CA1055041A - Ketone derivatives - Google Patents
Ketone derivativesInfo
- Publication number
- CA1055041A CA1055041A CA250,199A CA250199A CA1055041A CA 1055041 A CA1055041 A CA 1055041A CA 250199 A CA250199 A CA 250199A CA 1055041 A CA1055041 A CA 1055041A
- Authority
- CA
- Canada
- Prior art keywords
- hydrogen
- ethyl
- formula
- compound
- chlorophenyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
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Classifications
-
- 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
-
- 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
-
- 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
-
- 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
Abstract
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.
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
~ossal4~
1 This inverltion rel<~tes to a class or novel ben~henones, and derivatives thereof, to methods of preparing such derivatives, to phann3ceutical formulations and to methods of Lreating allergic conditions in-~olving use of o-hydroxybenzophenones.
There is a wealth of literature concerning the benzophenones, their preparation and their uses.- However, it has nor heretofore been appreciated that o-hydroxybenzophenones, and derivati~Tes 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 :-R2 ~ C Ar (I) wherein R2 is hydrogen or ethyl~ Rl and R represent hydrogen~ methyl or ethyl, at least one.of Rl, R2 and R3 not being hydrogen; Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine -fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is hydrogen or CoR5;
and Y is 0~ NOH or NOCOR ~ R being Cl 4 alkyl or phenyl~ provided that (l) when Ar is 4-chlorophenyl~ Y and Z are as defined above and Rl and R2 are hydrogen, R is methyl;
(ii)when Ar is unsubstituted phenyl~ Z is as defined above~ Rl and R
are hydrogen and R3 is ethyl, Y is O;
(iii)~hen * is ethyl, * and R3 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-fluorophenyl;
(iv)when Ar is unsubstituted phenyl~ Y and Z are as defined above, and ~05CiO41 1 and R are hydrogen~ R is ~thyl.
In a further aspect of the invention, there is provided a method of treating a mammal suffering from an allergic condition, and particularly a method of treating immediate hypersensitivity diseases such as asthma in animals, including humans, which comprises administering to said mammal an anti-allergically effective dose of a compound of formula (I) as defined above.
In the formulation and method aspects of the present invention, a preferred sub-genus of the compounds of formula (I) are those wherein Rl, R2 and R3 are as defined above, Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine, fluorine or methyl, Z is hydrogen or CoR5 and Y is 0, NOH or NoCoR5, R5 being as defined above. Advantageously, the compound of formula (I) is one wherein one of R , R and R3 is ethyl and the others are hydrogen; Ar is phenyl, 4-chlorophenyl~ 4-fluorophenyl or 4-methylphenyl; Z is hydrogen; and Y is O and, within the latter group, a preferred sub-class are those compounds of formula (I) wherein Z is hydrogen; Y is O and either (i) Rl is ethyl~ R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R3 is ethyl~ Rl and R2 are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R is ethyl~ Rl 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.
(c) one of Rl, R2 and R3 is ethyl, the other Rl, R2, R3 substituents being hydrogen.
(d) Rl is ethyl when R2 and R are hydrogen.
.-~ ., ~ ~
lOSSiO ~1 1 (e) Ar i a 4-chlorophenyl group, (f) Ar is a 4-fluorophenyl group.
(g) Ar is unsubstituted phenyl.
A number of the most useful compounds of formula (I) are novel and form a part of this invention. Such novel compounds are those of formula (I) wherein R , R and R represent hydroger or ethyl, at least one being ethyl, Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is hydrogen or co~5; and Y is O, NOH or NoCoR5, R5 being Cl 4 alkyl or phenyl~
provided thatJ
when Rl is ethyl, R2 and R3 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-fluorophenyl.
A preferred group of novel compounds are those wherein Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine or methyl. Particularly useful activity is found in those compounds wherein one of Rl, R2 and R3 is ethyl and the others are hydrogen, Ar is 4-chloropheny 4-fluorophenyl or 4-methylphenyl, Z is hydrogen, and Y is O~ and especially in these compounds wherein Z is hydrogen, Y is O and e~ther (i) Rl is ethyl, R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R is ethyl~ Rl and R are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R2 is ethyl, Rl and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
Compounds in which Y is not O 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 inventio~ is 4'-chloro-5-ethyl-2-iO'5504~
hydroxyben7~0r)1lenone .
¦ The present invention also provides a process for preparing the afore~
mentioned novel compounds of formula (I) characterised in that a carboxyli.c acid of the formula A-COOH or a derivative thereof wherein A is selected from the groups R2~0~
or Ar- is reacted 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 Y is O and thereafter, where desired~ the resultant product is reacted with hydroxylamine in the presence of a base to produce the corresponding oxime in which Y is NOH~ a compound in which Z is CoR5 and/or Y is NoCOR5 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 :
R3~oz ~
Z~ being hydrogen or a protecting group such as methyl.
The reaction may be represented by the following reaction scheme :
Rl R
~ R2 ~ + ArCOX ------------~R2 ~ 0 ~ O _ Ar 10550~i 1 ~herein X is a halo~en atom or hydroxyl.
h~en X is halogerl, the reaction may be 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 (CF3CO~20 are preerred catalysts, used with or without a suitable solvent.
If Z'is a protecting group, it may be removed in situ or subsequently5 should it be desired to form a compound of formula (I) in which Z~ 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 20C to the reflux temperature and preferably from 80C. up to reflux temperature.
Similarly, the benzophenones can be prepared by the following reaction
1 This inverltion rel<~tes to a class or novel ben~henones, and derivatives thereof, to methods of preparing such derivatives, to phann3ceutical formulations and to methods of Lreating allergic conditions in-~olving use of o-hydroxybenzophenones.
There is a wealth of literature concerning the benzophenones, their preparation and their uses.- However, it has nor heretofore been appreciated that o-hydroxybenzophenones, and derivati~Tes 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 :-R2 ~ C Ar (I) wherein R2 is hydrogen or ethyl~ Rl and R represent hydrogen~ methyl or ethyl, at least one.of Rl, R2 and R3 not being hydrogen; Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine -fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is hydrogen or CoR5;
and Y is 0~ NOH or NOCOR ~ R being Cl 4 alkyl or phenyl~ provided that (l) when Ar is 4-chlorophenyl~ Y and Z are as defined above and Rl and R2 are hydrogen, R is methyl;
(ii)when Ar is unsubstituted phenyl~ Z is as defined above~ Rl and R
are hydrogen and R3 is ethyl, Y is O;
(iii)~hen * is ethyl, * and R3 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-fluorophenyl;
(iv)when Ar is unsubstituted phenyl~ Y and Z are as defined above, and ~05CiO41 1 and R are hydrogen~ R is ~thyl.
In a further aspect of the invention, there is provided a method of treating a mammal suffering from an allergic condition, and particularly a method of treating immediate hypersensitivity diseases such as asthma in animals, including humans, which comprises administering to said mammal an anti-allergically effective dose of a compound of formula (I) as defined above.
In the formulation and method aspects of the present invention, a preferred sub-genus of the compounds of formula (I) are those wherein Rl, R2 and R3 are as defined above, Ar is a phenyl group optionally substituted by from one to three groups selected from chlorine, fluorine or methyl, Z is hydrogen or CoR5 and Y is 0, NOH or NoCoR5, R5 being as defined above. Advantageously, the compound of formula (I) is one wherein one of R , R and R3 is ethyl and the others are hydrogen; Ar is phenyl, 4-chlorophenyl~ 4-fluorophenyl or 4-methylphenyl; Z is hydrogen; and Y is O and, within the latter group, a preferred sub-class are those compounds of formula (I) wherein Z is hydrogen; Y is O and either (i) Rl is ethyl~ R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R3 is ethyl~ Rl and R2 are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R is ethyl~ Rl 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.
(c) one of Rl, R2 and R3 is ethyl, the other Rl, R2, R3 substituents being hydrogen.
(d) Rl is ethyl when R2 and R are hydrogen.
.-~ ., ~ ~
lOSSiO ~1 1 (e) Ar i a 4-chlorophenyl group, (f) Ar is a 4-fluorophenyl group.
(g) Ar is unsubstituted phenyl.
A number of the most useful compounds of formula (I) are novel and form a part of this invention. Such novel compounds are those of formula (I) wherein R , R and R represent hydroger or ethyl, at least one being ethyl, Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine, methyl, carboxy, CoOR5 and trifluoromethyl; Z is hydrogen or co~5; and Y is O, NOH or NoCoR5, R5 being Cl 4 alkyl or phenyl~
provided thatJ
when Rl is ethyl, R2 and R3 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-fluorophenyl.
A preferred group of novel compounds are those wherein Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine or methyl. Particularly useful activity is found in those compounds wherein one of Rl, R2 and R3 is ethyl and the others are hydrogen, Ar is 4-chloropheny 4-fluorophenyl or 4-methylphenyl, Z is hydrogen, and Y is O~ and especially in these compounds wherein Z is hydrogen, Y is O and e~ther (i) Rl is ethyl, R2 and R3 are hydrogen and Ar is 4-chlorophenyl;
(ii) R is ethyl~ Rl and R are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R2 is ethyl, Rl and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
Compounds in which Y is not O 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 inventio~ is 4'-chloro-5-ethyl-2-iO'5504~
hydroxyben7~0r)1lenone .
¦ The present invention also provides a process for preparing the afore~
mentioned novel compounds of formula (I) characterised in that a carboxyli.c acid of the formula A-COOH or a derivative thereof wherein A is selected from the groups R2~0~
or Ar- is reacted 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 Y is O and thereafter, where desired~ the resultant product is reacted with hydroxylamine in the presence of a base to produce the corresponding oxime in which Y is NOH~ a compound in which Z is CoR5 and/or Y is NoCOR5 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 :
R3~oz ~
Z~ being hydrogen or a protecting group such as methyl.
The reaction may be represented by the following reaction scheme :
Rl R
~ R2 ~ + ArCOX ------------~R2 ~ 0 ~ O _ Ar 10550~i 1 ~herein X is a halo~en atom or hydroxyl.
h~en X is halogerl, the reaction may be 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 (CF3CO~20 are preerred catalysts, used with or without a suitable solvent.
If Z'is a protecting group, it may be removed in situ or subsequently5 should it be desired to form a compound of formula (I) in which Z~ 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 20C to the reflux temperature and preferably from 80C. up to reflux temperature.
Similarly, the benzophenones can be prepared by the following reaction
2 R3~ COX + HAr --3 ~LC
similar reaction conditions be-ing 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 may be subjected to a Fries rearrangement using similar catalytic conditions : ~
R~ R~?lCOAr OCO Ar OH
~L055041 as those described above, for example using aluminium chloride.
A furtller example of the acylation lnvolving a der;vative of A-C00II
is the use of the compound Ar-CN as acylating agent. This modified process is known as the ~ouben-Hoesch Reaction which proceeds as shown below :
Rl R
R2 ~ R2 "~
R3 ~ Lew s cid ~ COAr Where a protected hydroxy group Z~ is used in the foregoin& reactions, it may be converted to the desired hydroxy group by cleavage with, for example, HBr, BF3~ AlC13 or HI.
As outlined above! preparation of ketonic derivatives such as the oxime can be 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-hydroxybenzophenone 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 - 70%), or by refluxing the o-hydroxybenzophenone or oxime with the acylating acid.
The o-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 ~re in vitro tests - the guinea pig and human chopped lung tests - and involve the direct measurement of the tnediators, histamine and slow reacting ~ , ~
:10550~1 1 substance in anaphyla~i~ (SRS-A), shown to be released by asthmatic human lullg. 1~or compolmds of the type comprising the present invention, a corl~poundis considered to be active if at least 30% inhibition of SRA-A release in the guinea pig chopped lung test is achieved at a dose of 10 ~g/ml or less. Depending on absorption, distribution and metabolism of the drug under test, activity in the chopped lung test at this level indicates' in vivo dosage ranging from 0.5 to about 100 mg/Kg orally.
The other two tests are in vivo tests - the Herxheimer and rat peritoneal anaphylaxis - and reflect oral activity in two different species.
In the Herxheimer test, sensitised guinea pigs are protected against the bronchospasm induced by an aerosol of antigen whilst, in the rat peritoneal anaphylaxis test, the SRS-A released on challenge is measured directly.
~here an active compound is tested in these in vivo tests~ activity at doses of 300 mg/Kg orless is normally achieved.
The compounds of the present invention display activity in one or more of the foregoing tests (the broadest spectrum compounds being those whic~
display anti-allergy activity in all four tests) and are therefore useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases including asthma and in the alleviation of status asthmaticus.
In certain cases the compounds have been found to be useful in diseases in which 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 administered by various routes and for this purpose may be formulated in a variety of forms. Thus the compounds or compositions may be administered by the oral and rectal routes, topically, parenterally, e.g. by injection and by continuous or discontinuous intra-arterial ir.fusion, in the form of~
for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base~ soft and ~OSS041 1 hflrd gelatin capsules~ slppositories~ injec~ion solutions and suspensions in physioLogicall~ acceptable media, and sterile packaged powders adsorbed onto a support material for making injection solutions. Advantageously for 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 rng~ in the case of oral or rectal administration) of a compound of formula (I).
As indicated by the tests referred to above, dosages of from 0.5 to 300 mg/kg per day~ preferably 0.5 to 20 mg/kg, of active ingredient may be administeredO It will however readily be understood that the amount of the compound or compounds of formula (I) 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 normally will consist of at ¦ least one compound of formula (I) associated with a ~harmaceutically acceptab4e ¦ 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, 1 sachet, cachet, paper or other container or by a disposable container sllcl- as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid materi 1 which serves as a vehicle, excipien~ or medium for the active therapeutic substance.
S . Some examples of the diluents or carriers which may be employed in tne pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbital, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxideS 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~, methylcellulose, 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 ingredientlsin the dies and on the punch of the tabletting machineO For such purpose there may be employed for instance aluminium, magnesium or calcium stearates~
talc or mineral oil.
1 The foilowing ~xa~lples f~lrther illus~rate tlle irlvention :
2-Hydroxy-5-Methyl-4'-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-hydrochloric 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-5-methyl-4'-chlorobenzophenone oxime (7 g.) m.p. 163C. (This was the stereo-isomer in which the oxime -OH group and the 4'-chlorophenyl group were in the syn positi~n 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 rela~ive to each other. (m.p. of product was 145-7C).
The C~H~N~Cl microanalysis for each isomer was satisfactory.
(c) 4'-Chloro-2-hydroxy-5-methyl-benzophenone-oxime diacetate.
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. 136C.) 10550~1 1 EX~MPLE 2 4~-Cl?loro-5-etllyl-2-1lydrox~
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 105C. 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 agueous fraction extracted twice with chloroform (200 mlc)~ and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main fractions: B (17.4 g) 150-160C @ 0.3 mmHg; C (110.8 g) 160-168 C. @ 0.3 mmHg.
The title compound was crystallised by cooling to -20C. and recrystallised from n-hexane at 0 C. to give a yellow crystalline solid m.p. 35-8 C.
Microanalysis: C15H13C102 requires 69.1~/oC, 5.0%H~ 13.6%Cl;
found 69.0%C, 5.~/~, 13~9%Cl~
4~-Chloro-5-ethyl-2-hydroxybenzophenone-oxime 4~-Chloro-5-ethyl-2-hydroxybenzophenone (65.2 g) and potassium hydroxide (170 g) in water (700 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 occurre~
during this time. The solution was acidified with 5N-hydrochloric acid and then extracted with ether (3 x 200 ml.). The combined ether solutions were washed with 10% aqueous sodium carbonate solution (2 x 200 ml.) and ¦ evaporated to dryness to give an off-~hite solid. This solid ~as ¦ recrystallised from 40% benzene / 60-80C petrol ether to give a white crystalline solid (29.9 g), second crop (14.5 g) m.p. 117C.
1Microa~alysis: ~1511l4C]N0? req~ s 65~3%C~ 5~]%H~ 5~1%N~ 12.9%Cl;
found 65~3%C~ 4.9%H~ 5.1C/oN, 12.9%Cl.
(Stereoisomer ~s in Example l(a)).
_ .
2-Hydroxy~ hyl-4 t -chlorobenzophenone Chlo~obenzene (78~79 g~ 71~6 ml; ~7 mole) and AlC13 (14 g~ 0~105 mole were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture w~s stirred and heated at 100C. overnight, ~le cooled mixture was added to conc HCl (10 ml) and ice, extracted with ether, and ether washed with saturated sodium bicarbonate solution~ dried (Na2S04), filtered and the filtrate distilled, to give (after removal of the ether ), a main fraction 2-hydroxy-
similar reaction conditions be-ing 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 may be subjected to a Fries rearrangement using similar catalytic conditions : ~
R~ R~?lCOAr OCO Ar OH
~L055041 as those described above, for example using aluminium chloride.
A furtller example of the acylation lnvolving a der;vative of A-C00II
is the use of the compound Ar-CN as acylating agent. This modified process is known as the ~ouben-Hoesch Reaction which proceeds as shown below :
Rl R
R2 ~ R2 "~
R3 ~ Lew s cid ~ COAr Where a protected hydroxy group Z~ is used in the foregoin& reactions, it may be converted to the desired hydroxy group by cleavage with, for example, HBr, BF3~ AlC13 or HI.
As outlined above! preparation of ketonic derivatives such as the oxime can be 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-hydroxybenzophenone 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 - 70%), or by refluxing the o-hydroxybenzophenone or oxime with the acylating acid.
The o-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 ~re in vitro tests - the guinea pig and human chopped lung tests - and involve the direct measurement of the tnediators, histamine and slow reacting ~ , ~
:10550~1 1 substance in anaphyla~i~ (SRS-A), shown to be released by asthmatic human lullg. 1~or compolmds of the type comprising the present invention, a corl~poundis considered to be active if at least 30% inhibition of SRA-A release in the guinea pig chopped lung test is achieved at a dose of 10 ~g/ml or less. Depending on absorption, distribution and metabolism of the drug under test, activity in the chopped lung test at this level indicates' in vivo dosage ranging from 0.5 to about 100 mg/Kg orally.
The other two tests are in vivo tests - the Herxheimer and rat peritoneal anaphylaxis - and reflect oral activity in two different species.
In the Herxheimer test, sensitised guinea pigs are protected against the bronchospasm induced by an aerosol of antigen whilst, in the rat peritoneal anaphylaxis test, the SRS-A released on challenge is measured directly.
~here an active compound is tested in these in vivo tests~ activity at doses of 300 mg/Kg orless is normally achieved.
The compounds of the present invention display activity in one or more of the foregoing tests (the broadest spectrum compounds being those whic~
display anti-allergy activity in all four tests) and are therefore useful in the prophylactic and therapeutic treatment of immediate hypersensitivity diseases including asthma and in the alleviation of status asthmaticus.
In certain cases the compounds have been found to be useful in diseases in which 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 administered by various routes and for this purpose may be formulated in a variety of forms. Thus the compounds or compositions may be administered by the oral and rectal routes, topically, parenterally, e.g. by injection and by continuous or discontinuous intra-arterial ir.fusion, in the form of~
for example, tablets, lozenges, sub-lingual tablets, sachets, cachets, elixirs, suspensions, aerosols, ointments, for example, containing from 1 to 10% by weight of the active compound in a suitable base~ soft and ~OSS041 1 hflrd gelatin capsules~ slppositories~ injec~ion solutions and suspensions in physioLogicall~ acceptable media, and sterile packaged powders adsorbed onto a support material for making injection solutions. Advantageously for 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 rng~ in the case of oral or rectal administration) of a compound of formula (I).
As indicated by the tests referred to above, dosages of from 0.5 to 300 mg/kg per day~ preferably 0.5 to 20 mg/kg, of active ingredient may be administeredO It will however readily be understood that the amount of the compound or compounds of formula (I) 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 normally will consist of at ¦ least one compound of formula (I) associated with a ~harmaceutically acceptab4e ¦ 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, 1 sachet, cachet, paper or other container or by a disposable container sllcl- as an ampoule. A carrier or diluent may be a solid, semi-solid or liquid materi 1 which serves as a vehicle, excipien~ or medium for the active therapeutic substance.
S . Some examples of the diluents or carriers which may be employed in tne pharmaceutical compositions of the present invention are lactose, dextrose, sucrose, sorbital, mannitol, propylene glycol, liquid paraffin, white soft paraffin, kaolin, fumed silicon dioxideS 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~, methylcellulose, 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 ingredientlsin the dies and on the punch of the tabletting machineO For such purpose there may be employed for instance aluminium, magnesium or calcium stearates~
talc or mineral oil.
1 The foilowing ~xa~lples f~lrther illus~rate tlle irlvention :
2-Hydroxy-5-Methyl-4'-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-hydrochloric 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-5-methyl-4'-chlorobenzophenone oxime (7 g.) m.p. 163C. (This was the stereo-isomer in which the oxime -OH group and the 4'-chlorophenyl group were in the syn positi~n 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 rela~ive to each other. (m.p. of product was 145-7C).
The C~H~N~Cl microanalysis for each isomer was satisfactory.
(c) 4'-Chloro-2-hydroxy-5-methyl-benzophenone-oxime diacetate.
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. 136C.) 10550~1 1 EX~MPLE 2 4~-Cl?loro-5-etllyl-2-1lydrox~
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 105C. 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 agueous fraction extracted twice with chloroform (200 mlc)~ and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main fractions: B (17.4 g) 150-160C @ 0.3 mmHg; C (110.8 g) 160-168 C. @ 0.3 mmHg.
The title compound was crystallised by cooling to -20C. and recrystallised from n-hexane at 0 C. to give a yellow crystalline solid m.p. 35-8 C.
Microanalysis: C15H13C102 requires 69.1~/oC, 5.0%H~ 13.6%Cl;
found 69.0%C, 5.~/~, 13~9%Cl~
4~-Chloro-5-ethyl-2-hydroxybenzophenone-oxime 4~-Chloro-5-ethyl-2-hydroxybenzophenone (65.2 g) and potassium hydroxide (170 g) in water (700 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 occurre~
during this time. The solution was acidified with 5N-hydrochloric acid and then extracted with ether (3 x 200 ml.). The combined ether solutions were washed with 10% aqueous sodium carbonate solution (2 x 200 ml.) and ¦ evaporated to dryness to give an off-~hite solid. This solid ~as ¦ recrystallised from 40% benzene / 60-80C petrol ether to give a white crystalline solid (29.9 g), second crop (14.5 g) m.p. 117C.
1Microa~alysis: ~1511l4C]N0? req~ s 65~3%C~ 5~]%H~ 5~1%N~ 12.9%Cl;
found 65~3%C~ 4.9%H~ 5.1C/oN, 12.9%Cl.
(Stereoisomer ~s in Example l(a)).
_ .
2-Hydroxy~ hyl-4 t -chlorobenzophenone Chlo~obenzene (78~79 g~ 71~6 ml; ~7 mole) and AlC13 (14 g~ 0~105 mole were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12 g, 0.07 mole) in chlorobenzene (20 ml). The mixture w~s stirred and heated at 100C. overnight, ~le cooled mixture was added to conc HCl (10 ml) and ice, extracted with ether, and ether washed with saturated sodium bicarbonate solution~ dried (Na2S04), filtered and the filtrate distilled, to give (after removal of the ether ), a main fraction 2-hydroxy-
3-methyl 4'-chlorobenzophenone, b.p. 148-152C/0.5 mm(8.18 g), which solidified to yellow microplates, m.p. 55-58 C~
found: C.68.23; H.4.71; Cl.14.61;
14 11 2 requires: C.68.16; H.4.49; Cl.14.37%
found: C.68.23; H.4.71; Cl.14.61;
14 11 2 requires: C.68.16; H.4.49; Cl.14.37%
4-Ethyl-4i-fluoro-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: B (11.4 g) 126-129 C, @ 0.07 mmHg; C (7.9 g)~ 129-132 C @ 0.06 mmHg; D (5.9 g)~ 132-15~ 1C.
@ 0.06 mmHg, all containing ~ 8~/o of the required isomer. B (4.0 g) was separated by preparative thin layer chromatography to give the title compound (2.6 g)~ m.p. 44-48C. The same compound was obtained using the method of Example 4.
; -13-~05504~
1 EX~MPl.r 6 4-Ethyi-L'-rlllo~-o-2-hydro~y-be-nzophenolle oxime.
4-Ethyl 4'-fluoro-2-1ydroxybenzophenone (2L~0 g~ 80% pure) was treated with hydroxylamine hydrochloride (24~0 g) in a manner similar to that in Example 3, to give, after recrystallisation from benzene, the title compound as a white crystalline solid ~10.7 g), m.p. 130~2C.
Microanalysis: C15H14FN02 requires 69.5%C~ 5~4~/oH~ 5~4/~N~ 7~3~/~;
found 69~2%C~ 5.5%H, 5.2~/~, 7.2/~.
2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime The ketone of Example 4 (7.5 g, 0.03 mole) in ethanol (18 ml.) was added with stirring to a solution of (85~/o) potassium hydroxide (20.74 g, 0~3 mole) in water (85 ml) at 10C, this colloidal solution was treated with solid hydroxylamine hydrochloride (8~54 g, 0.12 mole) and stirred overnight. The solution was acidified with SN HCl to give a solid~ which was filtered~
washed with water and stirred for 45 minutes, then treated with 5% Na2C03 l solution (30~5 ml)~ to remove unwanted oxime stereoisomer~ filtered~ washed with 5% Na2C03solution (100 ml) and then with water until free of alkali.
The dried solid had m.p. 175-177C. Recrystallisation from 54% benzene-light petroleum (b.p 60-80C) mixture gave the oxime, m.p. 178C ("bonded isomer") 5.45 g.
found: C~64~25; H.4.79; Cl.13.41; N~5~3%
C14H12Cl C2 requires : C~64~25; H~4~6; Cl.13.55; N~5~35%
~ EXAMPLE 8 2-Hydrox~r-3-methyl-4~-chlorobenzophenone oxime acetate.
Acetic anhydride (12 ml) was warmed to 60C. and treated with the oxime lOS~041 1 of Example 7 (5.25 g, 0.02 mole). The stirred mixture was wanned to 80C. to dissolve the oxir,le and the so]u~ion was thell immediately cooled in an ice bath. The precipitated solid was fi]tered off, washed with light petroleum (b.p. 40-60~C) to give the acetate, 4.8 g, m.p. 154-156C.
S found: C.63.18; H.4.86; Cl.11.5; N.~.77 C16H14ClN3 requires: C.63~26; H.4.64; Cl.11.67;N.4.6%
2-Hydroxy-3-ethylbenzophenone 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. J
0.14 mm~ ~ 2 1.6081~ ~ max. (film) 1630 cm 1. The same compound was obtained using the method of Example 2.
2~l4~Dichloro-3-ethyl-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 ror 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 10% 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 (156-172C at 0.06 mmHg) containing 85% of the required product.
(With ferric chloride solution a purple colour was obtained indicating the I iQ55041 1 presence o an o-hydroxyketone). The ke~one product ~s purified by chromatography on ~ silica column ~D 1.6163. The same product was obtained using the method of Example 4.
XAMPLE ll 4-Ethyl-3~-fluoro-2-hydroxybenzophenone This compound was prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl chloride (17.5 g) and aluminium chloride (26.7 g) in 1,1,2,2-tetrachloro-ethane (75 ml) using the same conditions as in Example 2, but heating under reflux, not at 105C. The product was purified by chromatography on a silica column m.p. between 0 and 20C r~o2 1.5962L The same product was obtained using the method of Example 4.
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 N 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. 66.5-67C.
The above ester (2.6 g) was heated with aluminium chloride (1.33 g!
in tetrachloroethane for 6 hours at 125C. 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 l sample showed the product to be 4~-chloro-5-ethyl-2-hydroxybenzophenone.
l I
l 10550~1 1 Similarly prepared were:
@ 0.06 mmHg, all containing ~ 8~/o of the required isomer. B (4.0 g) was separated by preparative thin layer chromatography to give the title compound (2.6 g)~ m.p. 44-48C. The same compound was obtained using the method of Example 4.
; -13-~05504~
1 EX~MPl.r 6 4-Ethyi-L'-rlllo~-o-2-hydro~y-be-nzophenolle oxime.
4-Ethyl 4'-fluoro-2-1ydroxybenzophenone (2L~0 g~ 80% pure) was treated with hydroxylamine hydrochloride (24~0 g) in a manner similar to that in Example 3, to give, after recrystallisation from benzene, the title compound as a white crystalline solid ~10.7 g), m.p. 130~2C.
Microanalysis: C15H14FN02 requires 69.5%C~ 5~4~/oH~ 5~4/~N~ 7~3~/~;
found 69~2%C~ 5.5%H, 5.2~/~, 7.2/~.
2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime The ketone of Example 4 (7.5 g, 0.03 mole) in ethanol (18 ml.) was added with stirring to a solution of (85~/o) potassium hydroxide (20.74 g, 0~3 mole) in water (85 ml) at 10C, this colloidal solution was treated with solid hydroxylamine hydrochloride (8~54 g, 0.12 mole) and stirred overnight. The solution was acidified with SN HCl to give a solid~ which was filtered~
washed with water and stirred for 45 minutes, then treated with 5% Na2C03 l solution (30~5 ml)~ to remove unwanted oxime stereoisomer~ filtered~ washed with 5% Na2C03solution (100 ml) and then with water until free of alkali.
The dried solid had m.p. 175-177C. Recrystallisation from 54% benzene-light petroleum (b.p 60-80C) mixture gave the oxime, m.p. 178C ("bonded isomer") 5.45 g.
found: C~64~25; H.4.79; Cl.13.41; N~5~3%
C14H12Cl C2 requires : C~64~25; H~4~6; Cl.13.55; N~5~35%
~ EXAMPLE 8 2-Hydrox~r-3-methyl-4~-chlorobenzophenone oxime acetate.
Acetic anhydride (12 ml) was warmed to 60C. and treated with the oxime lOS~041 1 of Example 7 (5.25 g, 0.02 mole). The stirred mixture was wanned to 80C. to dissolve the oxir,le and the so]u~ion was thell immediately cooled in an ice bath. The precipitated solid was fi]tered off, washed with light petroleum (b.p. 40-60~C) to give the acetate, 4.8 g, m.p. 154-156C.
S found: C.63.18; H.4.86; Cl.11.5; N.~.77 C16H14ClN3 requires: C.63~26; H.4.64; Cl.11.67;N.4.6%
2-Hydroxy-3-ethylbenzophenone 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. J
0.14 mm~ ~ 2 1.6081~ ~ max. (film) 1630 cm 1. The same compound was obtained using the method of Example 2.
2~l4~Dichloro-3-ethyl-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 ror 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 10% 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 (156-172C at 0.06 mmHg) containing 85% of the required product.
(With ferric chloride solution a purple colour was obtained indicating the I iQ55041 1 presence o an o-hydroxyketone). The ke~one product ~s purified by chromatography on ~ silica column ~D 1.6163. The same product was obtained using the method of Example 4.
XAMPLE ll 4-Ethyl-3~-fluoro-2-hydroxybenzophenone This compound was prepared from 3-ethylphenol (12.2 g), 3-fluorobenzoyl chloride (17.5 g) and aluminium chloride (26.7 g) in 1,1,2,2-tetrachloro-ethane (75 ml) using the same conditions as in Example 2, but heating under reflux, not at 105C. The product was purified by chromatography on a silica column m.p. between 0 and 20C r~o2 1.5962L The same product was obtained using the method of Example 4.
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 N 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. 66.5-67C.
The above ester (2.6 g) was heated with aluminium chloride (1.33 g!
in tetrachloroethane for 6 hours at 125C. 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 l sample showed the product to be 4~-chloro-5-ethyl-2-hydroxybenzophenone.
l I
l 10550~1 1 Similarly prepared were:
5 Ethyl-2-hyaroxy-4r-m2thyljellzoyhetlo}le~ m.p. 49-51C. and 4'-Chloro-3,5-diethyl-2-hydroxybenæophenone b.p. 18~Co at 1~4 mmtHg.
2-Benzoyloxy-5-ethyl-4~-chlorobenzophenone 2-Hydroxy-5-ethyl-4C-chlorobenzophenone (5 g, 0.019 mole) was stirred vigorously in a solution of NaO]I (7.5 g~ 0.187 mole) in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose ,o around 50C. 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 (Na2S04)~ filtered and evaporated to leave the productS
which was recrystallised from n-hexane to give white crystals of the desired product~ m.p. 79-81 C.
2-Acetoxy-4i-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 10% NaHC03 solution (50 ml), dried (MgS04) and evaporated to leave an oil which was distilled~
b.p. 160-165C. at 3.5 mm/Hg (2.3 g) to give the desired product.
~` -17-.' ~ ~
iOS5041 1 }~XAMrLE 15 5~Etllyl-2-hyd ~ _ ~ ~
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane (2 ml) and treated with 4-trifluoromethylbenzoyl chloridc (1 g, O.OG48 mole) (ice-bath cooling) ar.d then with 4-ethylanisole (0.6 g, 000044 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% NaHC03 solution (100 ml)9 dried (MgS04)~ filtered and evaporated to leave 5-ethyl-2-methoxy-4~-trifluoromethylbenzophenone (1.2 g) as a yellow oil. The latter was heated in 55% agueous hydrogen bromide (27.5 ml) at 110-120C. for 5 hours. The mixture was evaporated to dryness to leave the required product.
5-Ethyl-2-hydroxy-3~-carboxv- and 3i carbomethoxybenzophenone Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloro-methane (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-ethyl-2-methoxy-3~-carbomethoxybenzophenone. The Latter was heated in 55% aqueous hydrogen bromide (500 ml) at 110-120C 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 N microanalysis.
The 1atter carboxylic acid was then refluxed overnight in methanol (500 ml) containing concentrated s~lphuric acid (5 ml), poured into water (1 L
and extracted with ether. The combined ethereal extracts were washed with saturated NaHC03 solution, dried (MgS04), filtered and evaporated to leave the desired ester, which gave a satisfactory microanalysis.
2-Benzoyloxy-5-ethyl-4~-chlorobenzophenone 2-Hydroxy-5-ethyl-4C-chlorobenzophenone (5 g, 0.019 mole) was stirred vigorously in a solution of NaO]I (7.5 g~ 0.187 mole) in water (75 ml) and benzoyl chloride was added dropwise over 5 minutes. The temperature rose ,o around 50C. 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 (Na2S04)~ filtered and evaporated to leave the productS
which was recrystallised from n-hexane to give white crystals of the desired product~ m.p. 79-81 C.
2-Acetoxy-4i-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 10% NaHC03 solution (50 ml), dried (MgS04) and evaporated to leave an oil which was distilled~
b.p. 160-165C. at 3.5 mm/Hg (2.3 g) to give the desired product.
~` -17-.' ~ ~
iOS5041 1 }~XAMrLE 15 5~Etllyl-2-hyd ~ _ ~ ~
Aluminium chloride (0.6 g, 0.004 mole) was stirred in dichloromethane (2 ml) and treated with 4-trifluoromethylbenzoyl chloridc (1 g, O.OG48 mole) (ice-bath cooling) ar.d then with 4-ethylanisole (0.6 g, 000044 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% NaHC03 solution (100 ml)9 dried (MgS04)~ filtered and evaporated to leave 5-ethyl-2-methoxy-4~-trifluoromethylbenzophenone (1.2 g) as a yellow oil. The latter was heated in 55% agueous hydrogen bromide (27.5 ml) at 110-120C. for 5 hours. The mixture was evaporated to dryness to leave the required product.
5-Ethyl-2-hydroxy-3~-carboxv- and 3i carbomethoxybenzophenone Aluminium chloride (39.9 g, 0.3 mole) was stirred in dichloro-methane (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-ethyl-2-methoxy-3~-carbomethoxybenzophenone. The Latter was heated in 55% aqueous hydrogen bromide (500 ml) at 110-120C 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 N microanalysis.
The 1atter carboxylic acid was then refluxed overnight in methanol (500 ml) containing concentrated s~lphuric acid (5 ml), poured into water (1 L
and extracted with ether. The combined ethereal extracts were washed with saturated NaHC03 solution, dried (MgS04), filtered and evaporated to leave the desired ester, which gave a satisfactory microanalysis.
Claims (13)
1. Process for preparing a compound of the formula :
(I) wherein R1, R2 and R3 represent hydrogen or ethyl, at least one being ethyl, Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine, methyl, carboxy, COOR5 and trifluoromethyl; Z is hydrogen or COR5; and Y is O, NOH or NOCOR5, R5 being C1-4 alkyl or phenyl provided that, when R1 is ethyl, R2 and R3 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-fluorophenyl, characterised in that a carboxylic acid of the formula A-COOH or a derivative thereof where A is selected from the group or the group Ar is reacted 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 Y is O and thereafter, where desired, the resultant product is reacted with hydroxylamine in the presence of a base to produce the corresponding oxime in which Y is NOH, a compound in which Z is COR5 and/or Y is NOCOR5 being then obtained by acylation of the aforementioned compounds in which Z is hydrogen and/or Y is NOH.
(I) wherein R1, R2 and R3 represent hydrogen or ethyl, at least one being ethyl, Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine, methyl, carboxy, COOR5 and trifluoromethyl; Z is hydrogen or COR5; and Y is O, NOH or NOCOR5, R5 being C1-4 alkyl or phenyl provided that, when R1 is ethyl, R2 and R3 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-fluorophenyl, characterised in that a carboxylic acid of the formula A-COOH or a derivative thereof where A is selected from the group or the group Ar is reacted 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 Y is O and thereafter, where desired, the resultant product is reacted with hydroxylamine in the presence of a base to produce the corresponding oxime in which Y is NOH, a compound in which Z is COR5 and/or Y is NOCOR5 being then obtained by acylation of the aforementioned compounds in which Z is hydrogen and/or Y is NOH.
2. Process as claimed in claim 1, wherein a compound of the formula AR-CN or ArCOX where X is halogen is reacted with a compound of the formula :-
3. Process as claimed in claim 1, wherein a compound of the formula :- wherein X is as defined in claim 2, is reacted with a substituted benzene of formula Ar-H.
4. Process as claimed in claim 2, wherein the initial product obtained is a compound of formula :- which is then subjected to the Fries rearrangement to produce the desired compound of formula (I).
5. Process as claimed in any one of claims 1 to 3, wherein the catalyst for the Friedel-Crafts' acylation is a Lewis acid.
6. Process as claimed in any one or claims 1 to 3, wherein the catalyst for the Friedel-Crafts acylation is an aluminium halide.
7. Process as claimed in Claim 1, wherein Y, Z, R1, R2, R3 and R5 are as defined in Claim 1 and Ar is a phenyl group substituted by from one to three groups selected from chlorine, fluorine or methyl.
8. Process as claimed in Claim 1, wherein one of R , R and R3 is ethyl and the others are hydrogen, Ar is 4-chlorophenyl, 4-fluorophenyl or 4-methylphenyl, Z is hydrogen, and Y is 0.
9. Process as claimed in Claim 1, wherein R1 is ethyl, R2, R3 and Z are hydrogen, Y is 0 and Ar is 4-chlorophenyl.
10. An o-hydroxybenzophenone whenever prepared by the process claimed in any one of claims 1 to 3 or an obvious chemical equivalent thereof.
11. An o-hydroxybenzophenone whenever prepared by the process claimed in Claim 4, wherein Z is hydrogen, Y is O and either (i) R1 is ethyl, R2 and R3 are hydrogen and Ar is 4-chloro-phenyl; (ii) R is ethyl, R1 and R2 are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R is ethyl, R1 and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
12. An o-hydroxybenzophenone whenever prepared by the process claimed in Claim 7 or Claim 8, wherein Z is hydrogen, Y is 0 and either (i) R1 is ethyl, R2 and R3 are hydrogen and Ar is 4-chlorophenyl; (ii) R3 is ethyl, R1 and R2 are hydrogen and Ar is 2,4-dichlorophenyl; or (iii) R2 is ethyl, R1 and R3 are hydrogen and Ar is 3- or 4-fluorophenyl.
13. 4'-Chloro-5-ethyl-2-hydroxybenzophenone whenever prepared by the process of Claim 9 or an obvious chemical equivalent thereof.
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 (1)
| Publication Number | Publication Date |
|---|---|
| CA1055041A true CA1055041A (en) | 1979-05-22 |
Family
ID=10065798
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA250,199A Expired CA1055041A (en) | 1975-04-17 | 1976-04-13 | Ketone 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 |
| 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 |
| 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 |
| EP0983991B1 (en) * | 1992-04-22 | 2003-12-17 | Ligand Pharmaceuticals, Inc. | Compounds having selectivity for retinoid x receptors |
| 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 |
| CH1093669A4 (en) * | 1969-07-17 | 1971-02-15 | ||
| 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 DE DE19762615487 patent/DE2615487A1/en not_active Withdrawn
- 1976-04-09 NO NO761233A patent/NO146022C/en unknown
- 1976-04-12 AR AR262848A patent/AR217399A1/en active
- 1976-04-12 OA OA55796A patent/OA05301A/en unknown
- 1976-04-12 CH CH459876A patent/CH617654A5/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
- 1976-04-13 FI FI760999A patent/FI68609C/en not_active IP Right Cessation
- 1976-04-13 ES ES446993A patent/ES446993A1/en not_active Expired
- 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
- 1976-04-14 PL PL1976188773A patent/PL103084B1/en unknown
- 1976-04-14 PT PT65015A patent/PT65015B/en unknown
- 1976-04-15 AT AT278676A patent/AT347430B/en not_active IP Right Cessation
- 1976-04-15 BE BE6045444A patent/BE840826A/en not_active IP Right Cessation
- 1976-04-15 LU LU74773A patent/LU74773A1/xx unknown
- 1976-04-15 CS CS762506A patent/CS196305B2/en unknown
- 1976-04-16 BG BG7632930A patent/BG33275A3/en unknown
- 1976-04-16 YU YU00971/76A patent/YU97176A/en unknown
- 1976-04-16 HU HU76LI288A patent/HU176276B/en unknown
- 1976-04-16 SU SU762345332A patent/SU644372A3/en active
- 1976-04-17 JP JP51044159A patent/JPS51128950A/en active Pending
- 1976-04-17 EG EG76217A patent/EG12255A/en active
- 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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