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US3174994A - Hypocholesterolemic n-oxide compositions - Google Patents

Hypocholesterolemic n-oxide compositions Download PDF

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US3174994A
US3174994A US169944A US16994462A US3174994A US 3174994 A US3174994 A US 3174994A US 169944 A US169944 A US 169944A US 16994462 A US16994462 A US 16994462A US 3174994 A US3174994 A US 3174994A
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oxide
carbon atoms
diphenylpentanoate
diethylaminoethyl
alkyl
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US169944A
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Blaine M Sutton
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Smith Kline and French Laboratories Ltd
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Smith Kline and French Laboratories Ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C291/00—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00
    • C07C291/02—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds
    • C07C291/04—Compounds containing carbon and nitrogen and having functional groups not covered by groups C07C201/00 - C07C281/00 containing nitrogen-oxide bonds containing amino-oxide bonds

Definitions

  • the livers remained normal. Furthermore, the known pharmacodynamic activity of the parent compounds, such as spasmolytic or potentiating activity, has been favorably altered in the N-oxide derivatives.
  • the compounds of this invention are N-oxide aminoalkyl esters of diphenylacetic acids but are more specifically represented by the following formula:
  • R is alkylene having from 2 to 6 carbon atoms inclusive, separating the amine and the carboxylic functions by at least 2 carbon atoms, ethylene is preferred;
  • R is alkyl or alkenyl having from 1 to 8 carbon atoms inclusive
  • R and R are alkyl of from 1 to 8 carbon atoms inclusive or benzyl.
  • IT is alkylene of 2 to 4 carbon atoms; R is an alkyl of from 3 to 4 carbons; and R and R are alkyl of from 1 to 4 carbon atoms.
  • the preferred and advantageous compound of this invention is fi-diethylaminoethyl 2,-2-diphenylpentanoate N- oxide and its salts, especially the hydrochloride.
  • addition compounds may include hydrates, acid addition salts or alkyl halide addition salts.
  • the acid addition salts are those derived from inorganic or organic acids well-known to the art as being pharmaceutically acceptable, for example the hydrohalide such as hydrochloride or hydrobromide, the sulfate, phosphate, maleate or ethane disulfomate.
  • alkyl halide addition compounds are also those well-known to the art as being acceptable, such as the methyl iodide, methyl chloride, crotyl chloride, benzyl chloride, ethyl bromide, ethylene bromohydrin, ethyl chloride, dimethyl sulfate, ethyl toluene sulfonate, etc. salts.
  • N-oxide derivatives of Formula I are prepared by reacting the known tertiary amine bases with a mild oxidizing agent preferably hydrogen peroxide usually in excess at about room temperature in a solvent in which the base is substantially soluble such as in an aqueous lower alkyl alcohol solvent, preferably methanol, isopropanol or ethanol.
  • a mild oxidizing agent preferably hydrogen peroxide usually in excess at about room temperature
  • a solvent in which the base is substantially soluble
  • an aqueous lower alkyl alcohol solvent preferably methanol, isopropanol or ethanol.
  • the compounds of Formula I in which R is alkenyl must be oxidized carefully so that the vinylene moiety is retained. In this regard about 10% hydrogen peroxide concentration in the oxidation media is preferred. Also the reaction mixture should be preferably run in a vessel protected from light.
  • tertiary amines which act as starting materials for the compounds of this invention are well known to the art. They are prepared for instance as reported by Craig et al., J. Am. Chem. Soc, 73, 1339 (1951), Larsen et al., J. Am. Chem. Soc., 71, 532 (1949) or more specifically by Fellows in US. Patent No. 2,807,566.
  • the amine oxide derivatives claimed herein are administered to hypercholesterolemic mammal patients in dosage unit form combined with an inert pharmaceutical carrier such as lactose, talc etc. in the form of a pill, capsule, aqueous suspension etc.
  • the dosage unit will contain from about 25300 mg. of N-oxide and will be administered internally preferably orally from 1 to 6 times daily. A single large dose, i.e. from about 200- 250 mg., daily is preferred.
  • Example 1 A solution of 25 g. (0.066 mole) of B-diethylaminoethyl 2,2-diphenylpentanoate hydrochloride in a minimum of distilled water is adjusted to pH 8 with dilute sodium hydroxide. The suspension is extracted with ether. The washed ethereal extract is evaporated to leave the oily base which is dissolved in 200 ml. of methanol and reacted with 60 ml. of 30% hydrogen peroxide solution at room temperature for three days.
  • the oxidation mixture is stirred and cooled while 0.5 g. of platinum oxide is added. After stirring for three hours the filtered reaction mixture is concentrated in vacuo to about one third its volume. The concentrated solution is made up to 250 ml. then saturated with sodium chloride to give an oily layer which is removed and dried. This material is the desired fi-diethylaminoethyl 2,2-diphenylpentanoate N-oxide.
  • a third portion (500 mg.) in ether is treated on the 3 steam bath with an excess of methyl iodide to give the methiodide.
  • Example 2 The N-oxide derivatives of the following compounds are prepared by substituting e'quimolar quantities of the known tertiary bases (US. Patent No. 2,807,566) for the starting material in Example 1.
  • This base in ether, is reacted with sulfuric acid to give the Sulfate salt.
  • Example 4 A solution of 3.5 g. of B-dibutylaminopropyl 2,2-diphenylpentanoate, prepared by reacting ,B-dibutylaminopropanol in the Craig reaction, in ethanol is reacted with 10 ml. of hydrogen peroxide solution at room temperature overnight and Worked up as in Example 1 to give fi-dibutylaminopropyl 2,2-diphenylpentanoate N-oxide.
  • Example 5 A solution of 5.0 g. of B-dimethylaminoethyl 2,2-diphenylpropionate, prepared from the known ingredients 2,2-diphenylpropionic acid chloride and B-dimethylaminoethanol by the Craig method, in methanol is reacted with ml. of hydrogen peroxide solution for two days.
  • Working up as in Example 1 gives the desired fl-dirnethylaminoethyl 2,2-diphenylpropionate N-oxide and itsphosphate salt.
  • R is alkylene having from 2 to 6 carbon atoms; R is alkyl having from 1 to 8 carbon atoms; and R and R respectively are members selected from the group consisting of alkyl having from '1 to 8 carbon atoms and benzyl.
  • R is alkylene having from 2 to 4 carbon atoms;
  • R is an alkyl having from 3 to 4 carbon atoms;
  • R and R respectively are alkyl having from 1 to 4 carbon atoms; and X is a nontoxic, pharmaceutically acceptable anion.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Description

United States atent 3,174,994 HYPOCHGLESTEROLEMIC N-OXIDE COMPOSITTGNS Blaine M. Sutton, Philadelphia, Pa, assignor to Smith Kline & French Laboratories, Philadelphia, Pa, a corporation of Pennsylvania No Drawing. Filed Sam. 30, 1962, Ser. No. 169,944 7 Claims. (Cl. 260-469) This invention relates to new compounds of utility as cholesterol-lowering agents. More specifically, these compounds are N-oxide derivatives of known aminoalkyl esters of substituted diphenylacetic acids.
This invention is surprising in that I have found that certain known aminoalkyl esters of various diphenyl acetic acids have potent hypocholesterolemic activity but with toxic manifestations concomitantly occurring, such as enlarged or fatty infiltrated livers. When the new N- oxide derivatives of these parent compounds were prepared and tested, I unexpectedly found them to retain this .high hypocholesterolemic activity but without side efiiects,
for example, the livers remained normal. Furthermore, the known pharmacodynamic activity of the parent compounds, such as spasmolytic or potentiating activity, has been favorably altered in the N-oxide derivatives.
The compounds of this invention are N-oxide aminoalkyl esters of diphenylacetic acids but are more specifically represented by the following formula:
in which:
R is alkylene having from 2 to 6 carbon atoms inclusive, separating the amine and the carboxylic functions by at least 2 carbon atoms, ethylene is preferred;
R is alkyl or alkenyl having from 1 to 8 carbon atoms inclusive; and
R and R are alkyl of from 1 to 8 carbon atoms inclusive or benzyl.
The preferred compounds of this invention are those in which:
IT is alkylene of 2 to 4 carbon atoms; R is an alkyl of from 3 to 4 carbons; and R and R are alkyl of from 1 to 4 carbon atoms.
The preferred and advantageous compound of this invention is fi-diethylaminoethyl 2,-2-diphenylpentanoate N- oxide and its salts, especially the hydrochloride.
Also included in this invention, represented by structural Formula I, are various nontoxic, pharmaceuticallyacceptable addition compounds. Such addition compounds may include hydrates, acid addition salts or alkyl halide addition salts. The acid addition salts are those derived from inorganic or organic acids well-known to the art as being pharmaceutically acceptable, for example the hydrohalide such as hydrochloride or hydrobromide, the sulfate, phosphate, maleate or ethane disulfomate. The alkyl halide addition compounds are also those well-known to the art as being acceptable, such as the methyl iodide, methyl chloride, crotyl chloride, benzyl chloride, ethyl bromide, ethylene bromohydrin, ethyl chloride, dimethyl sulfate, ethyl toluene sulfonate, etc. salts.
The structures of these addition compounds may be represented as:
dd'l lfidd Patented Mar. 23, 1965 ICC FORMULA II by dissolving the parent compound of Formula I in a suitable solvent, such as a lower alkyl alcohol, reacting with one mole or preferably an excess of the desired acid or reactive halide to form the derivative of Formula II.
The derivatives of Formula II, particularly those in which R is hydrogen, are preferred.
The N-oxide derivatives of Formula I are prepared by reacting the known tertiary amine bases with a mild oxidizing agent preferably hydrogen peroxide usually in excess at about room temperature in a solvent in which the base is substantially soluble such as in an aqueous lower alkyl alcohol solvent, preferably methanol, isopropanol or ethanol.
The compounds of Formula I in which R is alkenyl must be oxidized carefully so that the vinylene moiety is retained. In this regard about 10% hydrogen peroxide concentration in the oxidation media is preferred. Also the reaction mixture should be preferably run in a vessel protected from light.
The tertiary amines which act as starting materials for the compounds of this invention are well known to the art. They are prepared for instance as reported by Craig et al., J. Am. Chem. Soc, 73, 1339 (1951), Larsen et al., J. Am. Chem. Soc., 71, 532 (1949) or more specifically by Fellows in US. Patent No. 2,807,566.
The amine oxide derivatives claimed herein are administered to hypercholesterolemic mammal patients in dosage unit form combined with an inert pharmaceutical carrier such as lactose, talc etc. in the form of a pill, capsule, aqueous suspension etc. The dosage unit will contain from about 25300 mg. of N-oxide and will be administered internally preferably orally from 1 to 6 times daily. A single large dose, i.e. from about 200- 250 mg., daily is preferred.
The following examples will illustrate the ease of preparation of the compounds of this invention and the availability of starting materials therefore but are not to be construed as limiting the scope of this invention.
Example 1 A solution of 25 g. (0.066 mole) of B-diethylaminoethyl 2,2-diphenylpentanoate hydrochloride in a minimum of distilled water is adjusted to pH 8 with dilute sodium hydroxide. The suspension is extracted with ether. The washed ethereal extract is evaporated to leave the oily base which is dissolved in 200 ml. of methanol and reacted with 60 ml. of 30% hydrogen peroxide solution at room temperature for three days.
The oxidation mixture is stirred and cooled while 0.5 g. of platinum oxide is added. After stirring for three hours the filtered reaction mixture is concentrated in vacuo to about one third its volume. The concentrated solution is made up to 250 ml. then saturated with sodium chloride to give an oily layer which is removed and dried. This material is the desired fi-diethylaminoethyl 2,2-diphenylpentanoate N-oxide.
Part of this oil is taken up in isopropanol and treated with gaseous hydrogen chloride to give a white product, the hydrochloride derivative, melting at 1423 C. Drying the sample at C. lowers the melting point to -135 C.
Another portion of the base (1 g.) in isopropanol is treated with an excess of ethyl bromide to give the ethobromide derivative.
A third portion (500 mg.) in ether is treated on the 3 steam bath with an excess of methyl iodide to give the methiodide.
Example 2 The N-oxide derivatives of the following compounds are prepared by substituting e'quimolar quantities of the known tertiary bases (US. Patent No. 2,807,566) for the starting material in Example 1.
fi-diethylaminoethyl 2,2-diphenyl-4-methylpentanoate B-dimethylaminoethyl 2,2-diphenylpentanoate B-piperidinoethyl 2,2-diphenylpentanoate B-benzylmethylaminoethyl 2,2-diphenylpentanoate hydrobromide [3-(cyclopentylethylamino)-ethy1 2,2-diphenylpentanoate hydrochloride ,8-(cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate ,B-dibenzylaminoethyl 2,2-diphenylhexanoate 1-diethylamino-2-ethyl-3-propyl 2,2-diphenyl-6-pentenoate l-dethylamino-G-hexyl 2,2-diphenyl-4-pentenoate hydrochloride l-diethylamino-S pentyl 2,2-diphenyl-4-pentenoate sulfate fl-diethylaminoethyl 2,2-diphenyl-4-pentenoate benzoate ,B-dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate -dibenzylaminopropyl 2,2-diphenyl-4-hexen0ate hydrochloride ,B-diethylaminoethyl -2,2-ditolylpropionate (US. Patent No. 2,423,025 I B-diethylaminoethyl Patent No. 641,573)
B-diethylaminoethyl 2,2-di(p-ethylphenyl)propionate (British Patent No. 641,573)
v-diethylaminobutyl 2,2-dixy1ylpropi0nate (British Patent No. 641,573)
2,2-dianisylpropionate (British Example 3 A solution of 6.4 g. of y-diethylaminohexyl 2,2-diphenylpentanoate, prepared from reacting 'y-diethylaminohexanol with the acid chloride of 2,2-diphenylpentanoic acid by the Craig method, in methanol is reacted with 15 ml. of hydrogen peroxide solution and Worked up as in Example 1 to give y-diethylaminohexyl 2,2-diphenylpentanoate N-oxide.
This base, in ether, is reacted with sulfuric acid to give the Sulfate salt.
Example 4 A solution of 3.5 g. of B-dibutylaminopropyl 2,2-diphenylpentanoate, prepared by reacting ,B-dibutylaminopropanol in the Craig reaction, in ethanol is reacted with 10 ml. of hydrogen peroxide solution at room temperature overnight and Worked up as in Example 1 to give fi-dibutylaminopropyl 2,2-diphenylpentanoate N-oxide.
This base, in ether, is reacted with an excess of methyl iodide at reflux to give the methiodide addition compound.
Example 5 A solution of 5.0 g. of B-dimethylaminoethyl 2,2-diphenylpropionate, prepared from the known ingredients 2,2-diphenylpropionic acid chloride and B-dimethylaminoethanol by the Craig method, in methanol is reacted with ml. of hydrogen peroxide solution for two days. Working up as in Example 1 gives the desired fl-dirnethylaminoethyl 2,2-diphenylpropionate N-oxide and itsphosphate salt.
A sample of 500 mg. of the N-oxide in ether is reacted with ethyl bromide on the steam bath to give the ethob pm d a dit on mp 4 Example 6 A solution of 2.0 g. of fi-diethylaminoethyl 2,2-diphenyl-4-pentenoate (US. Patent No. 2,807,566) in aqueous methanolic solution with a 10% hydrogen peroxide concentration is allowed to stand overnight in the dark at room temperature. After working up as in Ex ample 1, the desired B-diethylaminoethyl 2,2-diphenyl-4- pentenoate N-oxide is obtained, MP. 87-90 C.
What is claimed is:
l. A compound of the formula:
0 fl 5)2 C02-Rl TRiR in which R is alkylene having from 2 to 6 carbon atoms; R is alkyl having from 1 to 8 carbon atoms; and R and R respectively are members selected from the group consisting of alkyl having from '1 to 8 carbon atoms and benzyl. 2. A compound of the formula:
e (CGH5)2-CCO2-RNOR4 X in which R is alkylene having from 2 to 6 carbon atoms; R is alkyl having from 1 to 8 carbon atoms; and R and R respectively are members selected from the group consisting of alkyl having from 1 to 8 carbon atoms and benzyl; R is a member selected from the group consisting of hydrogen and alkyl having from 1 to 5 carbon atoms; and X represents a nontoxic, pharmaceutically acceptable anion. 3. A compound of theformula:
in which R is alkylene having from 2 to 4 carbon atoms; R is an alkyl having from 3 to 4 carbon atoms;
R and R respectively are alkyl having from 1 to 4 carbon atoms; and X is a nontoxic, pharmaceutically acceptable anion.
4. B-diethylaminoethyl 2,2-diphenylpentanoate N-oxide hydrochloride.
5. ,B-diethylaminoethyl 2,2-diphenylpentanoate N-ox ide.
6. fl-diethylaminoethyl 2,2-diphenylpentanoate N-oxide methiodide.
7. p-diethylaminoethyl 2,2-diphenyl-4-pentenoate N- oxide.
Relerences Cited by the Examiner UNITED STATES PATENTS 2,079,962 5/37 Miescher et al. 260-469 2,423,025 6/47 Holmes et a1 260469 2,500,131 3/50 Linsker et a1. 260-279 2,518,130 8/50 Evans et a1. 260250= 2,807,566 9/57 Fellows 260469 OTHER REFERENCES Culvenor: Rev. Pure App. Chem, vol. 3, pp. -6 (1953).
LEON ZITVER, Primary Examiner.
DUVAL T. MCCUTCHEN, Examiner.

Claims (1)

1. A COMPOUND OF THE FORMULA:
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132327A (en) * 1989-10-13 1992-07-21 National Research Development Corporation Anti-cancer compounds
US5447950A (en) * 1991-04-12 1995-09-05 British Technology Group Limited Anthra[1,9-c,d]pyrazol-6-(2H)-ones useful for treating anaerobic bacterial infections
US5461078A (en) * 1991-04-12 1995-10-24 British Technology Group Limited Anti-cancer compounds

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2079962A (en) * 1934-07-12 1937-05-11 Soc Of Chemical Ind Basic esters of polyarylacetic acids and process of making the same
US2423025A (en) * 1942-03-31 1947-06-24 American Cyanamid Co Alkamine esters of diarylpropionic acids
US2500131A (en) * 1945-06-27 1950-03-07 Ralph L Evans Di-nu-oxides of amino-substituted acridines and quinolines
US2518130A (en) * 1945-04-26 1950-08-08 Evans N-oxides of tertiary amines and process of preparing same
US2807566A (en) * 1953-10-30 1957-09-24 Smith Kline French Lab Method of potentiating drugs affecting the central nervous system and compositions therefor

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2079962A (en) * 1934-07-12 1937-05-11 Soc Of Chemical Ind Basic esters of polyarylacetic acids and process of making the same
US2423025A (en) * 1942-03-31 1947-06-24 American Cyanamid Co Alkamine esters of diarylpropionic acids
US2518130A (en) * 1945-04-26 1950-08-08 Evans N-oxides of tertiary amines and process of preparing same
US2500131A (en) * 1945-06-27 1950-03-07 Ralph L Evans Di-nu-oxides of amino-substituted acridines and quinolines
US2807566A (en) * 1953-10-30 1957-09-24 Smith Kline French Lab Method of potentiating drugs affecting the central nervous system and compositions therefor

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5132327A (en) * 1989-10-13 1992-07-21 National Research Development Corporation Anti-cancer compounds
US5447950A (en) * 1991-04-12 1995-09-05 British Technology Group Limited Anthra[1,9-c,d]pyrazol-6-(2H)-ones useful for treating anaerobic bacterial infections
US5461078A (en) * 1991-04-12 1995-10-24 British Technology Group Limited Anti-cancer compounds

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