg. magnesium stearate. stearic acid and talc.
  • inert diluents such as calcium phosphate. calcium sulphate dihydrate, lactose and talc.
  • granulating and disintegrating agents e.g., starch and alginic acid. binding agents. e.g. starch. gelatin, polyvinyl pyrrolidone and acacia.
  • lubricating agents cg. magnesium stearate. stearic acid and
  • the tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions. e.g.. suspending agents (methylcellulose. tragacanth and sodium alginate). wetting agents (lecithin. polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservativ es (ethylp-hydroxyhenzoate Capsules may contain the active ingredient alone or admixed with an inert liquid or solid diluent. cg. calcium car' bonate. calcium phosphate. kaolin. peanut oil. sesame oil and corn oil.
  • the preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions. particularly hardfilled capsules and tablets.
  • Capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in reducing the blood levels of cholesterol and triglycerides in mammals at a dose of one capsule 2 to 4 times a day.
  • Step A Preparation of l-tert.-hutyl-S-chloro-o-methyl-3-phenyl-2, henzisoxazolium tetrafluorohoratc precipitate formed is isolated by filtration to yield ltert.-hutyl-Schloro 6-methyl-3-phenyl-Z. l henzisoxazolium tetrafluorohorate, m.p. l64l66C.
  • Step B Preparation of l-tert.-hutyl-5-chloro-o-mcthyl-3-phenyl-2.
  • lhenzisoxazoline To a suspension of 24 g. of l-tert.-hutyl-5-chloro-6- methyl-3-phenyl-2. I -henzisoxazolium tetrafluorohorate in 200 ml. otahsolute ethanol is added in portions over minutes. 3.5 g. of sodium horohydride. The suspended solid slowly goes into solution and some heat is evolved. The colorless solution is allowed to stand at room temperature for l hour, during which time a crystalline precipitate is formed.
  • the mixture is then cooled [ice/water) and diluted with an equal volume of water.
  • the solid so produced is isolated by filtration and recrystallized from 50 percent aqueous ethanol to yield l-tert.-hutyl-S-chloro-6-methyl-3-phenyl- 2.1-henzisoxazoline. m.p. l l4l 15C.
  • Step B Preparation of l-tert.-hutyl-5-chloro-3-phenyl-2. l -henzisoxazoline
  • a suspension of 8 g. of l-tert. hutyl-5chloro-3- phenyl-Z,l-henzisoxazolium tetrafluorohorate in I35 ml of absolute ethanol is added in portions over 15 minutes.
  • I g. of sodium borohydride The suspended solid slowly goes into solution and some heat is evolved. The colorless solution is stirred for 1 hour at room temperature. during which time a crystalline precipitate is formed. The precipitate is washed with water and methylene chloride. and the methylene chloride layer separated, dried.
  • EXAMPLE 4 Following essentially the procedure of Example 2, and using in place of l-tert.-hutyl-5-ehloro-3-phenyl- 2.l-henzisoxazolium tetrallurorhorate in Step B. an equivalent amount of the respective compounds obtained in Example 3. there is obtained a. l-tert.-hutyl-6-methyl-3-phenyl-2, l-henzisoxazoline. h. l-tert.-hutyl-S-hromo 6methyl-3-phenyl-2. l
  • a method for treating lipidemia comprising administering to mammals in need of said treatment an effec tive amount of a compound of the formula:
  • R and R are independently hydrogen, halo of atomic weight of from l8 to 8U, lower alkyl of l to 4 carbon atoms. lower alkoxy of l to 4 carbon atoms or trit'luoromethyl.
  • Y and Y are independently hydrogen, halo of atomic weight of from l8 to 80 lower alkyl of l to 4 carbon atoms. lower alkoxy of l to 4 carbon atoms or tril'luoromethyl.
  • R and R are independently hydrogen halo of atomic weight of from 18 to 80 lower alkyl of l to 4 carbon atoms lower alkoxy of l to 4 carbon atoms or trifluoromethyl, and Y and Y are independently hydrogen. halo of atomic weight of from lit to 80. lower alkyl of l to 4 can hon atoms, lower alkoxy of l to 4 carbon atoms or tritluoromethyl and a pharmaceutically acceptable carrier therefor. said compound being present in said composition to the extent of from about 35 milligrams to about 750 milligrams.
  • the compound is:

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Hypolipidemic agents of the formula

wherein R* and R are independently hydrogen, halo, alkyl, alkoxy or CF3, and Y and Y'' are independently hydrogen, halo, alkyl, alkoxy or CF3.

Description

United States Patent [191 Coombs et al.
[ TREATING LIPIDEMIA WITH l-TERTlARY-BUTYL-3-ARYL-2,l- BENZISOXAZOLINES AND COMPOSITIONS THEREFOR [75] Inventors: Robert V. Coombs, Chutham; Goetz E. Hardtmann, Florham Park, both of NJ.
[73] Assignee: Sandoz, lnc., E. Hanover. NJ.
[22] Filed: Feb. 25, 1974 [2]] Appl No: 445,268
Primary Examiner-Albert T. Meyers Amislunl E.\uminerA. P. Fagelson Attorney. Agem, 0r FirmGerald D. Sharkin; Richard E. \"ilu; Joseph J. Borovian [57] ABSTRACT Hypolipidemic agents of the formula 1 Oct.7,1975
wherein R and R are independently hydrogen. halo ulkyl.
ulkoxy or CF and Y and Y' are independently hydrogen. hz1|0 ulkyl.
alkoxy or CF 13 Claims. No Drawings 1 2 TREATING LIPIDEMIA WITH l-TERTIARY-BUTYL-3-ARYL-2, 1 H (4H! BENZISOXAZOLINES AND COMPOSITIONS I THEREFOR N o I Y Y I Tertiary-butyl3-aryl-2, l-bcnzisoxazolincs have prcwhcrcin 5' been dlsclosed us unable mmrmcdmms m R and R are independently hydrogen, halo of atomic Pat NO. ,2 1.1 1- T OUT k gm P f' v eight of from 18 to 80, lower alkyl of to 4 earlnglcill has been hcrcmforc llssoclmcd hon atoms, lower alkox of l to 4 carbon atoms such compounds- I and tril'lurormethyl. and
The preserrt Invention IHVOlVCS the dlscovery that w and Y are independently hydrogen. halo ofalomie Cenflm y y y l l-bllnllsoxilllllncs weight of from [8 to 80 lower alkvl of l to 4 ear- Phllrmucologlclll p p P Y- f hon atoms lower alkoxy of l to 4 earhon atoms or has been found that these compounds possess hypollplfl m-L dQmiC prope e m ng them p y suimhlk for The compounds of formula I may he prepared in acmclrporutmn Phllrmwicuncul p cordanee with the two sle 1 procedure disclosed in U5v According lo U11 IH H H. ll ypo p Qflcfl 1S Pat. No. 354 I 5 I alluded to above. Essentially. the dlsplaycd by compounds of formula I: procedure involves the following reaction scheme:
Step 1 3 1 H J' H R LBuOH/HBF 0 0 Br, (H NO R Y C Y ll Ill Step 2 CH" CH:
CH;C'-CH; (H -C-CH e e I N+ N 0 BF, 0 Y
Y R R wherein R. R. Y and Y are as defined above.
The preparation of compounds 111 by the reaction of Step I may be carried out at temperatures in the range of from C. to bllC.. preferably C. to 35C.. and conveniently at about room temperature. A strong inorganic acid adapted to form a crystalline quaternary salt is required. Acids of this type are known. and inelude by way of illustration. tetratluoroboric acid and perchloric acid. The reaction is carried out in the presence of an organic solvent which is inert and adapted to dissolving the reactants and product compound of Formula lll. Suitable solvents are known and available. and include by way of illustration. the nitrated hydro carbons. e.g.. nitromethane. The resulting reaction product of Formula lll may be isolated from the reaction of Step 1 by working up by conventional techniques.
The preparation of compounds l involving the reduction of compound lll is desirably effected with a suitable borohydride as the reducing agent. more desirably, an alkali metal borohydride such as sodium borohydride. followed by working up in a manner conventional for borohydride reductions. The reduction may be carried out at temperatures in the range of 0C. to t-il)(.. preferably between l5C. to C. The reaction is carried out in an organic solvent of known type. preferably a lower alkanol such as methanol or ethanol. preferably ethanol. The reaction products of Formula I may be isolated from the reaction mixture of Step 2 by working up by conventional techniques.
The compounds of structural Formula l are useful because they possess pharmacological activity in animals. In particular. the compounds are useful as hypolipi delnic agents. as evidenced. for example. by lowering cholesterol and triglyceride blood serum levels in tests on a group of white rats which are given typically l5I5U milligrams per kilogram of body weight per diem of the compound orally. for 6 days. followed by extraction with isopropanol of serum or plasma after ancsthetiIing the rates with sodium hexobarbital. and then noting the cholesterol and triglyceride contents as compared to those of a control group. The cholesterol and triglyceride contents are determined by the methods described by Lofland. H.B.. Anal. Biochem. 9:393 1964111 Tcchnicon method N 24al1and (i. Kessler and H. Ledcrcr. Technicon Symposium, Mediad Inc. New York. Pages 345*347 (I965). respectively. For such usage. the compounds may be administered orally or parenterally. preferably orally. and in admixture with comentional pharmaceutical carriers. The dosage administered may vary depending upon known variables such as the particular compound employed and the severity of the condition being treated. In general, satisfactory results are obtained when administered at a daily dosage of from about 2 milligrams to about 250 milligrams per kilogram of animal body weight, preferably givcn orally and in divided doses. 2 to 4 times a day. or in sustained release form. For most mammals the total daily dosage is from about 140 milligrams to about l.5(l(l milligrams of the compound. and dosage forms suitable for internal administration comprise from about to 750 milligrams of the compound in admixture with a solid or liquid pharmaceutically acceptable carrier or diluent.
For above usage, the compounds of structural formula 1 may be administered orally in such forms as tablets. dispersible powders. granules. capsules. syrups and elixirs; and parenterally as solutions, suspensions, dispersions. emulsions, and the like. eg, a sterile injectable solution such as an aqueous suspension. These pharmaceutical preparations may contain 0.5 percent up to about 90 percent of the active ingredient in combination with the carrier or adjuvant. more usually between 3 percent and percent by weight. Such compositions may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions. and such compositions may contain one or more conventional adjuvants. such as sweetening agents. flavoring agents, coloring agents and pre serving agents. in order to provide an elegant and palatable preparation. Tablets may contain the active ingredient in admixture with conventional pharmaceutical excipients. e.g.. inert diluents such as calcium phosphate. calcium sulphate dihydrate, lactose and talc. granulating and disintegrating agents, e.g., starch and alginic acid. binding agents. e.g.. starch. gelatin, polyvinyl pyrrolidone and acacia. and lubricating agents, cg. magnesium stearate. stearic acid and talc. The tablets may be uncoated or coated by known techniques to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. Similarly. suspensions, syrups and elixirs may contain the active ingredient in admixture with any of the conventional excipients utilized for the preparation of such compositions. e.g.. suspending agents (methylcellulose. tragacanth and sodium alginate). wetting agents (lecithin. polyoxyethylene stearate and polyoxyethylene sorbitan monooleate) and preservativ es (ethylp-hydroxyhenzoate Capsules may contain the active ingredient alone or admixed with an inert liquid or solid diluent. cg. calcium car' bonate. calcium phosphate. kaolin. peanut oil. sesame oil and corn oil. The preferred pharmaceutical compositions from the standpoint of preparation and ease of administration are solid compositions. particularly hardfilled capsules and tablets.
Capsules containing the ingredients indicated below may be prepared by conventional techniques and are useful in reducing the blood levels of cholesterol and triglycerides in mammals at a dose of one capsule 2 to 4 times a day.
The following examples are merely illustrative of specific compounds of the invention and the manner in which they may be prepared.
EXAMPLE I l-Tertiary-butyl-S-chloro-6-mcthyl-3-phenyl-2. l
benzisoxazoline Step A: Preparation of l-tert.-hutyl-S-chloro-o-methyl-3-phenyl-2, henzisoxazolium tetrafluorohoratc precipitate formed is isolated by filtration to yield ltert.-hutyl-Schloro 6-methyl-3-phenyl-Z. l henzisoxazolium tetrafluorohorate, m.p. l64l66C.
Step B: Preparation of l-tert.-hutyl-5-chloro-o-mcthyl-3-phenyl-2. lhenzisoxazoline To a suspension of 24 g. of l-tert.-hutyl-5-chloro-6- methyl-3-phenyl-2. I -henzisoxazolium tetrafluorohorate in 200 ml. otahsolute ethanol is added in portions over minutes. 3.5 g. of sodium horohydride. The suspended solid slowly goes into solution and some heat is evolved. The colorless solution is allowed to stand at room temperature for l hour, during which time a crystalline precipitate is formed. The mixture is then cooled [ice/water) and diluted with an equal volume of water. The solid so produced is isolated by filtration and recrystallized from 50 percent aqueous ethanol to yield l-tert.-hutyl-S-chloro-6-methyl-3-phenyl- 2.1-henzisoxazoline. m.p. l l4l 15C.
EXAMPLE 2 l-'Iertiary-hutyl-5-chloro-3-phenyl-2, lhenzisoxazolinc Step A: Preparation of henzisoxazole, 19 ml. of terL-hutanol and 250 ml. of nitromethane is added dropwise 32 g. of a percent aqueous solution oftetrafluorohoric acid. The resulting suspension is stirred at room temperature for 24 hours. The reaction mixture is diluted with 1.5 liters of diethyl ether and the crystalline precipitate formed is isolated by filtration to yield l-tert.-hutyl-S-chloro-3-phenyl- 2. l -henzisoxazolium tetrafluoroborate. m.p. l l2l l4C.
Step B: Preparation of l-tert.-hutyl-5-chloro-3-phenyl-2. l -henzisoxazoline To a suspension of 8 g. of l-tert. hutyl-5chloro-3- phenyl-Z,l-henzisoxazolium tetrafluorohorate in I35 ml of absolute ethanol is added in portions over 15 minutes. I g. of sodium borohydride. The suspended solid slowly goes into solution and some heat is evolved. The colorless solution is stirred for 1 hour at room temperature. during which time a crystalline precipitate is formed. The precipitate is washed with water and methylene chloride. and the methylene chloride layer separated, dried. evaporated in vacuo to dryness and the residue recrystallized from ether/hexane to ohtain l-tert.-hutyl-5-chloro-3-phenyl 2. I henzisoxazoline. m.pv h5-67C.
EXAMPLE 3 Following essentially the procedure of Example and using in place of 5-chloro-3-phenyl-2.l henziso azole in Step A. an equivalent amount of a. o-methyl-fl-phenyl-Z. l -henzisoxa/.ole.
h. 5-l-iromo-(i-methyl-3-phenyl-2. l -henzisoxazole. c. 5-hromo-3-phenyl-2, l -henzisoxamle. d. 5-ehloro-6-ethyl-3phcnyl-2,lhenzisoxa/ole. e. (i-ethyl3-phenyl-2. l-henzisoxazole. l. 5-hromo-(i-ethyl3phenyl-2. l hen7isoxa/.ole there is obtained a. l-tert.-hutyl-6-methyl-B-phenylQ l-henzisoxazolium tetratluorohorate.
l-tert.-hutyl-5-hromo-(i-methyIJ-phenyl-2. henzisoxazolium tetrailuorohorate. c. ltert.hutyl-5hromo-3-phenyl-2 l henzisoxazolium tetrafluorohorate.
l-tert.-hutyl-5-chloro-o-ethyl-3-phenyl 2. l benzisoxazolium tetrafluorohorate. e. l-tert.-hutyl-o-ethyl-3-phenyl-2.l-hemisoxazolium tetrat'luorohorate. l. l-tert.-hutyl-5-hromo-o-ethyl-3-phenyl-Z, I
benzisoxazolium tetrafluorohorate. respectively.
EXAMPLE 4 Following essentially the procedure of Example 2, and using in place of l-tert.-hutyl-5-ehloro-3-phenyl- 2.l-henzisoxazolium tetrallurorhorate in Step B. an equivalent amount of the respective compounds obtained in Example 3. there is obtained a. l-tert.-hutyl-6-methyl-3-phenyl-2, l-henzisoxazoline. h. l-tert.-hutyl-S-hromo 6methyl-3-phenyl-2. l
henzisoxazoline,
c. l-tert.-hutyl-5-hromo-3-phenyl-2. l-henzisoxazoline.
d. l-tert.-hutyl-ichloro-o-ethyl-3-phenyl-2. I
henzisoxazoline.
e. l-tert.-hutyl-6-ethyI-3-phenyl-2. l -henzisoxazoline.
f. l-tert.-butyl-5-hromo-6-ethyl-3-phenyl-2. l
benzisoxazoline. respectively.
What is Claimed is:
l. A method for treating lipidemia comprising administering to mammals in need of said treatment an effec tive amount of a compound of the formula:
wherein R and R are independently hydrogen, halo of atomic weight of from l8 to 8U, lower alkyl of l to 4 carbon atoms. lower alkoxy of l to 4 carbon atoms or trit'luoromethyl.
Y and Y are independently hydrogen, halo of atomic weight of from l8 to 80 lower alkyl of l to 4 carbon atoms. lower alkoxy of l to 4 carbon atoms or tril'luoromethyl.
2. The method of claim 1 wherein the compound administered is:
wherein R and R are defined in claim 1.
3. The method of claim I wherein the compound administered is:
wherein R is as defined in claim I.
4. The method of claim I wherein the compound administered is:
Ill
Y I wherein R and R are independently hydrogen halo of atomic weight of from 18 to 80 lower alkyl of l to 4 carbon atoms lower alkoxy of l to 4 carbon atoms or trifluoromethyl, and Y and Y are independently hydrogen. halo of atomic weight of from lit to 80. lower alkyl of l to 4 can hon atoms, lower alkoxy of l to 4 carbon atoms or tritluoromethyl and a pharmaceutically acceptable carrier therefor. said compound being present in said composition to the extent of from about 35 milligrams to about 750 milligrams. 9. The pharmaceutical composition of claim 8 wherein the compound is:
(H ("-01 R" N 9 10 wherein R and R are as defined in claim 8.
10. The pharmaceutical composition of claim 8 .414 wherein the compound is: (H
R 0 G N R H wherein R is as defined in claim 8. I2. The pharmaceutical composition of claim 8 wherein the compound is l-tcrtiary-hutyl-S-chlorohmethyIBphenyI-Z l -hcnzisoxazoline.
13. The pharmaceutical composition of claim 8 wherein the compound is l-tertiary-hutyl-5-chloro-3- wherein R is as defined in claim 8.
phcnyl-Z, l-bcnzisoxazoline.
11. The pharmaceutical composition of claim 8 2( wherein the compound is: :k

Claims (13)

1. A METHOD FOR TREATING LIPIDEMIA COMPRISING ADMINISTERING TO MAMMALS IN NEED OF SAID TREATMENT AN EFFECTIVE AMOUNT OF A COMPOUND OF THE FORMULA:
2. The method of claim 1 wherein the compound administered is:
3. The method of claim 1 wherein the compound administered is:
4. The method of claim 1 wherein the compound administered is:
5. The method of claim 1 wherein the compound is administered in a daily amount of from 140 to 1,500 milligrams.
6. The method of claim 1 wherein the compound administered is 1-tertiary-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazoline.
7. The method of claim 1 wherein the compound administered is 1-tertiary-butyl-5-chloro-3-phenyl-2,1-benzisoxazoline.
8. A pharmaceutical composition in unit dosage form useful in the treatment of lipidemia in mammals comprising as the active ingredient thereof a compound of the formula:
9. The pharmaceutical composition of claim 8 wherein the compound is:
10. The pharmaceutical composition of claim 8 wherein the compound is:
11. The pharmaceutical composition of claim 8 wherein the compound is:
12. The pharmaceutical composition of claim 8 wherein the compound is 1-tertiary-butyl-5-chloro-6-methyl-3-phenyl-2,1-benzisoxazoline.
13. The pharmaceutical composition of claim 8 wherein the compound is 1-tertiary-butyl-5-chloro-3-phenyl-2,1-benzisoxazoline.
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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3541151A (en) * 1968-12-26 1970-11-17 Sandoz Ag Preparation of tertiary-butylamino-benzophenones

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3541151A (en) * 1968-12-26 1970-11-17 Sandoz Ag Preparation of tertiary-butylamino-benzophenones

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