CA1064933A - Benzoic acids, their derivatives and process for preparing them - Google Patents
Benzoic acids, their derivatives and process for preparing themInfo
- Publication number
- CA1064933A CA1064933A CA242,877A CA242877A CA1064933A CA 1064933 A CA1064933 A CA 1064933A CA 242877 A CA242877 A CA 242877A CA 1064933 A CA1064933 A CA 1064933A
- Authority
- CA
- Canada
- Prior art keywords
- benzoic acid
- chloro
- ethyl
- methoxy
- benzamido
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
- C07D213/82—Amides; Imides in position 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
- C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
- C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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 to ring carbon atoms
- C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
- C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
- C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
- C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom 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 to ring carbon atoms
- C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
Abstract
ABSTRACT OF THE DISCLOSURE
Acyl-aminoalkyl-benzoic acid and derivates thereof show a blood sugar lowering effect upon oral administration and can be used as orally applicable hypoglycemiants. These compounds have the formula
Acyl-aminoalkyl-benzoic acid and derivates thereof show a blood sugar lowering effect upon oral administration and can be used as orally applicable hypoglycemiants. These compounds have the formula
Description
1()6~33 The present invention provides substituted benzoic acids, their salts and esters. The compounds are distinguished by a blood sugar lowering action.
It is known that sulfonamide derivatives such as sulfonyl-ureas, sulfon~l-semicarbazides, sulfonamido-pyrimidines and some other sulfonamide heterocycles as well as sulfonyl-urethanes show a blood sugar lowering action in a not pre-treated test animal. Some of these compounds are also used in human therapy for the treatment of diabetes mellitus. It has been found that, ; surprisingly, substituted benzoic acids, theix salts and esters also provoke a lowering of the blood sugar level.
' Accordingly, the present invention relates to benzoic acids and their derivatives having blood sugar lowering action, in particular to compounds of the general formula I
, X_CO_N~_Y ~ W
~: : : Z
, in which W represents a carboxyl group or a salt or es~er thereo~
X represents an aromatic or heteroaromatic ring system, Y represents a single chemical bond or a hydrocarbon bridge, and Z represents hydrogen or one or several other substituents.
It is known that sulfonamide derivatives such as sulfonyl-ureas, sulfon~l-semicarbazides, sulfonamido-pyrimidines and some other sulfonamide heterocycles as well as sulfonyl-urethanes show a blood sugar lowering action in a not pre-treated test animal. Some of these compounds are also used in human therapy for the treatment of diabetes mellitus. It has been found that, ; surprisingly, substituted benzoic acids, theix salts and esters also provoke a lowering of the blood sugar level.
' Accordingly, the present invention relates to benzoic acids and their derivatives having blood sugar lowering action, in particular to compounds of the general formula I
, X_CO_N~_Y ~ W
~: : : Z
, in which W represents a carboxyl group or a salt or es~er thereo~
X represents an aromatic or heteroaromatic ring system, Y represents a single chemical bond or a hydrocarbon bridge, and Z represents hydrogen or one or several other substituents.
- 2 -., , ' ' .
,: ~' For the formation of salts of the carboxyl group that may be used as substituent W, there are suitable in the first instance the alkali metals and ammonium. However, other metals may also be used, for example alkaline earth metals. But, in view of the pharmaceutical use of the products, the use of the metals is limited to those which are physiologically tolerated.
For a possible esterification of the carboxyl group, on principle all alcohols may be used. The lower monohydric alco-hols such as methanol, e~hanol or propanol, and polyhydric alco-hols, for example glycol, or alcohols with other functional groups such as ethanolamine or glycol ethers are preferred.
As the substituent X in the above formula, there may be used in the first instance mono-nuclear aromatic or heteroaroma-tic ring systems, in particular the unsubstituted or singly or several times substituted phenyl radica}, the pyridine radical or the thiophene radical. In the same manner, there are also suitable poly-nuclear aromatic or heteroaromatic ring systems, among them also those which are partially hydrogenated, for example naphthalene, benzo~urane, dihydrobenzo~urane, chromane, chromene or homochromane, quinoline, benzthiophene.
As the member Y in the above ~ormula, there may be used, besides a single chemical bond, in particular lower hydrocarbon chains. These may be straight or branched and also substituted or interrupted by a heteroatom.
. . .
~64933 The member Z is in the first instance hydrogen, but a substitution of the central phenyl nucleus by one or several substituents is not excluded.
In the tests for the activity o the compounds of the in-vention, especially those of the general formula II showed out-standing properties.
T' X'-CO-NH-Y' ~ W' II
Z' In the above formula:
T' represents hydrogen or halogen, preferably chlorine or bromine, W' represents a carboxyl group, an ester or a salt thereof, R
a) ~ R
wherein R is:
- hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms;
- alkyloxy;
- methoxyethoxy;
- phenoxy;
- halogen;
- amino;
-alkylamino wherein the alkyl group contains 1 to 4 carbon atoms anilino; and - trifluoromethyl; and wherein Rl and R2 are - hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms; and - halogen; R
b) ~ 3 ~ o ~
wherein R3 is hydrogen and R4 is:
- hydrogen; and - halogen, wherein R5 is halogen;
d) ~ R
wherein R6 and R7 are:
; - alkoxy containing 1 to 4 carbon atoms; and - halogen; and R
e) 9 ~ OR or ~ O
wherein R8 is alkyl containing 1 to 4 carbon ~atams and R9 is halogen;
~ ' represents a single chemical bond or a hydrocarbon radical of 1 to 3 carbon atoms, and Z' represents hydrogen, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms.
' ~;7 i~
.. . .
Lg33 Alkyl or alkenyl and the alkyl portions in alkoxy, alken-oxy, alkoxy-alkoxy and alkylamino in the sense of the above definitions are straight chain or branched hydrocarbon radicals having not too large a number o carbon atoms. It has been found that the members which contain up to 6 carbon atoms showed the best activity. Halogen in the above sense is the first instance chlorine and bromine, but it may also be fluorine, especially if X' is a phenyl radical. The corresponding iodine compounds are, in general, also active, but their use is less advisable.
As the bridging member Y, the hydrocarbon bridges with 2 carbon atoms, which themselves may be substituted, also by alkyl groups, are preferably used. Accordingly, the group -CH2-CH~- and the group -CH(CH3)-CH2- are particularly preferred.
Less preferred are the other straight chain or branched hydrocarbon bridges containing up to 3 carbon atoms.
The present invention ~urthermore relates to a process for preparing the above-specified compounds of the invention, which process comprises a~ reacting an amino compound of the general formula 2 ~ W
Z ' or it~ formvl compound with a reactive derivative o~ the acid X'COOM, and optionally splitting off the formyl radical;
b) in a compound of the general formula X' - CONH - Y' ~ ~ - V
Z' : - `
~Q~ 33 in which v represents a radical which is convertible into a carboxyl group, converting said radical into a carboxyl group, c) replacing the sulfur atom by an oxygen atom in compounds of the general formula X'-C-NH-Y' ~ - W' " ~
S z' d) hydrolyzing compounds of the general formula X'-C=N-Y' ~ - W' Z ' in which U represents low molecular alkoxy, low molecular alkylthio or halogen, or e) alkylating in compounds of the general formula X'-CO-NH-Y' ~ - W;
OH
the hydroxy group or a hydroxy group present in the radical X', or f) rearranging a nitrone of the formula T' X' - CH = N - Y' - ~ - COOH
' ~0 Z' to an acid amide;
and optionally converting the compound obtained into a free benzoic acid or an ester or salt thereof.
The amino compounds serving as starting materials for method a) are known and may be prepared without difficulty according to methods known for analogous compounds.
, - 7 -106~933 These amino compounds are reacted, preferably in the pre-sence of bases, with reacti~e derivatives of the acid X'-COOH, for example with its halides, anhydrides, mixed anhydrides, azides or esters.
The starting substances for the method b) may be obtained by acylating an amine of the general formula H2N- Y, ~ V
with radical X'CO or acylating, for example a compound of the general formula X'CO - NH - Y' Z ' Depending on the nature of the group V, they may be converted by suitable reactions into the compounds of the invention. Such suitable reactions may be, for example a hydrolysis if the sub-stituent V is an amide, a nitrile, an acid halide or a keto-acid, or a hydrazlde. Oxydative conversion is used, for example if V
represents an alcohol-, aldehyde- or acyl-grouping. If V is halogen, it can be trans~ormed into a carboxyl group by a Grignard reaction.
The starting substances for method c) may be obtained, for example by reacting an amino compound of the formula H2N - yl ~ COOH
or its ester or salt with a reactive derivative of a thiocarboxy-lic acid X'CSOH. These thioamides may be desulfurized according to methods used for similar compounds, in particular those of the sulfonyl-urea series, the treatment with hydrogen peroxide or sodium peroxide having proved to be especially suitable.
The starting substances for method d) may be obtained, for example by methylating the thioamides mentioned under c), pre-ferably their esters, with diazomethane. They are hydrolyzed in an acid or alkaline medium, the alkaline hydrolysis being pre-ferred.
Etherification of the hydroxyl groups according to method e) is effected according to known methods, for example by the reaction with dialkyl sulfate or alkyl- or araklyl-halide.
Compounds o~ the general formula II in which X' represents a phenyl group which is substituted by an amino group can be obtained from the corresponding nitro-compounds by reduction.
The compounds of the invention have a blood-sugar lowering actiVity. This activity can be stated by feedlng the compounds as such, their salts or e.sters, in doses of 10 to 400 mg, pre-~rably about 100 mg/kg, to normally fed rabbits and determining the blood sugar level over a prolonged period o~ time according to the known method of Hagedorn-Jensen or with the aid of an autoanalyzer~
The compounds of the invention shall be used preferably for the preparation of orally administrable compositions having blood _ 9 _ a33 sugar lowering action for the treatment of diabetes mellitus and may be administered as such or, optionally, in the ~orm o-f their salts or esters, or in the presence o~ substances which provoke . ., , ~ ~
salt formation. For the salt formation, for example al~aline sub-stances such as alkali metal or alkaline earth metal ~ydroxides, carbonates or bicarbonates may be used.
As medicinal compositions, there are preferably used tablets which contain, in addition to the products of the invention, the usual carriers, excipients and adjuvants such as talc, starch, lactose, tragacanth or magnesium stearate.
A composition containing the compounds of the invention as active substance, for example a tablet or a powder, with or with-out additions is suitably brought into an appropriate dosage unit form. As the dose, such a dose is chosen which is adapted to the activity or potency o~ the active substance us~ and to the e~ect desired. Suitable, the dose per dosage unit is about 0.1 to 2 g, pre~erably 0.5 to 1 g, but higher or smaller dosage units may also be used which, i~ desired or required, are di-vided or multiplied before administration.
The benzoic acid derivatives o~ the invention may be used ~or the treatment o~ diabetes mellitus either alone or in com-bination with o~her oral antidiabetics. ~s such, there may used not only the blood sugar lowering sul~onyl-ur~as, but also com-pound~ o~ di~erent chemical structure, ~or example biguanides, in particular the phenylethyl-biguanide or the dimethyl-bi-guanide.
The ~ollowing ~xamples describe some o~ the numerous methods which may be used ~or the synthesis o~ the compounds oi the inventlon.
_ 10 --EXAh~LE 1:
4-(2-<3-Chloro-benzamido>-ethyl)-benzoic acid . . . _ _ . _ . .
50 ml o~ a l-molar solution of 4-(2-aminoethyl)-benzoic acid-sodium, which contained, in addition, 0 05 mole of sodium acetate and which had been prepared by saponification o~ 4-(2-acetylaminoethyl)-benzoic acid with sodium hydroxide solution, was.combined with 50 ml of acetone and then with the solution o~
9 g of 3-chlorobenzoyl chloride in a small amount of acetone.
The whole was stirred for about 1 hour, water and hydrochloric acid were added, filtered off with suction and the product was recrystallized from a mixture of water and isopropanol. The 4_~2-<3-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 200 to 202 C.
In analogous manner, there wore obtained:
4-(2-~4-chloro-benzamido~-ethyl)-benzoic acid; M.p. 242 - 24~ C
(~rom dilute ethanol), 4-(2-benzamido-ethyl)-benzoic acid, M.p.217 - 219 C (from di-lute methanol), 4-(2 C2-methoxy-benzamido>-ethyl)-benzoic acid, M.p. 153 - 155 C
(from dilute methanol), 4~ <3-methoxy-benzamido>-ethyl)-benzoic acid, M.p. 170 - 172 C
(~rom dilute methanol), 4-(2~<3-methyl-benzamido~-ethyl)-benzoic acid, M.p. 17~ - 181 C
(~rom dilute methanol), 4-(2-<2-n-butoxy-benzamido>-ethyl)-benoic acid, ~.p. 164 - 165 C
(~rom ethanol~., 4~(2-<a~n-pentyloxy-benzamido>-ethyl-benzoic acid, M.p. 130 -131 C (from ethanol), 4-(2-<2-anilino-benzamido>-ethyl)-benzoic acid, M.p. 165 - 167 C
rom dilute methanol), - 11 _ 4-(2-<2-methoxy-5-methyl-benzamido>-ethyl)-benzoic acid, Mop~
148 - 153 C (from dilute isopropanol), 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid, M.p.
170 - 172 C (from dilute methanol), 4-(2-<5-chloro-2-n-propyloxy-benzamido>-ethyl)-benzoic acid, M.p. 156 - 157 C (irom ethyl acetate), 4-(2-~2-n-butyloxy-5-chloro-benzamido>-ethyl)-benzoic acid, M.p.
166 C (from ethanol), 4-(2-<5-chloro-2-n-pentyloxy-benzamido>-ethyl)-benzoic acid, M.p. 170 - 171 C (from ethanol), 4-(2-<5-chloro-2-n-octyloxy-benzamido~-ethyl)-benzoic acid, M.p. 156 - 158 C (from ethanol), 4-(2-<2-allyloxy-5-chloro-benzamido>-ethyl)-benzoic acid, M.p, 149 - 151 C (~rom ethanol), 4-(2-<5-chloro-2-methoxyethoxy-benzamido>-ethyl)-benzoic acid, M.p. 144~ C (from ethanol), 4-(2-<5-chloro-2-phenoxy-benzamido>-ethyl)-benzoic acid, M.p.
172 - i73 C (~rom methanol), 4-(2 <3-chloro-2-methoxy~enzamido>-ethyl)-benzoic acid, M.p.
145 C (~rom ethanol), : ~ 4-(2-<4-chloro-2-methoxy-benzamido>~ethyl)-benæoic acid, ~.p, 184 _ 186 C (~rom ethanol), 4-(2-<3,5-dichloro-benzamido~-ethyl)-benæolc acld, M.p. 2~0 -262~ C (~rom dilu~e meth~nol), 4-(1-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid, M.p.
- 212 - 214 C ~rom dilute metharlol), 4-(2-<5-chloro-2-methoxy-benzamido~-propyl)-benzoic acid, M.p.
153 - 154 C (irom ethanol), ... .
~64~33 4- (2-~2~ethoxy~5-chloro~benzamido>-propyl)-benzoic acid, M.p.
180 - 182 C (~rom dilute methanol), 4- (2-~5-bromo-2-methoxy-benzamido>-ethyl)-benzoic acid, ~q.p.
169 - 172 C (Irom isopropanol), 4- (2-<3,5-dichloro_2-methoxy-benzarnido>~ethyl)-benzoic acid, M.p. 173 - 175 C (irom ethanol), 4- (2-<6-chloroquinoline-8-carboxamido>-ethyl)-benzoic acid, M.p. 206 - 208 C (from dilute ethanol), 4- (2-<6-chloro-chromane-8-carboxamido>-ethyl)-benzoic acid, M.p. 181 - 183 C (from dilute methanol), 4- ~2-<5-chloro-2-methyl-benzo[b]~urane-7-carboxamido>-ethyl~-benzoic acid, M.p. 214 - 216 C (from dilute methanol), 4- (2-~5-chloro-3-methoxy thiophene-2-carboxamido>-ethyl)-benzoic acid, M~p. 186 - 187 C (~rom dilute ethanol), 4- (2-<5-chloro-3-methoxy-thiophene-2-carboxamido>-propyl)-benzoic acid, M.p. 165 C (~rom dilute methanol), 4- (2-<2-octyloxy-benzamido>_ethyl)_benzoic acid, M.p. 113 C
(:Irom ethanol), 4-(3-chloro-benzamidomethyl)-benzoic acid, M.p. 210 - 2l2o C
(~rom dilute methanol), 4-(5-chloro-2-methoxy-benzamidomethyl)-benzoic acid, M.p. 208 210 C (from dilute methanol), 4-~5-bromo-2-methoxy-benzamidomethyl)-benzoic acid, M.p. 217 -219 C (i'rom dilute methanol), ~- (2-ethoxy-5_chloro-benzamido)-3-methyl-benzoic acid, M.p. 230 C
(i'rom ethanol), 4- (2-ethoxy-5-chloro-benzamido)-2-methyl-benzoic acid, M.p. 237 C
(lrom ethanol), 4-(2-ethoxy-5-chloro-benzamldo)-2-methoxy-ben~o~c acid, M.p.
220 - 221 C (from ethanol-DMF), -- 13 ~
4- (6-chloro-chromane-8-carboxamido)-2-methoxy-benzoic acid, M.p. 227 C tfrom ethanol-DMF~, 4- (5-chloro-2-methoxy-benzamido)--2-propoxy-benzoic acid, M.p.
179~ C (from ethanol), 4- (2- <5-chloro-2-methoxy-benzamido>-ethyl)-3-chloro-benzoic acid, M.p. 185 - 187 C (from ethanol),
,: ~' For the formation of salts of the carboxyl group that may be used as substituent W, there are suitable in the first instance the alkali metals and ammonium. However, other metals may also be used, for example alkaline earth metals. But, in view of the pharmaceutical use of the products, the use of the metals is limited to those which are physiologically tolerated.
For a possible esterification of the carboxyl group, on principle all alcohols may be used. The lower monohydric alco-hols such as methanol, e~hanol or propanol, and polyhydric alco-hols, for example glycol, or alcohols with other functional groups such as ethanolamine or glycol ethers are preferred.
As the substituent X in the above formula, there may be used in the first instance mono-nuclear aromatic or heteroaroma-tic ring systems, in particular the unsubstituted or singly or several times substituted phenyl radica}, the pyridine radical or the thiophene radical. In the same manner, there are also suitable poly-nuclear aromatic or heteroaromatic ring systems, among them also those which are partially hydrogenated, for example naphthalene, benzo~urane, dihydrobenzo~urane, chromane, chromene or homochromane, quinoline, benzthiophene.
As the member Y in the above ~ormula, there may be used, besides a single chemical bond, in particular lower hydrocarbon chains. These may be straight or branched and also substituted or interrupted by a heteroatom.
. . .
~64933 The member Z is in the first instance hydrogen, but a substitution of the central phenyl nucleus by one or several substituents is not excluded.
In the tests for the activity o the compounds of the in-vention, especially those of the general formula II showed out-standing properties.
T' X'-CO-NH-Y' ~ W' II
Z' In the above formula:
T' represents hydrogen or halogen, preferably chlorine or bromine, W' represents a carboxyl group, an ester or a salt thereof, R
a) ~ R
wherein R is:
- hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms;
- alkyloxy;
- methoxyethoxy;
- phenoxy;
- halogen;
- amino;
-alkylamino wherein the alkyl group contains 1 to 4 carbon atoms anilino; and - trifluoromethyl; and wherein Rl and R2 are - hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms; and - halogen; R
b) ~ 3 ~ o ~
wherein R3 is hydrogen and R4 is:
- hydrogen; and - halogen, wherein R5 is halogen;
d) ~ R
wherein R6 and R7 are:
; - alkoxy containing 1 to 4 carbon atoms; and - halogen; and R
e) 9 ~ OR or ~ O
wherein R8 is alkyl containing 1 to 4 carbon ~atams and R9 is halogen;
~ ' represents a single chemical bond or a hydrocarbon radical of 1 to 3 carbon atoms, and Z' represents hydrogen, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms.
' ~;7 i~
.. . .
Lg33 Alkyl or alkenyl and the alkyl portions in alkoxy, alken-oxy, alkoxy-alkoxy and alkylamino in the sense of the above definitions are straight chain or branched hydrocarbon radicals having not too large a number o carbon atoms. It has been found that the members which contain up to 6 carbon atoms showed the best activity. Halogen in the above sense is the first instance chlorine and bromine, but it may also be fluorine, especially if X' is a phenyl radical. The corresponding iodine compounds are, in general, also active, but their use is less advisable.
As the bridging member Y, the hydrocarbon bridges with 2 carbon atoms, which themselves may be substituted, also by alkyl groups, are preferably used. Accordingly, the group -CH2-CH~- and the group -CH(CH3)-CH2- are particularly preferred.
Less preferred are the other straight chain or branched hydrocarbon bridges containing up to 3 carbon atoms.
The present invention ~urthermore relates to a process for preparing the above-specified compounds of the invention, which process comprises a~ reacting an amino compound of the general formula 2 ~ W
Z ' or it~ formvl compound with a reactive derivative o~ the acid X'COOM, and optionally splitting off the formyl radical;
b) in a compound of the general formula X' - CONH - Y' ~ ~ - V
Z' : - `
~Q~ 33 in which v represents a radical which is convertible into a carboxyl group, converting said radical into a carboxyl group, c) replacing the sulfur atom by an oxygen atom in compounds of the general formula X'-C-NH-Y' ~ - W' " ~
S z' d) hydrolyzing compounds of the general formula X'-C=N-Y' ~ - W' Z ' in which U represents low molecular alkoxy, low molecular alkylthio or halogen, or e) alkylating in compounds of the general formula X'-CO-NH-Y' ~ - W;
OH
the hydroxy group or a hydroxy group present in the radical X', or f) rearranging a nitrone of the formula T' X' - CH = N - Y' - ~ - COOH
' ~0 Z' to an acid amide;
and optionally converting the compound obtained into a free benzoic acid or an ester or salt thereof.
The amino compounds serving as starting materials for method a) are known and may be prepared without difficulty according to methods known for analogous compounds.
, - 7 -106~933 These amino compounds are reacted, preferably in the pre-sence of bases, with reacti~e derivatives of the acid X'-COOH, for example with its halides, anhydrides, mixed anhydrides, azides or esters.
The starting substances for the method b) may be obtained by acylating an amine of the general formula H2N- Y, ~ V
with radical X'CO or acylating, for example a compound of the general formula X'CO - NH - Y' Z ' Depending on the nature of the group V, they may be converted by suitable reactions into the compounds of the invention. Such suitable reactions may be, for example a hydrolysis if the sub-stituent V is an amide, a nitrile, an acid halide or a keto-acid, or a hydrazlde. Oxydative conversion is used, for example if V
represents an alcohol-, aldehyde- or acyl-grouping. If V is halogen, it can be trans~ormed into a carboxyl group by a Grignard reaction.
The starting substances for method c) may be obtained, for example by reacting an amino compound of the formula H2N - yl ~ COOH
or its ester or salt with a reactive derivative of a thiocarboxy-lic acid X'CSOH. These thioamides may be desulfurized according to methods used for similar compounds, in particular those of the sulfonyl-urea series, the treatment with hydrogen peroxide or sodium peroxide having proved to be especially suitable.
The starting substances for method d) may be obtained, for example by methylating the thioamides mentioned under c), pre-ferably their esters, with diazomethane. They are hydrolyzed in an acid or alkaline medium, the alkaline hydrolysis being pre-ferred.
Etherification of the hydroxyl groups according to method e) is effected according to known methods, for example by the reaction with dialkyl sulfate or alkyl- or araklyl-halide.
Compounds o~ the general formula II in which X' represents a phenyl group which is substituted by an amino group can be obtained from the corresponding nitro-compounds by reduction.
The compounds of the invention have a blood-sugar lowering actiVity. This activity can be stated by feedlng the compounds as such, their salts or e.sters, in doses of 10 to 400 mg, pre-~rably about 100 mg/kg, to normally fed rabbits and determining the blood sugar level over a prolonged period o~ time according to the known method of Hagedorn-Jensen or with the aid of an autoanalyzer~
The compounds of the invention shall be used preferably for the preparation of orally administrable compositions having blood _ 9 _ a33 sugar lowering action for the treatment of diabetes mellitus and may be administered as such or, optionally, in the ~orm o-f their salts or esters, or in the presence o~ substances which provoke . ., , ~ ~
salt formation. For the salt formation, for example al~aline sub-stances such as alkali metal or alkaline earth metal ~ydroxides, carbonates or bicarbonates may be used.
As medicinal compositions, there are preferably used tablets which contain, in addition to the products of the invention, the usual carriers, excipients and adjuvants such as talc, starch, lactose, tragacanth or magnesium stearate.
A composition containing the compounds of the invention as active substance, for example a tablet or a powder, with or with-out additions is suitably brought into an appropriate dosage unit form. As the dose, such a dose is chosen which is adapted to the activity or potency o~ the active substance us~ and to the e~ect desired. Suitable, the dose per dosage unit is about 0.1 to 2 g, pre~erably 0.5 to 1 g, but higher or smaller dosage units may also be used which, i~ desired or required, are di-vided or multiplied before administration.
The benzoic acid derivatives o~ the invention may be used ~or the treatment o~ diabetes mellitus either alone or in com-bination with o~her oral antidiabetics. ~s such, there may used not only the blood sugar lowering sul~onyl-ur~as, but also com-pound~ o~ di~erent chemical structure, ~or example biguanides, in particular the phenylethyl-biguanide or the dimethyl-bi-guanide.
The ~ollowing ~xamples describe some o~ the numerous methods which may be used ~or the synthesis o~ the compounds oi the inventlon.
_ 10 --EXAh~LE 1:
4-(2-<3-Chloro-benzamido>-ethyl)-benzoic acid . . . _ _ . _ . .
50 ml o~ a l-molar solution of 4-(2-aminoethyl)-benzoic acid-sodium, which contained, in addition, 0 05 mole of sodium acetate and which had been prepared by saponification o~ 4-(2-acetylaminoethyl)-benzoic acid with sodium hydroxide solution, was.combined with 50 ml of acetone and then with the solution o~
9 g of 3-chlorobenzoyl chloride in a small amount of acetone.
The whole was stirred for about 1 hour, water and hydrochloric acid were added, filtered off with suction and the product was recrystallized from a mixture of water and isopropanol. The 4_~2-<3-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 200 to 202 C.
In analogous manner, there wore obtained:
4-(2-~4-chloro-benzamido~-ethyl)-benzoic acid; M.p. 242 - 24~ C
(~rom dilute ethanol), 4-(2-benzamido-ethyl)-benzoic acid, M.p.217 - 219 C (from di-lute methanol), 4-(2 C2-methoxy-benzamido>-ethyl)-benzoic acid, M.p. 153 - 155 C
(from dilute methanol), 4~ <3-methoxy-benzamido>-ethyl)-benzoic acid, M.p. 170 - 172 C
(~rom dilute methanol), 4-(2~<3-methyl-benzamido~-ethyl)-benzoic acid, M.p. 17~ - 181 C
(~rom dilute methanol), 4-(2-<2-n-butoxy-benzamido>-ethyl)-benoic acid, ~.p. 164 - 165 C
(~rom ethanol~., 4~(2-<a~n-pentyloxy-benzamido>-ethyl-benzoic acid, M.p. 130 -131 C (from ethanol), 4-(2-<2-anilino-benzamido>-ethyl)-benzoic acid, M.p. 165 - 167 C
rom dilute methanol), - 11 _ 4-(2-<2-methoxy-5-methyl-benzamido>-ethyl)-benzoic acid, Mop~
148 - 153 C (from dilute isopropanol), 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid, M.p.
170 - 172 C (from dilute methanol), 4-(2-<5-chloro-2-n-propyloxy-benzamido>-ethyl)-benzoic acid, M.p. 156 - 157 C (irom ethyl acetate), 4-(2-~2-n-butyloxy-5-chloro-benzamido>-ethyl)-benzoic acid, M.p.
166 C (from ethanol), 4-(2-<5-chloro-2-n-pentyloxy-benzamido>-ethyl)-benzoic acid, M.p. 170 - 171 C (from ethanol), 4-(2-<5-chloro-2-n-octyloxy-benzamido~-ethyl)-benzoic acid, M.p. 156 - 158 C (from ethanol), 4-(2-<2-allyloxy-5-chloro-benzamido>-ethyl)-benzoic acid, M.p, 149 - 151 C (~rom ethanol), 4-(2-<5-chloro-2-methoxyethoxy-benzamido>-ethyl)-benzoic acid, M.p. 144~ C (from ethanol), 4-(2-<5-chloro-2-phenoxy-benzamido>-ethyl)-benzoic acid, M.p.
172 - i73 C (~rom methanol), 4-(2 <3-chloro-2-methoxy~enzamido>-ethyl)-benzoic acid, M.p.
145 C (~rom ethanol), : ~ 4-(2-<4-chloro-2-methoxy-benzamido>~ethyl)-benæoic acid, ~.p, 184 _ 186 C (~rom ethanol), 4-(2-<3,5-dichloro-benzamido~-ethyl)-benæolc acld, M.p. 2~0 -262~ C (~rom dilu~e meth~nol), 4-(1-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid, M.p.
- 212 - 214 C ~rom dilute metharlol), 4-(2-<5-chloro-2-methoxy-benzamido~-propyl)-benzoic acid, M.p.
153 - 154 C (irom ethanol), ... .
~64~33 4- (2-~2~ethoxy~5-chloro~benzamido>-propyl)-benzoic acid, M.p.
180 - 182 C (~rom dilute methanol), 4- (2-~5-bromo-2-methoxy-benzamido>-ethyl)-benzoic acid, ~q.p.
169 - 172 C (Irom isopropanol), 4- (2-<3,5-dichloro_2-methoxy-benzarnido>~ethyl)-benzoic acid, M.p. 173 - 175 C (irom ethanol), 4- (2-<6-chloroquinoline-8-carboxamido>-ethyl)-benzoic acid, M.p. 206 - 208 C (from dilute ethanol), 4- (2-<6-chloro-chromane-8-carboxamido>-ethyl)-benzoic acid, M.p. 181 - 183 C (from dilute methanol), 4- ~2-<5-chloro-2-methyl-benzo[b]~urane-7-carboxamido>-ethyl~-benzoic acid, M.p. 214 - 216 C (from dilute methanol), 4- (2-~5-chloro-3-methoxy thiophene-2-carboxamido>-ethyl)-benzoic acid, M~p. 186 - 187 C (~rom dilute ethanol), 4- (2-<5-chloro-3-methoxy-thiophene-2-carboxamido>-propyl)-benzoic acid, M.p. 165 C (~rom dilute methanol), 4- (2-<2-octyloxy-benzamido>_ethyl)_benzoic acid, M.p. 113 C
(:Irom ethanol), 4-(3-chloro-benzamidomethyl)-benzoic acid, M.p. 210 - 2l2o C
(~rom dilute methanol), 4-(5-chloro-2-methoxy-benzamidomethyl)-benzoic acid, M.p. 208 210 C (from dilute methanol), 4-~5-bromo-2-methoxy-benzamidomethyl)-benzoic acid, M.p. 217 -219 C (i'rom dilute methanol), ~- (2-ethoxy-5_chloro-benzamido)-3-methyl-benzoic acid, M.p. 230 C
(i'rom ethanol), 4- (2-ethoxy-5-chloro-benzamido)-2-methyl-benzoic acid, M.p. 237 C
(lrom ethanol), 4-(2-ethoxy-5-chloro-benzamldo)-2-methoxy-ben~o~c acid, M.p.
220 - 221 C (from ethanol-DMF), -- 13 ~
4- (6-chloro-chromane-8-carboxamido)-2-methoxy-benzoic acid, M.p. 227 C tfrom ethanol-DMF~, 4- (5-chloro-2-methoxy-benzamido)--2-propoxy-benzoic acid, M.p.
179~ C (from ethanol), 4- (2- <5-chloro-2-methoxy-benzamido>-ethyl)-3-chloro-benzoic acid, M.p. 185 - 187 C (from ethanol),
3-ethoxy-4- (2- <5-chloro-2-methoxy-benzamido~-ethyl)-benzoic acid, M.p. 175 C (from ethanol),
4- (2-<5-chloro-2-methoxy-benzamido~ethyl)-3-methoxy-benzoic acid, M.p. 217 - 219 C (from ethanol), 4- (2-~2-butoxy-benzamido~-ethyl)-3-methoxy-benzoic acid, M.p.
115 C (from ethanol), The 4- (2-amino-ethyl)-3-substituted benzoic acids required for the 4 last mentioned substance examples were prepared in the following manner:
4- (2-Acetaminoethyl)-benzoic acid was reacted with nitrating acid to 4- ~2-acetaminoethyl)-3-nitro-benzoic acid, M.p. 189 C
tfrom methanol). The following catalytical hydrogenation yielded the 4- (2-acetaminoethyl)-3-aminoethyl)-3-amino-benzoic acid with a melting point of 143 C ~from ethanol/petroleum ether).
From this compQund, there was obtained by diazotation and Sandmeyer-reaction the 4- (2-acetamino-ethyl)-3-chloro-benzoic acid having a melting point oE 150 C or by boiling up the diazo solution, the 4- (2-acetaminoethyl)-3-chloro-benzoic acid M.p. 222 - 2~3 C. From 4- (2-acetaminoethyl) 3-hydroxy-benzoic acid, there were obtained with dimethyl sulEate or diethyl sul-fatel the corresponding 4- (2-acetaminoethyl)-3-methoxy-benzoic acid methyl ester and the 4- (2-acetaminoethyl)-3-ethoxy-benzoic acid ethyl ester.
, EXAMPLE 2:
4-(2-<6-Chloro-quinoline-8-carboxamido>-ethyl)-benzoic acid -50 ml o~ a l-molar solution of 4-(2-amino-ethyl)-benzoic acid sodium, which additionally contained 0.05 mole of sodium acetate, was combined with 50 ml of acetone. To this solution, there was added dropwise, while stirring and cooling with ice, the mixed anhydride of 6-chloro-quinoline-8-carboxylic acid, prepared from 10.3 g of the acid, 5.6 g o~ triethylamine and
115 C (from ethanol), The 4- (2-amino-ethyl)-3-substituted benzoic acids required for the 4 last mentioned substance examples were prepared in the following manner:
4- (2-Acetaminoethyl)-benzoic acid was reacted with nitrating acid to 4- ~2-acetaminoethyl)-3-nitro-benzoic acid, M.p. 189 C
tfrom methanol). The following catalytical hydrogenation yielded the 4- (2-acetaminoethyl)-3-aminoethyl)-3-amino-benzoic acid with a melting point of 143 C ~from ethanol/petroleum ether).
From this compQund, there was obtained by diazotation and Sandmeyer-reaction the 4- (2-acetamino-ethyl)-3-chloro-benzoic acid having a melting point oE 150 C or by boiling up the diazo solution, the 4- (2-acetaminoethyl)-3-chloro-benzoic acid M.p. 222 - 2~3 C. From 4- (2-acetaminoethyl) 3-hydroxy-benzoic acid, there were obtained with dimethyl sulEate or diethyl sul-fatel the corresponding 4- (2-acetaminoethyl)-3-methoxy-benzoic acid methyl ester and the 4- (2-acetaminoethyl)-3-ethoxy-benzoic acid ethyl ester.
, EXAMPLE 2:
4-(2-<6-Chloro-quinoline-8-carboxamido>-ethyl)-benzoic acid -50 ml o~ a l-molar solution of 4-(2-amino-ethyl)-benzoic acid sodium, which additionally contained 0.05 mole of sodium acetate, was combined with 50 ml of acetone. To this solution, there was added dropwise, while stirring and cooling with ice, the mixed anhydride of 6-chloro-quinoline-8-carboxylic acid, prepared from 10.3 g of the acid, 5.6 g o~ triethylamine and
5.2 g o~ chloro~ormic acid methyl ester in acetone, the whole was stirred for 1 hour without cooling, water was added, the whole was acidified and the product that had separated was iil-tered off with suction. After recrystallization from dilute etha-nol, the 4-(2 ~6-chloro-quinoline-8-carboxamido>-ethyl)-benzoic acid was iound to melt at 20G - 208 C.
, In analogous manner, there were obtained:
the 4-(2-butoxy-4-methyl-ben~amido>~ethyl)-benzoic acld, M~p~
156 - 158 C (~rom dilute methanol), the 4-(1-<2-allyloxy-5-chloro-benzamido>-ethyl)_benzoic acid, M.p. 192 - 194 C (fror~ dilute ethanol), the 4-(2-<2,5-dimethoxy-benzamido>-ethyl)-benzoic acid, M.p.
157 - 159 C (~rom diIute ethanol~.
EXAMPLE 3:
4_(2-<~-Ethoxy-5~chloro-benzam~do>-ethyl)-ben~olc acid 10 g o~ 4-(2-aminoethyl)-ben~oic acid . hydrochloride were dissolved in 60 ml o~ 2N-sodium hydroxide solution and, a~ter addition o~ 75 ml of acetone, a solu-tion of 11 g o~ 2-ethoxy-5-chloro-benzoylchloride in Z0 ml o~ acetone was added dropwise, while stirring. Stirring was continued ~or 2 hours, the mixture .
was diluted with water, filtered and acidii'ied with dilute hydro-chloric acid. A~ter filtration with suction, the product was re-crystallized irom ethanol. The 4-(2-~2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 180 C.
In analogous manner, there was obtained the 4-(5-chloro-2-methoxy-benzami~o3-benzoic acid, M.p. 265 - 266 C
(from ethanol-dioxane).
EXAMPLE 4:
4-(2-<5-Chloro-2-phenoxy-benzamido~-ethyl)-benzoic acid 5.5 g oi' 4-(2-aminoethyl)-benzoic acid were suspended in 50 ml of anhydrous pyridine and comblned portionwise, while stir-ring and cooling, with 8.0 g of 5-chloro-2-phenoxy benzoyl chlo-ride, The whole was heated to 100 C and stirred for 3 hours at this temperature. After coollng, it was concentrated under re-duced pressure, combined with ice-water, filtered wlth suction and the product was recrystallized ~rom methanol, The 4-(2-<5-chloro-2-phe~oxy-benzamido~-ethyl)-benzoic acid was ~ound to melt at 172 - 173 C.
In analogous manner, there was obtained the 4-(5-chloro-2-methoxy-benzamido)-2-chloro-benzoic acid, M.p.
~71 C (from ethanol).
EXAMPL~ 5:
4-(2-~2-Eth ~ -benzamido>-ethyl)-ben~oic acid 8.2 g oP N-ethyl-lsatoic acid anhydride and 7.~ g oi' 4-~2-amlnoethyl)_ben~oic acid were heated for 5 hours, while stir-ring, to 80 - 90 C in 150 ml oi' dimethylformamide. After cooling, the whole was ~iltered and th~ Piltrate wa~ diluted with 300 ml o~ water~ The precipitate tha~ had formed was filtered of~ with suction, The product was dissolved in a solutlon of sodium bi~
~, _ 16 -
, In analogous manner, there were obtained:
the 4-(2-butoxy-4-methyl-ben~amido>~ethyl)-benzoic acld, M~p~
156 - 158 C (~rom dilute methanol), the 4-(1-<2-allyloxy-5-chloro-benzamido>-ethyl)_benzoic acid, M.p. 192 - 194 C (fror~ dilute ethanol), the 4-(2-<2,5-dimethoxy-benzamido>-ethyl)-benzoic acid, M.p.
157 - 159 C (~rom diIute ethanol~.
EXAMPLE 3:
4_(2-<~-Ethoxy-5~chloro-benzam~do>-ethyl)-ben~olc acid 10 g o~ 4-(2-aminoethyl)-ben~oic acid . hydrochloride were dissolved in 60 ml o~ 2N-sodium hydroxide solution and, a~ter addition o~ 75 ml of acetone, a solu-tion of 11 g o~ 2-ethoxy-5-chloro-benzoylchloride in Z0 ml o~ acetone was added dropwise, while stirring. Stirring was continued ~or 2 hours, the mixture .
was diluted with water, filtered and acidii'ied with dilute hydro-chloric acid. A~ter filtration with suction, the product was re-crystallized irom ethanol. The 4-(2-~2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid obtained was found to melt at 180 C.
In analogous manner, there was obtained the 4-(5-chloro-2-methoxy-benzami~o3-benzoic acid, M.p. 265 - 266 C
(from ethanol-dioxane).
EXAMPLE 4:
4-(2-<5-Chloro-2-phenoxy-benzamido~-ethyl)-benzoic acid 5.5 g oi' 4-(2-aminoethyl)-benzoic acid were suspended in 50 ml of anhydrous pyridine and comblned portionwise, while stir-ring and cooling, with 8.0 g of 5-chloro-2-phenoxy benzoyl chlo-ride, The whole was heated to 100 C and stirred for 3 hours at this temperature. After coollng, it was concentrated under re-duced pressure, combined with ice-water, filtered wlth suction and the product was recrystallized ~rom methanol, The 4-(2-<5-chloro-2-phe~oxy-benzamido~-ethyl)-benzoic acid was ~ound to melt at 172 - 173 C.
In analogous manner, there was obtained the 4-(5-chloro-2-methoxy-benzamido)-2-chloro-benzoic acid, M.p.
~71 C (from ethanol).
EXAMPL~ 5:
4-(2-~2-Eth ~ -benzamido>-ethyl)-ben~oic acid 8.2 g oP N-ethyl-lsatoic acid anhydride and 7.~ g oi' 4-~2-amlnoethyl)_ben~oic acid were heated for 5 hours, while stir-ring, to 80 - 90 C in 150 ml oi' dimethylformamide. After cooling, the whole was ~iltered and th~ Piltrate wa~ diluted with 300 ml o~ water~ The precipitate tha~ had formed was filtered of~ with suction, The product was dissolved in a solutlon of sodium bi~
~, _ 16 -
6~3~
carbonate and, a~ter flltration with cbarcoal, precipi~ated again with dilute acetic acid. A~ter ~iltration with suction and recrystallization ~rom ethanol, the 4-(2-~2-ethylamino-benzamido>-ethyl)-benzoic acid was ~ound to melt at 209 - 211 C.
In analogous man~er, there was obtained from N-ethyl-5-chloro-isatoic acid anhydride and 4-(2-aminoethyl)-benzoic acid ethyl ester, the 4-(2-<2-ethylamino-5-chloro-benzamido>-ethyl~-benzoic acid ethyl ester (M.p. 113 - 115 C), which was trans-formed by alkaline hydrolysis into the 4-(2-<2-ethylamino-5-chloro-benzamido>-ethyl)-benzoic acid, M.p, 245 C (~rom ethanol).
EXAMPLE 6:
4-(2-<3-Chloro-2-m~thoxy-benzamido>-ethyl)-benzoic acid methyl ester 5.8 g oi' 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoyl-chloride (prepared ~rom the corresponding carboxylic acid with thionyl chloride, reacted as crude product) were introduced, while stirring and cooling, in 25 ml o~ anhydrous methanol.
A~ter having heated ~or 15 minutes on the steam bath, the mix-ture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with a NaHC03 solution and water, dried, con-centrated again and the residue was crystallized irQm a ~ixture o~ toluene and petroleum ether. The melting point o~ the 4-(2-~5-chloro-2-metho~y-benzamido~-ethyl)-benzoic acid methyl ester was found to be at 108 - 109 C.
In analogous manner, there was obtalned by the reaction with anhydrous e~hanol the 4-(2-~5-chloro-2-methoxy-benzamido>-ethylbenzoic acid ethyl ester, M.p. 74 - 76 C (~rom ethanol).
_ 17 -~`
.
lOG4~a33 EXAMPLE 7:
4-(2-<5-Chloro-2-methoxy-benzamido~-ethyl)-benzoic acid propyl ester ~
10 g of 4-(2-<5-chloro-2-methoxy-benzamido7-ethyl)-benzoic acid were heated for S hours under reflux in 30 ml of n-propanol after additi.on of 3 ml of concentrated sulfuric acid. After cooling the mixture was concentrated under reduced pressure, poured into ice-water, extracted twice with ether, the ether phase was washed with a sodium bicarbonate solution and water, dried, concentrated and the residue was recrystallized from a mixture of ethyl acetate and petroleum ether. The 4-(2-C5-chloro-2-methoxy-benxamido~-ethyl)-benzoic acid-n-propyl ester was found to melt at 67 - 68 CO
In analogous manner, there was obtained with isopropanol: the 4-(2-~5-chloro-2-methoxy-benzamido~
ethyl)-benzoic acid-isopropyl ester, M.p. 66 - 67 C (from a mixture of ethyl acetate and petroleum ether);
with n-butanol: the 4-(2-C5-chloro-2-methoxy-benzamido?-ethyl)-benzoic acid-n-butyl ester, M.p. 58 - 60 C (from a mixture of ethyl acetate and petroleum ether);
from 4-(2-<2-n-butyloxy-benzamido~-ethyl)-benzoic acid with ethanol: the 4-(2-<2-n-butyloxy-benzamido>-ethyl)-benzoic acid ethyl ester, M.p. 55 - 56 C (from ethyl acetate and petroleum ether).
EXAMPLE 8:
4-t2-<2-Ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid meth 1 ester Y _ _ _ . _ 10.5 g of 4-~2-aminoekhyl)-benzoic acid methyl ester-hydro-chloride were suspended in 40 ml of dioxane and 20 ml of acetone and the suspension was combined with 8 ml of pyridine. To this suspension, a solution of 10 g of 2-ethoxy-5-chloro-benzoyl chloride in a small amount of acetone was added dropwise, while ~tirring, and the whole was heated for 2 hours under reflux.
After cooling, the mixture was concentrated under reduced pressure, combined with ice-water, filtered with suction, stirred with dilute hydrochloric acid and with a NaHC03 solution and the re-sulting product was again filtered off with suction and re-crystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid methyl ester obtained was found to melt at In analogous manner, there was obtained the 4-(2-<5-chloro-2-phenoxy-benzamido>-ethyl)-benzoic acid methyl ester, M.p. 79 - 81 C (from petroleum ether); and ~ rom 4-(2-aminoethyl)-benzoic acid . hydrochloride:
the 4-(2-<2-ethoxy~~_chloro_benzamido>_ethyl)-benzoic acid ethyl ester, M.p. 79 - 80 C (from ethanol).
EXAMPLE 9:
4-(2-~5-Chloro-2-methoxy-benzamido>-ethyl)-benzoic acid . . . _ _ 59 g of 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl~-aceto-phenone (M.p. 103 - 105 C, prepared by acetylation of 5-chloro-2-methoxy-N-(2-phenylethyl)-benzamide in dichloroethane with acetyl chlor~de/AlC13) was added dropwise to a solution cooled to 0 C oi' 71 g o~ caustic soda in 380 ml o~ water and which had been combined with 27.4 ml of bromine, and the whole was stirred for 3 hours at room temperature~ Then, 1 liter of water was added, the mixture was filtereA and the filtrate was acidified with di-lute hydrochloric acid. The product that had precipitated was filtered off with suction and recrystallized from dilute methanol.
M.p. 170 - 172 C.
~XAMPLE 10:
4-(2-<2-Etho~y-5-chloro-benzamido>-ethyl)-benzoic acid 3,8 g of 4-(2-~2-ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid ethyl ester, prepared according to Example 8, were heated ~or 2 hours on the steam bath in 10 ml o~ 2N-sodium hydroxide solution and 50 ml of ethanol. After cooling, the mixture was concentrated under reduced pressur~, the residue was dis~olved in water, the solution was filtered and acidified with 2N~hydro-chloric acid, A~ter separation of the precipitate hy filtration, it was recrystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid was found to melt at 180 C.
EXAMPLE 11:
4-(2-<5-Chloro-2-methoxy-benzamido>-ethyl)-2-methoxy-benzoic acid 4 g of 4-(2-aminoethyl)-2-methoxy-benzoic acid (prepared by catalytical hydrogenation o~ 4-cyanomethyl-2-methoxy-benzoic acid in methanol in the prssence o~ ~aney nickel at 50 C, 100 atmo~pheres gauge pressure hydrogen) were combined, as crude pro-duct, with 50 ml o~ acetone and 4 - 5 g oi sodium acetate in a small amount of water. Then, 4.3 g of 5-chloro-2-methoxy-benzoyl chloride in a small amount of acetone was added dropwise, while stirring and cooling with ice, the mixture was stirrefl ~or 1 hour, comblned with wa~er and hydrochloric acid, ~ilt~red with suction~ the product wa9 di~olved and precipitated ~rom dilute ammonia and recrystallized ~rom a mixture o~ wat~r and methanol.
The 4-(2-~5_chloro-2-methoxy-benzamido>-ethyl)_2~methoxy_benzoic acid was ~ound to melt at 159 - 162 C.
_ 20 -i(~6~33 In analo~ous manner, there were obtained:
the 4-(2-~2 butoxy-5-chloro-benzamido>-ethyl~-2~methoxy-benzoic acid, M.p. 100 - 102 C (~rom dilute methanol), ~he 4-(2_<5-bromo-2-methoxy-benzamido>-ethyl)-2-methoxy-benzoic acid, M.p. 147 - 149 C (~rom dilute ethanol), the 4-(2-<5-bromo-2-methoxy-nicotinamido>-ethyl)-2-methoxy-benzoic acid, M~p. 94 - 96 C ~from dilute ethanol).
In analogous manner, there were obtained from the mixed a~hydride obtained using the acid~ triethylamine and chloro~ormic acid ethyl ester: .
.
the 4-(2-<5-chloro-2-propoxy-benzamido>-ethyl)-2-methoxy-benzoic acid, M.p. 120 - 122 C (~rom dilute methanol)~
the 4-(2-~5-chloro-2-(2-methoxy-ethoxy)-benzamido~-ethyl)-2_ methoxy~benzoic acid, M.p. 132 - 133 C (~rom dilute methanol), the 4-(2-<6-chloro-quinoline-8-carboxamldo~-ethyl)-2-methoxy-benzolc acid, M.p. 170 - 172 C (~rom dilute methanol)j the 4-(2-~2-allyloxy-5-chloro-benzamldo~-ethyl)-2-methoxy-benzoic acid, M.p. 126 - 128 C (~rom dilute methanol), the 4-(2-<2,5-dimethoxy-benzamido~-ethyl)-2-methoxy-benzoic acid, M.p. 155 - 157 C (~rom dilute methanol~, the 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-2-methoxy-b0nzoic acid, M.p. 154 - 156 C (~rom dilute methanol), the 4-(2-C6-chloro-chromane-8-carboxamldo~-ethyl)-2-meth benzoic acid, M.p. 165 ~ 167 C (~rom dilutc methanol), the 4-(2-~3,5-dichloro-benzamido>-ethyl)-2-methoxy-benzoic acid, ~,p. 158 - 160 C (from dilute methanol)~
BXAMPL~ 12:
2-Ethoxy-4-(2-<5-chloro-2-methoxy-benzamido~-ethyl)-benzoic acid 9~3 A solution of 5.1 ~ of 5-chloro-2-methoxy-benzoyl chloride in 30 ml of acetone was introduced dropwise, while stirring and cooling and in the presence of sodium acetate, into a solution o~ 0.025 mole o~ 2-ethoxy-4-(2-aminoethyl)-benzoic acid sodium (obtained by side chain bromination of 2-ethoxy-4-methylbenzoic acid, conversion of the 2-ethoxy-4 - (bromo-methyl)-benzoic acid, M.p. 108 - 110 C, into the 2-ethoxy-4-(cyanomethyl)-benzoic acid, M.p. 113 - 116 C, and reduction of this conpound in ammonia/methanol on Raney nickel to the amino compound) in about 40 ml of water, the whole was stirred for 1 hour at room temperature, the acetone was removed under reduced pressure, the a~ueous solution was acidi~ied, the reaction product that had precipitated was separated and re-precipitated from dilute ammonia. ~fter recrystallization from dilute methanol, the 2-ethoxy-4-(2-C5-chloro-2-methoxy-benzamido>-e-thyl)-benzoie acid so obtained was found to melt at 115 - 117 C.
In analogous manner, there were obtained, using the mixed anhydride:
the 2-ethoxy-4-(2-<6-chloro-chromane-8-carboxamido~-ethyl)-benzoic acid, M.p. 184 - 186 C (from dilute ethanol), the 2 -ethoxy-4-(2-<2-allyloxy-5-chloro-benzamido>-ekhyl)-benzoie acid, M.p. 73 C - 75 C (~rom ethyl acetate -petroleum ether), the 2-ethoxy~ 2-<2-ethoxy-5-ehloro-benzamido~-ethyl)-benzoie aeid, M.p. 111 ~ 112 C (~rom diisopropyl ether/:isopropanol), 4-t2-<2-ethoxy-5-ehloro-benzamido~-ethyl)-2-ethoxy-benzoie acid, M.p. 111 -112 C (from diisopropyl ether/isopropanol), 4 -ethoxy-4-(2-<2-butoxy-5-chloro-benzamido~-ethyl)-benzoic acid, M.p. 88 - 90 C (~rom dilute isopropanol), ~ - 22 -g~3 2-butoxy-4-(~-<5-chloro-2-methoxy-benzamido~-ethyl-benzoic acid, M.p, 98~ - 100 C (from dilute methanol).
EXAMPLE 13:
4-(2-<5-Chloro~2-methoxy-benzamido~-ethyl)-5-chloro-2-methoxy-benzoic acid 3 g of sulfuryl chloride were added dropwise, while stirring at room temperature, to 4.6 g o~ 4-(2-aminoethyl)-2-methoxy-\
\
_ 22 a -benzoic acid - HCl (M.p. 221 C, with decomposition) in 100 ml of glacial acetic acid, The reaction mixture was then heated to 60 C and kept for 6 hours at this temperature. The glacial acetic acid was removed by distillation under reduced pressure, the residue was treated with isopropanol and ~iltered of~ with suction.
The 4-(2-aminoethyl)-5-chloro-2-methoxy-benzoic acid hydrochloride was found to melt at 218 - 220 C (decomposition).
2,5 g of hydrochloride were disso~ved in 25 ml o~ acetone and 0.8 g of NaOH in 2Q ml of water. To this solution, there were added 2 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of acetone and the whole was stirred for 1 hour. Th@n, water and dilute hydrochloric acid were added and the product-was recrystal-lized ~rom methanol. The 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid so obtained was ~ound to melt at 171 - 173 C.
In analogous manner, there were obtained:
the 4-~2-<2-ethoxy-5-chloro-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid, M.p. 12& - 130 C (~rom ethanol), the 4-(2-c5-chloro-2-propoxy-benzamido~-ethyl)-~_chloro-2-methoxy-be~zoic acid, M.p. 139 ~ 141 C (~rom dilute ethanol), the 4-(2-<2-butoxy-5-chloro-benzamido~-ethyl)-5-chloro-2-methoxy-benzolc acid, M.p. 129 - 131 C (~rom dilute methanol), the 4-(2-<2~ethoxy-4-methyl-benz~midQ~-ethyl)-5-chloro-2-meth benzoic acid, M.p. 146~ - 148 C (~rom dilute methanol), the 4-(2-<6-chloro-quInollne-8-carboxam~do>-ethyl)-5-chloro-2-methoxy-benzoic acid, M.p. 198 - ~01 C (~rom methanol/dioxane), the 4-(2-<5-chloro-2_methoxy-benznmldo~_ethyl)-2-butoxy-5-chloro-benzoic acid, M.p. 11~ - llG C (~rom dilute methanol).
_ 2:3 -In analogous manner, there was obtained from the 4-(2~
aminoethyl)-2-methoxy-benzoic acid hydrochloride by bromination in glacial acetic acid the 4-(2-aminoethyl)-5-bromo-2-methoxy-benzoic acid salt and there~r~m, by reaction with 5-chloro-2-methoxy-benzoyl chloride, the 5-bromo-4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-2 methoxy-benzoic acid, M.p. 176 - 178 C ~from methanol) EXAMPL~ 14:
2-Ethoxy-5-bromo-4-(2-<5-chloro-2-methoxy-benzamido>~ethyl)-benzoic acid 1.9 g o~ 2-ethoxy-4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid were dissolved in 20 ml o~ glacial acetic acid. The quantity on the point o~ a spatula o~ iron powder was added and a solution oi 1 g o~ bromine in 10 ml o~ glacial acetic acld was slow~y added dropwise. A~ter termination oi the dropwise addiw tion, the mixture was stirred ~or hal~ an hour at 50 C, ~il-tered a~ter cooling, combined with water, the substance that had pre-c~pitated was ~iltered o~ with suction and recrystallized ~rom dilute methanol. The 2-ethoxy-5-bromo-4-(2-<5-chloro-2-methoxy benzamido>-ethyl~ benzoic acid so obtained was found -to melt at 155 - 157 C.
EXAMPLE 15:
2-Allyloxy-4-(2-~5-chloro-2-methoxy-benz.amido>~ethyl)-ben30ic acid 13.6 g o~ 4-(2-<5-chloro-2~-methoxy-benzamido>-ethyl)-2-hydroxy-benzoic acid ethyl ester, M.p. 88 - 89 C, (prepared by treat~ent o~ 4-(2-aminoethyl)-2-methoxy-ben~oic acid . HCl with hydrobromic acid/glacial acetic acid, reaction o~ the re-- 2~ -sulting 4-~2-<5-chloro-2-methoxy-benzamido>-ethyl)-2-hydroxy-benzoic acid with ethanol/IlCl) were dissolved in 75 ml o~ DMF
and combined with 1,2 g of sodium hydride /80% strength in white oil~ The whole was stirred for hal~ an hour, 4.4 g of allyl bromide were added and stirring was continued for 4 hours at 65 C~. The dimethyl~ormamide was then eliminated by distilla-tion under reduced pressure9 the residue was dissolved in ether, washed with sodium hydroxide solution and water, the ether so-lu~ton was concentrated by evaporation and the residue was hydro-lyzed by heating with 100 ml of 10~ sodium hydroxide solution in the presence o~ a small amount o~ ethanol. A~ter cooling, the solution was acidified, the substance that had precipitated was re-precipitated from ammonia with the aid of charcoal and then cry~tallized from dilute methanol. The 2-allyloxy-4-(2~<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid so obtained was ~ound to melt at 122 - 123 C.
EXAMPL~ 1.6:
(2-<5-Bromo-2-methoxy-nicotinamido~-ethyl)-benzoic acid 11.6 g of 5-bromo-2-methoxy-nicotinic acid were dissolved in 200 ml of tetrahydrofurane. After addition o~ 22 ml of tri-ethylam~ne, the mixture was cool ed to 0 C and ~.8 ml of chloro-~ormic acld methyl ester were addecl dropwi~e, The mixture was stirred for 1 hour at 0~ C, 11,5 g o~ 4-~2-aminoethyl)-ben20ic acid e~hyl ester hydrochloride were added and stirring was con-tinued for l hour at 0 C and for 4 hours at room temperature, The mixture.was evaporated, the residue was treated with water~
~odium bicarbonate solution and acetic acid and recrystallized from a mixture of ethanol and water. The 4-(2-<S-bromo-2-methoxy-_ 25 -33~
nicotinamido>-ethyl)-benzoic acid ethyl ester was ~ound to melt at 69 - 70 C.
The ester so obtained was boiled in 25 ml of 2N-sodium hydroxide solution and 50 ml o~ ethanol ~or 4 hours. A~ter re-moval of the alcohol by distillation, the mixture was acidified with dilute acetic acid, ~iltered with suction and the product was recrystallized from ethanol. The 4-(2-<5-bromo-Z-methoxy-nicotinamido>-ethyl)-benzoic acid obtained was ~ound to melt at 142 - 143 C.
In analogous manner, there was.obtained over the 4-(2-<2-methoxy-nicotinamido>-ethyl)-benzoic acid ethyl ester, Mop~ 88 - 90 C (from ethanol), the 4-(2-<2-methoxy-nicotinamido>-ethyl)-benzoic acid, M.p.
157 - 158 C t~rom ethanol);
over the 4-(2-<1-butyl-pyridone-(2~-3-carboxamiAo~-ethyl)-benzoic acid, M.p. 156 - 157 C (~rom methanol).
EXAMPLE 17:
2-Ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid 10.4 g o~ 2-ethoxy-4-amino-benzoic acid ethyl ester were suspended in a mixture oi 6.8 ml oi triethylamine and 200 ml o~
toluene and I0.3 g oi' 5-chloro~2-methoxy-benzoyl chloride dissolved in a small amount o~ toluene were added dropwise. The whole was stlrred ~or 3 hours under re~lux and, a~ter cooling, it was washed with water, dilute hydrochloric acid and a sodium bi-carbonate solution and dried over sodium suliate. Upon concen-tration oi' the solution under reduced pressure, the 2-ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid ethyl ester was ob~
tained in the ~orm of a solid product having a crude melting point o~ 108 - 111 C.
_ 26 -The ester so isolated was heated for 3 hours, while stirring, under reflux, in 200 ml of 2N-sodium hydroxide solution after addition of a small amount o ethanol. After cooling and acidification with dilute hydrochloric acid, the whole was filtered with suction and the 2-ethoxy-(5-chloro-2-methoxy-benzamido)-benzoic acid was recrystallized from ethanol. It was found to melt at 188 C.
In analogous manner, there was obtained over the 2-ethoxy-4-(2-ethoxy-5-chloro-benzamido)-benzoic acid ethyl ester, melting point of the crude product 115 - 118 C, the 2-ethoxy-4-(2-ethoxy-5-chloro-benzamido)-benzoic acid, melting point 199 C (from ethanol/DMF);
in analogous manner, there was obtained over the 4-(2-allyloxy-5-chloro-benzamido)-2-methoxy-benzoic acid ethyl ester, M.p. of the crude product 128 - 129 C, the 4-(2-allyloxy-5-chloro-benzamido)-2-methoxy-benzoic acid, M.p. 211 C (from ethanol);
in analogous manner, there was obtained the 4-(2-<4-trifluoromethyl-benzamido~-ethyl)-benzoic acid ethyl ester, M.p. 146 - 148 C (from ethanol).
EXAMPLE 18:
4-(2-~2-Amino-4-methyl-benzamido~-ethyl)-benzoic acid ll.S g o~ 4-~2-~-methyl-2-nitro- benzamido~-~thyl)-benzoic acld ~prepared in a manner analogous to that described in Example 1 from 4-methyl-2-nitrQ-benzoyl chloride), M.p. 241 C, were dissolved in hot state in a mixture of 200 ml of concentrated ammonia solution and 300 ml of water and, after addition of a solution of 80 g of iron-(II)-sulfate in 400 ml of water, the whole was heated for 90 minutes on the steam bath. After fil-11~645~3~
tration with suction, the filtrate was acidified with glacial acetic acid, the precipitate was filtered off with suction and recrystalliz0d from ethanol. The 4-(2-<2-amino-4-methyl-benzamido>-ethyl)-benzoic acid was found to melt at 211 C.
In analogous manner, there was obtained from 4-(2-<5-chloro-2-nitro-benzamido~-ethyl~-benzoic acid, M.p. 218 C, the 4- t2 ~2-ami~o-5-chloro-benzamido>-ethyl)-benzoic acid, ~i.p. 209 - 210 C (~rom methanol),
carbonate and, a~ter flltration with cbarcoal, precipi~ated again with dilute acetic acid. A~ter ~iltration with suction and recrystallization ~rom ethanol, the 4-(2-~2-ethylamino-benzamido>-ethyl)-benzoic acid was ~ound to melt at 209 - 211 C.
In analogous man~er, there was obtained from N-ethyl-5-chloro-isatoic acid anhydride and 4-(2-aminoethyl)-benzoic acid ethyl ester, the 4-(2-<2-ethylamino-5-chloro-benzamido>-ethyl~-benzoic acid ethyl ester (M.p. 113 - 115 C), which was trans-formed by alkaline hydrolysis into the 4-(2-<2-ethylamino-5-chloro-benzamido>-ethyl)-benzoic acid, M.p, 245 C (~rom ethanol).
EXAMPLE 6:
4-(2-<3-Chloro-2-m~thoxy-benzamido>-ethyl)-benzoic acid methyl ester 5.8 g oi' 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoyl-chloride (prepared ~rom the corresponding carboxylic acid with thionyl chloride, reacted as crude product) were introduced, while stirring and cooling, in 25 ml o~ anhydrous methanol.
A~ter having heated ~or 15 minutes on the steam bath, the mix-ture was concentrated under reduced pressure, dissolved in ethyl acetate, washed with a NaHC03 solution and water, dried, con-centrated again and the residue was crystallized irQm a ~ixture o~ toluene and petroleum ether. The melting point o~ the 4-(2-~5-chloro-2-metho~y-benzamido~-ethyl)-benzoic acid methyl ester was found to be at 108 - 109 C.
In analogous manner, there was obtalned by the reaction with anhydrous e~hanol the 4-(2-~5-chloro-2-methoxy-benzamido>-ethylbenzoic acid ethyl ester, M.p. 74 - 76 C (~rom ethanol).
_ 17 -~`
.
lOG4~a33 EXAMPLE 7:
4-(2-<5-Chloro-2-methoxy-benzamido~-ethyl)-benzoic acid propyl ester ~
10 g of 4-(2-<5-chloro-2-methoxy-benzamido7-ethyl)-benzoic acid were heated for S hours under reflux in 30 ml of n-propanol after additi.on of 3 ml of concentrated sulfuric acid. After cooling the mixture was concentrated under reduced pressure, poured into ice-water, extracted twice with ether, the ether phase was washed with a sodium bicarbonate solution and water, dried, concentrated and the residue was recrystallized from a mixture of ethyl acetate and petroleum ether. The 4-(2-C5-chloro-2-methoxy-benxamido~-ethyl)-benzoic acid-n-propyl ester was found to melt at 67 - 68 CO
In analogous manner, there was obtained with isopropanol: the 4-(2-~5-chloro-2-methoxy-benzamido~
ethyl)-benzoic acid-isopropyl ester, M.p. 66 - 67 C (from a mixture of ethyl acetate and petroleum ether);
with n-butanol: the 4-(2-C5-chloro-2-methoxy-benzamido?-ethyl)-benzoic acid-n-butyl ester, M.p. 58 - 60 C (from a mixture of ethyl acetate and petroleum ether);
from 4-(2-<2-n-butyloxy-benzamido~-ethyl)-benzoic acid with ethanol: the 4-(2-<2-n-butyloxy-benzamido>-ethyl)-benzoic acid ethyl ester, M.p. 55 - 56 C (from ethyl acetate and petroleum ether).
EXAMPLE 8:
4-t2-<2-Ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid meth 1 ester Y _ _ _ . _ 10.5 g of 4-~2-aminoekhyl)-benzoic acid methyl ester-hydro-chloride were suspended in 40 ml of dioxane and 20 ml of acetone and the suspension was combined with 8 ml of pyridine. To this suspension, a solution of 10 g of 2-ethoxy-5-chloro-benzoyl chloride in a small amount of acetone was added dropwise, while ~tirring, and the whole was heated for 2 hours under reflux.
After cooling, the mixture was concentrated under reduced pressure, combined with ice-water, filtered with suction, stirred with dilute hydrochloric acid and with a NaHC03 solution and the re-sulting product was again filtered off with suction and re-crystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-benzoic acid methyl ester obtained was found to melt at In analogous manner, there was obtained the 4-(2-<5-chloro-2-phenoxy-benzamido>-ethyl)-benzoic acid methyl ester, M.p. 79 - 81 C (from petroleum ether); and ~ rom 4-(2-aminoethyl)-benzoic acid . hydrochloride:
the 4-(2-<2-ethoxy~~_chloro_benzamido>_ethyl)-benzoic acid ethyl ester, M.p. 79 - 80 C (from ethanol).
EXAMPLE 9:
4-(2-~5-Chloro-2-methoxy-benzamido>-ethyl)-benzoic acid . . . _ _ 59 g of 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl~-aceto-phenone (M.p. 103 - 105 C, prepared by acetylation of 5-chloro-2-methoxy-N-(2-phenylethyl)-benzamide in dichloroethane with acetyl chlor~de/AlC13) was added dropwise to a solution cooled to 0 C oi' 71 g o~ caustic soda in 380 ml o~ water and which had been combined with 27.4 ml of bromine, and the whole was stirred for 3 hours at room temperature~ Then, 1 liter of water was added, the mixture was filtereA and the filtrate was acidified with di-lute hydrochloric acid. The product that had precipitated was filtered off with suction and recrystallized from dilute methanol.
M.p. 170 - 172 C.
~XAMPLE 10:
4-(2-<2-Etho~y-5-chloro-benzamido>-ethyl)-benzoic acid 3,8 g of 4-(2-~2-ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid ethyl ester, prepared according to Example 8, were heated ~or 2 hours on the steam bath in 10 ml o~ 2N-sodium hydroxide solution and 50 ml of ethanol. After cooling, the mixture was concentrated under reduced pressur~, the residue was dis~olved in water, the solution was filtered and acidified with 2N~hydro-chloric acid, A~ter separation of the precipitate hy filtration, it was recrystallized from ethanol. The 4-(2-<2-ethoxy-5-chloro-benzamido~-ethyl)-benzoic acid was found to melt at 180 C.
EXAMPLE 11:
4-(2-<5-Chloro-2-methoxy-benzamido>-ethyl)-2-methoxy-benzoic acid 4 g of 4-(2-aminoethyl)-2-methoxy-benzoic acid (prepared by catalytical hydrogenation o~ 4-cyanomethyl-2-methoxy-benzoic acid in methanol in the prssence o~ ~aney nickel at 50 C, 100 atmo~pheres gauge pressure hydrogen) were combined, as crude pro-duct, with 50 ml o~ acetone and 4 - 5 g oi sodium acetate in a small amount of water. Then, 4.3 g of 5-chloro-2-methoxy-benzoyl chloride in a small amount of acetone was added dropwise, while stirring and cooling with ice, the mixture was stirrefl ~or 1 hour, comblned with wa~er and hydrochloric acid, ~ilt~red with suction~ the product wa9 di~olved and precipitated ~rom dilute ammonia and recrystallized ~rom a mixture o~ wat~r and methanol.
The 4-(2-~5_chloro-2-methoxy-benzamido>-ethyl)_2~methoxy_benzoic acid was ~ound to melt at 159 - 162 C.
_ 20 -i(~6~33 In analo~ous manner, there were obtained:
the 4-(2-~2 butoxy-5-chloro-benzamido>-ethyl~-2~methoxy-benzoic acid, M.p. 100 - 102 C (~rom dilute methanol), ~he 4-(2_<5-bromo-2-methoxy-benzamido>-ethyl)-2-methoxy-benzoic acid, M.p. 147 - 149 C (~rom dilute ethanol), the 4-(2-<5-bromo-2-methoxy-nicotinamido>-ethyl)-2-methoxy-benzoic acid, M~p. 94 - 96 C ~from dilute ethanol).
In analogous manner, there were obtained from the mixed a~hydride obtained using the acid~ triethylamine and chloro~ormic acid ethyl ester: .
.
the 4-(2-<5-chloro-2-propoxy-benzamido>-ethyl)-2-methoxy-benzoic acid, M.p. 120 - 122 C (~rom dilute methanol)~
the 4-(2-~5-chloro-2-(2-methoxy-ethoxy)-benzamido~-ethyl)-2_ methoxy~benzoic acid, M.p. 132 - 133 C (~rom dilute methanol), the 4-(2-<6-chloro-quinoline-8-carboxamldo~-ethyl)-2-methoxy-benzolc acid, M.p. 170 - 172 C (~rom dilute methanol)j the 4-(2-~2-allyloxy-5-chloro-benzamldo~-ethyl)-2-methoxy-benzoic acid, M.p. 126 - 128 C (~rom dilute methanol), the 4-(2-<2,5-dimethoxy-benzamido~-ethyl)-2-methoxy-benzoic acid, M.p. 155 - 157 C (~rom dilute methanol~, the 4-(2-<2-ethoxy-5-chloro-benzamido>-ethyl)-2-methoxy-b0nzoic acid, M.p. 154 - 156 C (~rom dilute methanol), the 4-(2-C6-chloro-chromane-8-carboxamldo~-ethyl)-2-meth benzoic acid, M.p. 165 ~ 167 C (~rom dilutc methanol), the 4-(2-~3,5-dichloro-benzamido>-ethyl)-2-methoxy-benzoic acid, ~,p. 158 - 160 C (from dilute methanol)~
BXAMPL~ 12:
2-Ethoxy-4-(2-<5-chloro-2-methoxy-benzamido~-ethyl)-benzoic acid 9~3 A solution of 5.1 ~ of 5-chloro-2-methoxy-benzoyl chloride in 30 ml of acetone was introduced dropwise, while stirring and cooling and in the presence of sodium acetate, into a solution o~ 0.025 mole o~ 2-ethoxy-4-(2-aminoethyl)-benzoic acid sodium (obtained by side chain bromination of 2-ethoxy-4-methylbenzoic acid, conversion of the 2-ethoxy-4 - (bromo-methyl)-benzoic acid, M.p. 108 - 110 C, into the 2-ethoxy-4-(cyanomethyl)-benzoic acid, M.p. 113 - 116 C, and reduction of this conpound in ammonia/methanol on Raney nickel to the amino compound) in about 40 ml of water, the whole was stirred for 1 hour at room temperature, the acetone was removed under reduced pressure, the a~ueous solution was acidi~ied, the reaction product that had precipitated was separated and re-precipitated from dilute ammonia. ~fter recrystallization from dilute methanol, the 2-ethoxy-4-(2-C5-chloro-2-methoxy-benzamido>-e-thyl)-benzoie acid so obtained was found to melt at 115 - 117 C.
In analogous manner, there were obtained, using the mixed anhydride:
the 2-ethoxy-4-(2-<6-chloro-chromane-8-carboxamido~-ethyl)-benzoic acid, M.p. 184 - 186 C (from dilute ethanol), the 2 -ethoxy-4-(2-<2-allyloxy-5-chloro-benzamido>-ekhyl)-benzoie acid, M.p. 73 C - 75 C (~rom ethyl acetate -petroleum ether), the 2-ethoxy~ 2-<2-ethoxy-5-ehloro-benzamido~-ethyl)-benzoie aeid, M.p. 111 ~ 112 C (~rom diisopropyl ether/:isopropanol), 4-t2-<2-ethoxy-5-ehloro-benzamido~-ethyl)-2-ethoxy-benzoie acid, M.p. 111 -112 C (from diisopropyl ether/isopropanol), 4 -ethoxy-4-(2-<2-butoxy-5-chloro-benzamido~-ethyl)-benzoic acid, M.p. 88 - 90 C (~rom dilute isopropanol), ~ - 22 -g~3 2-butoxy-4-(~-<5-chloro-2-methoxy-benzamido~-ethyl-benzoic acid, M.p, 98~ - 100 C (from dilute methanol).
EXAMPLE 13:
4-(2-<5-Chloro~2-methoxy-benzamido~-ethyl)-5-chloro-2-methoxy-benzoic acid 3 g of sulfuryl chloride were added dropwise, while stirring at room temperature, to 4.6 g o~ 4-(2-aminoethyl)-2-methoxy-\
\
_ 22 a -benzoic acid - HCl (M.p. 221 C, with decomposition) in 100 ml of glacial acetic acid, The reaction mixture was then heated to 60 C and kept for 6 hours at this temperature. The glacial acetic acid was removed by distillation under reduced pressure, the residue was treated with isopropanol and ~iltered of~ with suction.
The 4-(2-aminoethyl)-5-chloro-2-methoxy-benzoic acid hydrochloride was found to melt at 218 - 220 C (decomposition).
2,5 g of hydrochloride were disso~ved in 25 ml o~ acetone and 0.8 g of NaOH in 2Q ml of water. To this solution, there were added 2 g of 5-chloro-2-methoxy-benzoyl chloride in 20 ml of acetone and the whole was stirred for 1 hour. Th@n, water and dilute hydrochloric acid were added and the product-was recrystal-lized ~rom methanol. The 4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid so obtained was ~ound to melt at 171 - 173 C.
In analogous manner, there were obtained:
the 4-~2-<2-ethoxy-5-chloro-benzamido>-ethyl)-5-chloro-2-methoxy-benzoic acid, M.p. 12& - 130 C (~rom ethanol), the 4-(2-c5-chloro-2-propoxy-benzamido~-ethyl)-~_chloro-2-methoxy-be~zoic acid, M.p. 139 ~ 141 C (~rom dilute ethanol), the 4-(2-<2-butoxy-5-chloro-benzamido~-ethyl)-5-chloro-2-methoxy-benzolc acid, M.p. 129 - 131 C (~rom dilute methanol), the 4-(2-<2~ethoxy-4-methyl-benz~midQ~-ethyl)-5-chloro-2-meth benzoic acid, M.p. 146~ - 148 C (~rom dilute methanol), the 4-(2-<6-chloro-quInollne-8-carboxam~do>-ethyl)-5-chloro-2-methoxy-benzoic acid, M.p. 198 - ~01 C (~rom methanol/dioxane), the 4-(2-<5-chloro-2_methoxy-benznmldo~_ethyl)-2-butoxy-5-chloro-benzoic acid, M.p. 11~ - llG C (~rom dilute methanol).
_ 2:3 -In analogous manner, there was obtained from the 4-(2~
aminoethyl)-2-methoxy-benzoic acid hydrochloride by bromination in glacial acetic acid the 4-(2-aminoethyl)-5-bromo-2-methoxy-benzoic acid salt and there~r~m, by reaction with 5-chloro-2-methoxy-benzoyl chloride, the 5-bromo-4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-2 methoxy-benzoic acid, M.p. 176 - 178 C ~from methanol) EXAMPL~ 14:
2-Ethoxy-5-bromo-4-(2-<5-chloro-2-methoxy-benzamido>~ethyl)-benzoic acid 1.9 g o~ 2-ethoxy-4-(2-<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid were dissolved in 20 ml o~ glacial acetic acid. The quantity on the point o~ a spatula o~ iron powder was added and a solution oi 1 g o~ bromine in 10 ml o~ glacial acetic acld was slow~y added dropwise. A~ter termination oi the dropwise addiw tion, the mixture was stirred ~or hal~ an hour at 50 C, ~il-tered a~ter cooling, combined with water, the substance that had pre-c~pitated was ~iltered o~ with suction and recrystallized ~rom dilute methanol. The 2-ethoxy-5-bromo-4-(2-<5-chloro-2-methoxy benzamido>-ethyl~ benzoic acid so obtained was found -to melt at 155 - 157 C.
EXAMPLE 15:
2-Allyloxy-4-(2-~5-chloro-2-methoxy-benz.amido>~ethyl)-ben30ic acid 13.6 g o~ 4-(2-<5-chloro-2~-methoxy-benzamido>-ethyl)-2-hydroxy-benzoic acid ethyl ester, M.p. 88 - 89 C, (prepared by treat~ent o~ 4-(2-aminoethyl)-2-methoxy-ben~oic acid . HCl with hydrobromic acid/glacial acetic acid, reaction o~ the re-- 2~ -sulting 4-~2-<5-chloro-2-methoxy-benzamido>-ethyl)-2-hydroxy-benzoic acid with ethanol/IlCl) were dissolved in 75 ml o~ DMF
and combined with 1,2 g of sodium hydride /80% strength in white oil~ The whole was stirred for hal~ an hour, 4.4 g of allyl bromide were added and stirring was continued for 4 hours at 65 C~. The dimethyl~ormamide was then eliminated by distilla-tion under reduced pressure9 the residue was dissolved in ether, washed with sodium hydroxide solution and water, the ether so-lu~ton was concentrated by evaporation and the residue was hydro-lyzed by heating with 100 ml of 10~ sodium hydroxide solution in the presence o~ a small amount o~ ethanol. A~ter cooling, the solution was acidified, the substance that had precipitated was re-precipitated from ammonia with the aid of charcoal and then cry~tallized from dilute methanol. The 2-allyloxy-4-(2~<5-chloro-2-methoxy-benzamido>-ethyl)-benzoic acid so obtained was ~ound to melt at 122 - 123 C.
EXAMPL~ 1.6:
(2-<5-Bromo-2-methoxy-nicotinamido~-ethyl)-benzoic acid 11.6 g of 5-bromo-2-methoxy-nicotinic acid were dissolved in 200 ml of tetrahydrofurane. After addition o~ 22 ml of tri-ethylam~ne, the mixture was cool ed to 0 C and ~.8 ml of chloro-~ormic acld methyl ester were addecl dropwi~e, The mixture was stirred for 1 hour at 0~ C, 11,5 g o~ 4-~2-aminoethyl)-ben20ic acid e~hyl ester hydrochloride were added and stirring was con-tinued for l hour at 0 C and for 4 hours at room temperature, The mixture.was evaporated, the residue was treated with water~
~odium bicarbonate solution and acetic acid and recrystallized from a mixture of ethanol and water. The 4-(2-<S-bromo-2-methoxy-_ 25 -33~
nicotinamido>-ethyl)-benzoic acid ethyl ester was ~ound to melt at 69 - 70 C.
The ester so obtained was boiled in 25 ml of 2N-sodium hydroxide solution and 50 ml o~ ethanol ~or 4 hours. A~ter re-moval of the alcohol by distillation, the mixture was acidified with dilute acetic acid, ~iltered with suction and the product was recrystallized from ethanol. The 4-(2-<5-bromo-Z-methoxy-nicotinamido>-ethyl)-benzoic acid obtained was ~ound to melt at 142 - 143 C.
In analogous manner, there was.obtained over the 4-(2-<2-methoxy-nicotinamido>-ethyl)-benzoic acid ethyl ester, Mop~ 88 - 90 C (from ethanol), the 4-(2-<2-methoxy-nicotinamido>-ethyl)-benzoic acid, M.p.
157 - 158 C t~rom ethanol);
over the 4-(2-<1-butyl-pyridone-(2~-3-carboxamiAo~-ethyl)-benzoic acid, M.p. 156 - 157 C (~rom methanol).
EXAMPLE 17:
2-Ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid 10.4 g o~ 2-ethoxy-4-amino-benzoic acid ethyl ester were suspended in a mixture oi 6.8 ml oi triethylamine and 200 ml o~
toluene and I0.3 g oi' 5-chloro~2-methoxy-benzoyl chloride dissolved in a small amount o~ toluene were added dropwise. The whole was stlrred ~or 3 hours under re~lux and, a~ter cooling, it was washed with water, dilute hydrochloric acid and a sodium bi-carbonate solution and dried over sodium suliate. Upon concen-tration oi' the solution under reduced pressure, the 2-ethoxy-4-(5-chloro-2-methoxy-benzamido)-benzoic acid ethyl ester was ob~
tained in the ~orm of a solid product having a crude melting point o~ 108 - 111 C.
_ 26 -The ester so isolated was heated for 3 hours, while stirring, under reflux, in 200 ml of 2N-sodium hydroxide solution after addition of a small amount o ethanol. After cooling and acidification with dilute hydrochloric acid, the whole was filtered with suction and the 2-ethoxy-(5-chloro-2-methoxy-benzamido)-benzoic acid was recrystallized from ethanol. It was found to melt at 188 C.
In analogous manner, there was obtained over the 2-ethoxy-4-(2-ethoxy-5-chloro-benzamido)-benzoic acid ethyl ester, melting point of the crude product 115 - 118 C, the 2-ethoxy-4-(2-ethoxy-5-chloro-benzamido)-benzoic acid, melting point 199 C (from ethanol/DMF);
in analogous manner, there was obtained over the 4-(2-allyloxy-5-chloro-benzamido)-2-methoxy-benzoic acid ethyl ester, M.p. of the crude product 128 - 129 C, the 4-(2-allyloxy-5-chloro-benzamido)-2-methoxy-benzoic acid, M.p. 211 C (from ethanol);
in analogous manner, there was obtained the 4-(2-<4-trifluoromethyl-benzamido~-ethyl)-benzoic acid ethyl ester, M.p. 146 - 148 C (from ethanol).
EXAMPLE 18:
4-(2-~2-Amino-4-methyl-benzamido~-ethyl)-benzoic acid ll.S g o~ 4-~2-~-methyl-2-nitro- benzamido~-~thyl)-benzoic acld ~prepared in a manner analogous to that described in Example 1 from 4-methyl-2-nitrQ-benzoyl chloride), M.p. 241 C, were dissolved in hot state in a mixture of 200 ml of concentrated ammonia solution and 300 ml of water and, after addition of a solution of 80 g of iron-(II)-sulfate in 400 ml of water, the whole was heated for 90 minutes on the steam bath. After fil-11~645~3~
tration with suction, the filtrate was acidified with glacial acetic acid, the precipitate was filtered off with suction and recrystalliz0d from ethanol. The 4-(2-<2-amino-4-methyl-benzamido>-ethyl)-benzoic acid was found to melt at 211 C.
In analogous manner, there was obtained from 4-(2-<5-chloro-2-nitro-benzamido~-ethyl~-benzoic acid, M.p. 218 C, the 4- t2 ~2-ami~o-5-chloro-benzamido>-ethyl)-benzoic acid, ~i.p. 209 - 210 C (~rom methanol),
Claims (5)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of a benzoic acid derivative of the general formula wherein T' represents hydrogen or halogen, W' represents a carboxyl group, an ester or a salt thereof, X' represents a) wherein R is - hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms;
- alkyloxy;
- methoxyethoxy;
- phenoxy;
- halogen;
- amino;
- alkylamino wherein the alkyl group contains 1 to 4 carbon atoms;
- anilino; and - trifluoromethyl; and wherein R1 and R2 are - hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms; and - halogen;
b) wherein R3 is hydrogen and R4 is:
-hydrogen; and - halogen; and wherein A represents a hydrocarbon chain of 2 to 4 carbon atoms c) wherein R5 is halogen;
d) wherein R6 and R7 are:
- alkoxy containing 1 to 4 carbon atoms; and - halogen; and e) or wherein R8 is alkyl containing 1 to 4 carbon atoms and R9 is halogen;
Y' represents a single chemical bond or a hydrocarbon radical of 1 to 3 carbon atoms, and Z' represents hydrogen, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms;
in which A) an amino compound of the general formula or its formyl compound is reacted with a reactive derivative of the acid X'COOH, and the formyl radical may be split off;
B) the radical V in a compound of the general formula wherein V represents a radical which is convertible into a carboxyl group, is converted into a carboxyl group, C) the sulfur atom in a compound of the general formula is replaced by an oxygen atom;
D) the compound of the general formula wherein U represents low molecular alkoxy, low molecular alkylthio or halogen, is hydrolyzed, or E) the hydroxy group or a hydroxy group present in the radical X' in a compound of the general formula is alkylated, or F) a nitrone of the formula is rearranged to an acid amide;
and the compound obtained may be converted into a free benzoic acid or a pharmaceutically acceptable ester or salt thereof.
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms;
- alkyloxy;
- methoxyethoxy;
- phenoxy;
- halogen;
- amino;
- alkylamino wherein the alkyl group contains 1 to 4 carbon atoms;
- anilino; and - trifluoromethyl; and wherein R1 and R2 are - hydrogen;
- alkyl containing 1 to 4 carbon atoms;
- alkoxy containing 1 to 8 carbon atoms; and - halogen;
b) wherein R3 is hydrogen and R4 is:
-hydrogen; and - halogen; and wherein A represents a hydrocarbon chain of 2 to 4 carbon atoms c) wherein R5 is halogen;
d) wherein R6 and R7 are:
- alkoxy containing 1 to 4 carbon atoms; and - halogen; and e) or wherein R8 is alkyl containing 1 to 4 carbon atoms and R9 is halogen;
Y' represents a single chemical bond or a hydrocarbon radical of 1 to 3 carbon atoms, and Z' represents hydrogen, alkyl containing 1 to 4 carbon atoms or alkoxy containing 1 to 4 carbon atoms;
in which A) an amino compound of the general formula or its formyl compound is reacted with a reactive derivative of the acid X'COOH, and the formyl radical may be split off;
B) the radical V in a compound of the general formula wherein V represents a radical which is convertible into a carboxyl group, is converted into a carboxyl group, C) the sulfur atom in a compound of the general formula is replaced by an oxygen atom;
D) the compound of the general formula wherein U represents low molecular alkoxy, low molecular alkylthio or halogen, is hydrolyzed, or E) the hydroxy group or a hydroxy group present in the radical X' in a compound of the general formula is alkylated, or F) a nitrone of the formula is rearranged to an acid amide;
and the compound obtained may be converted into a free benzoic acid or a pharmaceutically acceptable ester or salt thereof.
2. A benzoic acid derivative of the formula I as de-fined in claim 1, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.
3. A process for the preparation of 4-(2-[5-chloro-2-methoxy-benzamido]-ethyl)-benzoic acid in which 4-(2-[5-chloro-2-methoxy-benzamido]-ethyl)-acetophenone is aaded dropwise to a cooled solution of caustic soda in water con-taining bromine and the resultant product is subsequently isolated.
4. A process as claimed in claim 3 in which 4-(2-[5-chloro-2-methoxy-benzamido]-ethyl)-acetophenone has been prepared by acetylation of 5-chloro-2-methoxy-N-(2-phenylethyl) benzamide in dichloroethane with acetyl chloride/aluminum trichloride.
5. 4-(2-[5-Chloro-2-methoxy-benzamido]-ethyl)-benzoic acid, whenever obtained according to a process as claimed in claim 3 or claim 4 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2500157A DE2500157C2 (en) | 1975-01-03 | 1975-01-03 | N-acyl-4- (2-aminoethyl) benzoic acids, their salts and esters, process for their preparation and their use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1064933A true CA1064933A (en) | 1979-10-23 |
Family
ID=5935941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA242,877A Expired CA1064933A (en) | 1975-01-03 | 1975-12-31 | Benzoic acids, their derivatives and process for preparing them |
Country Status (24)
| Country | Link |
|---|---|
| US (1) | US4221815A (en) |
| JP (1) | JPS51131846A (en) |
| AT (1) | AT347922B (en) |
| AU (1) | AU501010B2 (en) |
| BE (1) | BE837311A (en) |
| CA (1) | CA1064933A (en) |
| CH (1) | CH619209A5 (en) |
| DE (1) | DE2500157C2 (en) |
| DK (1) | DK276A (en) |
| EG (1) | EG12067A (en) |
| ES (1) | ES443910A1 (en) |
| FI (1) | FI753721A (en) |
| FR (1) | FR2296407A1 (en) |
| GB (1) | GB1538482A (en) |
| HU (1) | HU174325B (en) |
| IE (1) | IE42391B1 (en) |
| IL (1) | IL48749A (en) |
| IT (1) | IT1052091B (en) |
| LU (1) | LU74129A1 (en) |
| NL (1) | NL7515129A (en) |
| NO (1) | NO760003L (en) |
| PT (1) | PT64670B (en) |
| SE (1) | SE7600012L (en) |
| ZA (1) | ZA767B (en) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DE2517229A1 (en) * | 1975-04-18 | 1976-10-28 | Boehringer Mannheim Gmbh | PHENYLALKYLCARBONIC ACID DERIVATIVES AND PROCESS FOR THEIR PRODUCTION |
| DE2532420A1 (en) * | 1975-07-19 | 1977-02-03 | Boehringer Mannheim Gmbh | PHENYL ACID DERIVATIVES AND THE PROCESS FOR THEIR PRODUCTION |
| DE2639935A1 (en) * | 1976-09-04 | 1978-03-09 | Hoechst Ag | BENZOESAEURS AND METHOD FOR THEIR PRODUCTION |
| DE2706977A1 (en) * | 1977-02-18 | 1978-08-24 | Hoechst Ag | BENZOESAEURS AND THEIR DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| LU79008A1 (en) * | 1978-02-03 | 1979-09-06 | Byk Gulden Lomberg Chem Fab | W- (N-ALKYL-N-BENZOYL-AMINO) -PHENYLALCANIC ACIDS, THEIR USE AND MANUFACTURING AND MEDICINAL PRODUCTS |
| EP0023569B1 (en) * | 1979-07-13 | 1983-06-22 | Dr. Karl Thomae GmbH | Derivatives of carboxylic acids, their preparation and medicaments containing them |
| DE3070865D1 (en) * | 1979-11-15 | 1985-08-14 | Beecham Group Plc | Secondary ethanol amines, their preparation and their use in pharmaceutical compositions |
| DE3100535A1 (en) * | 1981-01-10 | 1982-08-12 | Dr. Karl Thomae Gmbh, 7950 Biberach | "NEW CARBONIC ACID DERIVATIVES, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS" |
| DE3211934A1 (en) * | 1982-03-31 | 1983-10-13 | Hoechst Ag, 6230 Frankfurt | SALICYL ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE |
| PT77219B (en) * | 1982-08-24 | 1986-02-04 | May & Baker Ltd | PROCESS FOR THE PREPARATION OF BENZAMIDE DERIVATIVES |
| LU86258A1 (en) * | 1986-01-21 | 1987-09-03 | Rech Dermatologiques C I R D S | BENZAMIDO AROMATIC COMPOUNDS, PROCESS FOR THEIR PREPARATION AND THEIR USE IN HUMAN OR VETERINARY MEDICINE AND IN COSMETICS |
| GB8708833D0 (en) * | 1987-04-13 | 1987-05-20 | Lilly S A E | Organic compounds |
| GB8823040D0 (en) * | 1988-09-30 | 1988-11-09 | Lilly Sa | Organic compounds & their use as pharmaceuticals |
| GB8823042D0 (en) * | 1988-09-30 | 1988-11-09 | Lilly Sa | Organic compounds & their use as pharmaceuticals |
| GB8823041D0 (en) * | 1988-09-30 | 1988-11-09 | Lilly Sa | Organic compounds & their use as pharmaceuticals |
| KR960014911B1 (en) * | 1990-03-20 | 1996-10-21 | 시오노기세이야꾸 가부시끼가이샤 | Novel method for preparing benzoic acid derivatives |
| CA2057324A1 (en) * | 1990-12-18 | 1992-06-19 | Lora Louise Fitch | Benzamide and sulfonamide hypoglycemic agents |
| US6916489B2 (en) * | 1992-06-15 | 2005-07-12 | Emisphere Technologies, Inc. | Active agent transport systems |
| US20010003001A1 (en) | 1993-04-22 | 2001-06-07 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US6001347A (en) | 1995-03-31 | 1999-12-14 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| AU2595697A (en) | 1996-03-29 | 1997-10-22 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US6358504B1 (en) | 1997-02-07 | 2002-03-19 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| US6194458B1 (en) * | 1998-10-30 | 2001-02-27 | Merck & Co., Inc. | Benzamide potassium channel inhibitors |
| NZ534409A (en) * | 1999-04-05 | 2006-03-31 | Emisphere Tech Inc | Disodium salts, monohydrates, and ethanol solvates for delivering active agents |
| AU2274201A (en) * | 1999-12-16 | 2001-06-25 | Emisphere Technologies, Inc. | Compounds and compositions for delivering active agents |
| WO2001083421A1 (en) * | 2000-04-28 | 2001-11-08 | Nihon Nohyaku Co., Ltd. | Process for the preparation of 2-halobenzoic acids |
| CN100471838C (en) * | 2000-12-28 | 2009-03-25 | 第一制药株式会社 | VLA-4 inhibitors |
| TWI340134B (en) | 2003-07-24 | 2011-04-11 | Daiichi Seiyaku Co | Cyclohexanecarboxylic acids |
| CA2536870C (en) | 2003-09-03 | 2009-10-27 | Pfizer Inc. | Phenyl or pyridyl amide compounds as prostaglandin e2 antagonists |
| JP2005209106A (en) * | 2004-01-26 | 2005-08-04 | Nec Corp | Portable communication terminal, received e-mail management method, program and recording medium |
| ES2327760T3 (en) * | 2004-05-04 | 2009-11-03 | Raqualia Pharma Inc | ORGANOSTITUTED ARIL-HETEROARIL-AMIDA COMPOUNDS. |
| WO2007060162A1 (en) * | 2005-11-22 | 2007-05-31 | Bayer Cropscience Sa | New n-(1-methyl-2phenylethyl)benzamide derivatives |
| CA2648729A1 (en) | 2006-04-24 | 2007-11-01 | Merck Frosst Canada Ltd. | Indole amide derivatives as ep4 receptor antagonists |
| WO2012003145A2 (en) | 2010-07-02 | 2012-01-05 | Allergan, Inc. | Therapeutic agents for ocular hypertension |
| US9714238B2 (en) | 2010-07-02 | 2017-07-25 | Allergan, Inc. | Therapeutic agents for ocular hypertension |
| JO3296B1 (en) | 2012-06-29 | 2018-09-16 | Lilly Co Eli | Phenoxyethyl piperidine compounds |
| TWI636046B (en) | 2013-05-17 | 2018-09-21 | 美國禮來大藥廠 | Phenoxyethyl dihydro-1h-isoquinoline compounds |
| KR101807981B1 (en) | 2013-12-17 | 2017-12-11 | 일라이 릴리 앤드 캄파니 | Phenoxyethyl cyclic amine derivatives and their activity as ep4 receptor modulators |
| WO2018052967A1 (en) * | 2016-09-13 | 2018-03-22 | Arbutus Biopharma, Inc. | Substituted chromane-8-carboxamide compounds and analogues thereof, and methods using same |
Family Cites Families (7)
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|---|---|---|---|---|
| US3100226A (en) * | 1959-10-16 | 1963-08-06 | Amchem Prod | 2,5 dichloro-3 acylaminobenzoic acids |
| US3536753A (en) * | 1969-05-27 | 1970-10-27 | Geigy Chem Corp | O-(substituted benzamido)phenylacetic acids |
| US3636094A (en) * | 1969-07-25 | 1972-01-18 | Searle & Co | Norbornanecarboxylic acid amides of anthranilic acid |
| FR2088225A1 (en) * | 1970-05-29 | 1972-01-07 | Ugine Kuhlmann | Substd salicylanilides - having antiuric props |
| US3855285A (en) * | 1971-06-21 | 1974-12-17 | Pfizer | Acylmethylthio-trifluoromethyl-benzoic acids |
| DE2230383C3 (en) * | 1971-10-01 | 1981-12-03 | Boehringer Mannheim Gmbh, 6800 Mannheim | Phenoxyalkylcarboxylic acid derivatives and processes for making the same |
| DE2320387A1 (en) * | 1973-04-21 | 1974-10-31 | Boehringer Mannheim Gmbh | PHENOXYALKYLCARBONIC ACID DERIVATIVES AND METHOD FOR PREPARING THE SAME |
-
1975
- 1975-01-03 DE DE2500157A patent/DE2500157C2/en not_active Expired
- 1975-12-27 ES ES443910A patent/ES443910A1/en not_active Expired
- 1975-12-28 IL IL48749A patent/IL48749A/en unknown
- 1975-12-29 NL NL7515129A patent/NL7515129A/en not_active Application Discontinuation
- 1975-12-29 EG EG75768A patent/EG12067A/en active
- 1975-12-30 CH CH1689175A patent/CH619209A5/de not_active IP Right Cessation
- 1975-12-31 FR FR7540257A patent/FR2296407A1/en active Granted
- 1975-12-31 FI FI753721A patent/FI753721A/fi not_active Application Discontinuation
- 1975-12-31 CA CA242,877A patent/CA1064933A/en not_active Expired
- 1975-12-31 IT IT30935/75A patent/IT1052091B/en active
- 1975-12-31 AU AU87964/75A patent/AU501010B2/en not_active Expired
-
1976
- 1976-01-02 PT PT64670A patent/PT64670B/en unknown
- 1976-01-02 LU LU74129A patent/LU74129A1/xx unknown
- 1976-01-02 SE SE7600012A patent/SE7600012L/en not_active Application Discontinuation
- 1976-01-02 NO NO760003A patent/NO760003L/no unknown
- 1976-01-02 DK DK276*BA patent/DK276A/en unknown
- 1976-01-02 US US05/646,378 patent/US4221815A/en not_active Expired - Lifetime
- 1976-01-02 AT AT1876A patent/AT347922B/en not_active IP Right Cessation
- 1976-01-02 HU HU76HO1869A patent/HU174325B/en unknown
- 1976-01-02 ZA ZA00760007A patent/ZA767B/en unknown
- 1976-01-02 IE IE2/76A patent/IE42391B1/en unknown
- 1976-01-05 JP JP51000731A patent/JPS51131846A/en active Pending
- 1976-01-05 GB GB145/76A patent/GB1538482A/en not_active Expired
- 1976-01-05 BE BE163313A patent/BE837311A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| AT347922B (en) | 1979-01-25 |
| HU174325B (en) | 1979-12-28 |
| DK276A (en) | 1976-07-04 |
| ATA1876A (en) | 1978-06-15 |
| PT64670A (en) | 1976-05-01 |
| IL48749A0 (en) | 1976-02-29 |
| NL7515129A (en) | 1976-07-06 |
| IT1052091B (en) | 1981-06-20 |
| NO760003L (en) | 1976-07-06 |
| SE7600012L (en) | 1976-07-05 |
| FR2296407B1 (en) | 1979-06-29 |
| DE2500157A1 (en) | 1976-07-22 |
| FI753721A (en) | 1976-07-04 |
| BE837311A (en) | 1976-07-05 |
| GB1538482A (en) | 1979-01-17 |
| ZA767B (en) | 1976-12-29 |
| CH619209A5 (en) | 1980-09-15 |
| AU501010B2 (en) | 1979-06-07 |
| EG12067A (en) | 1978-12-31 |
| IE42391L (en) | 1976-07-03 |
| DE2500157C2 (en) | 1983-09-15 |
| LU74129A1 (en) | 1976-11-11 |
| AU8796475A (en) | 1977-07-07 |
| US4221815A (en) | 1980-09-09 |
| IE42391B1 (en) | 1980-07-30 |
| PT64670B (en) | 1977-08-08 |
| IL48749A (en) | 1979-09-30 |
| ES443910A1 (en) | 1977-04-16 |
| FR2296407A1 (en) | 1976-07-30 |
| JPS51131846A (en) | 1976-11-16 |
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