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Publication numberUS3787423 A
Publication typeGrant
Publication dateJan 22, 1974
Filing dateMar 8, 1972
Priority dateMar 8, 1972
Also published asDE2311240A1
Publication numberUS 3787423 A, US 3787423A, US-A-3787423, US3787423 A, US3787423A
InventorsW Bolhofer
Original AssigneeMerck & Co Inc
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Beta-picolyloxy ester of(3-trifluoromethylphenoxy)(4-chlorophenyl)acetic acid and derivatives
US 3787423 A
Abstract  available in
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Claims  available in
Description  (OCR text may contain errors)

United States Patent 3,787,423 fl-PICOLYLOXY ESTER 0F (3-TRIFLUOR0- ME'IHYLPHENOXY) (4-CHLOROPHENYL) ACETIC ACID AND DERIVATIVES William A. Bolhofer, Frederick, Pa., assignor to Merck & Co., Inc., Rahway, NJ. No Drawing. Filed Mar. 8, 1972, Ser. No. 232,966

Int. Cl. C07d 31/36 US. Cl. 260295.5 R 3 Claims ABSTRACT OF THE DISCLOSURE Heterocyclic methyl esters and N-(lower alkanesulfonyl) or N-(2-sulfoethyl)amides of (3-trifiuoromethylphenoxy) (4-chlorophenyl)acetic acid which are useful in the treatment of atherosclerosis. The heterocyclic methyl esters and N-(lower alkanesulfonyl) or N-(2-sulfoethyl)- amides of (3-trifinoromethylphenoxy) (4-chlorophenyl)- acetic acid are prepared by reacting a (3-trifluoromethylphenoxy) (4-chlorophenyl)acetyl halide with a hydroxymethyl substituted heterocycle, with an alkali metal salt of a lower alkanesulfonamide or Z-aminoethanesulfonic acid.

This invention relates to a new class of heterocyclic methyl esters and N-(lower alkanesulfonyl) or N-(2-sulfoethyl)amides of (3-trifiuoromethylphenoxy) (4-chlorophenyl) acetic acid and to the non-toxic, pharmacologically acceptable acid addition salts of the basic heterocyclic compounds and alkali metal salts of the sulfo-substituted compounds which compounds have hypocholesterolemic activity and thus are useful in the treatment of atherosclerosis.

Clinical studies show that cholesterol apparently plays a major role in the formation of atherosclerotic plaques by accelerating the deposition of blood lipids on the arterial wall. The purpose of this invention is to disclose a new class of chemical compounds which efiectively reduce the concentration of cholesterol, triglycerides and other lipids in blood serum and thus ameliorate the condition usually associated with lipid deposition.

The heterocyclic methyl esters and the N-(lower alkanesulfonyl) and N-(2-sulfoethyl)amides of (3-trifluoromethyl) (4-chlorophenyl)acetic acids of this invention are compounds having the following structural formula:

CFa

wherein R is a heterocyclic methoxy radical including pyridylmethoxy, for example, 3-pyridylmethoxy and the like, halo-substituted pyridylmethoxy, for example, 5- fiuoro-3-pyridylmethoxy, 5-chloro-3 pyridylmethoxy, 6- chloro-3-pyridylmethoxy and the like, methyl substituted pyrazolylmethoxy, for example, 5 methyl 3-pyrazolylmethoxy and the like, halo-substituted isoxazolylmethoxy, for example, 5-chloro-3-isoxazolylmethoxy and the like, methyl substituted isoxazolylmethoxy, for example, 5- methyl-3-isoxazolylmethoxy and the like, 2-methyloxazolinyl-4,4-dimethoxy, lower alkanesulfonylamino such as methanesulfonylamino, ethanesulfonylamino and the like or sulfoethylamino and n is an integer of one except when 3,787,423; Patented Jan. 22, 1974 R is 2-methyloxazolinyl-4,4-dimethoxy when n is an integer of two.

A preferred embodiment of this invention relates to compounds selected from the following formulae:

wherein R is 3-pyridylmethoxy (i.e., 3-picolyloxy) o1 sulfoethylamino. This group of compounds exhibits particularly good hypocholesterolemic and hypolipemic activity.

Included within the scope of this invention are the nontoxic, pharmacologically acceptable acid addition salts and the non-toxic, pharmacologically acceptable alkali metal salts of the instant products (I) which may be prepared by treating the products with an acid having a pharmacologically acceptable anion or with an alkali metal base, respectively. In general, any acid or base which will not cause an adverse physiological effect when ingested by the body system is considered as being within the scope of this invention; suitable acids include inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and the like and organic acids such as acetic acid, propionic acid, butyric acid, citric acid, tartaric acid and the like. Suitable alkali metal bases infllllde sodium hydroxide, potassium hydroxide and the The (3-trifiuoromethylphenoxy) (4-chlorophenyl)acetates and acetamides (I) are prepared by the reaction of a (3-trifluoromethylphen0xy) (4-chlorophenyl) acetyl halide with either a hydroxymethyl heterocyclic, an alkali metal salt of an alkanesulfonamide or 2-aminoethanesulfonic acid. The following equation illustrates this reaction:

0 OCIBH X wherein R and n are as defined above; X is halo, for example, chloro, bromo and the like and M is hydrogen or a cation derived from an alkali metal such as the cation derived from sodium and the like.

The reaction is conducted in a solvent which is inert or substantially inert to the reactants employed. Suitable solvents include tetrahydrofuran, diethyl ether, dimethylformamide, dioxane, chloroform, pyridine, triethylamine and the like. The process is conducted over a temperature range of from about 25 C. to ambient temperature with the initial mixing preferably occurring at a temperature in the range of from about 25 C. to C. and then continuing the reaction at a temperature in the range of 0 C. to ambient temperature.

When tanrine is employed, it is preferred to prepare its alkali metal salt in situ and to employ a slight excess of base to react with the hydrohalic acid produced in the reaction.

The following examples illustrate the novel products of this invention and the manner in which they may be prepared. The examples are illustrative only and it will be apparent to those skilled in the art that other reactants and reagents similar to those described in the examples may be employed to atford similar products.

EXAMPLE 1 3-pyridylmethyl (3-trifluoromethylphenoxy) (4-chlorophenyl) acetate hydrochloride Step A: (3-trifiuoromethylphenoxy) (4-chlorophenyl) acetyl chloride.-Thionyl chloride (44.5 g., 0.375 mole) is added over a five-minute period to a suspension of (3- trifluoromethylphenoxy) (4 chlorophenyDacetic acid (100 g., 0.30 mole) in 125 ml. of chloroform. The mixture is stirred at room temperature for 30 minutes and then heated under refiux for six hours. As soon as the temperature reaches the boiling point a clear homogeneous solution results. At the end of the reaction period, the solvent and volatile reaction products are removed by evaporation in vacuo. High purity (3-trifiuoromethylphenoxy) (4-chlorophenyl)acetyl chloride (105 g.) is obtained as a residual oil in almost theroretical yield.

Step B: 3-pyridylmethyl (3-trifluoromethylphenoxy) (4- chlorophenyl)acetate hydrochloride.A solution of 3- pyridylcarbinol (5.7 g., 0.0522 mole) in triethyla-mine (144 ml., 0.13 mole) is cooled to --15 C. To this solution is added (3-triflnoromethylphenoxy) (4-chlorophenyl) acetyl chloride (18 g., 0.0515 mole) in ether (25 ml.). The reaction mixture is stirred for four hours at C. and then at room temperature for four hours. The reaction mixture is filtered and the filtrate is washed successively with water, dilute sodium bicarbonate and then water until neutral. The ether solution is dried over magnesium sulfate, filtered and to this solution is added ethanolic HCl. An oil separated which slowly crystallized. The solid is collected and recrystallized from a mixture of isopropanol (30 ml.) and ether (30 ml.) to afford 8.6 g. of product. A small sample recrystallized for analysis has a melting point of l47-l49 C.

Elemental analysis for C H CIF NO -HCI: Cale. (percent): C, 55.04; H, 3.52; N, 3.06. Found (percent): C, 54.81;H, 3.41; N, 3.01.

EXAMPLE 2 4,4-bis [(B-trifluoromethylphenoxy) (4-chlorophenyl acetoxymethyl}2-methyloxazoline To a solution of 2-methyl-4,4-dihydroxymethyloxazoline (0.1 mole) in pyridine (25 ml.) is added a solution of (3 trifiuoromethylphenoxy) (4-chlorophenyl)acetyl chloride (0.2 mole) in ether (25 ml.). The reaction mixture is stirred for five hours at 5 C. and then at room temperature for two hours. The reaction mixture is filtered and the filtrate washed successively with water, dilute sodium bicarbonate and then water until neutral. The ether solution is dried over magnesium sulfate, filtered and the solvent removed to afford 4,4-bis [(3-trifluoromethylphenoxy (4 chlorophenyl)acetoxymethyl]2-rnethyloxazoline.

EXAMPLE 3 N-(Z-sulfoethyl) (3-trifluoromethylphenoxy) (4-chlorQ henyDaceta-mide sodium salt To a solution of Z-aminoethanesulfonic acid (5.38 g., 0.043 mole) in water (50 ml.), sodium hydroxide (l N, 43 ml.) and tetrahydrofuran (30 ml.) at 5 C. is added a solution of (3-trifluoromethylphenoxy) (4-chlorophenyl)acetyl chloride (15.0 g., 0.043 mole) in tetrahydrofuran (30 mL). The solution of the acid chloride is added in 1 ml. portions alternating with the addition of 1 ml. portions of sodium hydroxide (1 N). This addition is conducted at a temperature between 26 C. over a one hour period. The reaction mixture is allowed to stand overnight at room temperature. The solvents are removed under vacuum and the residue is treated with isopropyl ether and the insoluble material removed by filtration. The filtrate is concentrated under reduced pressure and the residue is crystallized from a mixture of n-butyl chloride (1 part), methylcyclohexane (6 parts and petroleum ether (5 parts) to afiord substantially pure product, melting point 175l80 C. with decomposition and preliminary softening at C.

Elemental analysis for C17H14C1F3NE1N05S'H3O: Calc. (percent): C, 42.73; H, 3.37; N, 2.93. Found (percent): C, 42.73; H, 3.18; N, 3.17.

The free acid is obtained by treating the sodium salt with an equivalent amount of dilute hydrochloric acid.

EXAMPLE 4 N-methanesulfonyl (3-trifluoromethylphenoxy) (4-chlorophenyl) acetamide (3 trifluoromethylphenoxy) (4 chlorophenyDacetyl chloride (0.02 mole) in tetrahydrofuran (50 ml.) is added over a 15-minute period to a solution of the sodium salt of methanesulfonamide (2.5 g., 0.021 mole) in tetrahydrofuran (50 ml.) at 0-5 C., under a nitrogen atmosphere. The mixture is stirred at 20 C. for 20 hours and then the solvent is evaporated under vacuum. The residue is dissolved in chloroform and the solution is extracted with water. The chloroform solution is dried over anhydrous magnesium sulfate, filtered and the sol vent removed to afiord N-methanesulfonyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetamide.

In a manner similar to that described in Example 1 for the preparation of S-pyridylmethyl (3-trifluoromethylphenoxy) (4-chlorophenyl)acetate hydrochloride all of the esters of this invention may be prepared. By substituting for the 3-pyridylcarbinol of Example 1, Step B, another hydroxymethyl substituted heterocyclic and by following substantially the procedure described therein, all of the heteroeyclie methyl esters of the invention may be obtained. The following equation together with Table I depict the products which may be obtained:

CF; CF;

TABLE I Example number R -0 CHr- I F OCH: I 01 --O OH I 8 0CH2Iu l' NiCHa What is claimed is: 1. A compound having the formula:

0 -O (Bi -R i o-r mo-ocn L 3. A compound according to claim 1 wherein R is ,B-picolyloxy.

References Cited UNITED STATES PATENTS 3,415,836 12/1968 Ekenstam et a1. 260-2955 R ALAN L. RO'TMAN, Primary Examiner US. Cl. X.R.

260307 F, 307 H, 310 R, 556 AR, 559* D; 424266, 272, 273, 309

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4055592 *Feb 13, 1976Oct 25, 1977Merck & Co., Inc.N-(Sulfo-lower alkyl) amides of (3-trifluoromethylphenoxy) (4-chlorophenyl)acetic acid
US7091230Feb 5, 2002Aug 15, 2006Merck & Co., Inc.2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US7495020Jan 18, 2006Feb 24, 2009Merck & Co., Inc.2-aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US8049022Jul 2, 2007Nov 1, 2011Merck Patent Gesellschaft Mit Beschrankter HaftungFluorosurfactants
US8067625Jul 2, 2007Nov 29, 2011Merck Patent Gesellschaft Mit Beschrankter HaftungFluorosurfactants
US20040092596 *Feb 5, 2002May 13, 2004Adams Alan D2-Aryloxy-2arylalkanoic acids for diabetes and lipid disorders
US20060122242 *Jan 18, 2006Jun 8, 2006Adams Alan D2-Aryloxy-2-arylalkanoic acids for diabetes and lipid disorders
US20090197201 *Jul 2, 2007Aug 6, 2009Wolfgang HierseFluorosurfactants
US20090264525 *Jul 2, 2007Oct 22, 2009Merck Patent GmbhFluorosurfactants
US20090312432 *Jul 2, 2007Dec 17, 2009Wolfgang HierseFluorosurfactants
US20090320718 *Jul 2, 2007Dec 31, 2009Wolfgang HierseFluorosurfactants
US20100152081 *Jul 2, 2007Jun 17, 2010Wolfgang HierseFluorosurfactants
WO2008003444A1 *Jul 2, 2007Jan 10, 2008Merck Patent GmbhFluorosurfacants
Classifications
U.S. Classification546/342, 548/376.1, 548/239, 564/99, 548/247
International ClassificationC07D231/12, C07D213/30
Cooperative ClassificationC07D213/30
European ClassificationC07D213/30