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Alkylbenzoylcarbinol phosphate esters

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US3660542A
US3660542A US3660542DA US3660542A US 3660542 A US3660542 A US 3660542A US 3660542D A US3660542D A US 3660542DA US 3660542 A US3660542 A US 3660542A
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Haruhiko Adachi
Takuichi Miki
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Takeda Pharmaceutical Co Ltd
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Takeda Pharmaceutical Co Ltd
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D213/00Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with heteroatoms or with carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78Carbon atoms having three bonds to hetero atoms, with at the most one to halogen, e.g. ester or nitrile radicals
    • C07D213/79Acids; Esters
    • C07D213/80Acids; Esters in position 3
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07FACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00Compounds containing elements of Groups 5 or 15 of the Periodic System
    • C07F9/02Phosphorus compounds
    • C07F9/06Phosphorus compounds without P—C bonds
    • C07F9/08Esters of oxyacids of phosphorus
    • C07F9/09Esters of phosphoric acids
    • C07F9/091Esters of phosphoric acids with hydroxyalkyl compounds with further substituents on alkyl

Abstract

ALKYBENZOYLCARBINOL ESTERS OF THE FORMULA

(4-R1,Y-PHENYL)-CO-CH2-O-R2

WHEREIN R1 IS A HYDROCARBON RESIDUE HAVING FROM 3 TO 10 CARBON ATOMS, R2 IS AN ACYL OF A CARBOXYLIC ACID HAVING UP TO 10 CARBON ATOMS OR AN INORGANIC RADICAL DERIVED FROM AN INORGANIC POLYBASIC ACID BY THE REMOVAL OF 0H THEREFROM, AND X IS HYDROGEN OR HALOGEN ATTACHED IN ORTHO- OR META-POSITION TO THE GROUP R1 IN THE BENZENE RING, HAVE HYPOTHERMIC OR ANTI-INFLAMMATORY ACTIVITY WITH LOW TOXICITY TO MAMMALS.

Description

United States Patent Office 3,660,542 Patented May 2, 1972 US. Cl. 260-94 Claims ABSTRACT OF THE DISCLOSURE Alkylbenzoylcarbinol esters of the formula InQ-o o CHzO-Rz wherein R is a hydrocarbon residue having from 3 to 10 carbon atoms, R is an acyl of a carboxylic acid having up to 10 carbon atoms or an inorganic radical derived from an inorganic polybasic acid by the removal of OH therefrom, and X is hydrogen or halogen attached in orthoor meta-position to the group R in the benzene ring, have hypothermic or anti-inflammatory activity with low toxicity to mammals.

This application is a divisional application of US. application Ser. No. 679,206, filed Oct. 30, 1967 and now Pat. No. 3,526,634.

The present invention relates to novel and useful compounds.

More particularly, this invention relates to alkylbenzoylmethyl derivatives of the formula:

wherein R is a hydrocarbon residue having from 3 to 10 carbon atoms, R is an acyl of a carboxylic acid having up to 10 carbon atoms or an inorganic radical derived from an inorganic polybasic acid by the removal of OH therefrom, and X is hydrogen or a halogen, attached in orthoor meta-position to the group R in the benzene ring.

1 As regards the above-mentioned formula, the hydrocarbon residue is exemplified by a straight or branched alkyl and a cycloalkyl radical, such as n-propyl, iso-butyl, sec-butyl, neo-pentylcyclopentyl, n-hexyl, cyclopentyl, cyclohexyl, cyclohexylethyl, n-octyl, n-decyl, etc.; the group R is exemplified by formyl, aceyl, valeryl, benzoyl, furoyl, nicotinoyl, phosphono, sulfo, etc.; and the halogen is exemplified by Cl, Br, I.

These novel alkylbenzoylmethyl derivatives of Formula I have remarkable hypothermic or anti-inflammatory activity with low toxicity to mammals.

It is an object of the present invention to provide the novel alkylbenzoylmethyl esters of Formula I. Another X (II) where R, and X have the same meanings as above, and Y stands for halogen (e.g. Cl, Br or I), with an acid of the formula:

where-R has the same meanings as above, or its metal salts- (e.g. salts of metals such as Hg, Ag, Na or K) or its tertiary amine salts (such as salts of pyridine, trimethylamino, etc.) or its quaternary ammonium salts (such as the trimethylbenzylammonium salt, etc.).

The organic acid represented by Formula HI embodies carboxylic acid of up to 10 carbon atoms (for example, acetic acid, propionic acid, isobutyric acid, caproic acid, cyclopentylpropionic acid, diethylaminoacetic acid, succinic acid, tartaric acid, malic acid, nicotinic acid, isonicotinic acid, benzoic acid, salicylic acid, anthranilio acid, indoleacetic acid, etc.) and inorganic polybasic acid (for example, sulfonic acid, phosphoric acid, etc.) 7

The reaction of the present invention is in general carried out in an organic solvent such as lower alcohol (e.g'.'methanol, ethanol, etc.), cycloether (e.g. tetrahydrofuran, dioxane, etc.), ketone (e.g. acetone, methyl ethyl ketone, cyclohexanone, etc.), halogenated hydrocarbon, acetonitrile, dimethylformamide, dimethylsulfoxide, pyridine, acetic acid, propionic acid, etc. A lower fatty acid such'as acetic acid or propionic acid can act as the reactant R OH as well as the solvent.

The reaction temperature is suitably selected depending on other reaction conditions such as the reactants or the solvent employed, usually ranging from room temperature (15 to 25 C.) to about C. It is recommended that the reaction be carried out under conditions which are as anhydrous as possible.

Alkylbenzoylmethyl derivvatives of Formula I thus produced are exemplified as follows:

p-isobutylbenzoylmethyl nicotinate; p-isobntylbenzoylmethyl phosphate; p-cyclohexylbenzoylmethyl acetate; p-cyclohexylbenzoylmethyl phosphate; p-isobutylbenzoylmethyl acetate; p-cyclohexylbenzoylmethyl nicotinate; p-sec-butylbenzoylmethyl acetate; p-tert-butylbenzoylmethyl nicotinate; p-sec-butylbenzoylmethyl phosphate; p-sec-butylbenzoylmethyl nicotinate; p-n-octylbenzoylmethyl phosphate; p-n-octylbenzoylmethyl nicotinate; p-cyclopentylmethylbenzoylmethyl acetate; p-cyclopentylmethylbenzoylmethyl phosphate; p-cyclopentylmethylbenzoylmethyl nicotinate; p-cyclohexyl-m-chlorobenzoylmethyl acetate; p-tert-butylbenzoylmethyl acetate; p-tert-butylbenzoylmethyl phosphate; p-n butylbenzoylmethyl acetate; p-n-butylbenzoylmethyl phosphate; p-n-butylbenzoylmethyl nicotinate; p-n-octylbenzoylmethyl acetate; p-cyclohexyl-m-chloro-benzoylmethyl phosphate; p-cyclohexyl-m-chloro-benzoylmethyl nicotinate; p-cyclohexyl-m-chloro-benzoylmethyl acetate; etc.

The compounds of Formula 1 exhibit hypothermic' or anti-inflammatory activity when administered to mammals, as shown, for example, in the following tests. In the tests, the test compounds are referred to as follows:

Test compound:

A=p-n-butylbenzoylmethyl acetate. =p-isobutylbenzoylmethyl acetate,

C=p-tert-butylbenzoylmethyl acetate.

=p-n-buty1benzoylmethyl phosphate (monosodium salt E=p-s ec-butylbenzoylmethyl phosphate (monosodium salt). =p-tert-butylbenzoylmethy1 phosphate (monosodium salt).

Control compound: (p-isobutylphenyl) acetic acid, known as ibufenac.

Hypothermic activities of 'compounds (I) were tested using mice, to which 150 milligrams of the test compound per kilogram of body weight was intra-peritoneally administered to give the result shown in Table I, where the activity is expressed in terms of the drop of body temperature in degree(s) centigrade.

TABLE 1 .DROP or BODY TEMPERATURE o.

T t Time after administration (minutes) Compound 15 30 60 90 120 150 180 Control. 1. 55 l. 65 O. 95 0.45 0.25 0. 10 0 'l EST II Anti-inflammatory activities were tested according to the method described in Proc. Soc. Exp. Biol. Med., vol. 3, page 544 (1962), against edema caused by the injection of carrageenin in rats. The results are shown in Table II in which the activities are expressed in terms of inhibition percentages.

TABLE II.INHIBITION PERCENTAGE IN CARRAGEENIN EDEMA Time alter administration (hours) Test Compound 1 2 3 4 5 Control. 50 66 51 46 47 TEST III Median lethal doses (LD of the compounds (I) in mice when administered intraperitoneally. are shown in Table III, from which it is noted that the compounds of the present invention show very low toxicity:

4 EXAMPLE 1 4.7 parts by weight of p-isobutylbenzoylmethyl iodide (M.P. 60 C.), 2.2 parts by weight of nicotinic acid and 4.5 parts by weight of triethylamine are dissolved in 30 partsby volume of acetone. The mixture is left standing at room temperature for five hours. After the acetone has distilled off, 50 parts by volume of ether and 20 parts by volume of water are added to the residue, and the mixture is shaken. The ether layer is extracted with 30 parts by volume of 10% hydrochloric acid, and the acid solution is alkalified with sodium carbonate and is extracted with ether. The ethereal extract is washed with Water and dehydrated over anhydrous sodium sulfate, and the ether is distilled ofif to leave 1.2 parts by weight of p-isobutylbenzoylmethyl nicotinate as pale yellow prisms melting at 93 C., the hydrochloride of which is soluble in water.

Analysis.Calculated for C H O N (percent): C, 72.70; H, 6.44; N, 4.70. Found (percent): C, 72.29; H 6.38; N, 4.64.

The starting material, p-isobutylbenzoylmethyl iodide,

.. is prepared, for example, by reacting p-isobutyl-benzoyl- As shown in the above tests, the compounds of Formula mammals, and also to suppress pain caused by infiammation.

When the group R of the compound (I) is one derived from a polybasic acid, irrespective of whether it is inorganic or organic, by the removal of an OH therefrom, the compound (I) constitutes a partial ester and can form a salt with a metal (such as sodium, potassium, magnesium) or an amine (such as diethylamine, triethylamine, ethylenediamine, diethanolamine or ammonium), and in so far as the salts are pharmaceutically acceptable, they are also used for the same purpose as the corresponding partial ester and on the same molar basis.

In human beings, the dose of present compound (I) is usually 500 to 2500 milligrams per day and the compounds (I) are generally administered in the form of capsule, tablet, syrup, injection, ointment, etc. I

The following examples show presently preferred embodiments of this invention but are not to be construed as restrictive. It is to be understood that the following examples are solely for the purpose of illustration and not for limitation of this invention, and that variations maybe resorted to without departing from the spirit of the invention. In the example, parts by weight bear the same relation to parts by volume as do grams to milliliters.

methyl chloride with sodium iodide in acetone.

EXAMPLE 2 To a mixture of 6.3 parts by weight of trisilver phosphate and 3.6 parts by weight of phosphoric acid, there are added 50 parts by volume of acetonitrile and 6 parts by weight of p-isobutylbenzoylmethyl iodide. After the whole mixture is refluxed for four hours under mild heating with agitation, the resultant precipitates are filtered off and from the filtrate the acetonitrile is distilled off. Water is added to the residue, followed by the addition of activated carbon to adsorb the product thereon. The carbon is filtered 01f, washed with water and eluted with an aqueous sodium hydroxide solution. The eluate is concentrated under reduced pressure, and acetone is added to the concentrate to precipitate sodium salt of p-isobutylbenzoylmethyl phosphate.

EXAMPLE 3 A mixture of 4.9 parts by weight of p-cyclohexyb benzoylmethyl iodide, 15 parts by weight of sodium acetate and 150 parts by volume of acetone is boiled for one hour, and the solvent is distilled off. Ether and water areadded to the residue, and the mixture is agitated. The ether layer is separated from the aqueous layer, and is concentrated. After the addition of about the equivolume of petroleum ether to the concentrate the mix ture is left standing to give 1.8 part by weight of pcyclohexylbenzoylmethyl acetate as colorless prisms, melting at 77 to 78 C.

The starting material, p-cyclohexylbenzoylmethyl iodide is prepared by, for example, reacting p-cyclohexylbenzoylmethyl chloride with sodium iodide in acetone.

EXAMPLE 4 49 parts by weight of p-cyclohexylbenzoylmethyl iodide is added to the slurry obtained by the reaction of 60 parts by weight of trisilver phosphate and 50 parts by weight of 85 phosphoric acid in parts by volume of acetonitrile in the presence of 5 parts by weight of diatomaceous earth, and the mixture is boiled while being agitated for 3.5 hours. After cooling, 200 parts by volume of water is added to the reaction mixture, and the resultant mixture .is adjusted to pH 7.5 by the addition of a 20% aqueous sodium hydroxide solution to precipitate silver iodide, which is then filtered off. The filtrate is concentrated under reduced pressure to remove acetonitrile. parts by weight of activated carbon is'added to the residue. After being adjusted to pH 2 with hydrochloric acid, the mixture is filtered to colto pH 8 by the addition of a 20% aqueous sodium hydroxide solution and is extracted with 2000 parts by volume of methanol. The methanol extract is concentrated under reduced pressure. Acetone is added to the 3. A compound according to claim 1, the compound being p-isobutylbenzoylmethyl phosphate.

4. A compound according to claim 1, the compound being p cyclohexylbenzoylmethyl phosphate.

5. A compound according to claim 1, the compound concentrate to precipitate sodium p-cyclohexylbenzoyl- 5 methylphosphate. being p-sec-butylbenzoylmethyl phosphate.

The NMR (nuclear-magnetic resonance) of the product 6. A compound according to claim 1, the compound in D shows doublet at 4.87, which reveals that methy1- being p-tert-butylbenzoylmethyl phosphate. ene is attached to 7. A compound according to claim 1, the compound 10 being p-n-butyl'benzoylmethyl phosphate. 8. A compound according to claim 1, the compound 0 being p-n-octylbenzoylmethyl phosphate.

In the same manner as in the preceding examples, the b i i g to the compound alkyl benzoylmethyl derivatives listed in the following emg P'CYC Openymet Y -y met y phosphate. Table IV, are produced.

TABLE IV RFQO demo- R Boiling point (2 mm. Example R1 R2 X NMR( 5 CH -CHz-CH- -COCH; H 4.826) 135-145 6 Same as above P0(0H)2 H 4.8(d) 7 CH3 -COCH3 H 14.87(S) 135445 CHs-JJ- 8 Same as above -PO(OH)3 H 4.8(d) 9. one-011501150112- CH3 H 14.85(S) 135-145 10-- CHz-CHz-CHz-CHr- PO(OH)z H 4. 8(d) 11 CHg-CH-CHzo0oH3 H 4.82(S) 135-145 12 CH3-(CH2)1 COOHa H 14.85(S) 175 13 CHa-(CH-zh- -PO(OH)2 H 4.801)

14 CH-CHCHz- -COCH5 H 4.85( 170 CH2- Hz 15 Same as above PO(OH)2 H "4.801)

16 CHz-CHz COGH3 m-Cl 4.s2(s) 20o H2C\ /CH- GHQ-CH2 17 Same as above..-.-.:'.2.;-:.-:. PO(OH)2 m-Cl 4.7(d)

l S=Sing1ed. 1 d=Doublet.

What is claimed is: 1. A compound of the formula m-Q-co-om-o-rotoan 10. A compound according to claim 1, the compound being p-cyclohexyl-m-chloro-benzoylmethyl phosphate.

References Cited UNITED STATES PATENTS 3,105,003 9/ 1963' Walsh et a1. 260--946 X JOSEPH REBOLD, Primary Examiner R. L. RAYMOND, Assistant Examiner US. Cl. X.R.

250 4s4 P; 424-214, 305 q

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US4547394A (en) * 1982-01-30 1985-10-15 Merck Patent Gesellschaft Mit Beschrankter Haftung Use of hydroxyalkylphenones as initiators for radiation curing of aqueous prepolymer dispersions
US5681380A (en) 1995-06-05 1997-10-28 Kimberly-Clark Worldwide, Inc. Ink for ink jet printers
US5709955A (en) 1994-06-30 1998-01-20 Kimberly-Clark Corporation Adhesive composition curable upon exposure to radiation and applications therefor
US5721287A (en) 1993-08-05 1998-02-24 Kimberly-Clark Worldwide, Inc. Method of mutating a colorant by irradiation
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