IE42968B1 - Pharmaceutical formulations containing o-hydroxy benzophenone derivatives - Google Patents
Pharmaceutical formulations containing o-hydroxy benzophenone derivativesInfo
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- IE42968B1 IE42968B1 IE586/76A IE58676A IE42968B1 IE 42968 B1 IE42968 B1 IE 42968B1 IE 586/76 A IE586/76 A IE 586/76A IE 58676 A IE58676 A IE 58676A IE 42968 B1 IE42968 B1 IE 42968B1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
- C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
- C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/46—Friedel-Crafts reactions
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
- C07C45/54—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition of compounds containing doubly bound oxygen atoms, e.g. esters
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
- C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
- C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
- C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
0-Hydroxybenzophenones and derivatives thereof are described together with a process for the their production. The compounds have anti-allergy activity and are characterised by the presence of an alkyl substituent on the hydroxyphenyl ring.
Description
This invention relates to pharmaceutical formulations containing o-hydroxybenzophenone derivatives.
There is a wealth of literature concerning the benzophenones, their preparation and their uses. However, it has not heretofore been appreciated that o-hydroxybenzophenones, and derivatives thereof, can be used in the treatment of allergic conditions.
According to the present invention therefore, there is provided a pharmaceutical formulation containing an active ingredient in association with a pharmaceutically acceptable carrier therefor, said active ingredient being a compound of the formula:-
13 wherein R is hydrogen or ethyl, R and R represent
3 hydrogen, methyl or ethyl, at least one of R , R and R not being hydrogen; Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine, fluorine, methyl, carboxy, COOR^ and trifluoromethyl; Z is
5 hydrogen or COR ; and Y is 0, NOH or NOCOR , R being C-^_^ alkyl or phenyl, provided that (i) when Ar is 4-chloro-phenyl, Y and Z are as defined above
3 and R and R are hydrogen, R is methyl;
(ii) where Ar is unsubstituted phenyl, Z is as defined above,
3
R and R are hydrogen and R is ethyl, Y is 0;
2 3 (iii) when R is ethyl, R and R are hydrogen and Y and Z are as defined above, Ar is not 2,4- or 3,4-dichlorophenyl, 2- or 3-chlorophenyl or 4-£lUorophenyl;
2 3 β g
In the formulation of the present invention, a preferred sub-genus of the compounds of formula (I) are those wherein 12 3
R , R , R , Z and Y are as defined above, Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine, fluorine or methyl. Advantageously,
2 the compound of formula (1) is one wherein one of R , R and
R is ethyl and the others are hydrogen, Ar is phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl; Z is hydrogen; and Y is 0 and, within the latter group a preferred sub-class are those compounds of formula (1) wherein Z is hydrogen; Y is 0 and either
(i) 1 2 R is ethyl, R and R3 are hydrogen and Ar is (ii) 4-chiorophenyl; R3 ethyl, R~ and R2 are hydrogen and Ar is 2, di chlorophenyi; or (iii). R2 is ethyl, R1 and R3 are hydrogen and Ar is 3- or 4-fluorophenyl
As well as the above particularly preferred groups of compounds of the present invention,it has been found that the compounds of formula (I) likely to possess the most useful therapeutic index, i.e. combination of efficacy and lack of toxicity, are those having one or more of the following features
(a) Z is hydrogen. (b) Y is 0. 25 (c) one of R, R2 and R5 is ethyl, the other R~, R2, R3 substitutents being hydrogen. (d) R3- is ethyl when R2 and R3 are hydrogen.
EJCS (e) te is a 4-chlorophenyl group, (f) Ar is a 4-fluorophenyl group.
(g) Ar is unsubstituted phenyl.
Compounds in which Y is not 0 can exist in both syn and anti forms and it is to be understood that both of these isomers, and mixtures thereof, are included within the scope of the invention.
The preferred compound of the invention is 4'{1ι1θΓθ-5“θϋιγ.1-2
2 3 6 3 hydroxybenzophenone.
The compounds of formula (I) useful in the formulations of the invention can be prepared by reacting a carboxylic acid of the formula A-COOH or a derivative thereof wherein A is selected from the groups
or Ar-, under Friedel-Crafts' acylating conditions with a substituted benzene of formula B-H wherein B is selected from the same groups as A but is different therefrom to produce a compound of formula (I) in which Ϊ is 0 and thereafter, if desired, reacting the resultant product with hydroxylamine in the presence of a base to aroduce the corresponding oxime in which Y is NOH, a compound in which 5 5
Z is COR and/or Y is NOCOR being then obtained by acylation of the aforementioned compounds in which Z is hydrogen and/or
Y is NOH.
Illustrative of a Friedel-Crafts' acylation as described above is the reaction between a compound of formula ArCOX and a compound of formula j^l
Z' being hydrogen
The reaction reaction scheme :
or a protecting group such as methyl, may be represented by the following
R’
ArCOX
G8 wherein X is a halogen atom or hydroxyl.
When X is halogen, the reaction may he carried out using a Lewis acid such as an aluminium halide (e.g. the chloride) as catalyst in a suitable inert solvent such as 1,1,2,2-tetrachloroethane or carbon disulphide.
When X is hydroxyl, boron trifluoride or (CP^CO^O are preferred catalysts, used with or without a suitable solvent.
If' z’is a protecting group, it may be removed in situ or subsequently, should it be desired to form a compound of formula (I) in which 2* is hydrogen
Reduction of unwanted isomer(s) can be achieved by suitable choice of reaction conditions, temperature control being especially important. Ideally the reaction temperature is from 20°C tp the reflux temperature and preferably from 80°C. up to reflux temperature.
Similarly, the benzophenones can be prepared by the following reaction scheme s
similar reaction conditions being applicable.
In the case of the reaction with a compound of the formula ArCOX, an initial.reaction product (A) below may .be obtained and isolated. This nay be subjected to a Fries rearrangement using similar catalytic conditions s «
-64 2 S S s as those described above, for example using aluminium chloride,
A further example of the acylation involving a derivative of A-COOi!
is the use of the compound Ar-CN as acylating agent. This modified process is known as the Bouoen-Koesch Reaction which proceeds as shown below :
Where a protected hydroxy group Z* is used in the foregoing reactions, it may be converted to the desired hydroxy group by cleavage with, for example, HBr, BFj, A1C13 or Hi.
As outlined above, preparation of ketonic derivatives such as the oxime can he effected by combining a solution of the ketone, for example, an aqueous or alcoholic solution, with a derivative, preferably the hydrochloride, of hydroxylamine in the presence of a base, for instance sodium or potassium hydroxide.
Also, as stated above, preparation of the acyl derivatives of the o-hydroxy or oxime groups can be carried out by a variety of methods, for example, by treating the o-hydrcxybenzophenone or oxime in a basic solution (e.g, pyridine or an aqueous solution of a group IA hydroxide such as sodium or potassium hydroxide) with an acid anhydride or halide (preferably the chloride) or with a solution of the acylating acid In the presence of the acid anhydride with a trace of catalyst (e.g. perchloric acid - 707.), or by refluxing the jo-hydrcxybenzophenone or oxime with the acylating acid.
The £-hydroxybenzophenones and derivatives thereof of the present invention have been shown to possess activity in one or more of the four tests regularly used to detect anti-allergy activity. Two of said tests are in vitro tests - the guinea pig and human chopped lung tests - and involve the direct measurement of the mediators, histamine and slow reacting
-73G8 substance in anaphylaxis (SRS-A), shovjn to be released by asthmatic human Lung. For compounds of the type comprising the present invention, a compound Ls considered to be active if at least 307. inhibition of SRA-A release Ln the guinea pig chopped lung test is achieved at a dose of 10 pg/ml or Less. Depending on absorption, distribution and metabolism of the drug mder test, activity In the chopped lung test at this level indicates'
Ln vivo dosage ranging from 0.5 to 100 mg/Kg orally .
The other two tests are in vivo tests - the Herxheimer and rat. jeritoneal anaphylaxis - and reflect oral activity in tiro different species.
Ln the Herxheimer test, sensitised guinea pigs are protected against the ironchospasm induced by an aerosol of antigen whilst, in the rat peritoneal maphylaxis test, the SRS-A released on challenge is measured directly.
Jhere an active compound is tested in these in vivo tests, activity at loses of 300 mg/Kg or lass is normally achieved.
The compounds of the present invention display activity in one or lore of the foregoing tests (the broadest spectrum compounds being those which lisplay anti-allergy activity in all four tests) and are therefore useful Ln the prophylactic and therapeutic treatment of immediate hypersensitivity iiseases including asthma and in the alleviation of status asthmaticus. in certain cases the compounds have been found to be useful in diseases in diich excessive amounts of prostaglandins are released and as a respiratory stimulant. The compounds have low toxicity.
The compounds or compositions of the present invention may be idministered by various routes and for this purpose may be formulated In i variety of forms. Thus the compositions Of tho Invention may fc administered) >y the oral and rectal routes, topically, parenteraily, e.g. by injection md by continuous or discontinuous intra-arterial infusion, in the form of,
Lor example, tablets, lozenges, sub-lingual tablets, sachets, cachets, ilixirs, suspensions, aerosols, ointments, for example, containing from L to 107. by weight of the active compound in a suitable base, soft and
-842368 bard gelatin capsules, suppositories, injection solutions and suspcnsiotis in physiologically acceptable media, and sterile packaged powders adsorbed onto a support material for making injection solutions. Advantageously fot· this purpose, compositions may be provided in dosage unit form, preferably each dosage unit containing from 5 to 500 mg. (from 5.0 to 50 mg. in the case of parenteral administration, from 5.0 to 50 mg. in the case of inhalation and from 25 to 500 mg. in the case of oral or rectal administration) of a compound of formulq (I)',
As indicated by' the tests referred to above, dosages of from 0,5 to 10 300 mg/kg per day, preferably 0.5 to 20 mg/kg, of active ingredient may be administered. It will however readily be understood that the amount of the compound or compounds of formula (1) actually to be administered will be determined by a physician, in the light of all the relevant circumstances including the condition to be treated, the choice of compound to be administered and the choice of route of administration and therefore the above preferred dosage range is not intended to limit the scope of the present invention in any way.
In this specification, the expression dosage unit form” is used as meaning a physically discrete unit containing an individual quantity of the active ingredient, generally in admixture with a pharmaceutical diluent therefor, or otherwise in association with a pharmaceutical carrier, the quantity of the active ingredient being such that one or more units are normally required for a single therapeutic administration or that, in the case of severable units such as scored tablets, at least one fraction, such as a half or a quarter of a severable unit is required for a single therapeutic administration.
The formulations of the present invention consist of at least one compound of formula (I) associated with a pharmaceutically acceptable carrier therefor, i.e. mixed with a carrier, or diluted by a carrier, or enclosed or encapsulated by an ingestible carrier in the form of a capsule,
-S3 68 sachet, cachet, paper of other container or by a disposable container su,ch as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid material, which serves as a vehicle, excipient or medium for the active therapeutic substance.
Some examples of the diluents or carriers which may be employed in the pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbital, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxide, microcrystalline cellulose, calcium silicate, silica, polyvinylpyrrolidine, cetostearyl alcohol, starch, modified starches, gum acacia, calcium phosphate, cocoa butter, ethoxylated esters, oil of theobroma, arachis oil, alginates, tragacanth, gelatin, syrup B.P., methyl cellulose, polyoxyethylene sorbitan monolaurate, ethyl lactate, methyl and propyl hydroxybenzoate, sorbitan trioleate, sorbitan sesquioleate and oleyl alcohol and propellants such as trichloromonofluoromethane, dichlorodifluoro . methane and dichlorotetrafluoroethane. In the case of tablets, a lubricant may be incorporated to prevent sticking and binding of the powdered ingredients in the dies and on the punch of the tabletting machine. For such purpose there may he employed.for instance aluminium, magnesium or calcium stearates, talc or mineral oil.
-104 2 3 C g
The following Examples illustrate hew compounds of use in the formulations of the invention may be prepared.
EXAMPLE 1
S-Hydroxy-S-Methyl^’-Chlorobenzophenone Oxime (syn and anti).
(a) 2-Hydroxy-5-methyl-4’chlorobenzophenone (13.5 g, 0.055 moles) was stirred with a solution of potassium hydroxide (44 g.) in water (150 ml.) and then hydroxylamine hydrochloride (17.4 g, 0.25 mole) was added with ice cooling. After stirring overnight at room temperature 100 ml. of water was added and the mixture was acidified with 5N-hydrochlorie acid to give an off-white precipitate which was filtered, washed and dried (14.7 g).
Recrystallisation of the product from benzene gave 2-hydroxy-5methyl-4’-chlorobenzophenone oxime (7 g.) m.p. 163°C. (This was the stereoisomer in which the oxime -OH group and the 4’-chlorophenyl group were in the syn position relative to each other).
(b) The above procedure was repeated this time using 192 g (0,78 mole) of the benzophenone used in (a). The benzene solution deposited a second and third crop of crystals. The second crop (31.5 g) was a mixture of the two forms of the oxime whereas the third crop (1.9 g) was the stereoisomer in which the oxime hydroxyl group and the 4’-chlorophenyl group were in the anti-position relative to each other, (m.p. of product was 145-7°C).
The C,H,N,C1 microanalysis for each isomer was satisfactory.
(c) 4*-Chloro-2-hydroxy-5-methyI-benzophenone-oxinie diaeetate.
The oxime produced in (a) above (26.2 g) was dissolved in warm acetic anhydride (50 ml.), and on cooling a solid separated. This was filtered off and the filtrate evaporated to dryness, leaving a residue which was crystallised from ethanol to give the diacetate as the second crop.
(m.p. 136°C.)
-11nos
EXAMPLE 2
41 -C.hloro-5- ethyl- 2-hydroxybenzophenone
Aluminium chloride (267 g) was added in portions over 30 minutes to a stirred solution of 4-ethylphenol (122.1 g.) and 4-chlorobenzoyl chloride (140 ml.) in dry 1,1,2,2-tetrachloroethane (800 ml.). The mixture was heated at 105°C. for 22 hours with stirring, and on cooling a mixture of ice (600 g) and concentrated hydrochloric acid was added slowly. A vigorous reaction occurred and some material was lost. The remaining material was separated, the aqueous fraction extracted twice with chloroform (200 ml.), and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main fractions: 13 (17,4 g) 15O-16O°C @ 0.3 mmHg; C (110.8 g) 160-168°C. @ 0.3 mmHg.
The title compound was crystallised by cooling to -20°C. and recrystallised from n-hexane at 0°C. to give a yellow crystalline solid m.p. 35-8°C. Microanalysis: C15^13C^°2 requires 69.17.0, 5.07H, 13.67.01;
found 69.O7.C, 5.O7.H, 13.97.01.
EXAMPLE 3
4c-Chloro-5-ethyl-2-hydroxybenzophenone-oxitne
4G-Chloro-5-ethyl-2-hydroxybenzophenone (65.2 g) and potassium hydroxide (170 g) in water (70D ml) and ethanol (150 ml.) were treated with hydroxylamine hydrochloride (70.0 g), with cooling, and the resulting mixture was stirred for 18 hours at ambient temperature. Dissolution occurred during this time. The solution was acidified with 5H-hydrochloric acid and then extracted with ether (3 x 200 ml.). The combined ether solutions were washed with 107. aqueous sodium carbonate solution (2 x 200 ml.) and evaporated to dryness to give an off-white solid. This solid was recrystallised from 407. benzene / 60-80°C petrol ether to give a white crystalline solid (29.9 g), second crop (14,5 g) m.p. 117°C.
-12·
296S
Microanalysis: CjgH,^ClKO, requires 65.37.C, 5.1%ii, 5.12JI, 12.97.C1;
round 65.37.C, 4.97.H, 5.1%N, 12.97.C1.
(Stereoisomer as in Example 1(a)).
EXAMPLE 4
2- Hydroxy-3-methyl-4’-chlorobenzophenone
Chlorobenzene (78.79 g, 71.6 ml; 0.7 mole) and AlCl, (14 gs 0.105 mole were mixed, stirred and treated with a solution of S-hydroxy-J-metliylbenzoic acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture was stirred and heated at 1OO°C. overnight. The cooled mixture was added to cone. HC1 (10 ml) and ice, extracted with ether, and ether washed with saturated sodium bicarbonate solution, dried (Ka?S0^), filtered and the filtrate distilled, to give (after removal of the ether ), a main fraction 2-hydroxy3- methyl-4’-chlorobenzophenone, b.p. 148-152°C/0.5 mm(8.13 g), which solidified to yellow microplates, m.p. 55-58°C.
found: C.68.23; H.4.71; Cl.14.61;
Cl4*‘llCl°2 requires: C.68.16; H.4.49; Cl.14.377.
EXAMPLE 5
4- Ethyl-4*-fiuoro-2-hydroxybenzophenone
3-Ethylphenol (24.4 g) and 4-fluorobenzoyl chloride (34.9 g) were reacted together as in Example 2 giving three main fractions: ii (11,4 g) 126-129°C.
-13»8
EXAMPLE 6
-Ethyl-4'-fluoro-2-h'ydroxybenzophenone-oxime.
4-Ethyl-4’-fluoro-2-hydroxybenzophenone (21.0 g, 807. pure) was reated with hydroxylamine hydrochloride (24.0 g) in a maimer similar ) that in Example 3, to give, after recrystallisation from benzene, the itle compound as a white crystalline solid (10.7 g), m.p. 130-2°C. icroanalysis: C^H^FNO^ requires 69.57.C, 5.47.H, 5.47N,'7.37P;
found 69.27.C, 5.57.H, 5.27.N, 7.2%F.
EXAMPLE 7
-Hydroxy-3-methyl-4 *-chlorobenzophenone oxime
The ketone of Example 4 (7.5 g, 0.03 mole) in ethanol (18 ml.) was added ith stirring to a solution of (857.) potassium hydroxide (20.74 g, 0.3 mole) n water (85 ml) at 10°C, this colloidal solution was treated with solid ydroxylamine hydrochloride (8.54 g, 0.12 mole) and stirred overnight. The olution was acidified with 5N HC1 to give a solid, which was filtered, 'ashed with water and stirred for 45 minutes, then treated with 57. Ma^CO^ olution (30.5 ml), to remove unwanted oxime stereoisomer, filtered, washed dth 57. Na^CO^solution (100 ml) and then with water until free of alkali, he dried solid had m.p. 175-177°C. RecryStallisation from 547. benzene.ight petroleum (b.p. 60-80°C) mixture gave the oxime, m.p. 178°C (syn Isomer) 5.45 g.
found: C.64.25; H.4.79; Cl.13.41; H.5.37.
Cl4Hi2Cl C02 reQuires : C.64.25; H.4.6 ; Cl.13.55; N.5.357.
EXAMPLE 8 i-Hydroxy-3-methyl-411-chlorobenzophenone oxime mono-oxime acetate.
Acetic anhydride (12 ml) was warmed to 60°C. and treated with the oxime
-144 2 3 0 8 of Example 7 (5.25 g, 0.02 mole). The stirred mixture was warmed to 60°C. to dissolve the oxime ana the solution was then immediately cooled in an ice hath. The precipitated solid was filtered off, washed with light petroleum (b.p. 40~60°C) to give the acetate, 4,8 g, m.p, 154-156°C.
founds C.63.18; H.4.86; 01.11,5; N.4.77 i
Cj^Hj^CINOj requires: C.63.26; H.4,64; Cl.11.67;N.4.67., '· ' EXAMPLE $
2-Hydroxy-3-ethylbeiizophenone
This compound (44.67 g) was prepared from benzene (172 g, 2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63,15 g, 0.34 mole), using the same conditions as in Example 4. The b.p. of the compound was 123-126°C. / “i
0.14 mm, 1.6081, -¾ max. (film) 1630 cm * The same compound was obtained using the method of Example 2.
EXAMPLE 10
21,4'-Dlchloro-3-sthyl-2-hydroxybenzophenone
Aluminium chloride (26.7 g) was added in portions to a stirred mixture of 2-ethylphenol (12.2 g) and 2,4-dichlorobenzoyl chloride (23.1 g) In 1,1,2,2-tetrachloroethane (100 ml), and then the mixture was heated under reflux for 21 hours. On cooling, the solution was poured onto concentrated hydrochloric acid (100 ml) cooled with ice (200 g). The organic fraction was separated and combined with two further chloroform washings of the aqueous fraction, and then this was twice washed with 107. aqueous sodium carbonate solution, dried over magnesium sulphate monohydrate and evaporated to a dark viscous oil (30.0 g). This oil was distilled in vacuo, the first fraction (Ι5ό-172°Ο at 0,06 mmHg) containing 857. of the required product. (With ferric chloride solution a purple colour was obtained indicating the
-15presence of an £-hydroxyketone). The ketone product was purified by chromatography on a silica column 1.6163. The same product was obtained using the method of Example 4.
EXAMPLE 11
4-Ethyl-38-fluoro-2-hydroxybenzophenone
This compound was prepared from 3-ethylphenol (12.2 g), 3-fltiorobenzoyI chloride (17.5 g) and aluminium chloride (26.7 g) in 1,1,2,2-tetrachloroethane (75 ml) using the same conditions as in Example 2, but heating under reflux, not at 105°C. The product was purified by chromatography on a o 22 silica column m.p. between 0 and 20 C. TV 1.5962. The same product was obtained using the method of Example 4.
EXAMPLE 12.
4-Chlorobenzoylchloride (1.35 g, 0.0077 mole) was added dropwise to a solution of 4-ethylphenol (0.86 g, 0.0070 mole) in 2.5 H aqueous sodium hydroxide (5.6 ml). The mixture was shaken vigorously for 15 minutes when a light brown solid separated out. The mixture was diluted with water (10 ml) and the solid was filtered off, washed with water (3 x 20 ml), and dried. The solid was recrystallised twice from n-hexane to yield pale brown crystals of 4-ethylphenyl-4-chlorobenzoate, m.p. 66.5-67°C.
The above ester (2.6 g) was heated with aluminium chloride (1.33 g) in tetrachloroethane for 6 hours at 125°C. A sample taken at the end of this time was added to dilute hydrochloric acid and the organic material was extracted into chloroform. Vapour phase chromatographic analysis of this solution detected no remaining ester, and comparison with an authentic sample showed the product to he 4“-chloro-5-ethyl-2-hydroxybenzophenone.
-164 2 3Gg
Similarly prepared wares
-£thyl-2~hydroxy-4s-methylbenzoohenone, m.p. 49-51°C, and
4'-Chloro-3,5-diethyI-2-hydroxybenzophenone b.p. 138°C, at 1,4 mm/Hg,
EXAMPLE 13
Z-Benzoylorz-j-etiyl-l’-chlorobenzophenone
2-Hydroxy-5-ethyl-4’-chlorobenzophenone (5 g, 0.019 mole) was stirred vigorously in a solution of NaOH (7.5 g, 0.187 mole) in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose to around 50°C. The mixture was stirred for 1.5 hours at room temperature and was then extracted with ether, the ether washed with saturated NaCl solution, dried (Na^SO^), filtered and evaporated to leave the product, which was recrystallised from n-hexane to give white crystals of the desired product, m.p. 79-81°C.
EXAMPLE 14
2-Acetoxy-48-chloro-5-ethylbenzophenone
2-Hydroxy-5-ethyl-4’-chlorobenzophenone (3 g), in acetic anhydride (10 ml) and acetic acid (1 ml) were refluxed for 3.5 hours, and allowed to cool. The mixture was poured into dilute NaOH solution and extracted with chloroform. The chloroform was washed with 107, NaHCO^ solution (50 ml), dried (MgSO^) and evaporated to leave an oil which was distilled, b.p. 16O-165°C« at 3.5 mm/Hg (2.3 g) to give the desired product.
-17EXAMPLE 15
-Ethyl-2-hydroxy-48-trifluoromethvl benzophenone
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane (2 ml) and treated with 4-trifluoromethylhenzoyl chloride (1 g, 0.0048 mole) (ice-bath cooling) and then with 4-ethylanisole (0.6 g, 0.0044 mole) in dichloromethane (1 ml). The mixture was stirred at room temperature overnight and then poured into ice and concentrated hydrochloric acid and extracted with chloroform. The chloroform solution was washed with 10% NaHCOg solution (100 ml), dried (MgSO^), filtered and evaporated to leave 5-ethyl-2-methoxy-48-trifluoromethylbenzophenone (1.2 g) as a yellow oil. The latter was heated in 55% aqueous hydrogen bromide (27.5 mij at 110-120°C. for 5 hours. The mixture was evaporated to dryness to leave the required product.
EXAMPLE 16
-Ethyi-2-hydroxy-38-carboxy- and 38-carbomethoxyben2ophenone
Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloromethane (133 ml) and treated with 3-carbomethoxybenzoyl chloride (59.5 g, 0.3 mole) (ice-bath cooling), over 0.5 hours.4-Ethylanisole (40.8 g,
0,3 mole) in dichloromethane (70 ml) was added to the stirred, cooled mixture, which was then stirred at room temperature overnight. The reaction mixture was processed as in Example 15 to leave 5-ethyi-2methoxy-3’-carbomethoxybenzophenone. The latter was heated in 55% aqueous hydrogen bromide (500 ml) at 110-120°C for 5 hours. The mixture was evaporated to dryness to leave 5-ethyl-2-hydroxy~3’-carboxybenzophenone, which was characterised by having the correct C, H and H microanalysis.
The latter carboxylic acid was then refluxed overnight in methanol (500 ml) containing concentrated sulphuric acid (5 ml), poured into water (11) and extracted with ether. The combined ethereal extracts were washed with saturated NaHCOj solution, dried (MgSO^), filtered and evaporated to leave the desired ester, which gave a satisfactory microanalysis.
Claims (5)
1. CLAIMS:1. A pharmaceutical formulation containing an active ingredient in association with a pharmaceutically acceptable carrier therefor, said active ingredient being a compound of the formula: 2. 13 wherein R is hydrogen or ethyl, R and R represent 12 3 hydrogen, methyl or ethyl, at least one of R , R and R not being hydrogen; Ar is a phenyl group optionally substituted by from one to three groups, selected from chlorine, fluorine, methyl, carboxy, COOR 5 and trifluoromethyl; Z 5 5 5 is hydrogen or COR ; and Y is 0, NOH or NOCOR , R being C^_^ alkyl or phenyl, provided that (i) when Ar is 4-chlorophenyl, Y and Z are as 12 3 defined above and R and R are hydrogen, R is methyl; (ii) when Ar is unsubstituted phenyl, Z is as defined 12 3 above, R and R are hydrogen and R is ethyl, Y is 0; 1 2 3 (iii) when R is ethyl, R and R are hydrogen and Y and Z are as defined above, Ar is not 2,4or 3,4-dichlorophenyl, 2- or 3-chlorophenyl or 4-f1uoropheny1; 1 2
2. A formulation as claimed in claim 1, wherein R , R , 3 5 25 R , R , Z and Y are as defined in claim 1, Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine, fluorine or methyl.
3. A formulation as claimed in cla m 1, wherein one of 12 3 R , R and R is ethyl and the other are hydrogen; Ar is G8 phenyl, 4-chlorophenyl, 4-fluorophenyl or 4-methy1-phenyl; Z is hydrogen; and Y is 0.
4. A formulation as claimed in claim 1, wherein Z is hydrogen; Y is 0 and either 1 2 3 (i) R is ethyl; R and R are hydrogen and Ar is 4-chlorophenyl; 3 12 (ii) R is ethyl; R and & are hydrogen and Ar is 2,4-dichlorophenyl; or 2 13 (iii) R is ethyl; R and R are hydrogen and Ar is 3- or 4-fluorophenyl.
5. A formulation as claimed in any one of claims 1 to 4, in a dosage unit form containing from 5 to 500 mg. of said active ingredient.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB15805/75A GB1549171A (en) | 1975-04-17 | 1975-04-17 | Pharmaceutical formulations containing hydrocy bezophenonederivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| IE42968L IE42968L (en) | 1976-10-17 |
| IE42968B1 true IE42968B1 (en) | 1980-11-19 |
Family
ID=10065798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IE586/76A IE42968B1 (en) | 1975-04-17 | 1976-03-19 | Pharmaceutical formulations containing o-hydroxy benzophenone derivatives |
Country Status (35)
| Country | Link |
|---|---|
| JP (1) | JPS51128950A (en) |
| AR (1) | AR217399A1 (en) |
| AT (2) | AT347430B (en) |
| AU (1) | AU502015B2 (en) |
| BE (1) | BE840826A (en) |
| BG (1) | BG33275A3 (en) |
| CA (1) | CA1055041A (en) |
| CH (1) | CH617654A5 (en) |
| CS (1) | CS196305B2 (en) |
| DD (1) | DD123596A5 (en) |
| DE (2) | DE2546738C2 (en) |
| DK (1) | DK146476A (en) |
| EG (1) | EG12255A (en) |
| ES (1) | ES446993A1 (en) |
| FI (1) | FI68609C (en) |
| FR (1) | FR2307524A1 (en) |
| GB (1) | GB1549171A (en) |
| GR (1) | GR59849B (en) |
| HU (1) | HU176276B (en) |
| IE (1) | IE42968B1 (en) |
| IL (1) | IL49280A (en) |
| LU (1) | LU74773A1 (en) |
| MX (1) | MX3394E (en) |
| NL (1) | NL7604164A (en) |
| NO (1) | NO146022C (en) |
| NZ (1) | NZ180379A (en) |
| OA (1) | OA05301A (en) |
| PH (1) | PH11507A (en) |
| PL (1) | PL103084B1 (en) |
| PT (1) | PT65015B (en) |
| RO (1) | RO71258A (en) |
| SE (1) | SE7604426L (en) |
| SU (2) | SU644372A3 (en) |
| YU (1) | YU97176A (en) |
| ZA (1) | ZA761737B (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2377202A2 (en) * | 1977-01-12 | 1978-08-11 | Pharmascience Lab | PHARMACEUTICAL COMPOSITIONS CONTAINING HEXAHYDROXY-2,3,4,3 ', 4', 5'-BENZOPHENONE |
| JPS6197240A (en) * | 1984-10-16 | 1986-05-15 | Sankyo Kasei Kk | Preparation of polyhydroxybenzophenone |
| GB8603578D0 (en) * | 1986-02-13 | 1986-03-19 | Ici Plc | Aromatic ketone |
| LU86387A1 (en) * | 1986-04-04 | 1987-12-07 | Oreal | AROMATIC COMPOUNDS, THEIR PREPARATION PROCESS AND THEIR USE IN HUMAN AND VETERINARY MEDICINE AND IN COSMETICS |
| FR2649975B1 (en) * | 1989-07-19 | 1991-11-22 | Inst Nat Rech Chimique | NOVEL ACETYLENIC DERIVATIVES, THEIR PREPARATION PROCESS, NOVEL ACETYLENIC POLYMERS AND THEIR APPLICATIONS |
| US5962731A (en) * | 1992-04-22 | 1999-10-05 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
| US5780676A (en) * | 1992-04-22 | 1998-07-14 | Ligand Pharmaceuticals Incorporated | Compounds having selective activity for Retinoid X Receptors, and means for modulation of processes mediated by Retinoid X Receptors |
| US7655699B1 (en) | 1992-04-22 | 2010-02-02 | Eisai Inc. | Compounds having selective activity for retinoid X receptors, and means for modulation of processes mediated by retinoid X receptors |
| ATE195716T1 (en) * | 1992-04-22 | 2000-09-15 | Ligand Pharm Inc | RETINOID-X RECEPTOR SELECTIVE COMPOUNDS |
| WO1994015901A1 (en) * | 1993-01-11 | 1994-07-21 | Ligand Pharmaceuticals Inc. | Compounds having selectivity for retinoid x receptors |
| GB9620202D0 (en) * | 1996-09-27 | 1996-11-13 | Rhone Poulenc Agriculture | New herbicides |
| GB2446397A (en) * | 2007-02-06 | 2008-08-13 | Gharda Chemicals Ltd | Improved processes for the production of poly(ether ketone) - PEK - and its monomer |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1060855A (en) * | 1963-09-20 | 1967-03-08 | Ici Ltd | Substituted aromatic ketones |
| CH510395A (en) * | 1969-07-17 | 1971-02-15 | Ciba Geigy Ag | Use of 2-hydroxybenzophenones for antimicrobial finishing or for protecting textile materials against harmful microorganisms |
| CH515871A (en) * | 1969-07-25 | 1971-11-30 | Sandoz Ag | Process for the preparation of new 2-hydroxy-3,5-tert-butyl-benzophenones |
-
1975
- 1975-04-17 GB GB15805/75A patent/GB1549171A/en not_active Expired
- 1975-10-18 DE DE2546738A patent/DE2546738C2/en not_active Expired
- 1975-10-20 DD DD188946A patent/DD123596A5/xx unknown
-
1976
- 1976-03-19 IE IE586/76A patent/IE42968B1/en unknown
- 1976-03-22 ZA ZA761737A patent/ZA761737B/en unknown
- 1976-03-23 GR GR50382A patent/GR59849B/en unknown
- 1976-03-24 IL IL49280A patent/IL49280A/en unknown
- 1976-03-30 DK DK146476A patent/DK146476A/en not_active IP Right Cessation
- 1976-04-01 NZ NZ180379A patent/NZ180379A/en unknown
- 1976-04-09 NO NO761233A patent/NO146022C/en unknown
- 1976-04-09 DE DE19762615487 patent/DE2615487A1/en not_active Withdrawn
- 1976-04-12 AR AR262848A patent/AR217399A1/en active
- 1976-04-12 CH CH459876A patent/CH617654A5/en not_active IP Right Cessation
- 1976-04-12 OA OA55796A patent/OA05301A/en unknown
- 1976-04-13 ES ES446993A patent/ES446993A1/en not_active Expired
- 1976-04-13 FI FI760999A patent/FI68609C/en not_active IP Right Cessation
- 1976-04-13 FR FR7610788A patent/FR2307524A1/en active Granted
- 1976-04-13 RO RO7685607A patent/RO71258A/en unknown
- 1976-04-13 CA CA250,199A patent/CA1055041A/en not_active Expired
- 1976-04-14 PT PT65015A patent/PT65015B/en unknown
- 1976-04-14 PL PL1976188773A patent/PL103084B1/en unknown
- 1976-04-14 PH PH18332A patent/PH11507A/en unknown
- 1976-04-14 MX MX000173U patent/MX3394E/en unknown
- 1976-04-14 SE SE7604426A patent/SE7604426L/en not_active Application Discontinuation
- 1976-04-15 CS CS762506A patent/CS196305B2/en unknown
- 1976-04-15 AT AT278676A patent/AT347430B/en not_active IP Right Cessation
- 1976-04-15 LU LU74773A patent/LU74773A1/xx unknown
- 1976-04-15 BE BE6045444A patent/BE840826A/en not_active IP Right Cessation
- 1976-04-16 BG BG7632930A patent/BG33275A3/en unknown
- 1976-04-16 YU YU00971/76A patent/YU97176A/en unknown
- 1976-04-16 SU SU762345332A patent/SU644372A3/en active
- 1976-04-16 HU HU76LI288A patent/HU176276B/en unknown
- 1976-04-17 EG EG76217A patent/EG12255A/en active
- 1976-04-17 JP JP51044159A patent/JPS51128950A/en active Pending
- 1976-04-20 NL NL7604164A patent/NL7604164A/en not_active Application Discontinuation
- 1976-04-20 AU AU13154/76A patent/AU502015B2/en not_active Expired
-
1977
- 1977-08-24 SU SU772514704A patent/SU679133A3/en active
- 1977-08-25 AT AT617077A patent/AT346829B/en not_active IP Right Cessation
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