CA1042904A - Isoxazole derivatives - Google Patents
Isoxazole derivativesInfo
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- CA1042904A CA1042904A CA297,648A CA297648A CA1042904A CA 1042904 A CA1042904 A CA 1042904A CA 297648 A CA297648 A CA 297648A CA 1042904 A CA1042904 A CA 1042904A
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- benzisoxazole
- formula
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Abstract
Isoxazole Derivatives ABSTRACT OF THE DISCLOSURE
This invention provides 1,2-benzisoxazole derivatives of the formula;
This invention provides 1,2-benzisoxazole derivatives of the formula;
Description
9( 1~
This invention relates to certain new heterocyclic compo~nds a~d in particular to certain novel 1,2-benzisoxa-zole derivatives which ~ve ~een found to possess valuable pharmacological activity a~d/or are useful as intermediates for preparing such active compounds and to a process by which such compounds may be prepared. The invention also includes pharmaceutical compositions containing said pharmacologically active compounds and a method of treating animals including humans comprising administering thereto an effective dose of said compounds or compositions.
According to the present invention there are provided novel 1,2-benzisoxazole derivatives of the formula:-N
R
wherein Rl represents one or more substituents which are at20 any one or more of the available positions in the benzene ring and which are selected from one or more of the . following atoms or groups: hydrogen, halogen, preferably chlorine or bromine Cl 4 alkyl, preferably methyl, Cl-C4 alkoxy, preferably methoxy, nitro, and trifluoromethyl, and R2 is a substituent at the 5-, 6-, or 7- position of the 1,2-benzisoxazole nucleus and is one of the following: Hydrogen, Cl 4 alkyl, preferably methyl, carboxy Cl 4 alkyl, preferably carboxymethyl, cyano Cl 4 alkyl, preferably cyanomethyl or . l-cyanoethyl, -CH(R )- COOH, -CH2.COOR , and -CH(R )-COOR , ~ ~ s"~
: - 2 -., ~. . . .
` ~04;~9Q4 ; where R3 is Cl 4 alkyl; except that when Rl represents a hydrogen ~tom R2 is not hydrogen.
- Compounds in which R is halo Cl 4 alkyl are useful as intermediates.
The terms Cl_4 alkyl and Cl_4 alkoxy" as used here-; in mean a straight or branched chain alkyl or alkoxy group containing from 1 to 4 carbon atoms, that is methyl-, ethyl-, n-propyl-, iso-propyl-, n-butyl, s-butyl- or t-butyl-.
. .
The term "carboxymethyl" as used herein means, of course, the group -CH2CO2H.
A preferred class of compounds of formula I are those in which R2 represents a carboxymethyl group or a group of formula -CH(R )COOH. In this preferred class there exists a still further preferred class, namely those in which R
represents a halogen substituent, particularly a para halo-substituent.
A presently preferred compound of the invention is ~-methyl-3-~-chlorophenyl-1,2-benzisoxazol-7-yl acetic acidO
The present invention also provides a process for preparing the novel 1,2-benzisoxazole derivatives of the ` invention which process comprises cyclising a compound of the following formula.
X
.. ~. ~
~ II
HO.
R
. ~ Y
- wherein R4 is hydroxy or halogen tpreferably chloro or bromo ; and especially the latter), X and Y are respectively Rl and R2 as hereinbefore defined or, independently, either or both of X and Y represent a group which is convertible to the ; desired groups R or R2, respectively, and thereafter when : , i ~0~2gQ~
either or both of X and Y represent a group which is convertible t~ the desired group Rl or R2, respectively, the said group - X and~or Y is converted to the group Rl and/or R2 in conventional manner.
Alternatively, an obvious chemical equivalent of the oxime such as a hydrazone can be used in the ring-closure reaction.
- Conveniently a precursor of the oxime of formula II, ~' or the hydrazone, is the corresponding benzophenone derivative, which may be synthesised by methods well known in the art.
The benzophenone may be reacted with hydroxylamine to produce ` the oxime, or reacted with a suitable hydrazine to yield the hydrazone.
; This reaction can be represented by the following reaction scheme:
: '.` X
~, ~C~
\=/ 11 ~
hydroxylamine or a hydrazine , . X ~
Y IV
Q
where Q is a hydroxyl or amino group. The above conversion, when X is not hydrogen, is novel and is thus provided in a further aspect of the invention. Similarly, when X is not hydrogen, the intermediates of formula IV are novel. The intermediates of formula IV where R is hydroxyl are particu-larly valuable since, as well as being convertible to benzis-~; oxazoles according to the invention, they are also (by :
~42g~4 choosing appropriate reaction conditions) convertible to the cl~ss of benzoxazoles described in Belgian Patent Specification -` No. 7~,7~0 or ~nited States Patent No. 3,912,74S. The appropriate reaction conditions to use when it is desired that a benzoxazole rather than a benzisoxazole should be prepared are well-known see, for example, Chapter 6, of Heterocyclic - Compounds", Volume 5, edited by Elderfield and published in 1957 by John Wiley. Briefly, to obtain the benzoxazole, acidic conditions (e.g. using polyphosphoric acid) should be used to effect a Beckmann rearrangement, whereas if it is desired to obtain a benzisoxazole basic conditions (e.g.
using Na2CO3 in triglyme) should be employed.
In the case where R4 is hydroxy, acylation of the appropriate oxime stereoisomer followed by heating, if necessary, effects the cyclisation, although it is possible to ring-close the oxime direct.
The hydrogen atom from the R4 hydroxyl group can be replaced by a group IA metal, such as sodium, a group IIA
metal or ammonium ion.
` 20 In the case where the compound of formula VI in which ` ` R4 is hydroxy is cyclised to the benzisoxazole, the con-figuration of the intermediate :-. .
X ~ ~ ~ VI
Q
should be such that the Q group is anti- to the phenolic ` hydroxyl group. When R4 is halo, the Q group should be syn thereto.
.. ..
When it is desired to prepare a benzoxazole from the intermediate of formula:
~04Z9Q4 I OH
the Q group should be anti- to the hydroxyl group. ~,.
In a fuxther aspect of this invention there is provided a process for preparing a 5- or 6- substituted benzoxazole of formula ~ O ~ R2 R
wherein Rl represents one or more substituents which are at any one or more of the available positions in the benzene . ring and which are selected from one or more of the following atoms or groups; hydrogen, halogen, Cl 4 alkyl, Cl_4 alkoxy, nitro, and trifluoromethyl, and R2 is a substituent at the 5-, 6-, or 7~ position of the 1,2-benzisoxazole nucleus and ~ 20 is one of the following: hydrogen, Cl 4 alkyl, carboxy Cl 4 alkyl, cyano Cl 4 alkyl, -CH(R )-COOH, -CH2-COOR , and--; : -CH(R3)-CooR3, where R3 is Cl 4 alkyl; except that when Rl represents a hydrogen atom R2 is not hydrogen, which process ~ comprises cylising, under acidic conditions an oxime or hydrazone of formula .
~ R ~ Q~ O~ R
;~ `
~4~
where ~ is hydroxyl or an amino group.
When R4 is haloyen, heating with an alkali such as - potassium hydroxide produces the benzisoxazole, which ~ in all cases has the formula :
X~
,',-~ ~ ~ VII
i~ - O
wherein X and Y are as previously defined.
. Thus, in general terms, the present invention provides a process for preparing a compound of formula I which com-prises the ring-closure under basic conditions of a compound of formula :
' ~
~J
Q - N = C
; R Y
where X and Y are as previously defined, Q is a hydroxyl, amino, acyloxy (preferably a group of formula -o-C-R3, where R3 is Cl 4 alkyl) or sulphonyloxy radical, and R4 is halogen or a group of formula -OM where M is hydrogen, ammonium or a group IA or IIA metal, followed, if necessary, by the conversion of X and/or Y to the desired Rl and/or R2 groups by conventional means.
For example, when Y represents alkyl, the alkyl group may be halogenated using conventional halogenating agents . such as chlorine, sulphuryl chloride, bromine, or N-bromo-succinnimide, preferably in the presence of a suitable i~zg~4 solvent such as carbon tetrachloride, and thereafter a cyano group substituted ~rom the halogen atom. Hydrolysis of the nitrile produces the corresponding carboxylic acid which may if desired be esteri~ied. Alternatively, the halogen atom can be replaced by a carboxylic acid gro~lp vla an organo-metallic compound such as a Grignard reagent. This procedure is fully described in Standard re~erence books, for example for the Grignard reaction, see page 11 72 of the ~erck Index, VIIIth Edition, published 1968. Acids or est~rs Formula I
may be alkylated at the ~-carbon atom using an alkyl halide such as methyl or ethyl iodide. An ester of formula I may also be converted to the hydroxamic acid derivative by reaction with hydroxylamine.
An acid of formula I may be salified by treatment with an appropriate base such as ammonium, alkylammonium, aralkyl-ammonium, alumium, alkali metal or alkaline earth metal hydroxide and of course a salt of formula I may readily be converted to the free acid by treatment with an acid such as hydrochloric or sulphuric acid. The salts, e.g. the sodium salt, are pharmaceutically active. An acid of formula I or a salt thereof may be converted to an ester by treatment with an appropriate alcohol or by treatment with a halide of the appropriate ester moiety or a salt of that halide if the ~ ester moiety contains a basic nitrogen atom. An ester of ; formula I may, of course, be hydrolysed to the corresponding acid of formula I by treatment with a suitable hydrolytic agent such as an inorganic base or acid. An acid of formula I
or an ester thereof may also be converted to an amide of formula I by reaction with ammonia or an appropriate primary or secondary amine.
It will be understood that the above described specific cyclisation procedure is not the only method of synthesising `:
~(34~904 the novel compounds of this invention; any obvious chemical equivalent cyclisation reaction may be employed, that is ' ~ any reaction, or sequence of reactions, which is capable of bringin~ a nitrogen atom and/or an oxygen atom into the desired relationship with the benzophenone derivative so as to produce a compound of formula VII.
- As mentioned above, the acids of formula I, i.e. those compounds in which R2 is carboxymethyl or -CH(R3) COOH are preferred compounds of the invention. These acids can be prepared by hydrolysis of the corresponding nitriles of formula VII where Y is cyano Cl 4 alkyl. Clearly, when it is desired to prepare the acid in which R2 is carboxymethyl, cyanomethyl is the group which needs to be hydrolysed.
Similarly, when it is desired to produce an acid group of formula -CH(R3)COOH it is necessary to hydrolyse a group ; of formula -CH(R3)CN.
Alternatively, the above class of acids can be pre-pared from derivatives of formula I where R is a Cl 4 ` haloalkyl group using the Grignard reaction. After reaction with magnesium and treatment with carbon dioxide a compound of formula I is formed in which R2 represents the group -C-OMgXl where Xl is a halogen atom. This group can then be converted to a carboxylic acid group simply by hydrolysis.
Thus, according to yet a further feature of the invention there is provided a method of preparing an acid of formula : Rl O ~ CHR5C02H
wherein Rl is as defined previously and the -CHR5Co2H group is at the 5-, 6-, or 7- position of the benzisoxazole nucleus ' _ g _ ~ 29Q4 and R represents hy~rogen or Cl 4 alkyl, which comprises hydrolysing a compound of formula:
. Rl ','' ~
CHR Z
where the group -CHR5Z is at the 5-, 6- or 7- position of the benzisoxazole nucleus and Z represents a nitrile, ester, carboxylate or hydroxamic acid group, or a group of formula:
, ~0 ~ OMgX
where Xl is a halogen atom.
The novel compounds of the present invention in which R is a carboxy or esterified caEboxy moiety have been found to possess anti-inflammatory activity and in some cases other pharmacological activity, whilst the other novel compounds of formula I are useful as intermediates in the synthesis of ` the aforementioned pharmacologically active compounds. The pharmacological activity has been demonstrated in tests , , carried out in animals, usually at doses of from 0_1 to 500 mg./Kg. In the treatment of humans, the dose administered ` may be for example, between 0.1 and 25 mg./kg. but, of course, doses outside this range may be used at the discretion of the physician treating the patient. The pharmacologically active compounds of formula I may be administered by the enteral or parenteral routes and for this purpose they will normally be formulated into pharmaceutical compositions comprising the active ingredient in associat~on with at least one pharmaceutically acceptable carrier therefor. Such compositions form a part of this invention and will normally consist of the active ingredient mixed with a carrier, or ::
1~2~Q4 diluted by a carrier, or enclosed or encapsulated by a carrier in the for~ o~ a capsule, sachet, cachet or other container.
The carrier may be a solid, semi-solid or liquid material which serves as a vehicle, excipient, coating agent, or medium for the active ingredient. Some examples of the carriers which may be used are lactose, dextrose, sucrose, sor~itol, mannitol, starch, gum acacia, calcium phosphate, liquid p~ra~fin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl - or propyl - hydroxybenzoate, ethyl cellulose acetate phthalate, low viscosity acetyl cellulose acetate, paraffin wax, mineral wax, vegetable wax, vegetable gum, silicone rubbers such as liquid polydimethyl-siloxane rubber, plasticised or unplasticised polyvinyl - chloride, plasticised polyethylene terephthalate, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol or cross-linked partially hydrolysed polyvinyl acetate.
Advantageously the compositions of the invention are formulated in a dosage unit form containing from 1 to 1000 mg.
(preferably 25 to 500 mg.) of the active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories as well as drug dispensing systems comprising the active ingredient contained in a flexible, imperforate polymeric material through which the drug may be released slowly by diffusion.
More generally, the term "dosage unit form" as used herein means a physically discrete unit containing the active ingredient, generally in admixture with and/or enclosed by a pharmaceutical carrier, the quantity of active ingredient being such that one or more units are normally required for a single therapeutic administration.
- ~ .
~4;~
~ a~tion to the active ingredient of formula I, the compositions of the present invention may al50 contain one or - more pharmacologically active ingredients, for example, acetylsalicyclic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and indomethacin.
The compositions of the present invention will of course be adapted to the particular route of administration.
. ~ Thus, for oral administration, tablets, pills, capsules, solutions or suspensions may be used; ~or parenteral administration, sterile injection solutions or suspensions may be used; for rectal administration, suppositories may be used; and for topical administration, creams, lotions or ointments may be used. Any of the foregoing compositions may, of course, be formulated in delayed or sustained release form in a manner well known in the art.
Compounds of formula I in which R2 is a Cl 4 alkyl group, preferably ethyl, and in which Rl is a hydrogen or hal-ogen are also useful in the treatment of immediate hypersensi-tivity diseases including asthma, and in the alleviation of status asthmaticus. This class of compounds i5 also useful for the treatment of diseases in which excessive amounts of prostaglandins are released.
The following-examples will further illustrate the invention. No examples of the formation of acids via the Grignard route are given. However, those skilled in the art will appreciate that the halo-alkyl intermediates described hereinafter can be converted to the corresponding acids by this method, if so desired.
~0912~
~.
Example 1 5-Methyl-3-~4-chl~rophenyl~-1,2-benzisoxazole
This invention relates to certain new heterocyclic compo~nds a~d in particular to certain novel 1,2-benzisoxa-zole derivatives which ~ve ~een found to possess valuable pharmacological activity a~d/or are useful as intermediates for preparing such active compounds and to a process by which such compounds may be prepared. The invention also includes pharmaceutical compositions containing said pharmacologically active compounds and a method of treating animals including humans comprising administering thereto an effective dose of said compounds or compositions.
According to the present invention there are provided novel 1,2-benzisoxazole derivatives of the formula:-N
R
wherein Rl represents one or more substituents which are at20 any one or more of the available positions in the benzene ring and which are selected from one or more of the . following atoms or groups: hydrogen, halogen, preferably chlorine or bromine Cl 4 alkyl, preferably methyl, Cl-C4 alkoxy, preferably methoxy, nitro, and trifluoromethyl, and R2 is a substituent at the 5-, 6-, or 7- position of the 1,2-benzisoxazole nucleus and is one of the following: Hydrogen, Cl 4 alkyl, preferably methyl, carboxy Cl 4 alkyl, preferably carboxymethyl, cyano Cl 4 alkyl, preferably cyanomethyl or . l-cyanoethyl, -CH(R )- COOH, -CH2.COOR , and -CH(R )-COOR , ~ ~ s"~
: - 2 -., ~. . . .
` ~04;~9Q4 ; where R3 is Cl 4 alkyl; except that when Rl represents a hydrogen ~tom R2 is not hydrogen.
- Compounds in which R is halo Cl 4 alkyl are useful as intermediates.
The terms Cl_4 alkyl and Cl_4 alkoxy" as used here-; in mean a straight or branched chain alkyl or alkoxy group containing from 1 to 4 carbon atoms, that is methyl-, ethyl-, n-propyl-, iso-propyl-, n-butyl, s-butyl- or t-butyl-.
. .
The term "carboxymethyl" as used herein means, of course, the group -CH2CO2H.
A preferred class of compounds of formula I are those in which R2 represents a carboxymethyl group or a group of formula -CH(R )COOH. In this preferred class there exists a still further preferred class, namely those in which R
represents a halogen substituent, particularly a para halo-substituent.
A presently preferred compound of the invention is ~-methyl-3-~-chlorophenyl-1,2-benzisoxazol-7-yl acetic acidO
The present invention also provides a process for preparing the novel 1,2-benzisoxazole derivatives of the ` invention which process comprises cyclising a compound of the following formula.
X
.. ~. ~
~ II
HO.
R
. ~ Y
- wherein R4 is hydroxy or halogen tpreferably chloro or bromo ; and especially the latter), X and Y are respectively Rl and R2 as hereinbefore defined or, independently, either or both of X and Y represent a group which is convertible to the ; desired groups R or R2, respectively, and thereafter when : , i ~0~2gQ~
either or both of X and Y represent a group which is convertible t~ the desired group Rl or R2, respectively, the said group - X and~or Y is converted to the group Rl and/or R2 in conventional manner.
Alternatively, an obvious chemical equivalent of the oxime such as a hydrazone can be used in the ring-closure reaction.
- Conveniently a precursor of the oxime of formula II, ~' or the hydrazone, is the corresponding benzophenone derivative, which may be synthesised by methods well known in the art.
The benzophenone may be reacted with hydroxylamine to produce ` the oxime, or reacted with a suitable hydrazine to yield the hydrazone.
; This reaction can be represented by the following reaction scheme:
: '.` X
~, ~C~
\=/ 11 ~
hydroxylamine or a hydrazine , . X ~
Y IV
Q
where Q is a hydroxyl or amino group. The above conversion, when X is not hydrogen, is novel and is thus provided in a further aspect of the invention. Similarly, when X is not hydrogen, the intermediates of formula IV are novel. The intermediates of formula IV where R is hydroxyl are particu-larly valuable since, as well as being convertible to benzis-~; oxazoles according to the invention, they are also (by :
~42g~4 choosing appropriate reaction conditions) convertible to the cl~ss of benzoxazoles described in Belgian Patent Specification -` No. 7~,7~0 or ~nited States Patent No. 3,912,74S. The appropriate reaction conditions to use when it is desired that a benzoxazole rather than a benzisoxazole should be prepared are well-known see, for example, Chapter 6, of Heterocyclic - Compounds", Volume 5, edited by Elderfield and published in 1957 by John Wiley. Briefly, to obtain the benzoxazole, acidic conditions (e.g. using polyphosphoric acid) should be used to effect a Beckmann rearrangement, whereas if it is desired to obtain a benzisoxazole basic conditions (e.g.
using Na2CO3 in triglyme) should be employed.
In the case where R4 is hydroxy, acylation of the appropriate oxime stereoisomer followed by heating, if necessary, effects the cyclisation, although it is possible to ring-close the oxime direct.
The hydrogen atom from the R4 hydroxyl group can be replaced by a group IA metal, such as sodium, a group IIA
metal or ammonium ion.
` 20 In the case where the compound of formula VI in which ` ` R4 is hydroxy is cyclised to the benzisoxazole, the con-figuration of the intermediate :-. .
X ~ ~ ~ VI
Q
should be such that the Q group is anti- to the phenolic ` hydroxyl group. When R4 is halo, the Q group should be syn thereto.
.. ..
When it is desired to prepare a benzoxazole from the intermediate of formula:
~04Z9Q4 I OH
the Q group should be anti- to the hydroxyl group. ~,.
In a fuxther aspect of this invention there is provided a process for preparing a 5- or 6- substituted benzoxazole of formula ~ O ~ R2 R
wherein Rl represents one or more substituents which are at any one or more of the available positions in the benzene . ring and which are selected from one or more of the following atoms or groups; hydrogen, halogen, Cl 4 alkyl, Cl_4 alkoxy, nitro, and trifluoromethyl, and R2 is a substituent at the 5-, 6-, or 7~ position of the 1,2-benzisoxazole nucleus and ~ 20 is one of the following: hydrogen, Cl 4 alkyl, carboxy Cl 4 alkyl, cyano Cl 4 alkyl, -CH(R )-COOH, -CH2-COOR , and--; : -CH(R3)-CooR3, where R3 is Cl 4 alkyl; except that when Rl represents a hydrogen atom R2 is not hydrogen, which process ~ comprises cylising, under acidic conditions an oxime or hydrazone of formula .
~ R ~ Q~ O~ R
;~ `
~4~
where ~ is hydroxyl or an amino group.
When R4 is haloyen, heating with an alkali such as - potassium hydroxide produces the benzisoxazole, which ~ in all cases has the formula :
X~
,',-~ ~ ~ VII
i~ - O
wherein X and Y are as previously defined.
. Thus, in general terms, the present invention provides a process for preparing a compound of formula I which com-prises the ring-closure under basic conditions of a compound of formula :
' ~
~J
Q - N = C
; R Y
where X and Y are as previously defined, Q is a hydroxyl, amino, acyloxy (preferably a group of formula -o-C-R3, where R3 is Cl 4 alkyl) or sulphonyloxy radical, and R4 is halogen or a group of formula -OM where M is hydrogen, ammonium or a group IA or IIA metal, followed, if necessary, by the conversion of X and/or Y to the desired Rl and/or R2 groups by conventional means.
For example, when Y represents alkyl, the alkyl group may be halogenated using conventional halogenating agents . such as chlorine, sulphuryl chloride, bromine, or N-bromo-succinnimide, preferably in the presence of a suitable i~zg~4 solvent such as carbon tetrachloride, and thereafter a cyano group substituted ~rom the halogen atom. Hydrolysis of the nitrile produces the corresponding carboxylic acid which may if desired be esteri~ied. Alternatively, the halogen atom can be replaced by a carboxylic acid gro~lp vla an organo-metallic compound such as a Grignard reagent. This procedure is fully described in Standard re~erence books, for example for the Grignard reaction, see page 11 72 of the ~erck Index, VIIIth Edition, published 1968. Acids or est~rs Formula I
may be alkylated at the ~-carbon atom using an alkyl halide such as methyl or ethyl iodide. An ester of formula I may also be converted to the hydroxamic acid derivative by reaction with hydroxylamine.
An acid of formula I may be salified by treatment with an appropriate base such as ammonium, alkylammonium, aralkyl-ammonium, alumium, alkali metal or alkaline earth metal hydroxide and of course a salt of formula I may readily be converted to the free acid by treatment with an acid such as hydrochloric or sulphuric acid. The salts, e.g. the sodium salt, are pharmaceutically active. An acid of formula I or a salt thereof may be converted to an ester by treatment with an appropriate alcohol or by treatment with a halide of the appropriate ester moiety or a salt of that halide if the ~ ester moiety contains a basic nitrogen atom. An ester of ; formula I may, of course, be hydrolysed to the corresponding acid of formula I by treatment with a suitable hydrolytic agent such as an inorganic base or acid. An acid of formula I
or an ester thereof may also be converted to an amide of formula I by reaction with ammonia or an appropriate primary or secondary amine.
It will be understood that the above described specific cyclisation procedure is not the only method of synthesising `:
~(34~904 the novel compounds of this invention; any obvious chemical equivalent cyclisation reaction may be employed, that is ' ~ any reaction, or sequence of reactions, which is capable of bringin~ a nitrogen atom and/or an oxygen atom into the desired relationship with the benzophenone derivative so as to produce a compound of formula VII.
- As mentioned above, the acids of formula I, i.e. those compounds in which R2 is carboxymethyl or -CH(R3) COOH are preferred compounds of the invention. These acids can be prepared by hydrolysis of the corresponding nitriles of formula VII where Y is cyano Cl 4 alkyl. Clearly, when it is desired to prepare the acid in which R2 is carboxymethyl, cyanomethyl is the group which needs to be hydrolysed.
Similarly, when it is desired to produce an acid group of formula -CH(R3)COOH it is necessary to hydrolyse a group ; of formula -CH(R3)CN.
Alternatively, the above class of acids can be pre-pared from derivatives of formula I where R is a Cl 4 ` haloalkyl group using the Grignard reaction. After reaction with magnesium and treatment with carbon dioxide a compound of formula I is formed in which R2 represents the group -C-OMgXl where Xl is a halogen atom. This group can then be converted to a carboxylic acid group simply by hydrolysis.
Thus, according to yet a further feature of the invention there is provided a method of preparing an acid of formula : Rl O ~ CHR5C02H
wherein Rl is as defined previously and the -CHR5Co2H group is at the 5-, 6-, or 7- position of the benzisoxazole nucleus ' _ g _ ~ 29Q4 and R represents hy~rogen or Cl 4 alkyl, which comprises hydrolysing a compound of formula:
. Rl ','' ~
CHR Z
where the group -CHR5Z is at the 5-, 6- or 7- position of the benzisoxazole nucleus and Z represents a nitrile, ester, carboxylate or hydroxamic acid group, or a group of formula:
, ~0 ~ OMgX
where Xl is a halogen atom.
The novel compounds of the present invention in which R is a carboxy or esterified caEboxy moiety have been found to possess anti-inflammatory activity and in some cases other pharmacological activity, whilst the other novel compounds of formula I are useful as intermediates in the synthesis of ` the aforementioned pharmacologically active compounds. The pharmacological activity has been demonstrated in tests , , carried out in animals, usually at doses of from 0_1 to 500 mg./Kg. In the treatment of humans, the dose administered ` may be for example, between 0.1 and 25 mg./kg. but, of course, doses outside this range may be used at the discretion of the physician treating the patient. The pharmacologically active compounds of formula I may be administered by the enteral or parenteral routes and for this purpose they will normally be formulated into pharmaceutical compositions comprising the active ingredient in associat~on with at least one pharmaceutically acceptable carrier therefor. Such compositions form a part of this invention and will normally consist of the active ingredient mixed with a carrier, or ::
1~2~Q4 diluted by a carrier, or enclosed or encapsulated by a carrier in the for~ o~ a capsule, sachet, cachet or other container.
The carrier may be a solid, semi-solid or liquid material which serves as a vehicle, excipient, coating agent, or medium for the active ingredient. Some examples of the carriers which may be used are lactose, dextrose, sucrose, sor~itol, mannitol, starch, gum acacia, calcium phosphate, liquid p~ra~fin, cocoa butter, oil of theobroma, alginates, tragacanth, gelatin, methyl cellulose, polyoxyethylene sorbitan monolaurate, methyl - or propyl - hydroxybenzoate, ethyl cellulose acetate phthalate, low viscosity acetyl cellulose acetate, paraffin wax, mineral wax, vegetable wax, vegetable gum, silicone rubbers such as liquid polydimethyl-siloxane rubber, plasticised or unplasticised polyvinyl - chloride, plasticised polyethylene terephthalate, modified collagen, cross-linked hydrophilic polyether gel, cross-linked polyvinyl alcohol or cross-linked partially hydrolysed polyvinyl acetate.
Advantageously the compositions of the invention are formulated in a dosage unit form containing from 1 to 1000 mg.
(preferably 25 to 500 mg.) of the active ingredient. Examples of suitable dosage unit forms are tablets, hard or soft gelatin capsules, microcapsules and suppositories as well as drug dispensing systems comprising the active ingredient contained in a flexible, imperforate polymeric material through which the drug may be released slowly by diffusion.
More generally, the term "dosage unit form" as used herein means a physically discrete unit containing the active ingredient, generally in admixture with and/or enclosed by a pharmaceutical carrier, the quantity of active ingredient being such that one or more units are normally required for a single therapeutic administration.
- ~ .
~4;~
~ a~tion to the active ingredient of formula I, the compositions of the present invention may al50 contain one or - more pharmacologically active ingredients, for example, acetylsalicyclic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and indomethacin.
The compositions of the present invention will of course be adapted to the particular route of administration.
. ~ Thus, for oral administration, tablets, pills, capsules, solutions or suspensions may be used; ~or parenteral administration, sterile injection solutions or suspensions may be used; for rectal administration, suppositories may be used; and for topical administration, creams, lotions or ointments may be used. Any of the foregoing compositions may, of course, be formulated in delayed or sustained release form in a manner well known in the art.
Compounds of formula I in which R2 is a Cl 4 alkyl group, preferably ethyl, and in which Rl is a hydrogen or hal-ogen are also useful in the treatment of immediate hypersensi-tivity diseases including asthma, and in the alleviation of status asthmaticus. This class of compounds i5 also useful for the treatment of diseases in which excessive amounts of prostaglandins are released.
The following-examples will further illustrate the invention. No examples of the formation of acids via the Grignard route are given. However, those skilled in the art will appreciate that the halo-alkyl intermediates described hereinafter can be converted to the corresponding acids by this method, if so desired.
~0912~
~.
Example 1 5-Methyl-3-~4-chl~rophenyl~-1,2-benzisoxazole
2-~lydroxy-5-methyl-41-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 over~ight 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 the oxime (7 g.) m.p. 163C. (This is the stereo isomer in which the oxime -OH group and the _-chlorophenyl group are in the syn positions relative to each other, and is therefore the correct isomer for the next stage.) The above oxime (5 g, 0.019 mole) was heated on the steam bath with acetic anhydride (10 ml.) until it all dissolved and then for 5 minutes longer. The solution was evaporated in vacuo to a clear oil which crystallised to give a white solid on cooling. This was heated under nitrogen at 290-300C. for 5 minutes and acetic acid distilled over. The product was distilled in vacuo to give 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (2.4 g.), b.p. 154-158C/0.2 mm. After purification by preparative t. 1. c. an off-white solid; m.p. 95C. was obtained. This compound was also prepared by boiling 2-bromo-5-methyl-41-chlorobenzophanone oxime with alcoholic potassium hydroxide solution.
Example 2 5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole . _ . . . _ N-Bromosuccinimide (26 g.) was added to a cold solution of 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (35 g.) in carbon tetrachloride (250 ml.). Benzoyl peroxide (500 mg.) was added and the mixture was heated under reflux for 3 hours .
~OglZ9~4 in the pxesence of U.V. light. The solid residue was filtered off, and the ~iltrate was evaporated to give 5-bromoethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (m.p. 142C.).
Example 3
Example 2 5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole . _ . . . _ N-Bromosuccinimide (26 g.) was added to a cold solution of 5-methyl-3-(4-chlorophenyl)-1,2-benzisoxazole (35 g.) in carbon tetrachloride (250 ml.). Benzoyl peroxide (500 mg.) was added and the mixture was heated under reflux for 3 hours .
~OglZ9~4 in the pxesence of U.V. light. The solid residue was filtered off, and the ~iltrate was evaporated to give 5-bromoethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (m.p. 142C.).
Example 3
3-(4-Chlorophenyl?-1,2-benzisoxazol-5-ylacetonitrile A mixture of 5-bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole (45 g.~ and sodium cyanide (7.4 g.) in dry : dimethylformamide (800 ml.) was hea~ed on a steam bath for3 hours. The mixture was filtered and the filtrate was evaporated to dryness, to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-ylacetonitrile (m.p. 118C.).
; .
- Exam~le 4 :
3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid A solution of the above nitrile (11 g.) in concentrated hydrochloric acid (100 ml.) was heated on a steam bath for 1 hour. The solution was then allowed to cool, evaporated ; to dryness and the product dissolved in chloroform. The chloroform solution was repeatedly extracted with sodium bicarbonate solution. The combined extracts were acidified to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid, (m.p. 189C.).
Example 5 Ethyl 3-(4-chlorophenyl-1,2-benzisoxazol-5-yl ace_ate A solution of 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid (20 g.) in ethanol (200 ml.) was heated under reflux for 6 hours, during which time dry hydrogen chloride gas was passed through the solution. The solution was evaporated to dryness, the residue treated with sodium bi-carbonate solution and the product extracted with ether. The extract, after drying (Na2SO4) and evaporation, gave ethyl 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetate.
~ .. ..
~29 Example 6 Ethyl 2-~3-(4-chloropheny1)-1,2-benzisoxazol-5-yll propionate A solution of ethyl 3- (4-chlorophenyl)-1,2-benzisoxazol-5-yl acetate (39 g.) in ether (200 ml.) was added to a stirred solution of sodamide (from 3.2 g. sodium) in liquid ammonia (500 ml.). This mixture was stirred for 15 minutes, then a solution of methyl iodide (~.5 ml.) in ether ~10 ml.) was added rapidly. When the reaction mixture became colourless the reaction was stopped by the addition of excess ammonium - 10 chloride. ~he mixture was evaporated to dryness and the residue was e~tracted with ether. The ethereal solution was evaporated to dryness to yield ethyl 2- E3- (4-chlorophenyl)-1,2-benzisoxazol-5-yl] propionate.
Example 7 2-[3-(4-Chlorophenyl?-1,2-benzisoxazol-5-yl] propionic ac d A solution of ethyl 2-[3-(4-chlorophenyl)-1,2-benzisoxa-zol-5-yl] propionate (15 g.) in concentrated hydrochloric acid (150 ml.) was heated on a steam bath for 6 hours. The solution was cooled and the crystals which formed were filtered off and recrystallised to yield 2-[3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl] propionic acid, (m.p. 137-9C.). ~he following compounds were prepared using methods analogous i to those described above:-6-Methyl-3-(4-chlorophenyl)-1,2-benzisoxazole.
7-Methy~3-(2,~dichlorophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole, 5-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole~
5-Methyl-3-(4-trifluoromethylphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
~LID4;~:9~
6-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-trifluoromethyl)-1,2-benzisoxazole~
Also the following acetic and propionic acids and their esters and corresponding nitriles:-3-Phenyl-1,2-benzisoxazol-5-ylacetic acid.
3~ Bromophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methylphenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methoxyphenyl)-1,2-benzisoxazol~5-ylacetic acid.
3-(4-Nitrophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-ylacetic acid.
2-[3-(4-Bromophenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Methylphenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-methoxyphenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Nitrophenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-yl]-propionic acid.
2-[3-phenyl-1,2-benzisoxazol-5-yl] propionic acid.
3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl acetic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl] propionic acid.
2-[3-phenyl-1,2-benzisoxazol-6-yl] propionic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-7-yl] propionic acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl acetic acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl propionic acid.
,r'' ~ .
~ ' ~4Z904 Confirmation of the correct structures of the above-named compounds was obtained by t.l.c. evidence.
Example 8 5-sromoethyl-3-(4-chlorophenyl)-1,2-benzisoxazole 3-(4-Chlorophenyl)-5-methyl-1,2-benzisoxazole (12.2 g.) and N-bromosuccinimide (9.6g.)were mixed in carbon tetrachloride (200ml~) and heated under reflux in the presence oE UV light.
(Hanovia medi~ pressure lamp 125 watts, emitting at 254, 265, 297, 313, 366 mp). On cooling, the mixture was filtered and the filtrate evaporated to dryness. The resulting solid was recrystallised from 33% toluene/60-80 petrol ether (150 ml.) to give the title compound as a white crystalline solid (10.0g.) m.p. 142C.
Microanalysis: C14HgBrClNO re~uires 52.1%C, 2.8%H, 4.3%N, 11.0%Cl, 24.8%Br found 51.9%C, 3.0%H, 4.6%N, 10.7%Cl, 24.7%Br Example 9 3-(4-Chloxophenyl)-1!2-benzisoxazol-5-ylacetonitrile 5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole ~6.5 g.), sodium cyanide (l.lg) and dry sodium iodide (0.3g) were stirred together in dry dimethylformamide (50ml) for 20 hours at ambient temperature. The mixture was poured into water (500ml.), stirred for one hour and the brown solid filtered off, washed and dried (5.lg). ~his was recrystallised, with charcoaling, from 50% toluene/60-80 petrol ether (lOOml.) to give the title compound as an off-white solid (3.4g) m.p. 118C.
Microanalysis : C15HgClN2O requires 67.0%C, 3.4%H, 10.4%N, 13.2%Cl.
found 67.2%C, 3.6%H, 10.2%N, 13.5%Cl 9~4 E mple 10 3-(4-Chlorophenyl)--1,2-benzisoxazol-~ tic acid 3-(4-Chlorophenyl-1,2-benzisoxazol-5-ylacetonitrile (4.7g) was mixed with concentrated hydrochloric acid (40ml.) and glacial acetic acid (20ml.) and heated at 80C. for three hours. The mixture was poured into water (300ml.) and the residue filtered off and washed with water. This solid was stirred with 5~ aqueous sodium carbonate solution ~200ml.) and the solution was then filtered. The filtrate was acidified with 2N-hydrochloric acid giving a white precipitate which was filtered, washed and dried to give the title compound (4.2g) m.p. 189C.
Microanalysis : C15HloClNO3 requires 62.6%C, 3.5%H, 4.9~N, 12.3~Cl found 62.5%C, 3.7%H, 5.0~N, 12.6~Cl Example 11
; .
- Exam~le 4 :
3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid A solution of the above nitrile (11 g.) in concentrated hydrochloric acid (100 ml.) was heated on a steam bath for 1 hour. The solution was then allowed to cool, evaporated ; to dryness and the product dissolved in chloroform. The chloroform solution was repeatedly extracted with sodium bicarbonate solution. The combined extracts were acidified to give 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid, (m.p. 189C.).
Example 5 Ethyl 3-(4-chlorophenyl-1,2-benzisoxazol-5-yl ace_ate A solution of 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetic acid (20 g.) in ethanol (200 ml.) was heated under reflux for 6 hours, during which time dry hydrogen chloride gas was passed through the solution. The solution was evaporated to dryness, the residue treated with sodium bi-carbonate solution and the product extracted with ether. The extract, after drying (Na2SO4) and evaporation, gave ethyl 3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl acetate.
~ .. ..
~29 Example 6 Ethyl 2-~3-(4-chloropheny1)-1,2-benzisoxazol-5-yll propionate A solution of ethyl 3- (4-chlorophenyl)-1,2-benzisoxazol-5-yl acetate (39 g.) in ether (200 ml.) was added to a stirred solution of sodamide (from 3.2 g. sodium) in liquid ammonia (500 ml.). This mixture was stirred for 15 minutes, then a solution of methyl iodide (~.5 ml.) in ether ~10 ml.) was added rapidly. When the reaction mixture became colourless the reaction was stopped by the addition of excess ammonium - 10 chloride. ~he mixture was evaporated to dryness and the residue was e~tracted with ether. The ethereal solution was evaporated to dryness to yield ethyl 2- E3- (4-chlorophenyl)-1,2-benzisoxazol-5-yl] propionate.
Example 7 2-[3-(4-Chlorophenyl?-1,2-benzisoxazol-5-yl] propionic ac d A solution of ethyl 2-[3-(4-chlorophenyl)-1,2-benzisoxa-zol-5-yl] propionate (15 g.) in concentrated hydrochloric acid (150 ml.) was heated on a steam bath for 6 hours. The solution was cooled and the crystals which formed were filtered off and recrystallised to yield 2-[3-(4-chlorophenyl)-1,2-benzisoxazol-5-yl] propionic acid, (m.p. 137-9C.). ~he following compounds were prepared using methods analogous i to those described above:-6-Methyl-3-(4-chlorophenyl)-1,2-benzisoxazole.
7-Methy~3-(2,~dichlorophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
5-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole, 5-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole~
5-Methyl-3-(4-trifluoromethylphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-bromophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-methylphenyl)-1,2-benzisoxazole.
~LID4;~:9~
6-Methyl-3-(4-methoxyphenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-nitrophenyl)-1,2-benzisoxazole.
6-Methyl-3-(4-trifluoromethyl)-1,2-benzisoxazole~
Also the following acetic and propionic acids and their esters and corresponding nitriles:-3-Phenyl-1,2-benzisoxazol-5-ylacetic acid.
3~ Bromophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methylphenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Methoxyphenyl)-1,2-benzisoxazol~5-ylacetic acid.
3-(4-Nitrophenyl)-1,2-benzisoxazol-5-ylacetic acid.
3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-ylacetic acid.
2-[3-(4-Bromophenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Methylphenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-methoxyphenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Nitrophenyl)-1,2-benzisoxazol-5-yl] propionic acid.
2-[3-(4-Trifluoromethylphenyl)-1,2-benzisoxazol-5-yl]-propionic acid.
2-[3-phenyl-1,2-benzisoxazol-5-yl] propionic acid.
3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl acetic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-6-yl] propionic acid.
2-[3-phenyl-1,2-benzisoxazol-6-yl] propionic acid.
2-[3-(4-chlorophenyl)-1,2-benzisoxazol-7-yl] propionic acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl acetic acid.
3-(2,4-dichlorophenyl)-1,2-benzisoxazol-7-yl propionic acid.
,r'' ~ .
~ ' ~4Z904 Confirmation of the correct structures of the above-named compounds was obtained by t.l.c. evidence.
Example 8 5-sromoethyl-3-(4-chlorophenyl)-1,2-benzisoxazole 3-(4-Chlorophenyl)-5-methyl-1,2-benzisoxazole (12.2 g.) and N-bromosuccinimide (9.6g.)were mixed in carbon tetrachloride (200ml~) and heated under reflux in the presence oE UV light.
(Hanovia medi~ pressure lamp 125 watts, emitting at 254, 265, 297, 313, 366 mp). On cooling, the mixture was filtered and the filtrate evaporated to dryness. The resulting solid was recrystallised from 33% toluene/60-80 petrol ether (150 ml.) to give the title compound as a white crystalline solid (10.0g.) m.p. 142C.
Microanalysis: C14HgBrClNO re~uires 52.1%C, 2.8%H, 4.3%N, 11.0%Cl, 24.8%Br found 51.9%C, 3.0%H, 4.6%N, 10.7%Cl, 24.7%Br Example 9 3-(4-Chloxophenyl)-1!2-benzisoxazol-5-ylacetonitrile 5-Bromomethyl-3-(4-chlorophenyl)-1,2-benzisoxazole ~6.5 g.), sodium cyanide (l.lg) and dry sodium iodide (0.3g) were stirred together in dry dimethylformamide (50ml) for 20 hours at ambient temperature. The mixture was poured into water (500ml.), stirred for one hour and the brown solid filtered off, washed and dried (5.lg). ~his was recrystallised, with charcoaling, from 50% toluene/60-80 petrol ether (lOOml.) to give the title compound as an off-white solid (3.4g) m.p. 118C.
Microanalysis : C15HgClN2O requires 67.0%C, 3.4%H, 10.4%N, 13.2%Cl.
found 67.2%C, 3.6%H, 10.2%N, 13.5%Cl 9~4 E mple 10 3-(4-Chlorophenyl)--1,2-benzisoxazol-~ tic acid 3-(4-Chlorophenyl-1,2-benzisoxazol-5-ylacetonitrile (4.7g) was mixed with concentrated hydrochloric acid (40ml.) and glacial acetic acid (20ml.) and heated at 80C. for three hours. The mixture was poured into water (300ml.) and the residue filtered off and washed with water. This solid was stirred with 5~ aqueous sodium carbonate solution ~200ml.) and the solution was then filtered. The filtrate was acidified with 2N-hydrochloric acid giving a white precipitate which was filtered, washed and dried to give the title compound (4.2g) m.p. 189C.
Microanalysis : C15HloClNO3 requires 62.6%C, 3.5%H, 4.9~N, 12.3~Cl found 62.5%C, 3.7%H, 5.0~N, 12.6~Cl Example 11
4'-Chloro-5-ethyl-2-hydroxybenzophenone Aluminum chloride (267g) was added in portions over 30 minutes to a stirred solution of 4-ethylphenol (122.lg.) and 4-chloro-benzoyl chloride -~140ml.) in dry 1,1,2,2-tetra-chloroethane (800ml.~. The mixture was heated at 105C.
for 22 hours with stirring, and on cooling a mixture of ice (600g) and concentrated hydrochloric acid was added slowly. A vigorous reaction occurred and some material was lo~t. The remaining material was separated and the aqueous fraction extracted twice with chloroform (200ml.), and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main ~ractions: B (17.4g) 150-160C ~ 0.3mmHg, C (110.8g) 160-168C 0 0.3mmHg. Both remained liquid on cooling.
: ~ ,: , ~4Z9(~
icroanalysis : C15H13C1O2 requires 69.1%C, 5.0%H, 13.6%C1;
found 69.0%C, 5.0%H, 13.9%Cl Example 12 4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime , . .
4'-Chloro-5-ethyl-2-hydroxybenzophenone (65.2g) and potassium hydroxide (170g) in water (700ml) and ethanol (150ml.) were treated with hydroxylamine hydrochloride (70.0g), with cooling, ana the resulting mixture was stirred for 18 hours at ambient temperature. Dissolution occurred during this time. The solution was acidified with 5N-hydrochloric acid and then extracted with~ether (3x200ml.).
The combined ether solutions were washed with 10% aqueous sodium carbonate solution (2x200~1) and evaporated to dryness to give an off-white solid. This solid was recrystallised from 40% benzene/60-80 petrol ether to give a white crystal-line solid ~29.9g), second crop (14.5g.) m.p. 117C.
Microanalysis : C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1~N, 12.9%C1;
found 65.3~C, 4.9%H, 5.1%N, 12.9%C1 (Stereoisomer as in Example 1) Example 13 3-(4-Chlorophenyl)5-ethyl-1,2-benzlsoxazole 4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime (22.0g) was dissolved in hot acetic anhydride (45ml) and immediately cooled, causing the oxime mono-acetate to crystallise. This was filtered and dried (19.7g) m.p. 105C. The oxime mono-acetate (19.0g) and sodium carbonate (13.3g) were heated together in triglyme, under reflux, for 30 minutes. On cooling, the mixture was poured into water (1.01.) this was extracted with ether (3x250ml). The combined ether extracts were washed with water (3x250ml) and evaporated to dryness to 9~4 give a yellow oil which crystallised at room t~mperature (16.4g). A sample (3.0g) of this solid was recrystallised from methanol/water to give a white solid (1.5g) m.p. 42-45C.
Microanaly5is : C15H12ClNO requires 69.9%C, 4.7%H, s.4%
13.8%Cl;
found 69.6%C, 4.8~H, 5.4%N, 13.8%Cl Example 14
for 22 hours with stirring, and on cooling a mixture of ice (600g) and concentrated hydrochloric acid was added slowly. A vigorous reaction occurred and some material was lo~t. The remaining material was separated and the aqueous fraction extracted twice with chloroform (200ml.), and the combined organic layers evaporated to a dark oil which was distilled in vacuo giving two main ~ractions: B (17.4g) 150-160C ~ 0.3mmHg, C (110.8g) 160-168C 0 0.3mmHg. Both remained liquid on cooling.
: ~ ,: , ~4Z9(~
icroanalysis : C15H13C1O2 requires 69.1%C, 5.0%H, 13.6%C1;
found 69.0%C, 5.0%H, 13.9%Cl Example 12 4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime , . .
4'-Chloro-5-ethyl-2-hydroxybenzophenone (65.2g) and potassium hydroxide (170g) in water (700ml) and ethanol (150ml.) were treated with hydroxylamine hydrochloride (70.0g), with cooling, ana the resulting mixture was stirred for 18 hours at ambient temperature. Dissolution occurred during this time. The solution was acidified with 5N-hydrochloric acid and then extracted with~ether (3x200ml.).
The combined ether solutions were washed with 10% aqueous sodium carbonate solution (2x200~1) and evaporated to dryness to give an off-white solid. This solid was recrystallised from 40% benzene/60-80 petrol ether to give a white crystal-line solid ~29.9g), second crop (14.5g.) m.p. 117C.
Microanalysis : C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1~N, 12.9%C1;
found 65.3~C, 4.9%H, 5.1%N, 12.9%C1 (Stereoisomer as in Example 1) Example 13 3-(4-Chlorophenyl)5-ethyl-1,2-benzlsoxazole 4'-Chloro-5-ethyl-2-hydroxybenzophenone-oxime (22.0g) was dissolved in hot acetic anhydride (45ml) and immediately cooled, causing the oxime mono-acetate to crystallise. This was filtered and dried (19.7g) m.p. 105C. The oxime mono-acetate (19.0g) and sodium carbonate (13.3g) were heated together in triglyme, under reflux, for 30 minutes. On cooling, the mixture was poured into water (1.01.) this was extracted with ether (3x250ml). The combined ether extracts were washed with water (3x250ml) and evaporated to dryness to 9~4 give a yellow oil which crystallised at room t~mperature (16.4g). A sample (3.0g) of this solid was recrystallised from methanol/water to give a white solid (1.5g) m.p. 42-45C.
Microanaly5is : C15H12ClNO requires 69.9%C, 4.7%H, s.4%
13.8%Cl;
found 69.6%C, 4.8~H, 5.4%N, 13.8%Cl Example 14
5~ Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole 3-(4-Chlorophenyl)-5-ethyl-1,2-benzisoxazoIe (12.3g) was brominated similarly to Example 8, to give the title compound (11.3g), m.p. 111-6C.
MiCroanalysis: C15HllBrClNO requires 53.5%C, 3.3%H, 4.2%N, 10.5%Cl, 23.7%Br;
found 53.6%C, 3.5%H, 4.0%N, 10.3%Cl, 24.0%Br.
Example 15 2-[3-_4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionitrile 5-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole (9.Og) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as a viscous yellow oil (6.4g).
Example 16 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionic acid 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionitrile (6~4g) was hydrolysed similarly -to Example 10 to give an off-white solid (5.lg). This was recrystallised from toluene with charcoaling to give the title compound (3.9g) m.p. 137-9C.
Example 17 4'-Chloro-4-ethyl-2-hydroxybenzophenone .
3-Ethylphenol (122.lg) was reacted with 4 chlorobenzoyl -- ~0 ----~4Z9~)~
chloride (140ml) similarly to Example 11, giving two main fractions on distillation A (141.8g) 155-160C @ 0.09 mmHg;
B (15.3g.) 150~170C ~ 0.09 mmHg. Both ~ractions contained about 80% o~ the title compound~ plus 20% of the isomer.
4'-Chloro-2-ethyl-4-hydroxybenzophenone, and the mixture used in Example 18.
Example 18 4'-Chloro-4-ethyl-2-hydroxybenzophenone-oxime 4'-Chloro-4-ethyl-2-hydroxybenzophenone (130.4g) was treated withhydroxylamine hydrochloride (140g) similarly to Example 12, to give the title compound, one isomer only (81.2g), m.p. 159-161C.
Microanalysis C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1%N, 12.9%Cl;
~ound 65.6%C, 5.1%H, 5.4%N, 12.8~Cl.
Stereoisomer as in Example 1.
Example 19 3-(4-Chlorophenyl)-6-ethyl-1,2-benzisoxazole 4'-Chloro-4-ethyl-2-hydroxybenzophenone (44.0g) was treated with acetic anhydride similarly to Example 13, to give the oxime-monoacetate (42.7g). This was immediately converted to the title compound as in Example 13 (34.7g).
8.9g of this was recrystallised ~rom methanol/water to give a white crystalline solid (6.5g), m.p. 78-9C.
Microanalysis : C15H12ClNO requires 69.9%C, 4.7%H, 5.4%N, 13.8%Cl;
found 69.6~C, 4.7%H, 5.2%N, 13.8%Cl.
Example 20
MiCroanalysis: C15HllBrClNO requires 53.5%C, 3.3%H, 4.2%N, 10.5%Cl, 23.7%Br;
found 53.6%C, 3.5%H, 4.0%N, 10.3%Cl, 24.0%Br.
Example 15 2-[3-_4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionitrile 5-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole (9.Og) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as a viscous yellow oil (6.4g).
Example 16 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionic acid 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-5-yl]-propionitrile (6~4g) was hydrolysed similarly -to Example 10 to give an off-white solid (5.lg). This was recrystallised from toluene with charcoaling to give the title compound (3.9g) m.p. 137-9C.
Example 17 4'-Chloro-4-ethyl-2-hydroxybenzophenone .
3-Ethylphenol (122.lg) was reacted with 4 chlorobenzoyl -- ~0 ----~4Z9~)~
chloride (140ml) similarly to Example 11, giving two main fractions on distillation A (141.8g) 155-160C @ 0.09 mmHg;
B (15.3g.) 150~170C ~ 0.09 mmHg. Both ~ractions contained about 80% o~ the title compound~ plus 20% of the isomer.
4'-Chloro-2-ethyl-4-hydroxybenzophenone, and the mixture used in Example 18.
Example 18 4'-Chloro-4-ethyl-2-hydroxybenzophenone-oxime 4'-Chloro-4-ethyl-2-hydroxybenzophenone (130.4g) was treated withhydroxylamine hydrochloride (140g) similarly to Example 12, to give the title compound, one isomer only (81.2g), m.p. 159-161C.
Microanalysis C15H14ClNO2 requires 65.3%C, 5.1%H, 5.1%N, 12.9%Cl;
~ound 65.6%C, 5.1%H, 5.4%N, 12.8~Cl.
Stereoisomer as in Example 1.
Example 19 3-(4-Chlorophenyl)-6-ethyl-1,2-benzisoxazole 4'-Chloro-4-ethyl-2-hydroxybenzophenone (44.0g) was treated with acetic anhydride similarly to Example 13, to give the oxime-monoacetate (42.7g). This was immediately converted to the title compound as in Example 13 (34.7g).
8.9g of this was recrystallised ~rom methanol/water to give a white crystalline solid (6.5g), m.p. 78-9C.
Microanalysis : C15H12ClNO requires 69.9%C, 4.7%H, 5.4%N, 13.8%Cl;
found 69.6~C, 4.7%H, 5.2%N, 13.8%Cl.
Example 20
6-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole _ 3-(4-Chlorophenyl)-6-ethyl-1,2-benzisoxazole (25.8g) was ~4Z9~4 brominated similarly to Exa~ple 8 to give the title compound (22.2g), which was used without further purification.
Example 21 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile .. _ .. .. . . _ . _ .
6-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole (16.8g) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as an off-white solid (lO.Og), which was used without further purification.
Example 22 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionic acid 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-pro-pionitrile (lO.Og) was hydrolysed similarly to Example 10 to give the title compound as a white solid (1.8g), m.p. 176-9C.
Microanalysis : C16H12ClNO3 requires 63.7%C, 4.0%H, 4.6%N, 11.8~Cl;
found 63.4%C, 4.1~H, 4.6%N, 11.5~Cl.
Example 23 4-Ethyl-4'-fluoro-2-hydroxybenzophenone 3-Ethylphenol (24.4g) and 4-fluorobenzoyl chlaride (34.9g) was reacted together as in Example 11 giving three main fractions: B (11.4g) 126-129C ~ 0.07 mmHg; C (7.9g), 129-132C ~ 0.06 mmHg; D (5.9g), 132-150C @ 0.06 mmHg, all containing ^- 80~ of the required isomer. B (4.0g) was separated by preparative thin layer chromatography to give the title compound (2.6g), m.p. 44-48C.
Example 24 4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime 4-Ethyl-4'-fluoro-2-hydroxybenzophenone (21.0g, 80%
pure) was treated with hydroxylamine hydrochloride (24.0g) similarly to Example 12, to give, after recrys-tallisation from benzene, the title compound as a white crystalline solid ~ - 22 -1~4Z9a~
(10.7g) m.p. 130-2C.
Microanalysis : C15H14FN02 requires 69.5~C, 5.4%H, 5.4~N,
Example 21 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile .. _ .. .. . . _ . _ .
6-(1-Bromoethyl)-3-(4-chlorophenyl)-1,2-benzisoxazole (16.8g) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as an off-white solid (lO.Og), which was used without further purification.
Example 22 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-propionic acid 2-[3-(4-Chlorophenyl)-1,2-benzisoxazol-6-yl]-pro-pionitrile (lO.Og) was hydrolysed similarly to Example 10 to give the title compound as a white solid (1.8g), m.p. 176-9C.
Microanalysis : C16H12ClNO3 requires 63.7%C, 4.0%H, 4.6%N, 11.8~Cl;
found 63.4%C, 4.1~H, 4.6%N, 11.5~Cl.
Example 23 4-Ethyl-4'-fluoro-2-hydroxybenzophenone 3-Ethylphenol (24.4g) and 4-fluorobenzoyl chlaride (34.9g) was reacted together as in Example 11 giving three main fractions: B (11.4g) 126-129C ~ 0.07 mmHg; C (7.9g), 129-132C ~ 0.06 mmHg; D (5.9g), 132-150C @ 0.06 mmHg, all containing ^- 80~ of the required isomer. B (4.0g) was separated by preparative thin layer chromatography to give the title compound (2.6g), m.p. 44-48C.
Example 24 4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime 4-Ethyl-4'-fluoro-2-hydroxybenzophenone (21.0g, 80%
pure) was treated with hydroxylamine hydrochloride (24.0g) similarly to Example 12, to give, after recrys-tallisation from benzene, the title compound as a white crystalline solid ~ - 22 -1~4Z9a~
(10.7g) m.p. 130-2C.
Microanalysis : C15H14FN02 requires 69.5~C, 5.4%H, 5.4~N,
7.3%F;
found 69.2~C, 5.5%H, 5.2~N, 7.2%F
Example 25 6-Ethyl-3-(4-fluorophenyl)-1,2-benzisoxazole 4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime t9.6g) was treated with acetic anhydride similarly to Example 13 to give the oxime mono-acetate (7.5g). This was immediately converted to the title compound as in Example 19 t5.7g).
Example 26 6-~1-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole 6-Ethyl-3-t4-fluorophenyl)-1,2-benzisoxazole t3.5g) was brominated similar to Example 8 to give the title compound t4-1g), which was used without further purification.
Example 27 2-[3-t4-Fluo~Ee~heny ~ -6-yl]-propionitrile 6-tl-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole (4.1g) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as a brown solid t3.Bg) which was used without further purification.
Example 28 . . .
2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionlc acid 2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile t3.8g) was hydrolysed similarly to Example 10 to give the title compound as an off-white solid tO.45g) m.p. 151-4C.
Example 29 . . _ 3-t4-chlorophenyl)-5-methyl-l~2-benzisoxazole . _ .. . . _ .
4'-Chloro-2-hydroxy-4-methylbenzophenone-oxime tO.2g) and anhydrous sodium carbonate tO~2g) were heated together ~ - 22a -, . .
l~Z9~4 under reflux in triglyome (5ml) for 30 minutes. On cooling, the mixture was poured into water ~50ml`.) and filtered. On standing a solid separated from the filtrate and was filtered, washed, dried and examined by NMR. The NMR spectrum was consistent with the preparation of the title compound (~ 30~).
T . L .C. also confirmed the presence of the benzisoxazole.
Example 30 2-Hydroxy-3-methyl-4'-chlorobenzophenone Chlorobenzene (78.79g, 71.6ml; 0.7mole), AlC13 10 ~ (14g, 0.105mo1e) were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12g, 0.07mole) ln chlorobenzene (20ml.). The mixture was stirred and heated at 100C overnight. The cooled mixture was added to conc. HCl (lOml) and ice, extraction with ether, and ether washed with saturated sodium bicarbonate solution, dried (Na2SO4), 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/0.5mm (8.13g), which solidified to yellow microplates, m.p. 55-58C.
Found : C.68.23; H.4.71; Cl.14.61. C14HllClO2 Requires : C.68.16; H.4.49; Cl.14.37%.
Example 31 2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime The ketone of Example 30 (7.5g, 0.03mole) in ethanol (18ml) was added with stirring to a solution of (85%) potassium hydroxide (20.74g, 0.3mole) in water (85ml) at 10C, this colloidal solution was treated with solid hydroxyl-amine hydrochloride (8.54g, 0.12 mole) and stirred overnight.
The solution was acidified with 5NHCl to give a solid, which was filtered, washed with water and stirred for 45 minutes, with 5~ Na2CO3 solution (30.5ml), to remove unwanted oxime ~ - 22b -:: .
~0429~4 stereoisomer, filtered, washed with 5% Na2C03 solution (lOOml) 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") 5.45g.
Foun~: C.64.25; H.4.79; C1.13.41; N.5.3% C14H12Cl C02 Requires: C.64.25; H.4.6; Cl.13.55; N.5.35 Example 32 2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime acetate Acetic anhydride (12ml) was warmed to 60C and treated with the oxime of Example 31 (5.25g. 0.02mole). The stirred mixture was warmed to 80C. to dissolve the oxime and the solution was then immediately cooled in an ice bath. The precipitated solid was filtered off, washed with light petroleum (b.p. 40-60) to give the acetate, 4.8g, m.p. 154-Found: C.63.18; H.4.86; Cl.11.5; N.4.77. C16H14ClN03 Requires C.63.26; H.4.64; C1.11.67; N.4.6%
Example 33 3-p-Chlorophen ~ -1,2-benzisoxazole The oxime acetate of Example 32 (4.36g, 0.014mole) was refluxed with sodium carbonate (3.3g; 0.031mole) in triethylene glycol dimethyl ether (44ml) for 35 minutes. The mixture was poured into water (200ml), cooled in ice filtered and washed neutral with water. After drying the benzisoxazole (3.4g) had m.p. 88-90C and m.p. 97-99 on recrystallisation from EtOH.
Found: C.68.87; H.4.37; Cl.14.82; N.5.83. C14HloClNO
Requires: C.68.99; H.4.14; C1.14.55; N.5.75 3n - 22c -~0~3Q4 1 Example 34 3-p-Chlorophenyl-7-bromomethyl-1,2-benzisoxazole The above benzisoxazole of Example 33 (28.9g, O.lmole) with N-bromosuccimide (19.59g, O.llmole) was refluxed in carbon tetrachloride-(309ml) under illumination from an ultra-violet lamp (Hanovia type MPC) with stirring for three hours. The mixture was cooled and the so~d was succinimide /filtered off and washed with-CC14. The-~filtrate-was =~ -evaporated to dryness and the product recrystallised from light pet'roleum (b.p. 60-80)-CC14 to give the bromo-methyl compound (26.59g) m.p. 117-120 C.
(;containing a little 7 methyL starting material ).
Found : Br. 25.68; Cl. 10.75; No 4.24; C14~ BrClN0 Requires: Br. 24.77j Cl. 10.99; N. 4.34%
Example 35 3-p-Chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid _ The bromomethyl compound of Example 34 (20g, 0.062mole) was stirred 5 at room temperature in dimethyl formamide (190ml.) with sodium cyanide (3.03g 0.062 mole ) and sodium iodide (0.93g, 0.0062 mole) for 22 hours. The solution was evaporated to dryness to yie'ld a solid which was treated with water/ ground up~ filtered and washed with water until the filtrate was free of halidoions. The dried crude nitrile (21.45g) had m.p. 110-125C, NMR
showed that it contained 50% of the required product. The crude nitrile ~20.67g, Ca 0.04 mole ) was refluxed for four hours in conc.HCl.(207ml) and acetic acid (103 ml.). The mixture was poured into water (21.) to give a solid which was extracted with sodium carbonate solution, this was extracted with ether and the sodium carbonate solution was acidified to give the acetic acid which was recrystallised from 50% ethanol to give the acetic acid (2.76g), m.p. 198-200 C.
Found : C. 62.84; H. 3.56; Cl. 12.55; N. 5.07; C15HloClN03 Requires:C. 62.62; H. 3.5; Cl. 12.32; N. 4.87%
Example 36 ~-Methyl-3-p-chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid n-Butyl lithium (31ml, 46m Mole of 1.5M) was cooled to -30cunder nitrogen with stirring and treated with a solution of diisopropylamine (6.25 . 23.
, ' '- '1'1-~4 1 ml. 4.65g., 4~m Mole) in tetrahydrofuran (38ml) keeping the temperature at-30 to -50 C. A solution of the acetic acid of Example 35 (4.5g,15.64m Mole in THF (38ml) and hexamethylphosphoramide (38ml) was added dropwise to the Bu ~i solution and the solution stirred at -30 to ~40C for 1.5 hours. -It -was then transferred to a solution of methyliodide (150ml) which was stirred and had been cooled to 5 ~C. in an ice bath. The mixture was stirred in the melting ice bath for 1.5 hours~ acidified with a litt-le conc.HCl, evaporated to small bulk and treated with water (500ml). The mixture was extracted with chloroform which was dried (Na2~04) and evaporated to leave the a methyl acetic acid as a mixture with its methyl ester. This was refluxed with conc.
HCl (60ml) and acetic acid (30ml) for four hours, diluted with water, extrac-ted with chloroform, which was dried (Na2S04)~ evaporated to leave a gum which was purified on preparative thin layer chromotography to give the ~-methyl acetic acid (0.85g), m.p. 136-138 C.
Found : C.6~88; H.4.27; Cl.11.46; N.4.65; C16H12ClN3 Requires: C.63.69; H.4~1; Cl.11.75; N.4.64%
Example 37 2-Hydroxy-3-ethylbenzophenone . ~
This compound (44.67g) was prepared from benzene (172g.,2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63.15g,0.34 mole)~ using the same conditi~ns as in Example 30. The h.p. of the compound was 123-126C./
0.14mm~ bD 1.6081,~ max.(film) 1630cm 1.
Example 38 2-Hydroxy-3-ethylbenzophenone oxime Using the conditions of Example 31, the ketone of Example 37 (45.34g,0.2mole) and hydroxylamine hydrochloride (56g~0.8 mole) gave the oxime (43.82g), m.p. 146-148C, ~ max.(Nujol),3340,1650,1608~1600 cm Example 39 2-Hydroxy-3-ethylbenzophenone oxime acetate . . .
The oxime of Example 38 (39.76g, 0.185 mole) (using the conditions of Example 32 above, followed by evaporation of the acetic a~hydride and ~2~
washing the product with light petroleum (b.p. 40-60)), gave the acetate (40.45g), m.p. 63-65C, ~ max. (Nujol) 1770 cm 1.
- Example 40 3-Phenyl-7-ethyl-1,2-benzisoxazole Using the conditions of Example 33, the acetate of Example 39 (39.34g, 0.145 mole) wi~h sodium carbonate (31.86g, 0.3mole) in triethyleneglycol dimethyl ether (425ml) gave 3-phenyl-7-ethyl-1,2-benzisoxazole (27.32g) b.p. 129-130C/
0.3mm, nD 1.6045, ~max. (film) 1625, 1608. NMR ~ 1.42(3H) 3.05 (2H), ~ 7.0-7.3 (8H) Example 41 3-Phenyl-7 ~bromoethyl-1,2-benzisoxazole The 7-ethyl compound of Example 40 (2.23g, lOm Mole~
in carbon tetrachloride (30ml) with N-bromosuccinimide (1.96g, llm Mole) and a trace of benzoyl peroxide or ~-azo-isobutyronitrile was stirred and refluxed while being illuminated with ultra violet light for 2 hours. The cooled solution was filtered and the carbon tetrachloride evaporated orf to leave the ~-bromoethyl compound (3.18g) as an oil n23 1.6280. ~ max (film) 780, ll90cm 1 NMR S 1.22 (3H), 5.62 ~lH), ~ 7.0-8.0 (8H).
Example 42 3-Phenyl-1,2-benzisoxazol-7-yl The ~-bromoethyl compound of Example 41, (18.6g, 61.55 m Mole) in dimethyl formamide (19Oml) with sodium cyanide (3.02g, 61.55 m Mole) and sodium iodide (0.92g, 6.15m Mole) was stirred at room temperature for 22 hours. The solution was evaporated to small bulk, the residue treated with ~ 30 water (200ml), extracted with chloxoform (4x200ml), the CHC13 - was washed with saturated sodium chloride solution and dried :
(Na2S04), filtered and evaporated to give the crude ~-cyano-ethyl nitrile (25g) nD 1.5838, ~max. (film) 750cm The crude nitrile (25g) was stirred and refluxed in acetic acid (125ml) and conc. HCl (250ml) for four hours. The mixture was poured into water (2500ml), extracted with CHC13, which was then extracted with sodium bicarbonate solution.
` The latter was acidified to yield an oil which was extracted with chloroform, dried (Na2SO4), filtered and evaporated to leave 3-phenyl-1,2-benzisoxazol-7-yl acetic acid (5.94g) as an oil, n2D1 1.5830. ~max Ifilm) 2620, 1710, 750, 700 cm 1, NMR ~ 1.71 (3H), 4.42 (lH), 7.12-8.25 (8H), 9.95 (lH). Mass spectrum Parent ion m/e 267, others at 223 (loss of CO2), 222 (loss of CO2H), 208 (loss of CH3CO~), 195 (loss of CH3C.CO2H).
In the following examples of pharmaceutical compositions of the present invention, the term "medicament" is used to indicate the compound ~-methyl-3-_-chlorophenyl-1,2-benz-isoxazol-7-yl acetic acid. That compound may, of course, be replaced by any other active compound of formula I and the amount of medicament may be increased or decreased depending ~n the degree of activity of the medicament used.
Example 43 Tablets each containing lOOmg of medicament are made as follows:-..
. . .
Medicament 1~ 4 lOOmg Potato starch 38mg Lactose 25mg - Ethyl cellulose (as 20~ solution in industrial alcohol) 2mg .- Alginic acid 7mg Magnesium stearate lmg Talc 2mg Total 175mg The medicament, starch and lactose are passed through 1~
a No. 44 mesh B.S.S. sieve and mixed thoroughly. The solution of ethyl cellulose is mixed with the resultant powders which are then passed through a No. 12 mesh B.S.S. sieve.
The granules produced are dried at 50-60C. and then passed through a No. 16 mesh B.S.S. sieve. The alginic acid, magnesium stearate and talc, previously passed through a No. 60 mesh B.S.S. sieve, are added to the granules, mixed and compressed in a tabletting machine to yield tables each weighing 175 mg.
Exam~le 44 ` 20 Capsules each containing 200 mg of medicament are , . ~ .
made as follows:-Medicament 200 mg Lactose 48 mg Magnesium stearate 2 mg The medicament, lactose and magnesium stearate are ` passed through a No. 44 mesh B.S.S. sieve and filled into hard gelatine capsules in 250 mg quantities.
Example 45 Injection solutions each containing 100 mg of30 medicament per 5 ml solution are made as follows:-.
, Medicament 100 mg Sodium hydroxide (10~ solution) q.s.
Water for injection to 5 ml The medicament is suspended in the water and the sodium hydroxide solution added drop by drop with stirring until the medicament is in solution. The pH of the solution is adjusted to between 8.0 and 8.5, the solution is sterilised by filtration through a bacteria-proof filter and filled into previously sterilised glass ampoules which are then hermetically sealed under aseptic conditions.
Example 46 Suppositories each containing 250 mg of medicament are ; made as follows:-Medicament 250 mg Theobroma Oil to 2000 mg The medicament is passed through a No. 60 mesh B.S.S.
sieve and suspended in the theobroma oil previously melted using the minimum of heat necessary. The mixture is then poured into a suppository mould of nominal 2 g capacity and allowed to cool.
,.;
,;~ ,, '.
' ' . .
.:
`
: ', . ~
found 69.2~C, 5.5%H, 5.2~N, 7.2%F
Example 25 6-Ethyl-3-(4-fluorophenyl)-1,2-benzisoxazole 4-Ethyl-4'-fluoro-2-hydroxybenzophenone-oxime t9.6g) was treated with acetic anhydride similarly to Example 13 to give the oxime mono-acetate (7.5g). This was immediately converted to the title compound as in Example 19 t5.7g).
Example 26 6-~1-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole 6-Ethyl-3-t4-fluorophenyl)-1,2-benzisoxazole t3.5g) was brominated similar to Example 8 to give the title compound t4-1g), which was used without further purification.
Example 27 2-[3-t4-Fluo~Ee~heny ~ -6-yl]-propionitrile 6-tl-Bromoethyl)-3-t4-fluorophenyl)-1,2-benzisoxazole (4.1g) was treated with sodium cyanide in a similar manner to Example 9 to give the title compound as a brown solid t3.Bg) which was used without further purification.
Example 28 . . .
2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionlc acid 2-[3-t4-Fluorophenyl)-1,2-benzisoxazol-6-yl]-propionitrile t3.8g) was hydrolysed similarly to Example 10 to give the title compound as an off-white solid tO.45g) m.p. 151-4C.
Example 29 . . _ 3-t4-chlorophenyl)-5-methyl-l~2-benzisoxazole . _ .. . . _ .
4'-Chloro-2-hydroxy-4-methylbenzophenone-oxime tO.2g) and anhydrous sodium carbonate tO~2g) were heated together ~ - 22a -, . .
l~Z9~4 under reflux in triglyome (5ml) for 30 minutes. On cooling, the mixture was poured into water ~50ml`.) and filtered. On standing a solid separated from the filtrate and was filtered, washed, dried and examined by NMR. The NMR spectrum was consistent with the preparation of the title compound (~ 30~).
T . L .C. also confirmed the presence of the benzisoxazole.
Example 30 2-Hydroxy-3-methyl-4'-chlorobenzophenone Chlorobenzene (78.79g, 71.6ml; 0.7mole), AlC13 10 ~ (14g, 0.105mo1e) were mixed, stirred and treated with a solution of 2-hydroxy-3-methylbenzoic acid chloride (12g, 0.07mole) ln chlorobenzene (20ml.). The mixture was stirred and heated at 100C overnight. The cooled mixture was added to conc. HCl (lOml) and ice, extraction with ether, and ether washed with saturated sodium bicarbonate solution, dried (Na2SO4), 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/0.5mm (8.13g), which solidified to yellow microplates, m.p. 55-58C.
Found : C.68.23; H.4.71; Cl.14.61. C14HllClO2 Requires : C.68.16; H.4.49; Cl.14.37%.
Example 31 2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime The ketone of Example 30 (7.5g, 0.03mole) in ethanol (18ml) was added with stirring to a solution of (85%) potassium hydroxide (20.74g, 0.3mole) in water (85ml) at 10C, this colloidal solution was treated with solid hydroxyl-amine hydrochloride (8.54g, 0.12 mole) and stirred overnight.
The solution was acidified with 5NHCl to give a solid, which was filtered, washed with water and stirred for 45 minutes, with 5~ Na2CO3 solution (30.5ml), to remove unwanted oxime ~ - 22b -:: .
~0429~4 stereoisomer, filtered, washed with 5% Na2C03 solution (lOOml) 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") 5.45g.
Foun~: C.64.25; H.4.79; C1.13.41; N.5.3% C14H12Cl C02 Requires: C.64.25; H.4.6; Cl.13.55; N.5.35 Example 32 2-Hydroxy-3-methyl-4'-chlorobenzophenone oxime acetate Acetic anhydride (12ml) was warmed to 60C and treated with the oxime of Example 31 (5.25g. 0.02mole). The stirred mixture was warmed to 80C. to dissolve the oxime and the solution was then immediately cooled in an ice bath. The precipitated solid was filtered off, washed with light petroleum (b.p. 40-60) to give the acetate, 4.8g, m.p. 154-Found: C.63.18; H.4.86; Cl.11.5; N.4.77. C16H14ClN03 Requires C.63.26; H.4.64; C1.11.67; N.4.6%
Example 33 3-p-Chlorophen ~ -1,2-benzisoxazole The oxime acetate of Example 32 (4.36g, 0.014mole) was refluxed with sodium carbonate (3.3g; 0.031mole) in triethylene glycol dimethyl ether (44ml) for 35 minutes. The mixture was poured into water (200ml), cooled in ice filtered and washed neutral with water. After drying the benzisoxazole (3.4g) had m.p. 88-90C and m.p. 97-99 on recrystallisation from EtOH.
Found: C.68.87; H.4.37; Cl.14.82; N.5.83. C14HloClNO
Requires: C.68.99; H.4.14; C1.14.55; N.5.75 3n - 22c -~0~3Q4 1 Example 34 3-p-Chlorophenyl-7-bromomethyl-1,2-benzisoxazole The above benzisoxazole of Example 33 (28.9g, O.lmole) with N-bromosuccimide (19.59g, O.llmole) was refluxed in carbon tetrachloride-(309ml) under illumination from an ultra-violet lamp (Hanovia type MPC) with stirring for three hours. The mixture was cooled and the so~d was succinimide /filtered off and washed with-CC14. The-~filtrate-was =~ -evaporated to dryness and the product recrystallised from light pet'roleum (b.p. 60-80)-CC14 to give the bromo-methyl compound (26.59g) m.p. 117-120 C.
(;containing a little 7 methyL starting material ).
Found : Br. 25.68; Cl. 10.75; No 4.24; C14~ BrClN0 Requires: Br. 24.77j Cl. 10.99; N. 4.34%
Example 35 3-p-Chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid _ The bromomethyl compound of Example 34 (20g, 0.062mole) was stirred 5 at room temperature in dimethyl formamide (190ml.) with sodium cyanide (3.03g 0.062 mole ) and sodium iodide (0.93g, 0.0062 mole) for 22 hours. The solution was evaporated to dryness to yie'ld a solid which was treated with water/ ground up~ filtered and washed with water until the filtrate was free of halidoions. The dried crude nitrile (21.45g) had m.p. 110-125C, NMR
showed that it contained 50% of the required product. The crude nitrile ~20.67g, Ca 0.04 mole ) was refluxed for four hours in conc.HCl.(207ml) and acetic acid (103 ml.). The mixture was poured into water (21.) to give a solid which was extracted with sodium carbonate solution, this was extracted with ether and the sodium carbonate solution was acidified to give the acetic acid which was recrystallised from 50% ethanol to give the acetic acid (2.76g), m.p. 198-200 C.
Found : C. 62.84; H. 3.56; Cl. 12.55; N. 5.07; C15HloClN03 Requires:C. 62.62; H. 3.5; Cl. 12.32; N. 4.87%
Example 36 ~-Methyl-3-p-chlorophenyl-1,2-benzisoxazol-7-yl-acetic acid n-Butyl lithium (31ml, 46m Mole of 1.5M) was cooled to -30cunder nitrogen with stirring and treated with a solution of diisopropylamine (6.25 . 23.
, ' '- '1'1-~4 1 ml. 4.65g., 4~m Mole) in tetrahydrofuran (38ml) keeping the temperature at-30 to -50 C. A solution of the acetic acid of Example 35 (4.5g,15.64m Mole in THF (38ml) and hexamethylphosphoramide (38ml) was added dropwise to the Bu ~i solution and the solution stirred at -30 to ~40C for 1.5 hours. -It -was then transferred to a solution of methyliodide (150ml) which was stirred and had been cooled to 5 ~C. in an ice bath. The mixture was stirred in the melting ice bath for 1.5 hours~ acidified with a litt-le conc.HCl, evaporated to small bulk and treated with water (500ml). The mixture was extracted with chloroform which was dried (Na2~04) and evaporated to leave the a methyl acetic acid as a mixture with its methyl ester. This was refluxed with conc.
HCl (60ml) and acetic acid (30ml) for four hours, diluted with water, extrac-ted with chloroform, which was dried (Na2S04)~ evaporated to leave a gum which was purified on preparative thin layer chromotography to give the ~-methyl acetic acid (0.85g), m.p. 136-138 C.
Found : C.6~88; H.4.27; Cl.11.46; N.4.65; C16H12ClN3 Requires: C.63.69; H.4~1; Cl.11.75; N.4.64%
Example 37 2-Hydroxy-3-ethylbenzophenone . ~
This compound (44.67g) was prepared from benzene (172g.,2.2 mole) and 2-hydroxy-3-ethyl benzoic acid chloride (63.15g,0.34 mole)~ using the same conditi~ns as in Example 30. The h.p. of the compound was 123-126C./
0.14mm~ bD 1.6081,~ max.(film) 1630cm 1.
Example 38 2-Hydroxy-3-ethylbenzophenone oxime Using the conditions of Example 31, the ketone of Example 37 (45.34g,0.2mole) and hydroxylamine hydrochloride (56g~0.8 mole) gave the oxime (43.82g), m.p. 146-148C, ~ max.(Nujol),3340,1650,1608~1600 cm Example 39 2-Hydroxy-3-ethylbenzophenone oxime acetate . . .
The oxime of Example 38 (39.76g, 0.185 mole) (using the conditions of Example 32 above, followed by evaporation of the acetic a~hydride and ~2~
washing the product with light petroleum (b.p. 40-60)), gave the acetate (40.45g), m.p. 63-65C, ~ max. (Nujol) 1770 cm 1.
- Example 40 3-Phenyl-7-ethyl-1,2-benzisoxazole Using the conditions of Example 33, the acetate of Example 39 (39.34g, 0.145 mole) wi~h sodium carbonate (31.86g, 0.3mole) in triethyleneglycol dimethyl ether (425ml) gave 3-phenyl-7-ethyl-1,2-benzisoxazole (27.32g) b.p. 129-130C/
0.3mm, nD 1.6045, ~max. (film) 1625, 1608. NMR ~ 1.42(3H) 3.05 (2H), ~ 7.0-7.3 (8H) Example 41 3-Phenyl-7 ~bromoethyl-1,2-benzisoxazole The 7-ethyl compound of Example 40 (2.23g, lOm Mole~
in carbon tetrachloride (30ml) with N-bromosuccinimide (1.96g, llm Mole) and a trace of benzoyl peroxide or ~-azo-isobutyronitrile was stirred and refluxed while being illuminated with ultra violet light for 2 hours. The cooled solution was filtered and the carbon tetrachloride evaporated orf to leave the ~-bromoethyl compound (3.18g) as an oil n23 1.6280. ~ max (film) 780, ll90cm 1 NMR S 1.22 (3H), 5.62 ~lH), ~ 7.0-8.0 (8H).
Example 42 3-Phenyl-1,2-benzisoxazol-7-yl The ~-bromoethyl compound of Example 41, (18.6g, 61.55 m Mole) in dimethyl formamide (19Oml) with sodium cyanide (3.02g, 61.55 m Mole) and sodium iodide (0.92g, 6.15m Mole) was stirred at room temperature for 22 hours. The solution was evaporated to small bulk, the residue treated with ~ 30 water (200ml), extracted with chloxoform (4x200ml), the CHC13 - was washed with saturated sodium chloride solution and dried :
(Na2S04), filtered and evaporated to give the crude ~-cyano-ethyl nitrile (25g) nD 1.5838, ~max. (film) 750cm The crude nitrile (25g) was stirred and refluxed in acetic acid (125ml) and conc. HCl (250ml) for four hours. The mixture was poured into water (2500ml), extracted with CHC13, which was then extracted with sodium bicarbonate solution.
` The latter was acidified to yield an oil which was extracted with chloroform, dried (Na2SO4), filtered and evaporated to leave 3-phenyl-1,2-benzisoxazol-7-yl acetic acid (5.94g) as an oil, n2D1 1.5830. ~max Ifilm) 2620, 1710, 750, 700 cm 1, NMR ~ 1.71 (3H), 4.42 (lH), 7.12-8.25 (8H), 9.95 (lH). Mass spectrum Parent ion m/e 267, others at 223 (loss of CO2), 222 (loss of CO2H), 208 (loss of CH3CO~), 195 (loss of CH3C.CO2H).
In the following examples of pharmaceutical compositions of the present invention, the term "medicament" is used to indicate the compound ~-methyl-3-_-chlorophenyl-1,2-benz-isoxazol-7-yl acetic acid. That compound may, of course, be replaced by any other active compound of formula I and the amount of medicament may be increased or decreased depending ~n the degree of activity of the medicament used.
Example 43 Tablets each containing lOOmg of medicament are made as follows:-..
. . .
Medicament 1~ 4 lOOmg Potato starch 38mg Lactose 25mg - Ethyl cellulose (as 20~ solution in industrial alcohol) 2mg .- Alginic acid 7mg Magnesium stearate lmg Talc 2mg Total 175mg The medicament, starch and lactose are passed through 1~
a No. 44 mesh B.S.S. sieve and mixed thoroughly. The solution of ethyl cellulose is mixed with the resultant powders which are then passed through a No. 12 mesh B.S.S. sieve.
The granules produced are dried at 50-60C. and then passed through a No. 16 mesh B.S.S. sieve. The alginic acid, magnesium stearate and talc, previously passed through a No. 60 mesh B.S.S. sieve, are added to the granules, mixed and compressed in a tabletting machine to yield tables each weighing 175 mg.
Exam~le 44 ` 20 Capsules each containing 200 mg of medicament are , . ~ .
made as follows:-Medicament 200 mg Lactose 48 mg Magnesium stearate 2 mg The medicament, lactose and magnesium stearate are ` passed through a No. 44 mesh B.S.S. sieve and filled into hard gelatine capsules in 250 mg quantities.
Example 45 Injection solutions each containing 100 mg of30 medicament per 5 ml solution are made as follows:-.
, Medicament 100 mg Sodium hydroxide (10~ solution) q.s.
Water for injection to 5 ml The medicament is suspended in the water and the sodium hydroxide solution added drop by drop with stirring until the medicament is in solution. The pH of the solution is adjusted to between 8.0 and 8.5, the solution is sterilised by filtration through a bacteria-proof filter and filled into previously sterilised glass ampoules which are then hermetically sealed under aseptic conditions.
Example 46 Suppositories each containing 250 mg of medicament are ; made as follows:-Medicament 250 mg Theobroma Oil to 2000 mg The medicament is passed through a No. 60 mesh B.S.S.
sieve and suspended in the theobroma oil previously melted using the minimum of heat necessary. The mixture is then poured into a suppository mould of nominal 2 g capacity and allowed to cool.
,.;
,;~ ,, '.
' ' . .
.:
`
: ', . ~
Claims (8)
1. A process for preparing a 1,2-benzisoxazole acid of formula :
wherein R1 represents one or more substituents which are any one of more of the available positions in the benzene ring and which are selected from one or more of the following atoms or groups; hydrogen, halogen, C1-4 alkyl, C1-C4 alkoxy, nitro, and trifluoromethyl, wherein the -CHR5CO2H group is at the 5-, 6- or 7- position of the benzisoxazole nucleus and wherein R5 is hydrogen or C1-4 alkyl; which comprises hydrolysing a compound of formula :
wherein the group -CHR5Z is at the 5-, 6- or 7- position of the benzisoxazole nucleus and Z represents a nitrile, ester, carboxylate or hydroxamic acid group, or represents a group of formula :
wherein X1 is a halogen atom.
wherein R1 represents one or more substituents which are any one of more of the available positions in the benzene ring and which are selected from one or more of the following atoms or groups; hydrogen, halogen, C1-4 alkyl, C1-C4 alkoxy, nitro, and trifluoromethyl, wherein the -CHR5CO2H group is at the 5-, 6- or 7- position of the benzisoxazole nucleus and wherein R5 is hydrogen or C1-4 alkyl; which comprises hydrolysing a compound of formula :
wherein the group -CHR5Z is at the 5-, 6- or 7- position of the benzisoxazole nucleus and Z represents a nitrile, ester, carboxylate or hydroxamic acid group, or represents a group of formula :
wherein X1 is a halogen atom.
2. A process according to claim 1, wherein z is a nitrile group.
3. A process according to Claim 1, wherein Z is a group of formula wherein X1 is a halogen atom.
4. A process according to Claim 1 wherein R1 is a halo substituent.
5. A process according to Claim 4, wherein R5 is hydrogen or methyl.
6. A process according to Claim 1, 2 or 3 wherein, in the definition for substituent R1, the halogen is chlorine or bromine, the C1-4 alkyl is methyl and the C1-4 alkoxy is methoxy.
7. A 1,2-benzisoxazole acid of the formula as defined in Claim 1 whenever prepared by the process according to any one of Claims 1 to 3 or an obvious chemical equivalent thereof.
8. A 1,2-benzisoxazole acid of the formula as defined in Claim 1 wherein R1 is a halo substituent whenever prepared by a process according to Claim 4 or 5, or an obvious chemical equivalent thereof.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB49259/73A GB1488003A (en) | 1973-10-23 | 1973-10-23 | 1,2-benzisoxazole derivatives processes for their preparation and their use as pharmaceuticals |
| CA212,030A CA1042005A (en) | 1973-10-23 | 1974-10-22 | Isoxazole derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1042904A true CA1042904A (en) | 1978-11-21 |
Family
ID=25667729
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA297,649A Expired CA1042006A (en) | 1973-10-23 | 1978-02-24 | Isoxazole derivatives |
| CA297,648A Expired CA1042904A (en) | 1973-10-23 | 1978-02-24 | Isoxazole derivatives |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA297,649A Expired CA1042006A (en) | 1973-10-23 | 1978-02-24 | Isoxazole derivatives |
Country Status (1)
| Country | Link |
|---|---|
| CA (2) | CA1042006A (en) |
-
1978
- 1978-02-24 CA CA297,649A patent/CA1042006A/en not_active Expired
- 1978-02-24 CA CA297,648A patent/CA1042904A/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| CA1042006A (en) | 1978-11-07 |
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