CA1038393A - 2,5 or 2,6 disubstituted benzoxazoles - Google Patents
2,5 or 2,6 disubstituted benzoxazolesInfo
- Publication number
- CA1038393A CA1038393A CA212,029A CA212029A CA1038393A CA 1038393 A CA1038393 A CA 1038393A CA 212029 A CA212029 A CA 212029A CA 1038393 A CA1038393 A CA 1038393A
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- Prior art keywords
- benzoxazolyl
- group
- acid
- formula
- methyl
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/56—Benzoxazoles; Hydrogenated benzoxazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/52—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings condensed with carbocyclic rings or ring systems
- C07D263/54—Benzoxazoles; Hydrogenated benzoxazoles
- C07D263/58—Benzoxazoles; Hydrogenated benzoxazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A compound of formula II:
(II) where the group is in the 5- or 6-position of the benzo-xazole nucleus, A is -CH2-, -CO-, , -NH or NCH3-;
R4 is a phenyl group, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH
or an alkali or alkaline earth metal, aluminium or ammonium salt thereof. The phenyl group may be substituted by one or two groups selected from the group consisting of halogen, trifluo-romethyl, methyl, methoxy, acetyl and methylsulphonyl. The specification also discloses a process for preparing the above compound. The above compound has valuable pharmacological activities such as analgestic, antipyretic and/or anti-inflammatory activities.
A compound of formula II:
(II) where the group is in the 5- or 6-position of the benzo-xazole nucleus, A is -CH2-, -CO-, , -NH or NCH3-;
R4 is a phenyl group, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH
or an alkali or alkaline earth metal, aluminium or ammonium salt thereof. The phenyl group may be substituted by one or two groups selected from the group consisting of halogen, trifluo-romethyl, methyl, methoxy, acetyl and methylsulphonyl. The specification also discloses a process for preparing the above compound. The above compound has valuable pharmacological activities such as analgestic, antipyretic and/or anti-inflammatory activities.
Description
~ 103839;~ ~' 1 This invention relates to certain new benzoxazole derivatives which have been found to possess valuable pharma^
cological activity 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 composit iong ~ The invention also provides novel intermediates from which the benzoxazole derivatives o the present invention may be prepared.
According to the present invention therefore, there are provided novel benzoxazole derivatives of the formula:
~ R4-~ 1 ~ CRIR2R3 wherein the group -CRlR R3 is in the 5- or 6- position of the - benzoxazole nucleus, Rl is hydrogen, Cl 6 alkyl or halogen, R2`~i is hydrogen, Cl 6 alkyl, halogen, hydroxy, Cl 6alkoxy, C2 7 acyloxy o~ .
: NRllR12 where Rll is hydrogen or Cl 6 alkyl and Rl is hydrogen, Cl 6 alkyl or C2 7 acyl, R3 is a nitrile group, carboxy or a salt, ester, amide or hydroxamic acid derivative thereof, or a group of formula:-~13 3n ~/ or -. Ia Ib '~ ~
' 1038393 l where R13 and R are independently hydrogen, Cl 6 alkyl or Cl 6 hydroxyalkyl, R is phenyl optionally substituted in any available position by one or more Cl 6 alkylsulphonyl, Cl 6 alkyl, Cl_6 alkoxy, Cl_6 haloalkyl, C2_7 aCyl~ nitro, amino, hydroxy or halogen or optionally substituted in two adjacent positions by methylene- or ethylene-dioxy, and A represents -CH2-, -CO-, -CHOR-, or -NR- where R is hydrogen, Cl 6 alkyl or C2 7 acyl, The term "Cl 6 alkyl" as used herein means a straight or branched chain alkyl group containing from l to 6 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, s-butyl, t-butyl, n-amyl, s-amyl, n-hexyl, 2-ethylbutyl and 4-methylamyl. ~Imilarly the terms "Cl 6 alkoxy", "Cl 6 alkylsulphonyl", ''C2 7 acyl" and'~2 7 acyloxy" mean the aforementioned Cl 6 alkyl groups linked through an oxygen atom, or an -SO2-, -CO- or -CO-O- group respectively, The terms "Cl 6 hydroxyalkyl" and "Cl 6 haloalkyl" as used herein mean the aforementioned Cl 6 alkyl groups substituted by one or more hydroxy or halogen respectively, such as, for example, 2-chloroethyl, 2-hydroxyethyl, trifluoromethyl, chloromethyl, 3-hydroxypropyl, 3-bromopropyl,
cological activity 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 composit iong ~ The invention also provides novel intermediates from which the benzoxazole derivatives o the present invention may be prepared.
According to the present invention therefore, there are provided novel benzoxazole derivatives of the formula:
~ R4-~ 1 ~ CRIR2R3 wherein the group -CRlR R3 is in the 5- or 6- position of the - benzoxazole nucleus, Rl is hydrogen, Cl 6 alkyl or halogen, R2`~i is hydrogen, Cl 6 alkyl, halogen, hydroxy, Cl 6alkoxy, C2 7 acyloxy o~ .
: NRllR12 where Rll is hydrogen or Cl 6 alkyl and Rl is hydrogen, Cl 6 alkyl or C2 7 acyl, R3 is a nitrile group, carboxy or a salt, ester, amide or hydroxamic acid derivative thereof, or a group of formula:-~13 3n ~/ or -. Ia Ib '~ ~
' 1038393 l where R13 and R are independently hydrogen, Cl 6 alkyl or Cl 6 hydroxyalkyl, R is phenyl optionally substituted in any available position by one or more Cl 6 alkylsulphonyl, Cl 6 alkyl, Cl_6 alkoxy, Cl_6 haloalkyl, C2_7 aCyl~ nitro, amino, hydroxy or halogen or optionally substituted in two adjacent positions by methylene- or ethylene-dioxy, and A represents -CH2-, -CO-, -CHOR-, or -NR- where R is hydrogen, Cl 6 alkyl or C2 7 acyl, The term "Cl 6 alkyl" as used herein means a straight or branched chain alkyl group containing from l to 6 carbon atoms such as methyl, ethyl, isopropyl, n-butyl, s-butyl, t-butyl, n-amyl, s-amyl, n-hexyl, 2-ethylbutyl and 4-methylamyl. ~Imilarly the terms "Cl 6 alkoxy", "Cl 6 alkylsulphonyl", ''C2 7 acyl" and'~2 7 acyloxy" mean the aforementioned Cl 6 alkyl groups linked through an oxygen atom, or an -SO2-, -CO- or -CO-O- group respectively, The terms "Cl 6 hydroxyalkyl" and "Cl 6 haloalkyl" as used herein mean the aforementioned Cl 6 alkyl groups substituted by one or more hydroxy or halogen respectively, such as, for example, 2-chloroethyl, 2-hydroxyethyl, trifluoromethyl, chloromethyl, 3-hydroxypropyl, 3-bromopropyl,
2-(2-chloroethyl)-3-chloropropyl,pentafluoroethyl, 2 hydroxybutyl, 4-bromobutyl and 6-chlorohexyl.
Within the aforementioned group of compounds of formula l, there is a sub-group preferred for the ease of availab~ity of the necessary starting materials, which sub-group comprises compounds wherein the group -CRlR2R3 is in the 5- or 6- position of the benzoxazole nucleus, R is phenyl substituted in any available position by one or two groups selected from Cl 4 alkyl, Cl 4 alkoxy, C2 4 acyl, Cl 4 alkylsulphonyl, Cl 4-monohaloalkyl, trifluoromethyl, halogen, nitro, amino, hydroxy, or optionaliy substituted in two adjacent positions by methyiene-dioxy, A
represents -CH2-, -oD-, -CHOR-, or -NR- where R is ! 3.
~ 1038393 1 hydrogen, methyl~ ethyl or acetyl, Rl is hydrogen, methyl, chloro or bromo, R is hydrogen, methyl, ethyl, chloro, bromo, hydroxy, Cl_4 alkoxy, C2 4 acyloxy or NRll R 2 where Rll is hydrogen, methyl or ethyl and R12 is hydrogen, methyl, ethyl or acetyl, and R3 is:
(i) the group -COOR where R is Cl_4 alkyl; or (ii) the group -COR where R is -MHOH or -NR7R8 in which R7 and R8 are independently hydrogen or Cl_4 alkyl; or (iii) the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof; or . (iv) a nitrile group; or (v) a group of formula Ia or Ib in which R and R
are independently hydrogen, methyl, ethyl, or hydroxyethyl.
An especially useful group of compounds of the present invention are those of the formula:-C -A 1 ~ CH-R3 11 where the group -CH-R is in the 5- or 6- position of the OH , CH3 Ç)COCH3 benzoxazole nucleus, A is -CH2-, -GO-, -CH-, -CH-, -CH-, -NH- or-NCH3-, R4 is a phenyl group optionally substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl or methylsulphonyl, .
R is hydrogen or preferably methyl, and R3 is as defined at (i) or (iii) above.
j 1038393 1 ~xam~les of compounds falling within the scope of this invention are:-(i) 2^[2-benzyl-5-benzoxazolyl] acetic acid 2-[2-benzyl-5-benzoxazolyl] propionic acid .
2-[2-t4-methylsulphonylbenzyl)-5-benzoxazolyl] propionic acid 2-[2-(3,4-dimethylbenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-methoxybenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-~-chloroethylbenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-trifluoromethylbenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-acetylbenzyl)-6-benzoxazolyl] propionic acid 2-[2-(3,4-dinitrobenzyl)-5-benzoxazolyl] butyric acid 2-[2-(3-aminobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-hydroxybenzyl)-6-benzoxazolyl] propionic acid 2-[2-(2,4-dichlorobenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-bromobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(3~4-methylenedioxybenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]-2-methylpropionic acid 2-[2-benzyl-5-benzoxszolyl]-2-ethylacetic acid .~ 2-[2-(4-trifluoromethylbenzyl)-5-benzoxazolyl]-2-bromopropionic acid 2-[2-(3,4-dichlorobenzyl)-5-benzoxazolyl]-2-methoxybutyric acid 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]-2-aminopropionic acid 2-[2-(4-methylbenzyl)-5-benzoxazolyl]-2-(N-methylamino) propionic acid 2-[2-(4-methoxybenzyl)-5-benzoxazolyl]-2-(N-acetylamino) acetic acid 2-benzyl-5-[1-(5-tetrazolyl)ethyl] benzoxazole 2-(4-chlorobenzyl)-5-[1-(5-tetrazolyl)ethyl] benzoxazole 2-(4-chlorobenzyl)-5-tetrazolylmethylbenzoxazole 2-(4-chlorobenzyl)-5- 1-(4,4-dimethyl-2-oxazolinyl)ethyl]benzoxazole 30 . 2-[2-(4-chlorobenzoyl)-5-benzoxazolyl]acetic acid 2-[2-(4-bromobR~y1)-5-benzoxazolyl] propionic acid 2-[2-(3,4-methylenedioxybenzoyl)-5-benzoxazolyl]propionic acid 5.
1 2-[2-benzoyl-5-benzoxazolyl]-2-ethylacetic acid 2-[2-(4-chlorobenzoyl)-6-benzoxazolyl]-2-hydroxyacetic acid 2-[2-(4-methoxyben~;oyl)-5-benzoxazolyl]-2-(N-methylacetylami~o)acetl~ d 2-[2-benzoyl-5-benzoxazolyl]ace.tic acid 2-[2-benzoyl-5-benzoxazolyl]propionic acid 2-[2-(4-methylsulphonylbenzoyl)-6-benzoxazolyl]propionic acid 2[2-(3,4-dimethylbenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(4-~-chloroethylbenzoyl)-6-benzoxazolyl]acetic acid 2-[2-(4-trifluoromethylbenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(3-nLtro-4-chlorobenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(4-aminobenzoyl)-6-benzoxazolyl]propionic acid 2-[2-(4-hydroxybenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(2,4-dichlorobenzoyl)-5-benzoxazolyl]acetic acid 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-hydroxybenzyl)-5-benzox~zolyl]propionic acid 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl]propionic acid : 2-[2-(a-hydroxy-3,4-diethylbenzyl)-6-benzoxazolyl]acetic acid 2-[2-(a-hydroxy-4-methoxybenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a-hydroxy-4-trifluoromethylbenzyl)-5-benzoxazolyl3propionic acid 2-[2-(a-hydroxy-4-acetylbenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a,4-dihydroxybenzyl)-6-benzoxazolyl]acetic acid 2-[2-a-hydroxy-2,4-dichlorobenzyl)-5-benzoxazolyl]propionic acid 2-[2-~-hydroxy-4-bromobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl]-2-hydroxypropionic acid 2-[2-(-hydroxy-4-methylbenzyl)-6-benzoxazolyl]-2,2-dibromoacetic acid 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]-2-methoxypropionic acid 2-(a-hydroxy-4-chlorobenzyl)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-[2-(a-methoxybenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-ethoxybenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-acetoxybenzyl)-5-benzoxazolyl]butyric acid 2-[2-(a-methoxy-4-methylsulphonylbenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-ethoxy-3,4-dimethylbenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a,4-dimethoxybenzyl)-6-benzoxazolyl]propionic acid 1 2-[2-( a - acetoxy-4-~-chloroethylbenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-acetoxy-4-trifluoromethylbenzyl)-5-benzoxazolyl]acetic acid 2-[2-(~-ethoxy-4-acetylbenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a-methoxy-3,4-dinitrobenzyl)-5-benzoxazolyl]butyric acid 2-[2-(a-methoxy-3-aminobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(-acetoxy-2~4-dichlorobenzyl)-6-benzoxazolyl~propionic acid 2-[2-(a-acetoxy-4-chlorobenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-methoxy-4-chlorobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(~-ethoxy-4-bromobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(~-acetoxy-3~4-methylenedioxybenzyl)-5-benzoxazoiyl]propionic acid 2-[2-(~-methoxy-4-chlorobenzyl)-6-benzoxazolyl]2-propionic acid 2-[2-(-methoxybenzyl)-5-benzoxaæolyl]-2-ethylpropionic acid 2-[2-(~-acetoxy-4-trifluoromethylbenzyl)-5-benzoxazolyl]-2-acetoxyacetic a~ id 2-[2-(a-methoxy-3,4-dichlorobenzyl)-6-benzoxazolyl]-2-methoxyacetic acid 2-[2-(-ethoxy-4-chlorobenzyl)-5-benzoxazolyl]-2-ethoxypropionic acid 2-[2-(~,4-dimethoxybenzyl)-5-benzoxazolyl]-2-chloropropionic acid 2-(~-methoxybenzyl)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-6rnethoxy-4-chlorobenzyl)-6-(5-tetrazolylmethyl)benzoxazole 2-(-methoxy-4-chlorobenzyl)-5-[1-(2-oxazolinyl )ethyl]benzoxazole 2-[2-anilino - 5-benzoxazolyl]propionic acid 2-[2-(N-methylanilino)-5-benzoxazolyl]propionic acid 2-~2-(N-acetylanilino)-5-benzoxazolyl]acetic acid . 2-[2-(4-chloroanilino)-6-benzoxazolyl]butyric acid 2-[2-(4-methylsulphonylanilino)-6-benzoxazolyl]acetic acid . 2-[2-(N,3,4-trimethylanilino)-5-benzoxazolyl]propionic acid 2-[2-(4-methoxyanilino)-5-benzoxazolyl]propionic acid 2-[2-(4-~-chloroethylanilino)-6-benzoxazolyl]propionic acid 2-[2-(4-trifluoromethylanilino)-6-benzoxazolyl]acetic acid 2-[2-(N,4-diacetylanilino)-5-benzoxazolyl] acetic acid 2-[2-(N-methyl-3,4-dinitroanilino)-5-benzoxazolyl]propionic acid .
. 2-[2-(4-hydroxyanilino)-6-benzoxazolyl]propionic acid ! 2-[2-(2,4-dichloroanilino)-6-benzoxazolyl]propionic acid ~ 2-[2-(N-methyl-4-bromoanilino)-5-benzoxazolyl]acetic acid .Z ' .
, . ' -: - . - ., . -' . - .. , ... , : - , ~038393 2-[2-~nilino-6-benzoxazolyl]acetic acid 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionic acid 2-(4-chloroanilino)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-(anilino)-5-[L~4,4-di-~-hydroxyethyl-2-oxazolinyl)ethyl]benzoxazole 2-(4-chloroanilino)-5-[1-(4,4-dimethyl-2-oxazolinyl)ethyl]benzoxazole 2-[2-(3,4-methylenedioxyanilino)-5-benzoxazolyl]acetic acid 2-[2-(4-chloroanilino)-6-benzoxazolyl]-2-methylpropionic acid 2-[2-(4-trifluoromethylanilino)-5-benzoxazolyl]-2-aminopropionic acid 2-[2-(4-bromoanilino)-5-benzoxazolyl]-2,2-dibromoacetic acid 2-[2-(N~4-dimethylanilino)-6-benzoxazolyl]-2-(N-methylamino)propionic acid 2-[2~(4-methoxyanilino)-5-benzoxazolyl]-2-methoxypropionic acid 2-[2-anilino-6-benzoxazolyl]propionic acid : 1031~393 1 (ii) the sodiwll, po~a~sium, calcium, aluminium and ammonium salts of the acids described at ti) above;
(iii) the Cl_4 alkyl, especially the methyl and ethyl, esters of the acids described at (i) above;
(iv) the acetonitriles, propionitriles and butyronitriles corresponding to the acids described at (i) above;
(v) the acetamides, propionamides and butyramides, and their N-methyl or N-ethyl derivatives, corresponding to the acids described at (i) above; and (vi) the acethydroxamic acids, propionylhydroxamic acids and butyrylhydroxamic acids corresponding to the carboxylic acids described at (i) above.
The present invention also provides a process for the preparation of the foregoing compounds of formula I, which process comprises cyclising a compound of the formula:
HO ~ CRIR2-Z hll wherein Z is the group R3 or is a group convertible to R , using a cyclising agent capable of donating the required group C.) R -A- or another group which is convertible to R4-A-, and thereafter where necessary the resultant compound is converted to the desired compound of formula I in conventional manner.
- In the case where A in the end-product of formula I is -CH2- or -CHOR where R is hydrogen or Cl 6 alkyl, the compound of formula I may be obtained directly by reacting an appropriate cyclising agent such as a compound of the formu~a R -A-COOH, . (R4-A-Co)20, R -ArCOCl~ R -A-CONH2, R -A-CONHNH2 or R -A-CN,.
with the compound of formula III, the reaction-being carried out under the influence of heat and/or under acidic conditions, for example in the presence of hydrochloric acid, phosphorus 1 oxychloride or polyphosphoric acid, or under basic conditions, for example in the presence of pyridine or triethylamine depending on the particular reactants involved.
It is believed that the above cyclisation proceeds via an intermediate in which one or more of the hydrogen atoms in the amino or phenolic groups have been replaced by a radical from the cyclising agent.~ For example, when the cyclising agent is a compound of formula R4-A-CooH, R4-A-COCl, R -A-CONH2, R4-A-CoNHNH2 or R4-A-CHo, the hydrogen atom in the phenolic hydroxyl group can be replaced by a R -A-CO- group and one or both of the hydrogen atoms in the amino group can be replaced by R4-A-Co- as before or by the group R4-A-CH- (when the aldehyde is used ascyclising agent). When A is -CH2-, the intermediates are stable and can, if desired, be isolated prior to ring-closure to the benzoxazole.
In the case where the cyclising agent is R -A-CHO, the ring closure , 15 can be carried out in t~e presence of an oxidising agent such as lead tetra-acetate or n1ckel peroxide.
In the case where'A in the end-product of formula I is -CO- or -CHOR-where R is C2 7 acyl, the desired compound may be obtained from the corresponding compound, prepared as described above, in which A is -CHOH-by oxidation, for example using manganese dioxide or chromium trioxide, or by conventional acylation respectively.
In the case where A in the end-product of formula I is -NH- the intermediate of formula III can be ring-closed with an isocyanate of formula R CNO to yield directly the compound of formula I. Alternatively, the intermediate of formula III can be cyclised to a benzox'azolyl-2-thione, for example by using an alkali metal alkyl xanthate such as potassium ethyl xanthate as the cyclising agent, and the thione can then be converted to the corresponding 2-halo compound, for example 2-chlorobenzoxazole, by halogenation for example with chlorine gas. To obtain the compound'of fonmula I in which A 'is -NR-, the 2-halocompound is then reacted with the appropriate aniline of formula R -NHR. Alternatively, the thione can be reacted directly with the aniline. 1 ~ ' 1038~J93 Those benzoxazole 2-thiones and haLides in which R3 is a nitrile, carboxylic acid or salt, amido, ester or hydroxamic acid group, are novel compounds. Writing the thione group in its thiol form, these compounds can be represented by the formula:
~ ' where Q is SH or halogen.
As will immediately be apparent to those skilled in the art, internediates of formula IV in which Q is a halogen atom, for example iodine, can also be converted to 2-phenyl derivatives using,for example, the well-known Ullmann reaction (see for instance page 1222-The Mèrck Index, VIII the edition published 1968). The reactants and reaction conditions necessary for this reaction will be well known to those skilled in the art, however, for illustrative purposes the following reaction scheme may be considered typical:
~ ~
X CBlB2~3 wherein Xl is hydrogen or halogen, and wherein Q and x2 are also halogen.
' 3Ll , 1(~3~393 1 In carrying out the foregoing reactions, it will be appreciated that, if group Z in the starting material of formula III is capable of reacting with the cyclising agent or other reactants used, the reaction may produce a mixture of products rather than the desired compound of formula I alone. Although the undesired products could be separated from the reaction mixture, it is obviously desirable to use a compound of formula III in which Z is a group which is incapable of reaction with the other reactants. Thus where Z is a group convertible to R , Z is preferably hydrogen or halogen and where Z is one of the groups encompassed by R , it is preferably a nitrile group or an estérified carboxy, salified carboxy or carboxyamide group.
As stated above, when Z is not the group R , completion of the cyclisation step must be followed by conversion of group Z to the des'ired group R . As is well known inthe art, many different types of groups may be ~onverted to the R3 functions in the desired compounds of this invention. However, it is preferred for the purposes of the''present invention ~hat, whére Z is not the group R3, it is hydrogen or halogen.
When Z is hydrogen, the compound resulting from the cyclisation reaction may be halogenated in conventional manner, for examplé using chlorine, sulphur'yIchloride, bromine or N-bromosuccinimide, preferably in the presence of a suitabLe solvent such as carbon tetrachloride to produce the corresponding compound in which Z is halogen. This compound~ or the same compound obtained from the above cyclisation reaction, may then be reacted with an alkali metal cyanide in a suitable diluent or solvent, usually under the influence of heat, to produce a compound of formula I
in which R is CN. - -The latter compound, or the same compound obtained directly from the above cyclisation reaction, 'may then be treated in a number o ways l to achieve its conversion to another compound of formula I. For example, ; 30 the nitrile may be reacted with an appropriate alcohol under acidic 10:1~1393 1 conditions to produce a compound of formula I in which R is an esterified carboxy group. Alternatively, the nitrile can be hydrolysed, for example using sulphuric acid, to produce a compound of formula I in which R i~ a carboxyamide group. Hydrolysis of the nitrile, or the last mentioned .
- carboxyamide, with a strong base or an acid such as concentrated -hydrochloric acid results in the formation of a compound of formula I.
in which R3 is a carboxy group. A resultant compound of formula I in which R is esterified carboxy may be converted to a hydroxamic scid derivative by reaction with hydroxylamine.
A nitrile of formula I may also be converted to a'compound in which R is a group of formula Ia by reaction with ammonium azide, usually under the influence of heat~ Similarly, a resultant'compound of formula ' I in which R3 is carboxy can be converted to a compound i'n which R3 is a ' group of formula Ib by reaction with an appropriate amino alcohol of ' formula H2N-CR R -CH2-OH. . . .
A resultant compound of formula I in which Rl or R2 is.hydrogen ' may be halogenated to produce a~compound in which Rl or R2 is~ha~ogen~
or exsmple a bromine atom may be introdoced by reaction uith N-bromosuccin-imide, and if desired, the resultant halo-compound may be rehalogenated to produce a compound in which R1 and R2 are halogen. A resultant compound in which R is halogen may in turn, be used to prepare a number of other ' compounds of formula I. Thus, by hydrolysis, for example using sodium .
hydroxide, it may be converted to the corresponding compound in which ' . R is hydroxy and the latter may be acylated to yield a compound in which ' R is acyloxy; by reaction with an alkali metal alkoxide such as sodium alkoxide, the corresponding compound in which R is alkoxy, may be obtained; and by reaction ~ith ammonia, an N-alkylamine.or an N,N-dialkylamine, the compound in which R2 is halogen may be converted to the corresponding compound of formula I in which R IB amino, N-alkylsmino or . . ' '.
lQ38393 N,N-dialkylamino. Furthermore, a resultant compound in which R is amino or N-alkylamino may be acylated in conventional manner to produce A
compound of fo'rmula'I in which R is N-acylamino or~N-Acyl-N-alkylamino respectively. ' In addition,'a resultant compound of formula I in which R is a halogen can be converted to the corresponding acid using the well-known Grignard reaction (see for example page 1172 of the Merck Index, VIIIth Edition published 1968 or any'other standard reference text).~ After reaction with Magnesium 'an'd treatment with CO2~ a compound of formula I is formed in which R is''the group - ~OMgX where X is a halogen atom.
This group c~n then be cobverted to a carboxylic scid group-simply by hydrolysis. ' ' '' Accordingly, in a further a~pect of this invention, there is provided a compound of the formula II:
R4~ ~ CH-R3 (II) .
~2 where the group -CH-R3 is in the 5- or 6- position of the benzo-~ H (;~CH ,OCOCH
xazole nucleus, A is -CH2, -CO-, -CH-, -CH-3, -CH- 3, -NH- or -NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methyl-sulphonyl, R2 is hydrogen or methyl, and R3 is the group -CooR5, where R is Cl 4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof, which process .
comprises hydrolysing a compound of formula V:
$~ 14 .
~038~93 R4-A CH-Z (V) where A, R2 and R4 are as defined above and Z represents a nitrile,-ester, carboxylate, amido, hydroxamic acid group or a group of formula: ~ O
OMgX
where X is a halogen atom.
An acid o'f formula I may be salified by treatment with an ' appropriate base such as'an ammonium, alkylammonium, ara'ikylammonium, aluminium, 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~aci-d. 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 formuls I may of:course'be hydrolysed to the cor}esponding 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.
' A resultant compound of formula I in which R and/o~ R2 is hydrogen may be alkylated to produce the correspondin~ compound of formula 1 in which R and/or R is Cl 6 alkyl. The alkylation may be carried out by' interaction of an alkali metal-derivative of the approp~iate benzoxazole -' derivate with nn al~l halide such as, for example, methyl or ethyl iodide.
~' . ' , . ., ~
' ' '',, ' ' ,. ' ' , ~ -14a-, 1 As mentioned above~ the compounds of formula II are especially useful. Such compounds can be prepared by a process which comprises the hyd~olys o _ h-~
where Z represents a nitrile, ester, carboxylate, amido, hydroxamic acid group, or a group of formula: - C where X is a halogen atom.
The compounds of formula III above may be prepared by reducing the corresponding nitro compounds~ which may themselves be readily obtained from known or easily prepared chemicals according to,the following reaction scheme:-' , ' ~ ' L 1 _3 .o; Z~
(~:" ; 1 `' ~ ~;
Within the aforementioned group of compounds of formula l, there is a sub-group preferred for the ease of availab~ity of the necessary starting materials, which sub-group comprises compounds wherein the group -CRlR2R3 is in the 5- or 6- position of the benzoxazole nucleus, R is phenyl substituted in any available position by one or two groups selected from Cl 4 alkyl, Cl 4 alkoxy, C2 4 acyl, Cl 4 alkylsulphonyl, Cl 4-monohaloalkyl, trifluoromethyl, halogen, nitro, amino, hydroxy, or optionaliy substituted in two adjacent positions by methyiene-dioxy, A
represents -CH2-, -oD-, -CHOR-, or -NR- where R is ! 3.
~ 1038393 1 hydrogen, methyl~ ethyl or acetyl, Rl is hydrogen, methyl, chloro or bromo, R is hydrogen, methyl, ethyl, chloro, bromo, hydroxy, Cl_4 alkoxy, C2 4 acyloxy or NRll R 2 where Rll is hydrogen, methyl or ethyl and R12 is hydrogen, methyl, ethyl or acetyl, and R3 is:
(i) the group -COOR where R is Cl_4 alkyl; or (ii) the group -COR where R is -MHOH or -NR7R8 in which R7 and R8 are independently hydrogen or Cl_4 alkyl; or (iii) the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof; or . (iv) a nitrile group; or (v) a group of formula Ia or Ib in which R and R
are independently hydrogen, methyl, ethyl, or hydroxyethyl.
An especially useful group of compounds of the present invention are those of the formula:-C -A 1 ~ CH-R3 11 where the group -CH-R is in the 5- or 6- position of the OH , CH3 Ç)COCH3 benzoxazole nucleus, A is -CH2-, -GO-, -CH-, -CH-, -CH-, -NH- or-NCH3-, R4 is a phenyl group optionally substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl or methylsulphonyl, .
R is hydrogen or preferably methyl, and R3 is as defined at (i) or (iii) above.
j 1038393 1 ~xam~les of compounds falling within the scope of this invention are:-(i) 2^[2-benzyl-5-benzoxazolyl] acetic acid 2-[2-benzyl-5-benzoxazolyl] propionic acid .
2-[2-t4-methylsulphonylbenzyl)-5-benzoxazolyl] propionic acid 2-[2-(3,4-dimethylbenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-methoxybenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-~-chloroethylbenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-trifluoromethylbenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-acetylbenzyl)-6-benzoxazolyl] propionic acid 2-[2-(3,4-dinitrobenzyl)-5-benzoxazolyl] butyric acid 2-[2-(3-aminobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-hydroxybenzyl)-6-benzoxazolyl] propionic acid 2-[2-(2,4-dichlorobenzyl)-6-benzoxazolyl] propionic acid 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] acetic acid 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-bromobenzyl)-5-benzoxazolyl] propionic acid 2-[2-(3~4-methylenedioxybenzyl)-5-benzoxazolyl] propionic acid 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]-2-methylpropionic acid 2-[2-benzyl-5-benzoxszolyl]-2-ethylacetic acid .~ 2-[2-(4-trifluoromethylbenzyl)-5-benzoxazolyl]-2-bromopropionic acid 2-[2-(3,4-dichlorobenzyl)-5-benzoxazolyl]-2-methoxybutyric acid 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]-2-aminopropionic acid 2-[2-(4-methylbenzyl)-5-benzoxazolyl]-2-(N-methylamino) propionic acid 2-[2-(4-methoxybenzyl)-5-benzoxazolyl]-2-(N-acetylamino) acetic acid 2-benzyl-5-[1-(5-tetrazolyl)ethyl] benzoxazole 2-(4-chlorobenzyl)-5-[1-(5-tetrazolyl)ethyl] benzoxazole 2-(4-chlorobenzyl)-5-tetrazolylmethylbenzoxazole 2-(4-chlorobenzyl)-5- 1-(4,4-dimethyl-2-oxazolinyl)ethyl]benzoxazole 30 . 2-[2-(4-chlorobenzoyl)-5-benzoxazolyl]acetic acid 2-[2-(4-bromobR~y1)-5-benzoxazolyl] propionic acid 2-[2-(3,4-methylenedioxybenzoyl)-5-benzoxazolyl]propionic acid 5.
1 2-[2-benzoyl-5-benzoxazolyl]-2-ethylacetic acid 2-[2-(4-chlorobenzoyl)-6-benzoxazolyl]-2-hydroxyacetic acid 2-[2-(4-methoxyben~;oyl)-5-benzoxazolyl]-2-(N-methylacetylami~o)acetl~ d 2-[2-benzoyl-5-benzoxazolyl]ace.tic acid 2-[2-benzoyl-5-benzoxazolyl]propionic acid 2-[2-(4-methylsulphonylbenzoyl)-6-benzoxazolyl]propionic acid 2[2-(3,4-dimethylbenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(4-~-chloroethylbenzoyl)-6-benzoxazolyl]acetic acid 2-[2-(4-trifluoromethylbenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(3-nLtro-4-chlorobenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(4-aminobenzoyl)-6-benzoxazolyl]propionic acid 2-[2-(4-hydroxybenzoyl)-5-benzoxazolyl]propionic acid 2-[2-(2,4-dichlorobenzoyl)-5-benzoxazolyl]acetic acid 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-hydroxybenzyl)-5-benzox~zolyl]propionic acid 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl]propionic acid : 2-[2-(a-hydroxy-3,4-diethylbenzyl)-6-benzoxazolyl]acetic acid 2-[2-(a-hydroxy-4-methoxybenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a-hydroxy-4-trifluoromethylbenzyl)-5-benzoxazolyl3propionic acid 2-[2-(a-hydroxy-4-acetylbenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a,4-dihydroxybenzyl)-6-benzoxazolyl]acetic acid 2-[2-a-hydroxy-2,4-dichlorobenzyl)-5-benzoxazolyl]propionic acid 2-[2-~-hydroxy-4-bromobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl]-2-hydroxypropionic acid 2-[2-(-hydroxy-4-methylbenzyl)-6-benzoxazolyl]-2,2-dibromoacetic acid 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]-2-methoxypropionic acid 2-(a-hydroxy-4-chlorobenzyl)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-[2-(a-methoxybenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-ethoxybenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-acetoxybenzyl)-5-benzoxazolyl]butyric acid 2-[2-(a-methoxy-4-methylsulphonylbenzyl)-5-benzoxazolyl]propionic acid 2-[2-(a-ethoxy-3,4-dimethylbenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a,4-dimethoxybenzyl)-6-benzoxazolyl]propionic acid 1 2-[2-( a - acetoxy-4-~-chloroethylbenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-acetoxy-4-trifluoromethylbenzyl)-5-benzoxazolyl]acetic acid 2-[2-(~-ethoxy-4-acetylbenzyl)-6-benzoxazolyl]propionic acid 2-[2-(a-methoxy-3,4-dinitrobenzyl)-5-benzoxazolyl]butyric acid 2-[2-(a-methoxy-3-aminobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(-acetoxy-2~4-dichlorobenzyl)-6-benzoxazolyl~propionic acid 2-[2-(a-acetoxy-4-chlorobenzyl)-5-benzoxazolyl]acetic acid 2-[2-(a-methoxy-4-chlorobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(~-ethoxy-4-bromobenzyl)-5-benzoxazolyl]propionic acid 2-[2-(~-acetoxy-3~4-methylenedioxybenzyl)-5-benzoxazoiyl]propionic acid 2-[2-(~-methoxy-4-chlorobenzyl)-6-benzoxazolyl]2-propionic acid 2-[2-(-methoxybenzyl)-5-benzoxaæolyl]-2-ethylpropionic acid 2-[2-(~-acetoxy-4-trifluoromethylbenzyl)-5-benzoxazolyl]-2-acetoxyacetic a~ id 2-[2-(a-methoxy-3,4-dichlorobenzyl)-6-benzoxazolyl]-2-methoxyacetic acid 2-[2-(-ethoxy-4-chlorobenzyl)-5-benzoxazolyl]-2-ethoxypropionic acid 2-[2-(~,4-dimethoxybenzyl)-5-benzoxazolyl]-2-chloropropionic acid 2-(~-methoxybenzyl)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-6rnethoxy-4-chlorobenzyl)-6-(5-tetrazolylmethyl)benzoxazole 2-(-methoxy-4-chlorobenzyl)-5-[1-(2-oxazolinyl )ethyl]benzoxazole 2-[2-anilino - 5-benzoxazolyl]propionic acid 2-[2-(N-methylanilino)-5-benzoxazolyl]propionic acid 2-~2-(N-acetylanilino)-5-benzoxazolyl]acetic acid . 2-[2-(4-chloroanilino)-6-benzoxazolyl]butyric acid 2-[2-(4-methylsulphonylanilino)-6-benzoxazolyl]acetic acid . 2-[2-(N,3,4-trimethylanilino)-5-benzoxazolyl]propionic acid 2-[2-(4-methoxyanilino)-5-benzoxazolyl]propionic acid 2-[2-(4-~-chloroethylanilino)-6-benzoxazolyl]propionic acid 2-[2-(4-trifluoromethylanilino)-6-benzoxazolyl]acetic acid 2-[2-(N,4-diacetylanilino)-5-benzoxazolyl] acetic acid 2-[2-(N-methyl-3,4-dinitroanilino)-5-benzoxazolyl]propionic acid .
. 2-[2-(4-hydroxyanilino)-6-benzoxazolyl]propionic acid ! 2-[2-(2,4-dichloroanilino)-6-benzoxazolyl]propionic acid ~ 2-[2-(N-methyl-4-bromoanilino)-5-benzoxazolyl]acetic acid .Z ' .
, . ' -: - . - ., . -' . - .. , ... , : - , ~038393 2-[2-~nilino-6-benzoxazolyl]acetic acid 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionic acid 2-(4-chloroanilino)-5-[1-(5-tetrazolyl)ethyl]benzoxazole 2-(anilino)-5-[L~4,4-di-~-hydroxyethyl-2-oxazolinyl)ethyl]benzoxazole 2-(4-chloroanilino)-5-[1-(4,4-dimethyl-2-oxazolinyl)ethyl]benzoxazole 2-[2-(3,4-methylenedioxyanilino)-5-benzoxazolyl]acetic acid 2-[2-(4-chloroanilino)-6-benzoxazolyl]-2-methylpropionic acid 2-[2-(4-trifluoromethylanilino)-5-benzoxazolyl]-2-aminopropionic acid 2-[2-(4-bromoanilino)-5-benzoxazolyl]-2,2-dibromoacetic acid 2-[2-(N~4-dimethylanilino)-6-benzoxazolyl]-2-(N-methylamino)propionic acid 2-[2~(4-methoxyanilino)-5-benzoxazolyl]-2-methoxypropionic acid 2-[2-anilino-6-benzoxazolyl]propionic acid : 1031~393 1 (ii) the sodiwll, po~a~sium, calcium, aluminium and ammonium salts of the acids described at ti) above;
(iii) the Cl_4 alkyl, especially the methyl and ethyl, esters of the acids described at (i) above;
(iv) the acetonitriles, propionitriles and butyronitriles corresponding to the acids described at (i) above;
(v) the acetamides, propionamides and butyramides, and their N-methyl or N-ethyl derivatives, corresponding to the acids described at (i) above; and (vi) the acethydroxamic acids, propionylhydroxamic acids and butyrylhydroxamic acids corresponding to the carboxylic acids described at (i) above.
The present invention also provides a process for the preparation of the foregoing compounds of formula I, which process comprises cyclising a compound of the formula:
HO ~ CRIR2-Z hll wherein Z is the group R3 or is a group convertible to R , using a cyclising agent capable of donating the required group C.) R -A- or another group which is convertible to R4-A-, and thereafter where necessary the resultant compound is converted to the desired compound of formula I in conventional manner.
- In the case where A in the end-product of formula I is -CH2- or -CHOR where R is hydrogen or Cl 6 alkyl, the compound of formula I may be obtained directly by reacting an appropriate cyclising agent such as a compound of the formu~a R -A-COOH, . (R4-A-Co)20, R -ArCOCl~ R -A-CONH2, R -A-CONHNH2 or R -A-CN,.
with the compound of formula III, the reaction-being carried out under the influence of heat and/or under acidic conditions, for example in the presence of hydrochloric acid, phosphorus 1 oxychloride or polyphosphoric acid, or under basic conditions, for example in the presence of pyridine or triethylamine depending on the particular reactants involved.
It is believed that the above cyclisation proceeds via an intermediate in which one or more of the hydrogen atoms in the amino or phenolic groups have been replaced by a radical from the cyclising agent.~ For example, when the cyclising agent is a compound of formula R4-A-CooH, R4-A-COCl, R -A-CONH2, R4-A-CoNHNH2 or R4-A-CHo, the hydrogen atom in the phenolic hydroxyl group can be replaced by a R -A-CO- group and one or both of the hydrogen atoms in the amino group can be replaced by R4-A-Co- as before or by the group R4-A-CH- (when the aldehyde is used ascyclising agent). When A is -CH2-, the intermediates are stable and can, if desired, be isolated prior to ring-closure to the benzoxazole.
In the case where the cyclising agent is R -A-CHO, the ring closure , 15 can be carried out in t~e presence of an oxidising agent such as lead tetra-acetate or n1ckel peroxide.
In the case where'A in the end-product of formula I is -CO- or -CHOR-where R is C2 7 acyl, the desired compound may be obtained from the corresponding compound, prepared as described above, in which A is -CHOH-by oxidation, for example using manganese dioxide or chromium trioxide, or by conventional acylation respectively.
In the case where A in the end-product of formula I is -NH- the intermediate of formula III can be ring-closed with an isocyanate of formula R CNO to yield directly the compound of formula I. Alternatively, the intermediate of formula III can be cyclised to a benzox'azolyl-2-thione, for example by using an alkali metal alkyl xanthate such as potassium ethyl xanthate as the cyclising agent, and the thione can then be converted to the corresponding 2-halo compound, for example 2-chlorobenzoxazole, by halogenation for example with chlorine gas. To obtain the compound'of fonmula I in which A 'is -NR-, the 2-halocompound is then reacted with the appropriate aniline of formula R -NHR. Alternatively, the thione can be reacted directly with the aniline. 1 ~ ' 1038~J93 Those benzoxazole 2-thiones and haLides in which R3 is a nitrile, carboxylic acid or salt, amido, ester or hydroxamic acid group, are novel compounds. Writing the thione group in its thiol form, these compounds can be represented by the formula:
~ ' where Q is SH or halogen.
As will immediately be apparent to those skilled in the art, internediates of formula IV in which Q is a halogen atom, for example iodine, can also be converted to 2-phenyl derivatives using,for example, the well-known Ullmann reaction (see for instance page 1222-The Mèrck Index, VIII the edition published 1968). The reactants and reaction conditions necessary for this reaction will be well known to those skilled in the art, however, for illustrative purposes the following reaction scheme may be considered typical:
~ ~
X CBlB2~3 wherein Xl is hydrogen or halogen, and wherein Q and x2 are also halogen.
' 3Ll , 1(~3~393 1 In carrying out the foregoing reactions, it will be appreciated that, if group Z in the starting material of formula III is capable of reacting with the cyclising agent or other reactants used, the reaction may produce a mixture of products rather than the desired compound of formula I alone. Although the undesired products could be separated from the reaction mixture, it is obviously desirable to use a compound of formula III in which Z is a group which is incapable of reaction with the other reactants. Thus where Z is a group convertible to R , Z is preferably hydrogen or halogen and where Z is one of the groups encompassed by R , it is preferably a nitrile group or an estérified carboxy, salified carboxy or carboxyamide group.
As stated above, when Z is not the group R , completion of the cyclisation step must be followed by conversion of group Z to the des'ired group R . As is well known inthe art, many different types of groups may be ~onverted to the R3 functions in the desired compounds of this invention. However, it is preferred for the purposes of the''present invention ~hat, whére Z is not the group R3, it is hydrogen or halogen.
When Z is hydrogen, the compound resulting from the cyclisation reaction may be halogenated in conventional manner, for examplé using chlorine, sulphur'yIchloride, bromine or N-bromosuccinimide, preferably in the presence of a suitabLe solvent such as carbon tetrachloride to produce the corresponding compound in which Z is halogen. This compound~ or the same compound obtained from the above cyclisation reaction, may then be reacted with an alkali metal cyanide in a suitable diluent or solvent, usually under the influence of heat, to produce a compound of formula I
in which R is CN. - -The latter compound, or the same compound obtained directly from the above cyclisation reaction, 'may then be treated in a number o ways l to achieve its conversion to another compound of formula I. For example, ; 30 the nitrile may be reacted with an appropriate alcohol under acidic 10:1~1393 1 conditions to produce a compound of formula I in which R is an esterified carboxy group. Alternatively, the nitrile can be hydrolysed, for example using sulphuric acid, to produce a compound of formula I in which R i~ a carboxyamide group. Hydrolysis of the nitrile, or the last mentioned .
- carboxyamide, with a strong base or an acid such as concentrated -hydrochloric acid results in the formation of a compound of formula I.
in which R3 is a carboxy group. A resultant compound of formula I in which R is esterified carboxy may be converted to a hydroxamic scid derivative by reaction with hydroxylamine.
A nitrile of formula I may also be converted to a'compound in which R is a group of formula Ia by reaction with ammonium azide, usually under the influence of heat~ Similarly, a resultant'compound of formula ' I in which R3 is carboxy can be converted to a compound i'n which R3 is a ' group of formula Ib by reaction with an appropriate amino alcohol of ' formula H2N-CR R -CH2-OH. . . .
A resultant compound of formula I in which Rl or R2 is.hydrogen ' may be halogenated to produce a~compound in which Rl or R2 is~ha~ogen~
or exsmple a bromine atom may be introdoced by reaction uith N-bromosuccin-imide, and if desired, the resultant halo-compound may be rehalogenated to produce a compound in which R1 and R2 are halogen. A resultant compound in which R is halogen may in turn, be used to prepare a number of other ' compounds of formula I. Thus, by hydrolysis, for example using sodium .
hydroxide, it may be converted to the corresponding compound in which ' . R is hydroxy and the latter may be acylated to yield a compound in which ' R is acyloxy; by reaction with an alkali metal alkoxide such as sodium alkoxide, the corresponding compound in which R is alkoxy, may be obtained; and by reaction ~ith ammonia, an N-alkylamine.or an N,N-dialkylamine, the compound in which R2 is halogen may be converted to the corresponding compound of formula I in which R IB amino, N-alkylsmino or . . ' '.
lQ38393 N,N-dialkylamino. Furthermore, a resultant compound in which R is amino or N-alkylamino may be acylated in conventional manner to produce A
compound of fo'rmula'I in which R is N-acylamino or~N-Acyl-N-alkylamino respectively. ' In addition,'a resultant compound of formula I in which R is a halogen can be converted to the corresponding acid using the well-known Grignard reaction (see for example page 1172 of the Merck Index, VIIIth Edition published 1968 or any'other standard reference text).~ After reaction with Magnesium 'an'd treatment with CO2~ a compound of formula I is formed in which R is''the group - ~OMgX where X is a halogen atom.
This group c~n then be cobverted to a carboxylic scid group-simply by hydrolysis. ' ' '' Accordingly, in a further a~pect of this invention, there is provided a compound of the formula II:
R4~ ~ CH-R3 (II) .
~2 where the group -CH-R3 is in the 5- or 6- position of the benzo-~ H (;~CH ,OCOCH
xazole nucleus, A is -CH2, -CO-, -CH-, -CH-3, -CH- 3, -NH- or -NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methyl-sulphonyl, R2 is hydrogen or methyl, and R3 is the group -CooR5, where R is Cl 4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof, which process .
comprises hydrolysing a compound of formula V:
$~ 14 .
~038~93 R4-A CH-Z (V) where A, R2 and R4 are as defined above and Z represents a nitrile,-ester, carboxylate, amido, hydroxamic acid group or a group of formula: ~ O
OMgX
where X is a halogen atom.
An acid o'f formula I may be salified by treatment with an ' appropriate base such as'an ammonium, alkylammonium, ara'ikylammonium, aluminium, 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~aci-d. 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 formuls I may of:course'be hydrolysed to the cor}esponding 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.
' A resultant compound of formula I in which R and/o~ R2 is hydrogen may be alkylated to produce the correspondin~ compound of formula 1 in which R and/or R is Cl 6 alkyl. The alkylation may be carried out by' interaction of an alkali metal-derivative of the approp~iate benzoxazole -' derivate with nn al~l halide such as, for example, methyl or ethyl iodide.
~' . ' , . ., ~
' ' '',, ' ' ,. ' ' , ~ -14a-, 1 As mentioned above~ the compounds of formula II are especially useful. Such compounds can be prepared by a process which comprises the hyd~olys o _ h-~
where Z represents a nitrile, ester, carboxylate, amido, hydroxamic acid group, or a group of formula: - C where X is a halogen atom.
The compounds of formula III above may be prepared by reducing the corresponding nitro compounds~ which may themselves be readily obtained from known or easily prepared chemicals according to,the following reaction scheme:-' , ' ~ ' L 1 _3 .o; Z~
(~:" ; 1 `' ~ ~;
3 0 D ~ ~
. . l 1 16.
~038393 1 In the above scheme, step (a) is accomplished by diazotization followed by treatment of the resultant diazonium salt with dilute sulphuric acid. Step (b) is carried out by nitration, for example by addition of nitric acid to a solution of the nitrile in glacial acetic acid. Steps (c), (d) and (e) are as described above in connection with the conversion of ~=H-~Z=Halogen-~Z=CN-~Z=R3.
The compounds of formula I above in which R3 is a nitrile group are, as can be seen from the foregoing description, useful as intermediates for conversion to other compounds of formula I.
The other compounds of formula I are useful in that they are pharmacologically active. In particular, they have been shown to have low toxicity and to possess analgesic " antipyretic and/or anti-inflammatory activity.
The foregoing activities have been demonstrated in tests : carried out ill animals usually at doses of from 0.1 to 250 mg/kg.
In the treatment of humans, the dose administered may be, for example, between 0.1 and 25 mg/ikg, 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 association with atleast 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 diiuted by a carrier, or enclosed or encapsulated by a carrier in the orm of a capsule, satchet, 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 u~hich may be used are lactose, dextrose, sucrose, ., . . "" .~__ 1 sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gel~tin, methyl cellulose, polyoxyethylene, sorbitan monolaurate, methyl- or propyl-hydroxybenzoate, ethyi 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.
C, Advantageously the compositions of the,invention are formulated in a dosage unit form containing from 1 to 1000 mg.
(preferably 25 to 500 mgD) 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 O with and/or enclosed by a pharmaceutical carrier, the quantityof active ingredient being such that one or more units are normally required for a single therapeutic administration.
In addition to the active ingredient of formula I, the compositions of the present invention may also contain one or more pharmacologically active ingredients, for example, acetylsalicylic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and l indomethaci . , .
18.
1 The compositions of the present l~l~ention will~ of course be adapted to the particular route of administration. ~hus~ for oral administration, tablets, pills, capsules,~ solutions or suspensions may be usea; for'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. '' ' ' ' lO ' The following examples 'will further illustrate the preparation' of the compounds of formula I-- ' ' Example'l ' ' ' ' ' ' (a) Phenylacetyl chioride (2.'2 ml.) was added to a stirred soiution of ethyl 2-(3-amino-4-hydroxyphenyi')propionate(3.15g.) in anhydrous 5 - pyridine (50 ml.~ an-d the solution was heated at 100 C for two hours.
Excess pyridine'was remo~ed by distillation and the residue heated ' until the temperature-of the distillate immediately above''the~reaction mixture was 200C. 'The resultant dark brown gum was dissolved in ether (75 ml.) and then washed'with water (3 x 50 ml.) The ether 0 solut'ion was extracted with lN s~dium hydroxide (50 ml.)~'washed with ' ~ water (2 x 50'ml.) a~ evaporated to give ethyl 2-(2-benzyl-5-benzoxazolyl) propionate as a light brown mobiie gum~ which was shown to be pure by thin layer chromatography. Similarly the following esters were prepared and characterised:
(b) 'Ethyl 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] acetate -' (c) Ethyl 2-t2-(4-chlorobenzyl)-6-benzoxazolyl] acetate (d) Ethyl 2-r2-(4-chlorobenzyl)-6-benzoxazolyl] propionate ' .
(~) Ethyl 2-[2-benzyl-6-benzoxazolyl] acetate , (f) Ethyl 2-t2-(3,4-dichloTobenzyl)-5-benzoxazolyl] propionate . " ' "'': " ' " " .
. . , .
.
.' ''' , , ~ ~
lQ38393 1 (g) 4-Chlorophenylacetyl chloride (5.5g.) was added aropwise to a solution of ethyl 2-(3-amino-4-hydroxyphenyl)prop'ionate (5.5g ) in pyridine (20m1.). The soiution was heated on 8 steam bath for 2 hours.
Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate immediately above the reaction mixture ' was 230 C~ The resultant dark-brown gum was dissolved in chloroform.
The chloroform solution was washed with 2N-sodium hydroxide, water, 2N-hydrochloric acid and water; The chloroform solution was then stirred with charcoal and anhydrous sodiu~ sulphate, filtered and evaporated to give ethyl 2-~2-(4-chlorobenzyl)-5-benzoxazolyl3 propionate as a brown gUN. ' " .
Example 2 ~-(a) 2N-sodium hydroxide (15 ml.) was-added'to ethyl'2-[2-benzyl-5-benzoxazolyl]'propionate (3.1 g.)''in ethanol'(~0 ml.).'After two''hours at room temperature~ water (50 ml.) was ad~ed and'the volume''reduced to a guarter by evaporation at 40 ~. The resulting cooled solution was extracted with ethe~ (i x Z5 ml.), acidified with co~ce~trated -hydrochloric acid and ag-i;n extracted with ether (3 x 50 mi.)''The ether extracts were washed with water (2 x 25 ml.), dried over sodium sulphate and evaporated. The residue was recrystallised from acetone to yield 2-[2-benzyl-5-bënzoxazoiyl]`propionic acid, m.p 136-8'C.
Similarly the followIng acids were prepared (the structuresiof the acids being confirmed by microanalysis)~ ' '~(b? 2-[2-(4-chlorobeniyV-5-benzoxazolyl]acetic acid '' '~
!5 '(c) 2-t2-(4-chlorobenzyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]propionic acid (e) 2-~2-benzyl-6-benzoxazolyl]acetic acid ' ' -(f) 2-t2-~3,4-dichlorobenzyl)-5-benzoxa-zoly~propionic acid.
' (g) 2N-Sodium hydroxide solution (30 ml.) was'adaed to the ethyl ester 0 ts.8 g.) prepared in Ex'ample l(g) in ethanol (40 mi). After Z hour~
~tirring at room temperature the volume was reduced by evaporation at . . , -- ' ~ .
. ., '-.
~ 1 20 ~
. .
10~393 ~ ~
40 C and the solut'ion diluted with water (120 ml.). It was then extracted with ether (x2~acidified with concentrated hydrochloric acid and then extracted with chloroform (x3). The combined chloroform extracts were washed with water, dried over anhydrous sodium sulphate and evaporated ~
to give an oil. This oil was purified using'prep. tlc plates to give ' 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]propi~nic acid~ m.p. 135-7 C~
which was characterised by 1~ UV and NMR spectroscopy and by micro -analysis which ~ave C 64.417.'H 4.71% N 4.57Z. C17H14 Cl N03 requires C64.66Z H 4.44~ N 4.44Z ' -(h) A mixture of ethyl'2-(3-amino-4-hydroxy-phenyl)-propionate (4 g.),
. . l 1 16.
~038393 1 In the above scheme, step (a) is accomplished by diazotization followed by treatment of the resultant diazonium salt with dilute sulphuric acid. Step (b) is carried out by nitration, for example by addition of nitric acid to a solution of the nitrile in glacial acetic acid. Steps (c), (d) and (e) are as described above in connection with the conversion of ~=H-~Z=Halogen-~Z=CN-~Z=R3.
The compounds of formula I above in which R3 is a nitrile group are, as can be seen from the foregoing description, useful as intermediates for conversion to other compounds of formula I.
The other compounds of formula I are useful in that they are pharmacologically active. In particular, they have been shown to have low toxicity and to possess analgesic " antipyretic and/or anti-inflammatory activity.
The foregoing activities have been demonstrated in tests : carried out ill animals usually at doses of from 0.1 to 250 mg/kg.
In the treatment of humans, the dose administered may be, for example, between 0.1 and 25 mg/ikg, 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 association with atleast 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 diiuted by a carrier, or enclosed or encapsulated by a carrier in the orm of a capsule, satchet, 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 u~hich may be used are lactose, dextrose, sucrose, ., . . "" .~__ 1 sorbitol, mannitol, starch, gum acacia, calcium phosphate, liquid paraffin, cocoa butter, oil of theobroma, alginates, tragacanth, gel~tin, methyl cellulose, polyoxyethylene, sorbitan monolaurate, methyl- or propyl-hydroxybenzoate, ethyi 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.
C, Advantageously the compositions of the,invention are formulated in a dosage unit form containing from 1 to 1000 mg.
(preferably 25 to 500 mgD) 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 O with and/or enclosed by a pharmaceutical carrier, the quantityof active ingredient being such that one or more units are normally required for a single therapeutic administration.
In addition to the active ingredient of formula I, the compositions of the present invention may also contain one or more pharmacologically active ingredients, for example, acetylsalicylic acid and salts thereof, caffeine, codeine phosphate, phenylbutazone, paracetamol, dextropropoxyphene and l indomethaci . , .
18.
1 The compositions of the present l~l~ention will~ of course be adapted to the particular route of administration. ~hus~ for oral administration, tablets, pills, capsules,~ solutions or suspensions may be usea; for'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. '' ' ' ' lO ' The following examples 'will further illustrate the preparation' of the compounds of formula I-- ' ' Example'l ' ' ' ' ' ' (a) Phenylacetyl chioride (2.'2 ml.) was added to a stirred soiution of ethyl 2-(3-amino-4-hydroxyphenyi')propionate(3.15g.) in anhydrous 5 - pyridine (50 ml.~ an-d the solution was heated at 100 C for two hours.
Excess pyridine'was remo~ed by distillation and the residue heated ' until the temperature-of the distillate immediately above''the~reaction mixture was 200C. 'The resultant dark brown gum was dissolved in ether (75 ml.) and then washed'with water (3 x 50 ml.) The ether 0 solut'ion was extracted with lN s~dium hydroxide (50 ml.)~'washed with ' ~ water (2 x 50'ml.) a~ evaporated to give ethyl 2-(2-benzyl-5-benzoxazolyl) propionate as a light brown mobiie gum~ which was shown to be pure by thin layer chromatography. Similarly the following esters were prepared and characterised:
(b) 'Ethyl 2-[2-(4-chlorobenzyl)-5-benzoxazolyl] acetate -' (c) Ethyl 2-t2-(4-chlorobenzyl)-6-benzoxazolyl] acetate (d) Ethyl 2-r2-(4-chlorobenzyl)-6-benzoxazolyl] propionate ' .
(~) Ethyl 2-[2-benzyl-6-benzoxazolyl] acetate , (f) Ethyl 2-t2-(3,4-dichloTobenzyl)-5-benzoxazolyl] propionate . " ' "'': " ' " " .
. . , .
.
.' ''' , , ~ ~
lQ38393 1 (g) 4-Chlorophenylacetyl chloride (5.5g.) was added aropwise to a solution of ethyl 2-(3-amino-4-hydroxyphenyl)prop'ionate (5.5g ) in pyridine (20m1.). The soiution was heated on 8 steam bath for 2 hours.
Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate immediately above the reaction mixture ' was 230 C~ The resultant dark-brown gum was dissolved in chloroform.
The chloroform solution was washed with 2N-sodium hydroxide, water, 2N-hydrochloric acid and water; The chloroform solution was then stirred with charcoal and anhydrous sodiu~ sulphate, filtered and evaporated to give ethyl 2-~2-(4-chlorobenzyl)-5-benzoxazolyl3 propionate as a brown gUN. ' " .
Example 2 ~-(a) 2N-sodium hydroxide (15 ml.) was-added'to ethyl'2-[2-benzyl-5-benzoxazolyl]'propionate (3.1 g.)''in ethanol'(~0 ml.).'After two''hours at room temperature~ water (50 ml.) was ad~ed and'the volume''reduced to a guarter by evaporation at 40 ~. The resulting cooled solution was extracted with ethe~ (i x Z5 ml.), acidified with co~ce~trated -hydrochloric acid and ag-i;n extracted with ether (3 x 50 mi.)''The ether extracts were washed with water (2 x 25 ml.), dried over sodium sulphate and evaporated. The residue was recrystallised from acetone to yield 2-[2-benzyl-5-bënzoxazoiyl]`propionic acid, m.p 136-8'C.
Similarly the followIng acids were prepared (the structuresiof the acids being confirmed by microanalysis)~ ' '~(b? 2-[2-(4-chlorobeniyV-5-benzoxazolyl]acetic acid '' '~
!5 '(c) 2-t2-(4-chlorobenzyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]propionic acid (e) 2-~2-benzyl-6-benzoxazolyl]acetic acid ' ' -(f) 2-t2-~3,4-dichlorobenzyl)-5-benzoxa-zoly~propionic acid.
' (g) 2N-Sodium hydroxide solution (30 ml.) was'adaed to the ethyl ester 0 ts.8 g.) prepared in Ex'ample l(g) in ethanol (40 mi). After Z hour~
~tirring at room temperature the volume was reduced by evaporation at . . , -- ' ~ .
. ., '-.
~ 1 20 ~
. .
10~393 ~ ~
40 C and the solut'ion diluted with water (120 ml.). It was then extracted with ether (x2~acidified with concentrated hydrochloric acid and then extracted with chloroform (x3). The combined chloroform extracts were washed with water, dried over anhydrous sodium sulphate and evaporated ~
to give an oil. This oil was purified using'prep. tlc plates to give ' 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]propi~nic acid~ m.p. 135-7 C~
which was characterised by 1~ UV and NMR spectroscopy and by micro -analysis which ~ave C 64.417.'H 4.71% N 4.57Z. C17H14 Cl N03 requires C64.66Z H 4.44~ N 4.44Z ' -(h) A mixture of ethyl'2-(3-amino-4-hydroxy-phenyl)-propionate (4 g.),
4-fluoro-phenyl-acetic acid (3 g.)~ p-toluene sulphonic acid ~0.1 g.) and xylene (50 ml.) was heated under reflux'for 20 hours and the water -which formed was removed using a Dean and Stark apparatus. The' ' solution was evaporated to dryness and the residue dissolved in;e'ther.
The solution was washed with ZN~sodium hydroxide solution (x2) and water~
'then stirred with charcoai 'and anhydrous sodium sulphate, fil~ered an'd~~~ ' -evaporated to dryness. ~he resldual oil (3.7 g.~ ND 1.5469) was '' dissolved in ethanol (30 ml.) and 2N-sodium hydroxide solution ~30 ml) '' . was added with stirring over 15 minutes. The reaction mixture was' ) stirred for 2~ hours, during which time water (250 ml) was slowly added. ' The solution was extracted with ether (x2'), acidified with concentrated hydro^chloric acid and then extracted with ether (x3). These ethereal extracts were washed with water, dried-over anhydrous sodiu~ sulphate and evaporated to give an oil. This oil was purified using prep. tic i plates to give 2-[2-~ ~;uorobenzyl)-5-benzoxazolyljpropionic acid as a white solid, mpt 91-93 G~ which was characterised by IR, W and NMR
spectroscopy and by microanalysis which gave C 68.40I H 3.86% N4.64~.
C17H14FN03 requires'C6~.~3% N 4.68Z N 4.68Z ; : ~
) ' , -, .' ,,; , .' ." ''~ - ' . . ,, .,, ,. i .' '~''' .
~ ~ ' 21 ' '' ' 1 (i) 2~ 6-Dichloro-phenyl-acetic acid (15.1 g.) was added portionwise with warming to'~thionyl chloride (30 ml.). The solution was heated on a steam bath for half an hour and then allowed to stand at room temperature for'2~ hours. The excess of thionyl chloride was removed by S distillation under reduced pressure and the residue was distilled to ' 'give the acid chloride as a colourless oil, bpt 149-l5ooc/~5 mm.
This oil ~14,8g) was added in small portions to'a solution of ethyl 2-(3-amino-4-hydroxy-phenyl)-propionate (13 g.) in pyridine (30 ml.) The resulting solution was heated on a steam bath for 2 hours. Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate rmmediately above the reaction mixture was 210 C. A~ter 5 minutes the reaction mixture was aliowed to cool and was then dissolved'in'ether. The ethe~eal solution was w'ashed with ' 2N-sodium'hydroxide solution ~ 2) and water~ dried over anhydrous sodium sulphate and evaporated to dryness. The residue was triturated with a small amount of ether to give-a white solid (1.6g? which was removed ' by filtration (the'lr spectrum of the solid suggested that it was uncyc'lised material). The ethereal solution was evaporated to give an oil. ' This'oil (ll'g;) was'dissolved in eth~nbl (40 ml.) and 2N-sodium'hydroxide solution (40 ml.) was added in port;ons'during 13 mindtes. The reaction mixture was stirred at room temperature for 2 hours and was then diluted with water (400 ml.). The solution-was extracted with ether (x2)~ acidified with concentrated hydrochloric'acid and then extrscted with'ether (x3). These last ethereal extracts were wa'shed ' with water~ dried over anhydrous sodium sulphate and evaporsted to give an oil. This oil was ;purified using prep. tlc plates to give 2-[2-~,6-dichlorobenzyl)-5-benzoxazoiyl] propionic acid as a'white~solid~
mpt lZ2-124 C,'which`was 'characterised'by rR, W'and NNR'~spectroscopy ' ' and by microanalys~s which ~aYe C58.58~ B .78Z N3.90~. C17H13C12N03 -requires C58.297. H3.71~ N4.
' 22 ' ' ~ ' 1 (j) The compound 2-[2-(2-chlorobenzyl)-5-benzoxazoly~ propionic acid was prepared in an exactly analogous manner to the procedure adopted in Example 2(h). The product was isolated as a white powder~ m.p.
92-4C.
S Example 3 (a) A mixture of-2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.)~
potassium ethylxanthate (5.3 g.)~ ethanol (30 ml.) and water (5.0 ml.) waS heated under reflux for four hours. The mixture was filtered~
diluted with water (15 ml.)~ acidified with acetic acid and then diluted With more ~ater. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2~3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173-6 C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and di~tilled chlorofonm (200 ml.). After 20 hours~ most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.)~ lN sodium hydroxide (50 ml.`~ and water (3 x 100 ml.) The dried (Na2S04) organic solution was evaporated to yield 2-~2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was-shown to be a single compound by thin layer chromatography. The oil distilled at 128-134 C/0.3 mm.Hg. -A mixture of the 2-chloro compound (6.15 g.) and p-chloroaniline (10.0 g.) was heated at 100 C for 3~ hours. The residue was equilibrated between chloroform (100 ml.) and 2N hydrochloric acid (100 ml.).
The chloroform layer was washed with water (2 X 100 ml.)~ LN sodium hydroxide (100 ml.) and water (3 x 100 ml.). Evaporation of the dried (Na2S04) solution gave 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile as a cream solid which was characterised b~ NMR ; spectroscopy~ .
Similarly~ the followi~g nitriles were prepared;and characterised:-.
.' . . ''' ; ~ ~ 23 10JI~39:~
1 (b) 2-t2-anilino-5-benzoxazolyl]propionitrile (c) 2-[2-(N-methylanilino)-5-benzoxazolyl]propionitrile (d) 2-[2-(N,4-dimethylanilino)-6-benzoxazolyl]acetonitrile (e) 2-[2-(4-chloroanilino)-6-benzoxazolyl]acetonitrile (f) 2-[2-(4-chloroanilino)-5-benzoxa~olyl)acetonitrile ~g) 2-[2-(N-methyl-3,4-dichloroanilino)-5-benzoxazolyl]propionitrile (h) 2-[2-(N-acetyl-4-chloroanilino)-5-benzoxazolyl]propionitrile (i) 2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionitrile (~) A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.)~ potassium ethylxanthate (6.33 g.)~ ethanol (3B ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate~ and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2S04) organic solution was evsporated to yield ethyl 2-(2-chloro-
The solution was washed with ZN~sodium hydroxide solution (x2) and water~
'then stirred with charcoai 'and anhydrous sodium sulphate, fil~ered an'd~~~ ' -evaporated to dryness. ~he resldual oil (3.7 g.~ ND 1.5469) was '' dissolved in ethanol (30 ml.) and 2N-sodium hydroxide solution ~30 ml) '' . was added with stirring over 15 minutes. The reaction mixture was' ) stirred for 2~ hours, during which time water (250 ml) was slowly added. ' The solution was extracted with ether (x2'), acidified with concentrated hydro^chloric acid and then extracted with ether (x3). These ethereal extracts were washed with water, dried-over anhydrous sodiu~ sulphate and evaporated to give an oil. This oil was purified using prep. tic i plates to give 2-[2-~ ~;uorobenzyl)-5-benzoxazolyljpropionic acid as a white solid, mpt 91-93 G~ which was characterised by IR, W and NMR
spectroscopy and by microanalysis which gave C 68.40I H 3.86% N4.64~.
C17H14FN03 requires'C6~.~3% N 4.68Z N 4.68Z ; : ~
) ' , -, .' ,,; , .' ." ''~ - ' . . ,, .,, ,. i .' '~''' .
~ ~ ' 21 ' '' ' 1 (i) 2~ 6-Dichloro-phenyl-acetic acid (15.1 g.) was added portionwise with warming to'~thionyl chloride (30 ml.). The solution was heated on a steam bath for half an hour and then allowed to stand at room temperature for'2~ hours. The excess of thionyl chloride was removed by S distillation under reduced pressure and the residue was distilled to ' 'give the acid chloride as a colourless oil, bpt 149-l5ooc/~5 mm.
This oil ~14,8g) was added in small portions to'a solution of ethyl 2-(3-amino-4-hydroxy-phenyl)-propionate (13 g.) in pyridine (30 ml.) The resulting solution was heated on a steam bath for 2 hours. Excess pyridine was removed by distillation and the residue heated until the temperature of the distillate rmmediately above the reaction mixture was 210 C. A~ter 5 minutes the reaction mixture was aliowed to cool and was then dissolved'in'ether. The ethe~eal solution was w'ashed with ' 2N-sodium'hydroxide solution ~ 2) and water~ dried over anhydrous sodium sulphate and evaporated to dryness. The residue was triturated with a small amount of ether to give-a white solid (1.6g? which was removed ' by filtration (the'lr spectrum of the solid suggested that it was uncyc'lised material). The ethereal solution was evaporated to give an oil. ' This'oil (ll'g;) was'dissolved in eth~nbl (40 ml.) and 2N-sodium'hydroxide solution (40 ml.) was added in port;ons'during 13 mindtes. The reaction mixture was stirred at room temperature for 2 hours and was then diluted with water (400 ml.). The solution-was extracted with ether (x2)~ acidified with concentrated hydrochloric'acid and then extrscted with'ether (x3). These last ethereal extracts were wa'shed ' with water~ dried over anhydrous sodium sulphate and evaporsted to give an oil. This oil was ;purified using prep. tlc plates to give 2-[2-~,6-dichlorobenzyl)-5-benzoxazoiyl] propionic acid as a'white~solid~
mpt lZ2-124 C,'which`was 'characterised'by rR, W'and NNR'~spectroscopy ' ' and by microanalys~s which ~aYe C58.58~ B .78Z N3.90~. C17H13C12N03 -requires C58.297. H3.71~ N4.
' 22 ' ' ~ ' 1 (j) The compound 2-[2-(2-chlorobenzyl)-5-benzoxazoly~ propionic acid was prepared in an exactly analogous manner to the procedure adopted in Example 2(h). The product was isolated as a white powder~ m.p.
92-4C.
S Example 3 (a) A mixture of-2-(3-amino-4-hydroxyphenyl)propionitrile (4.86 g.)~
potassium ethylxanthate (5.3 g.)~ ethanol (30 ml.) and water (5.0 ml.) waS heated under reflux for four hours. The mixture was filtered~
diluted with water (15 ml.)~ acidified with acetic acid and then diluted With more ~ater. The resulting brown precipitate was filtered off and recrystallised from aqueous ethanol to give 2-(2-thioxo-2~3-dihydrobenzoxazol-5-yl) propionitrile, m.p. 173-6 C. Dry chlorine was passed into a suspension of the thione (8.0 g.) in freshly dried and di~tilled chlorofonm (200 ml.). After 20 hours~ most of the solid had dissolved and the mixture was filtered. The filtrate was washed with water (100 ml.)~ lN sodium hydroxide (50 ml.`~ and water (3 x 100 ml.) The dried (Na2S04) organic solution was evaporated to yield 2-~2-chloro-5-benzoxazolyl]propionitrile as a brown oil which was-shown to be a single compound by thin layer chromatography. The oil distilled at 128-134 C/0.3 mm.Hg. -A mixture of the 2-chloro compound (6.15 g.) and p-chloroaniline (10.0 g.) was heated at 100 C for 3~ hours. The residue was equilibrated between chloroform (100 ml.) and 2N hydrochloric acid (100 ml.).
The chloroform layer was washed with water (2 X 100 ml.)~ LN sodium hydroxide (100 ml.) and water (3 x 100 ml.). Evaporation of the dried (Na2S04) solution gave 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile as a cream solid which was characterised b~ NMR ; spectroscopy~ .
Similarly~ the followi~g nitriles were prepared;and characterised:-.
.' . . ''' ; ~ ~ 23 10JI~39:~
1 (b) 2-t2-anilino-5-benzoxazolyl]propionitrile (c) 2-[2-(N-methylanilino)-5-benzoxazolyl]propionitrile (d) 2-[2-(N,4-dimethylanilino)-6-benzoxazolyl]acetonitrile (e) 2-[2-(4-chloroanilino)-6-benzoxazolyl]acetonitrile (f) 2-[2-(4-chloroanilino)-5-benzoxa~olyl)acetonitrile ~g) 2-[2-(N-methyl-3,4-dichloroanilino)-5-benzoxazolyl]propionitrile (h) 2-[2-(N-acetyl-4-chloroanilino)-5-benzoxazolyl]propionitrile (i) 2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionitrile (~) A stirred mixture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate (8.4 g.)~ potassium ethylxanthate (6.33 g.)~ ethanol (3B ml.) and water (6.5 ml.) was heated under reflux for 4 hours. The solution was evaporated to half volume and diluted with water (65 ml.). The mixture was acidified with 2N-hydrochloric acid and extracted several times with ether. The ethereal solution was washed with water, then dried with anhydrous sodium sulphate~ and evaporated to give ethyl 2-(2-thioxo-2,3-dihydrobenzoxazol-5-yl)propionate as an oil. Dry chlorine was passed into a solution of the thione (9 g.) in freshly dried and distilled chloroform (150 ml.) with stirring for 4 hours. The solution was then washed with water, N-sodium hydroxide solution, then water (3x). The dried (Na2S04) organic solution was evsporated to yield ethyl 2-(2-chloro-
5-benzoxazolyl)propionate as a brown oil which was shown to be a single compound by thin layer chromatography.
(k) A mixture of the 2-chloro compound (12.5 g.) of Example 3(3) and p-chloroaniline (25 g.) was heated on a steam bath for one hour. The reaction mixture was dissolved in chloroform and the solution was washed w1th 2N hydrochloric acid (2x), water, 2N sodium hydroxide solution (2x) and water (3x). The chloroform solution was stirred with charcoal and anhydrous sodium sulphate~ then filtere~ and evaporated. The residue was purified using prep t.l.c. plates to give ethyl-2-[2-(4:chloroanilino) -5-benaoxazolyl]propionate, mpt 135-7 ~ which was characterlsed by IR, UV and ~R spectroscopy and by micro analysis which gave C62.45~H5.11~ N7,97Z
C18~ 302 requires c62.70q. H4.93~ NB.13 "~ ~ l 24 1~38393 1 Example 4 (a) 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile (2.7S g.) and~
concentrated hydrochloric acid (20 ml.) were heated together under reflux for 2~ hours. The cooled mixture was neutralised to pH5 with 5N sodium hydroxide and the resultant solid filtered off, washed with a small amount of ice-water and dried. The solid was partitioned between 0.1 N
~odium hydroxide and chlorofonm. The aqueous layer was washed several times with chlorofonm~ adjusted to pH3 and the product extracted with chloroform. The chloroform extract was then washed with water, dried over sodium sulphate and evaporated to yield 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionic acid, which was shown to be pUTe by thin layer chromatography (m.p. 206-8 C.).
Similarly the following acids were prepared:-(b) 2-[2-anilino-5-benzoxazolyl]propionic acid (c) 2-[2-(N-methylanilino)-5-benzoxazolyl)propionic acid (d) 2-[2-(N,4-dimethylanilino)-6-benzoxazolyl]acetic acid (e) 2-[2-(4-chloroanilino)-6-benzoxazolyl]acetic acid (f) 2-[2-(4-chloroanilino)-5-benzoxazolyl~acetic acid (g) 2-[2-(N-methyl-3,4-dichloroanilino)-5-benzoxazolyl]propionic acid (h) 2-[2-(N-acetyl-4-chloroanilino)-5-benzoxazolyl]propionic acid (i) 2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionic acid. Production of the acids was confirmed by thin-layer chromatography.
(~) ~ stirred mixture of ethyl 2-[2-(4-chloroanilino) 5-benzoxazolyl]
propionate (2.9g.), dry lithium iodide (lOg.), sodium cyanide (0.4g.) and methyl ethyl ~etone (35 ml.) was heated under reflux for 18 hours. The solution was diluted with water and made aLkaline with sodium bicarbonate.
The solution was washed several times with chloroform, filtered through a 'Supercel' pad and acidified with concentrated hydrochloric acid. The solid obtained was filtered off, washed with water and recrystallised from ~0 aqueous methanol to give 2-t2-(4-chloroanilino)-5-benz~xazolyl]propionic acid as a buff powder, mpt 206-8 C, which was characterised by rR, W and . ., ' . ' '.
Il ``1038;~93 ~ ~
1 N~ spectroscopy and by micro snalysis which gave:
C60.457. H4.317. N8.757...... C16H13ClN203 requires ~ C60.667 H4.117.
N 8.85~
Example 5 (a) A mixture of e'thyl 2-(3-amino-4-hydroxyphenyl)propionate (1.2 g.), mandelic acid (l g.) and xylene (50 ml.) was heated using a Dean and Stark apparatus. After 24 hours, the solution was evaporated to dryness and the residue was taken up in chlorofonm. This solution was washed first with sodium hydroxide solution, and then with hydrochloric acid and finally dried over sodium carbonate. The solution was evaporated to dryness to give ethyl 2-[2-(~-hydroxybenzyl)-5-benzoxazolyl3propionate, the structure of which was confirmed by n.m.r. spectroscopy.
Similarly the following esters were prepared and characterised:
(b) ethyl 2-~2-(a-methoxybenzyl)-5-benzoxazolyl]propionate.
'i5 (c) ethyl 2-[2-(a-hydroxy-3~4-dichlorobenzyl)-6-benzoxazolyl] acetate (d) ethyl 2-[2-(-hydroxy-4-chlorobenzyl)-6-benzoxazolyl]propionate.
~e) ethyl 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetate ~f) A mlxture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate ~10 g.), 4-chloromandelic acid (9.33 g.) and xylene (150 ml.) was heated under reflux for 22 hours and the water which formed was removed using a Dean and Stark apparatus. The solution was evaporated to dryness and the residue dissolved iD ether. The solution was washed with NaOH~ HCl and water, then stirred with charcoal and anhydrous'sodium sulphate, filtered and evaporated to dryness. The residual oil (15 g.) was dissolved in a small amount of chloroform and chromatographed on a silica gel column u~ing chloroform as eluting sol~ent; the first fractions containing a carbonyl compound being discarded. The'crude product obtained was purified using silica prep. tlc plates t'o gi~e ethyl 2-[2-(a-h~drOxy-4-chlorobenzyl) -5-benzoxazolyl~propionate as h gum~ ND 1.5681. The structure was confirmed by ~R, W and ~MR spectroscopy and by ~icroanalys~s which gave C62.54%) H5.20Z~ N3.79% , ClgH18ClN04 requires C63.4%, H5.01~, N3-89%-.
~ 6 103839;~
1 Example 6 (a) A mixture of 3-amino-4-hydroxyhydratroponitrile (10 g.), mandelic acid (14 g.) and xylene (300 ml.) was heated using a Dean and Stark .
apparatus for 24 hours. The solution was filtered, evaporated to dryness and the residue dissolved in chloroform. The solution was washed with acid and base, dried over sodiu~ carbonate and was eluted down a silica gel column with ether to give 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]
propionitrile, the structure of which was confirmed by n.m.r. spectroscopy.
Similarly the following nitriles were prepared and characterised:-(b) 2-[2-(a-methoxybenzyl)-5-benzoxazolyl]propionitrile.
(c) 2-[2-(-hydroxy-4-chlorobenzyl)-5-benzoxazolyl~propionitrile.
(d) 2-[2-(a-hydroxy-3,4-dichlorobenzyl)-6-benzoxazolyl]acetonitrile.
(e) 2-[2-(a-hydroxy-4-chlorobenzyl)-6-benzoxazolyl]propionitrile.
. (f) 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetonitrile.
Example 7 by hydrolysis of the esters of Example 5 using the method of Example 2 or by hydrolysis-of-the nitriles of Example 6 using the method of Example 4~ the following acids were obtained:-(a) 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]propionic acid (b) 2-[2-(a-methoxybenzyl)-5-benzoxazolyl3propionic acid (c) 2-[2-(a-hydroxy-3,4-dichlorobenzyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl~propionic acid.
(e) 2-[2-(-hyd~Qxy-4-chlorobenzyl)-6-benzoxazolyl3propionic acid (~j 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetic acid.
Microanalysis carried out on the aboYe acids was in full accord with the expected structures.
Example 8 . (a) A solution of ethyl 2-[2-(a-hydroxy-4-chlorobenzyl-5-benzoxazolyl]
propiona~e (5 g.) in g~acial acetlc acid ~25 ml.) was slowly added to a ' ;' 103t~93 1 sti}red solution of chromium trioxide (1.4 g.) in glacial acetic acid (75 ml). The temperature of the reaction mixture was slowly raised to 115 C. and maintained at this temperature for 30 minutes. The solution was evaporated to a small bulk and the residue diluted with water and extracted with chlorofonm. The chloroform solution was dried over anhydrous sodium sulphate and evaporated to give ~n oil which was partially purified using prep tlc plates. The oil thus obtained was triturated with 40-600 ml. petroleum ether to give ethyl 2-r2-(4-chlorobenzoyl)-s-b propionate as a white solid, m.p. 66-7 C. The structure was confirmed by 1~ W and NMR spectroscopy and by microanalysis which gave C64.01~
H4.64% N4.11~,- ClgH16ClN04 requires C63.78% H4.48~ N3.92Z
Similarly, on oxidation of the a-hydroxybenzyl compounds of Example 7, the following other benzoyl compounds were obtained:-(b) 2-[2-benzoyl-5-benzoxazolyl]propionic acid (c) 2-[2-(3,4-dichlorobenzoyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(~-chlorobenzoyl)-5-benzoxazolyl]propionic acid (e) 2-[2-(4-chlorobenzoyl)-6-beDzoxazolyl]propionic acid (f) 2-[2-benzoyl-5-benzoxazolyl3acetic acid (g) The benzoyl compounds of Examples 8(b~ to (f) were also prepared from the a-hydroxybenzyl compounds of Example 7 using manganese dioxide as the oxidising agent. The compounds oE Examples (b) to (g) were characterised by thin layer chromatography.
Example 9 On acylation of the -hydroxybenzyl compounds of Example 7 using acetyl chloride, the acylation being carried out in the presence of sodium bicarbonate and in toluene as solvent, the following a-acetoxybenzyl compounds were obtained:-(a) 2-[2-(-acetoxybenzyl)-5-benzoxazolyl]propionic acid (b) 2-t2-(a-acetoxy-3,4-dichlorobenzyl)-6-benzoxazolyl] acetic acid (c) 2-~2-(a-acetoxy-4-chlorobenzyl)-5-benzoxazolyl] propionic acid.
. .~' ,.............................. .
.~ .:
~ 28 1 ~d) 2-[2-(a-acetoxy-4-chlorobenzyl)-6-benzoxazolyl] propionic acid (e) 2-[2-(a-acetoxybenzyl)-5-benzoxazolyl] acetic acid.
Microanalysis for the above compounds was in accord with their `
expected structures.
Example 10 (a) Phenylacetyl chloride (28.0 g.) was added over 20 minutes to a cooled stirred solution of 2-(3-amino-4-hyd~oxyphenyl) propionitrile (29,0 g.) in anhydrous pyridine (200 ml.) at 0~3 C. After addition was complete, the mixture was heated at 100 C. for 1 hour. After evaporation under reduced pressure, 2-(3-phenylacetamido-4-hydroxyphenyl)propionitrile was isolated as an oil.
This oil was isolated and then boiled for 30 minutes, during which time the temperature of the vapour above the oil rose to 200 C. On cooling the residue solidified. Recrystallisation of the solid fro~ methanol yielded 2-(2-benzyl-5-benzoxazolyl)propionitrile which was shown to be pure by thin layer chromatography.
Similarly the following nitr$1es were prepared and characterised:-(b) 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]propionitrile (c) 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]acetonitrile (d) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]acetonitrile (e) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl~propionitrile (f) 2-[2-benzyl-6-~enzoxazolyl]acetonitrile (g) 2-[2-(3,4-dichlorobenzyl)-5-benzoxazolyl]propionitrile (h) 2-[2-(4-fluorobenzyl)-5-benzoxazolyl]propionitrile Example 11 Example l(a) was repeated with the exception that:
(a) phenylacetic acid.
(b) phenylacetic anhydride, (c) phenylacetamide, and (d) phenylacetylhydràzide were used instead ~f the phenylacetyl chloride as the cyclising agent.
.
``'.~`'J. .
~ ~9 L
~ . . _ ~ ~ .~_~ . . ~ .. _~. ~
1 In each case, ethyl 2-(2-benzyl-5-benzoxazolyl) propionate was shown to have been formed by thin layer chromatography.
Example 12 (a) 4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g.) in xylene (35 ml,) at room temperature. When the addition was complete p-toluene-sulphonlc acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness.
The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl]
propionitrile as a creme solid which was characterised by n.m.r. spectroscopy (b) Similarly, there was prepared:
2 [2-anilino-5-benzoxazolyl]propionitrile In the following Examples of pharmaceutical compositions of the present invention, the term "medicament" is used to indicate the compound 2-(2-benzyl-5-benzoxazolyl) propionic 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 on the degree of activity of the medicament used.
Example 13 Tablets each containing 100 mg. of medicament are made as follows:-Medicament 100 mg Potato starch 38 mg Lactose 25 mg Ethyl cellulose (as 20Z solution in industrial alcohol) 2 mg Alginic acid 7 mg Magnesium stearate 1 mg Talc 2 mg Total175 mg :~038393 l The medicament, starch and lactose are passed through 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 50-60 C. 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 tablets each weighing 175 mg.
Example 14 _ . , 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.
Injection solutions e~ch containing 100 mg. of 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.
. .' ~0;~839;~
Example 16 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. , -
(k) A mixture of the 2-chloro compound (12.5 g.) of Example 3(3) and p-chloroaniline (25 g.) was heated on a steam bath for one hour. The reaction mixture was dissolved in chloroform and the solution was washed w1th 2N hydrochloric acid (2x), water, 2N sodium hydroxide solution (2x) and water (3x). The chloroform solution was stirred with charcoal and anhydrous sodium sulphate~ then filtere~ and evaporated. The residue was purified using prep t.l.c. plates to give ethyl-2-[2-(4:chloroanilino) -5-benaoxazolyl]propionate, mpt 135-7 ~ which was characterlsed by IR, UV and ~R spectroscopy and by micro analysis which gave C62.45~H5.11~ N7,97Z
C18~ 302 requires c62.70q. H4.93~ NB.13 "~ ~ l 24 1~38393 1 Example 4 (a) 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionitrile (2.7S g.) and~
concentrated hydrochloric acid (20 ml.) were heated together under reflux for 2~ hours. The cooled mixture was neutralised to pH5 with 5N sodium hydroxide and the resultant solid filtered off, washed with a small amount of ice-water and dried. The solid was partitioned between 0.1 N
~odium hydroxide and chlorofonm. The aqueous layer was washed several times with chlorofonm~ adjusted to pH3 and the product extracted with chloroform. The chloroform extract was then washed with water, dried over sodium sulphate and evaporated to yield 2-[2-(4-chloroanilino)-5-benzoxazolyl]propionic acid, which was shown to be pUTe by thin layer chromatography (m.p. 206-8 C.).
Similarly the following acids were prepared:-(b) 2-[2-anilino-5-benzoxazolyl]propionic acid (c) 2-[2-(N-methylanilino)-5-benzoxazolyl)propionic acid (d) 2-[2-(N,4-dimethylanilino)-6-benzoxazolyl]acetic acid (e) 2-[2-(4-chloroanilino)-6-benzoxazolyl]acetic acid (f) 2-[2-(4-chloroanilino)-5-benzoxazolyl~acetic acid (g) 2-[2-(N-methyl-3,4-dichloroanilino)-5-benzoxazolyl]propionic acid (h) 2-[2-(N-acetyl-4-chloroanilino)-5-benzoxazolyl]propionic acid (i) 2-[2-(4-methoxyanilino)-6-benzoxazolyl]propionic acid. Production of the acids was confirmed by thin-layer chromatography.
(~) ~ stirred mixture of ethyl 2-[2-(4-chloroanilino) 5-benzoxazolyl]
propionate (2.9g.), dry lithium iodide (lOg.), sodium cyanide (0.4g.) and methyl ethyl ~etone (35 ml.) was heated under reflux for 18 hours. The solution was diluted with water and made aLkaline with sodium bicarbonate.
The solution was washed several times with chloroform, filtered through a 'Supercel' pad and acidified with concentrated hydrochloric acid. The solid obtained was filtered off, washed with water and recrystallised from ~0 aqueous methanol to give 2-t2-(4-chloroanilino)-5-benz~xazolyl]propionic acid as a buff powder, mpt 206-8 C, which was characterised by rR, W and . ., ' . ' '.
Il ``1038;~93 ~ ~
1 N~ spectroscopy and by micro snalysis which gave:
C60.457. H4.317. N8.757...... C16H13ClN203 requires ~ C60.667 H4.117.
N 8.85~
Example 5 (a) A mixture of e'thyl 2-(3-amino-4-hydroxyphenyl)propionate (1.2 g.), mandelic acid (l g.) and xylene (50 ml.) was heated using a Dean and Stark apparatus. After 24 hours, the solution was evaporated to dryness and the residue was taken up in chlorofonm. This solution was washed first with sodium hydroxide solution, and then with hydrochloric acid and finally dried over sodium carbonate. The solution was evaporated to dryness to give ethyl 2-[2-(~-hydroxybenzyl)-5-benzoxazolyl3propionate, the structure of which was confirmed by n.m.r. spectroscopy.
Similarly the following esters were prepared and characterised:
(b) ethyl 2-~2-(a-methoxybenzyl)-5-benzoxazolyl]propionate.
'i5 (c) ethyl 2-[2-(a-hydroxy-3~4-dichlorobenzyl)-6-benzoxazolyl] acetate (d) ethyl 2-[2-(-hydroxy-4-chlorobenzyl)-6-benzoxazolyl]propionate.
~e) ethyl 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetate ~f) A mlxture of ethyl 2-(3-amino-4-hydroxyphenyl)propionate ~10 g.), 4-chloromandelic acid (9.33 g.) and xylene (150 ml.) was heated under reflux for 22 hours and the water which formed was removed using a Dean and Stark apparatus. The solution was evaporated to dryness and the residue dissolved iD ether. The solution was washed with NaOH~ HCl and water, then stirred with charcoal and anhydrous'sodium sulphate, filtered and evaporated to dryness. The residual oil (15 g.) was dissolved in a small amount of chloroform and chromatographed on a silica gel column u~ing chloroform as eluting sol~ent; the first fractions containing a carbonyl compound being discarded. The'crude product obtained was purified using silica prep. tlc plates t'o gi~e ethyl 2-[2-(a-h~drOxy-4-chlorobenzyl) -5-benzoxazolyl~propionate as h gum~ ND 1.5681. The structure was confirmed by ~R, W and ~MR spectroscopy and by ~icroanalys~s which gave C62.54%) H5.20Z~ N3.79% , ClgH18ClN04 requires C63.4%, H5.01~, N3-89%-.
~ 6 103839;~
1 Example 6 (a) A mixture of 3-amino-4-hydroxyhydratroponitrile (10 g.), mandelic acid (14 g.) and xylene (300 ml.) was heated using a Dean and Stark .
apparatus for 24 hours. The solution was filtered, evaporated to dryness and the residue dissolved in chloroform. The solution was washed with acid and base, dried over sodiu~ carbonate and was eluted down a silica gel column with ether to give 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]
propionitrile, the structure of which was confirmed by n.m.r. spectroscopy.
Similarly the following nitriles were prepared and characterised:-(b) 2-[2-(a-methoxybenzyl)-5-benzoxazolyl]propionitrile.
(c) 2-[2-(-hydroxy-4-chlorobenzyl)-5-benzoxazolyl~propionitrile.
(d) 2-[2-(a-hydroxy-3,4-dichlorobenzyl)-6-benzoxazolyl]acetonitrile.
(e) 2-[2-(a-hydroxy-4-chlorobenzyl)-6-benzoxazolyl]propionitrile.
. (f) 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetonitrile.
Example 7 by hydrolysis of the esters of Example 5 using the method of Example 2 or by hydrolysis-of-the nitriles of Example 6 using the method of Example 4~ the following acids were obtained:-(a) 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]propionic acid (b) 2-[2-(a-methoxybenzyl)-5-benzoxazolyl3propionic acid (c) 2-[2-(a-hydroxy-3,4-dichlorobenzyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(a-hydroxy-4-chlorobenzyl)-5-benzoxazolyl~propionic acid.
(e) 2-[2-(-hyd~Qxy-4-chlorobenzyl)-6-benzoxazolyl3propionic acid (~j 2-[2-(a-hydroxybenzyl)-5-benzoxazolyl]acetic acid.
Microanalysis carried out on the aboYe acids was in full accord with the expected structures.
Example 8 . (a) A solution of ethyl 2-[2-(a-hydroxy-4-chlorobenzyl-5-benzoxazolyl]
propiona~e (5 g.) in g~acial acetlc acid ~25 ml.) was slowly added to a ' ;' 103t~93 1 sti}red solution of chromium trioxide (1.4 g.) in glacial acetic acid (75 ml). The temperature of the reaction mixture was slowly raised to 115 C. and maintained at this temperature for 30 minutes. The solution was evaporated to a small bulk and the residue diluted with water and extracted with chlorofonm. The chloroform solution was dried over anhydrous sodium sulphate and evaporated to give ~n oil which was partially purified using prep tlc plates. The oil thus obtained was triturated with 40-600 ml. petroleum ether to give ethyl 2-r2-(4-chlorobenzoyl)-s-b propionate as a white solid, m.p. 66-7 C. The structure was confirmed by 1~ W and NMR spectroscopy and by microanalysis which gave C64.01~
H4.64% N4.11~,- ClgH16ClN04 requires C63.78% H4.48~ N3.92Z
Similarly, on oxidation of the a-hydroxybenzyl compounds of Example 7, the following other benzoyl compounds were obtained:-(b) 2-[2-benzoyl-5-benzoxazolyl]propionic acid (c) 2-[2-(3,4-dichlorobenzoyl)-6-benzoxazolyl]acetic acid (d) 2-[2-(~-chlorobenzoyl)-5-benzoxazolyl]propionic acid (e) 2-[2-(4-chlorobenzoyl)-6-beDzoxazolyl]propionic acid (f) 2-[2-benzoyl-5-benzoxazolyl3acetic acid (g) The benzoyl compounds of Examples 8(b~ to (f) were also prepared from the a-hydroxybenzyl compounds of Example 7 using manganese dioxide as the oxidising agent. The compounds oE Examples (b) to (g) were characterised by thin layer chromatography.
Example 9 On acylation of the -hydroxybenzyl compounds of Example 7 using acetyl chloride, the acylation being carried out in the presence of sodium bicarbonate and in toluene as solvent, the following a-acetoxybenzyl compounds were obtained:-(a) 2-[2-(-acetoxybenzyl)-5-benzoxazolyl]propionic acid (b) 2-t2-(a-acetoxy-3,4-dichlorobenzyl)-6-benzoxazolyl] acetic acid (c) 2-~2-(a-acetoxy-4-chlorobenzyl)-5-benzoxazolyl] propionic acid.
. .~' ,.............................. .
.~ .:
~ 28 1 ~d) 2-[2-(a-acetoxy-4-chlorobenzyl)-6-benzoxazolyl] propionic acid (e) 2-[2-(a-acetoxybenzyl)-5-benzoxazolyl] acetic acid.
Microanalysis for the above compounds was in accord with their `
expected structures.
Example 10 (a) Phenylacetyl chloride (28.0 g.) was added over 20 minutes to a cooled stirred solution of 2-(3-amino-4-hyd~oxyphenyl) propionitrile (29,0 g.) in anhydrous pyridine (200 ml.) at 0~3 C. After addition was complete, the mixture was heated at 100 C. for 1 hour. After evaporation under reduced pressure, 2-(3-phenylacetamido-4-hydroxyphenyl)propionitrile was isolated as an oil.
This oil was isolated and then boiled for 30 minutes, during which time the temperature of the vapour above the oil rose to 200 C. On cooling the residue solidified. Recrystallisation of the solid fro~ methanol yielded 2-(2-benzyl-5-benzoxazolyl)propionitrile which was shown to be pure by thin layer chromatography.
Similarly the following nitr$1es were prepared and characterised:-(b) 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]propionitrile (c) 2-[2-(4-chlorobenzyl)-5-benzoxazolyl]acetonitrile (d) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl]acetonitrile (e) 2-[2-(4-chlorobenzyl)-6-benzoxazolyl~propionitrile (f) 2-[2-benzyl-6-~enzoxazolyl]acetonitrile (g) 2-[2-(3,4-dichlorobenzyl)-5-benzoxazolyl]propionitrile (h) 2-[2-(4-fluorobenzyl)-5-benzoxazolyl]propionitrile Example 11 Example l(a) was repeated with the exception that:
(a) phenylacetic acid.
(b) phenylacetic anhydride, (c) phenylacetamide, and (d) phenylacetylhydràzide were used instead ~f the phenylacetyl chloride as the cyclising agent.
.
``'.~`'J. .
~ ~9 L
~ . . _ ~ ~ .~_~ . . ~ .. _~. ~
1 In each case, ethyl 2-(2-benzyl-5-benzoxazolyl) propionate was shown to have been formed by thin layer chromatography.
Example 12 (a) 4-chlorophenylisocyanate (3.1 g.) was slowly added to a stirred solution of 2-(3-amino-4-hydroxyphenyl propionitrile (3.3 g.) in xylene (35 ml,) at room temperature. When the addition was complete p-toluene-sulphonlc acid (250 mg.) was added, and the solution was heated under reflux using a Dean and Stark apparatus. On cooling, the solution was washed with aqueous sodium bicarbonate solution and evaporated to dryness.
The residue was recrystallised to give 2-[2-(4-chloroanilino)-5-benzoxazolyl]
propionitrile as a creme solid which was characterised by n.m.r. spectroscopy (b) Similarly, there was prepared:
2 [2-anilino-5-benzoxazolyl]propionitrile In the following Examples of pharmaceutical compositions of the present invention, the term "medicament" is used to indicate the compound 2-(2-benzyl-5-benzoxazolyl) propionic 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 on the degree of activity of the medicament used.
Example 13 Tablets each containing 100 mg. of medicament are made as follows:-Medicament 100 mg Potato starch 38 mg Lactose 25 mg Ethyl cellulose (as 20Z solution in industrial alcohol) 2 mg Alginic acid 7 mg Magnesium stearate 1 mg Talc 2 mg Total175 mg :~038393 l The medicament, starch and lactose are passed through 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 50-60 C. 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 tablets each weighing 175 mg.
Example 14 _ . , 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.
Injection solutions e~ch containing 100 mg. of 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.
. .' ~0;~839;~
Example 16 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 compound of formula II:
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , , , -NH-or-NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methyl-sulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof, which process comprises hydrolysing a compound of formula V:
(V) where A, R2 and R4 are as defined above and Z represents a nitrile, ester, carboxylate, amido, hydroxamic acid group or a group of formula:
where X is a halogen atom.
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , , , -NH-or-NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methyl-sulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof, which process comprises hydrolysing a compound of formula V:
(V) where A, R2 and R4 are as defined above and Z represents a nitrile, ester, carboxylate, amido, hydroxamic acid group or a group of formula:
where X is a halogen atom.
2. A process according to claim 1 wherein A is -CH2-, -CO-, , or .
3. A process according to claim 1 wherein A is -CH2-.
4. A process according to claim 1, 2, or 3, wherein R2 is methyl.
5. A process according to claim 1 or 2 wherein A
is -CH2-, and R2 is methyl.
is -CH2-, and R2 is methyl.
6. A process according to claim 1, or 2 wherein A
is -CH2-, R2 is methyl, R3 is the group -COOH and R4 is selected from phenyl and 4-chlorophenyl.
is -CH2-, R2 is methyl, R3 is the group -COOH and R4 is selected from phenyl and 4-chlorophenyl.
7. A compound of formula II:
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , , , -NH- or -NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methylsulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , , , -NH- or -NCH3-, R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methylsulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4 alkyl, or the group -COOH or an alkali or alkaline earth metal, aluminium or ammonium salt thereof whenever prepared by the process of Claim 1 or by an obvious chemical equivalent thereof.
8. A compound of formula II:
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , or , R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methylsulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4, alkyl or the group -COOH or an alkali or alkaline earth metal, aluminum or ammonium salt thereof whenever prepared by the process of Claim 2 or by an obvious chemical equivalent thereof.
(II) where the group is in the 5- or 6- position of the benzo-xazole nucleus, A is -CH2-, -CO-, , or , R4 is selected from the group consisting of a phenyl group and phenyl groups substituted by one or two groups selected from halogen, trifluoromethyl, methyl, methoxy, acetyl and methylsulphonyl, R2 is hydrogen or methyl, and R3 is the group -COOR5, where R5 is C1-4, alkyl or the group -COOH or an alkali or alkaline earth metal, aluminum or ammonium salt thereof whenever prepared by the process of Claim 2 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB49260/73A GB1491863A (en) | 1973-10-23 | 1973-10-23 | 2,5-or 2,6-disubstituted benzoxazoles |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1038393A true CA1038393A (en) | 1978-09-12 |
Family
ID=10451725
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA212,029A Expired CA1038393A (en) | 1973-10-23 | 1974-10-22 | 2,5 or 2,6 disubstituted benzoxazoles |
Country Status (22)
| Country | Link |
|---|---|
| JP (1) | JPS5070362A (en) |
| AR (2) | AR207232A1 (en) |
| AT (1) | AT341519B (en) |
| BE (1) | BE821350A (en) |
| BG (1) | BG26197A3 (en) |
| CA (1) | CA1038393A (en) |
| CH (1) | CH605863A5 (en) |
| CS (1) | CS188927B2 (en) |
| DD (1) | DD114609A5 (en) |
| DE (1) | DE2450042A1 (en) |
| DK (1) | DK552774A (en) |
| FR (1) | FR2248039B1 (en) |
| GB (1) | GB1491863A (en) |
| HU (1) | HU170452B (en) |
| IE (1) | IE40080B1 (en) |
| IL (1) | IL45837A (en) |
| NL (1) | NL7413788A (en) |
| PL (1) | PL94057B1 (en) |
| RO (1) | RO72841A (en) |
| SE (1) | SE7413352L (en) |
| SU (1) | SU577992A3 (en) |
| ZA (1) | ZA746341B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206255A (en) * | 1989-09-29 | 1993-04-27 | Mitsubishi Kasei Corporation | Heterocyclic compound |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1435721A (en) * | 1972-05-18 | 1976-05-12 | Lilly Industries Ltd | Benzoxazole derivatives |
| US3888864A (en) | 1973-06-29 | 1975-06-10 | Hoffmann La Roche | Amino lower alkyl ether derivatives of opium alkaloids |
| IT1099589B (en) * | 1978-08-04 | 1985-09-18 | Ravizza Spa | PROCESS FOR THE PREPARATION OF PROPIONIC BENZOXAZOLYL ACID DERIVATIVES |
| IT1157295B (en) * | 1982-07-19 | 1987-02-11 | Ravizza Spa | PROCESS PERFECTED FOR THE PREPARATION OF DERIVATIVES OF BENZOXAZOLYL PROPIONIC ACID |
| DE102006021878A1 (en) * | 2006-05-11 | 2007-11-15 | Sanofi-Aventis | Phenylamino-benzoxazole substituted carboxylic acids, process for their preparation and their use as medicaments |
-
1973
- 1973-10-23 GB GB49260/73A patent/GB1491863A/en not_active Expired
-
1974
- 1974-01-01 AR AR256198A patent/AR207232A1/en active
- 1974-10-04 ZA ZA00746341A patent/ZA746341B/en unknown
- 1974-10-11 IL IL45837A patent/IL45837A/en unknown
- 1974-10-16 CS CS747094A patent/CS188927B2/en unknown
- 1974-10-21 BG BG028005A patent/BG26197A3/en unknown
- 1974-10-22 RO RO7480290A patent/RO72841A/en unknown
- 1974-10-22 DE DE19742450042 patent/DE2450042A1/en not_active Withdrawn
- 1974-10-22 DK DK552774A patent/DK552774A/da unknown
- 1974-10-22 NL NL7413788A patent/NL7413788A/en not_active Application Discontinuation
- 1974-10-22 FR FR7435407A patent/FR2248039B1/fr not_active Expired
- 1974-10-22 SU SU7402074061A patent/SU577992A3/en active
- 1974-10-22 AT AT849374A patent/AT341519B/en not_active IP Right Cessation
- 1974-10-22 CA CA212,029A patent/CA1038393A/en not_active Expired
- 1974-10-22 HU HULI265A patent/HU170452B/hu unknown
- 1974-10-22 CH CH1414374A patent/CH605863A5/xx not_active IP Right Cessation
- 1974-10-22 IE IE2168/74A patent/IE40080B1/en unknown
- 1974-10-22 BE BE6044793A patent/BE821350A/en unknown
- 1974-10-23 DD DD181873A patent/DD114609A5/xx unknown
- 1974-10-23 PL PL1974175042A patent/PL94057B1/pl unknown
- 1974-10-23 JP JP49122355A patent/JPS5070362A/ja active Pending
- 1974-10-23 SE SE7413352A patent/SE7413352L/xx unknown
-
1975
- 1975-01-01 AR AR259897A patent/AR207369A1/en active
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206255A (en) * | 1989-09-29 | 1993-04-27 | Mitsubishi Kasei Corporation | Heterocyclic compound |
Also Published As
| Publication number | Publication date |
|---|---|
| RO72841A (en) | 1982-05-10 |
| IL45837A (en) | 1978-03-10 |
| HU170452B (en) | 1977-06-28 |
| AR207369A1 (en) | 1976-09-30 |
| PL94057B1 (en) | 1977-07-30 |
| JPS5070362A (en) | 1975-06-11 |
| DE2450042A1 (en) | 1975-04-24 |
| ZA746341B (en) | 1976-06-30 |
| SU577992A3 (en) | 1977-10-25 |
| BG26197A3 (en) | 1979-02-15 |
| IL45837A0 (en) | 1974-12-31 |
| AR207232A1 (en) | 1976-09-22 |
| DD114609A5 (en) | 1975-08-12 |
| NL7413788A (en) | 1975-04-25 |
| CH605863A5 (en) | 1978-10-13 |
| BE821350A (en) | 1975-04-22 |
| AT341519B (en) | 1978-02-10 |
| FR2248039A1 (en) | 1975-05-16 |
| SE7413352L (en) | 1975-04-24 |
| FR2248039B1 (en) | 1978-07-28 |
| DK552774A (en) | 1975-06-16 |
| GB1491863A (en) | 1977-11-16 |
| IE40080L (en) | 1975-04-23 |
| ATA849374A (en) | 1977-06-15 |
| AU7454674A (en) | 1976-04-29 |
| IE40080B1 (en) | 1979-03-14 |
| CS188927B2 (en) | 1979-03-30 |
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