Search Images Maps Play YouTube News Gmail Drive More »
Sign in
Screen reader users: click this link for accessible mode. Accessible mode has the same essential features but works better with your reader.

Patents

  1. Advanced Patent Search
Publication numberUS3660542 A
Publication typeGrant
Publication date2 May 1972
Filing date11 Dec 1969
Priority date11 Dec 1969
Publication numberUS 3660542 A, US 3660542A, US-A-3660542, US3660542 A, US3660542A
InventorsHaruhiko Adachi, Takuichi Miki
Original AssigneeTakeda Chemical Industries Ltd
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Alkylbenzoylcarbinol phosphate esters
US 3660542 A
Abstract  available in
Images(3)
Previous page
Next page
Claims  available in
Description  (OCR text may contain errors)

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

Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4347111 *26 Nov 197931 Aug 1982Merck Patent Gesellschaft Mit Beschrankter HaftungPhotosensitive hydroxyalkylphenones
US4477681 *16 Aug 198216 Oct 1984Merck Patent Gesellschaft Mit Beschrankter HaftungPhotosensitive hydroxyalkylphenones
US4547394 *28 Jan 198315 Oct 1985Merck Patent Gesellschaft Mit Beschrankter HaftungUse of hydroxyalkylphenones as initiators for radiation curing of aqueous prepolymer dispersions
US4721734 *31 Aug 198426 Jan 1988Merck Patent Gesellschaft Mit Beschrankter HaftungPhotosensitive hydroxylalkylphenones
US568138019 Dec 199628 Oct 1997Kimberly-Clark Worldwide, Inc.Ink for ink jet printers
US570995516 Oct 199620 Jan 1998Kimberly-Clark CorporationAdhesive composition curable upon exposure to radiation and applications therefor
US57212875 Jun 199524 Feb 1998Kimberly-Clark Worldwide, Inc.Method of mutating a colorant by irradiation
US57336932 Jan 199731 Mar 1998Kimberly-Clark Worldwide, Inc.Method for improving the readability of data processing forms
US57731825 Jun 199530 Jun 1998Kimberly-Clark Worldwide, Inc.Method of light stabilizing a colorant
US578296327 Nov 199621 Jul 1998Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US578613229 May 199628 Jul 1998Kimberly-Clark CorporationPre-dyes, mutable dye compositions, and methods of developing a color
US58374295 Jun 199617 Nov 1998Kimberly-Clark WorldwidePre-dyes, pre-dye compositions, and methods of developing a color
US585565515 Apr 19975 Jan 1999Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US585858616 May 199712 Jan 1999Kimberly-Clark CorporationDigital information recording media and method of using same
US586547121 Dec 19942 Feb 1999Kimberly-Clark Worldwide, Inc.Photo-erasable data processing forms
US588533731 Oct 199723 Mar 1999Nohr; Ronald SinclairColorant stabilizers
US589122931 Jul 19976 Apr 1999Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US590849524 Sep 19971 Jun 1999Nohr; Ronald SinclairInk for ink jet printers
US600826822 Jan 199828 Dec 1999Kimberly-Clark Worldwide, Inc.Photoreactor composition, method of generating a reactive species, and applications therefor
US601747123 Apr 199725 Jan 2000Kimberly-Clark Worldwide, Inc.Colorants and colorant modifiers
US60176618 Oct 199725 Jan 2000Kimberly-Clark CorporationTemporary marking using photoerasable colorants
US60334655 Apr 19967 Mar 2000Kimberly-Clark Worldwide, Inc.Colorants and colorant modifiers
US60542563 Dec 199825 Apr 2000Kimberly-Clark Worldwide, Inc.Method and apparatus for indicating ultraviolet light exposure
US60602003 Feb 19989 May 2000Kimberly-Clark Worldwide, Inc.Photo-erasable data processing forms and methods
US60602233 Dec 19989 May 2000Kimberly-Clark Worldwide, Inc.Plastic article for colored printing and method for printing on a colored plastic article
US606355116 Nov 199816 May 2000Kimberly-Clark Worldwide, Inc.Mutable dye composition and method of developing a color
US60664393 Dec 199823 May 2000Kimberly-Clark Worldwide, Inc.Instrument for photoerasable marking
US607197926 Dec 19976 Jun 2000Kimberly-Clark Worldwide, Inc.Photoreactor composition method of generating a reactive species and applications therefor
US609023631 Dec 199718 Jul 2000Kimberly-Clark Worldwide, Inc.Photocuring, articles made by photocuring, and compositions for use in photocuring
US609962823 Jan 19978 Aug 2000Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US61209493 Dec 199819 Sep 2000Kimberly-Clark Worldwide, Inc.Photoerasable paint and method for using photoerasable paint
US61270733 Dec 19983 Oct 2000Kimberly-Clark Worldwide, Inc.Method for concealing information and document for securely communicating concealed information
US61686546 Apr 19992 Jan 2001Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US616865515 Dec 19982 Jan 2001Kimberly-Clark Worldwide, Inc.Colorant stabilizers
US621138310 Feb 19983 Apr 2001Kimberly-Clark Worldwide, Inc.Nohr-McDonald elimination reaction
US622815720 Jul 19998 May 2001Ronald S. NohrInk jet ink compositions
US62350951 Jun 199922 May 2001Ronald Sinclair NohrInk for inkjet printers
US624205729 Apr 19985 Jun 2001Kimberly-Clark Worldwide, Inc.Photoreactor composition and applications therefor
US626545828 Sep 199924 Jul 2001Kimberly-Clark Worldwide, Inc.Photoinitiators and applications therefor
US62778973 Jun 199921 Aug 2001Kimberly-Clark Worldwide, Inc.Photoinitiators and applications therefor
US629469816 Apr 199925 Sep 2001Kimberly-Clark Worldwide, Inc.Photoinitiators and applications therefor
US633105624 Feb 200018 Dec 2001Kimberly-Clark Worldwide, Inc.Printing apparatus and applications therefor
US634230528 Dec 199929 Jan 2002Kimberly-Clark CorporationColorants and colorant modifiers
US636839512 May 20009 Apr 2002Kimberly-Clark Worldwide, Inc.Subphthalocyanine colorants, ink compositions, and method of making the same
US636839619 Jan 20009 Apr 2002Kimberly-Clark Worldwide, Inc.Colorants, colorant stabilizers, ink compositions, and improved methods of making the same
US65035593 Jun 19997 Jan 2003Kimberly-Clark Worldwide, Inc.Neonanoplasts and microemulsion technology for inks and ink jet printing
US652437912 Jan 200125 Feb 2003Kimberly-Clark Worldwide, Inc.Colorants, colorant stabilizers, ink compositions, and improved methods of making the same
US74707229 Jun 200530 Dec 2008Kalypsys, Inc.Multicyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease
US20060030543 *9 Jun 20059 Feb 2006Malecha James WMulticyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease
WO2005123089A2 *9 Jun 200529 Dec 2005Kalypsys, Inc.Multicyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease
WO2005123089A3 *9 Jun 200530 Mar 2006Christian HassigMulticyclic sulfonamide compounds as inhibitors of histone deacetylase for the treatment of disease
Classifications
U.S. Classification558/178, 560/254, 560/255, 987/224, 558/107
International ClassificationC07D213/80, C07F9/09
Cooperative ClassificationC07F9/091, C07D213/80, C07C45/63
European ClassificationC07F9/09A1, C07C45/63, C07D213/80