Patent SE-311916-B (SE)
Inventor: SCHULTZ E
IPC: C07C45/67
Filed: 1963-11-12
Abstract: New compounds of formula <FORM:1065647/C2/1> where A is oxygen or sulphur; B is alkylene, phenylene, benzylene, sulphur-interrupted alkylene or oxygen-interrupted alkylene; R2 is hydrogen, halogen, alkyl, haloalkyl, cycloalkyl, alkyl-cycloalkyl, carboxyalkyl, morpholinoalkyl, piperidinoalkyl, pyrrolidinoalkyl or a radical of formula <FORM:1065647/C2/2> where A DEG  is oxygen or sulphur, X1 is hydrogen, halogen, halomethyl, C1- 5 alkyl or C1- 5 alkoxy, and n is 1-5; each of R3, R4R5 and R6 is hydrogen, halogen, C1- 5 alkyl, C1- 5 alkoxy, carboxyalkyloxy, nitro, C1- 6 alknoylamino or trifluormethyl, or two such adjacent radicals may join in a 5- or 6-membered carbocyclic ring; X is hydroxy or alkoxy; each of Y and Y1 is C1- 5 alkyl or they join in a pyrrolidino, piperidino or N-methyl-piperazino ring; and their pharmaceutically acceptable acid addition salts; are prepared by reaction of corresponding R2-CH2-CO-Phcompounds with compounds YY1NH or a salt thereof in the presence of formaldehyde or paraformaldehyde; esters, X being alkoxy, are preparable from the acids via their chlorides.  Starting materials prepared in examples are: (1) 21,31 - dichloro - 41 - hydroxy - 1 - cyclopentaneacetophenone; (2) 3 - chlorophenyl propionate; (3) 2-propionyl-5-chlorophenol; (4) 3,5-dimethylphenyl butyrate and 2-butyryl-3,5-dimethylphenol; (5) 3,5-dichlorophenyl butyrate and 2-butyryl-3,5-dichlorophenol; (6) 2,6 - dichloro - 3 - methoxy - a  - propyl - benzyl alcohol, 21,61 - dichloro - 31 - methoxybutyrophenone and the 31-hydroxy compound, and (7) the corresponding 2-monochloro compounds; (8) 21 - methoxy - 61 - methylbutyrophenone and the 21-hydroxy compound; (9) 2,4-dimethyl - 5 - butyrylphenol; (10-14) the following 4 - butyrylphenols - 3 - chloro -, 3,5-dichloro -, 2 - bromo - 3 - chloro -, 2 - nitro-3 - methyl -, 3 - acetylamino; (15) 3 - chloro-4 - (2,2 - dimethylbutyryl) phenol; (16-18) 2,3 - dichloro - 4 - (2 - methylbutyryl -, 3,3, dimethylbutyryl- or cyclohexylacetyl)phenols; (19) 3-chloro-4-phenylacetylphenol; (20) 2,3,5,6 tetramethylphenoxyacetic acid; (21) 3-(3-chlorophenylmercapto) propionic acid; (22) 3-chloro - 4 - propionylphenoxyacetic acid; (23) 3 - propionylphenoxyacetic acid; (24) 2 - (3-chloro - 4 - butyryl - phenoxy) - butyric acid and ethyl ester; (25) 31,51-dichloro-41 -hydroxybutyrophenone and 2,6 - dichloro - 4 - butyrylphenoxyacetic acid; (26) 2-chloro-3-methylphenoxy-acetic acid; (27) 3-hydroxy-4-butyrylphenoxyacetic acid and the 3-methoxy compound; (28) 2-chloro-5-nitropropiophenone and the 5-amino, 5-hydroxy and 5-carboxymethoxy compounds; (29) 3 - (2, 4 - dimethyl - 5 - butyrylphenoxy) propionic acid; (30-31) 3 - chloro-4-acetyl phenoxyacetic acid and the 4-(3-Aracryloyl) condensation products with benzaldehyde and its p-chloro, p-propyl and p-methoxy deriatives and the 4-(3-Ar-propionyl) compounds; (32) 3 - methyl - 4 - (4-chlorobutyryl) - phenoxy-acetic acid; (33) 3-methyl-4-(4-phenylmercaptobutyryl) phenoxyacetic acid and the 4 - (p - tolylmercaptoacetyl) compound; (34) 3 - methyl - 4 - [4 - (4 - morpholiny)butyryl] phenoxyacetic acid and ethyl ester hydrochloride; (35) 2-(3-chloro-4-butyrylphenoxy) ethanol and the corresponding 2-substituted ethoxyacetic acid, ethyl chloride and ethylthioacetic acid; (36-37) 3-methyl-4-chloroacetylphenoxyacetic acid and the 4-phenoxyacetyl, 4 - benzylmercaptoacetyl and 4 - (3-carboxypropionyl) compounds; (38-72, Table II) compounds <FORM:1065647/C2/3> wherein the radicals R3, R4, R5, R6 are variously H, F, Cl, Br, I, di-Cl, one or more alkyl, trimethylene, radical B is -CH2- or -CH2CH2- and R2 is H, alkyl, CF3CH(CH3)-, cyclopentyl, cyclohexyl, 4-CH3-cyclohexyl; (73-74) 4-propionyl - 3 - chloro or methyl - phenylthioacetic acid; (75) 4-propionyl-3-chloro-phenylthiopropionic acid; (76-86, Table IV) compounds <FORM:1065647/C2/4> wherein the radicals R3, R4, R5, R6 are variously H, mono or di-CH3, Cl, di-Cl, radical R2CH2CO is in positions 2, 3, 4, 5 and R2 is alkyl, cyclopenthyl, cyclohexyl, phenyl; (87, 89) 2-nitro-and 2,3 - tetramethylene - 4 - butyrylphenoxyacetic acid; (88) 3-chloro-4-butyrylphenoxy(a -isopropyl) acetic acid; (90-95, Table VI) compounds of the last general formula above, wherein the radicals R3, R4, R5, R6 are variously H, Cl, di-Cl, Cl + Br, NHCOCH3, OCH2 COOH and R2CH2CO is in position 4, R2 being alkyl; (98) 3-trifluoromethyl-4-bromophenyl allyl ether and the 4-(1-hydroxybutyl) and 4-butyryl compounds and 3-trifluoromethyl-4-butyrylphenoxyacetic acid; (178) 4-(3-chloro-4-propionylphenoxymethyl) benzoic acid and ethyl ester; (179) 4-chloromethylbenzonitrile, the corresponding benzoic acid and ethyl ester and 4 - (3 - chloro - 4 - butyrylphenoxymethyl) benzoic acid and ethyl ester; (180, 181) methyl 3-(bromomethyl)benzoate and the 3-(3 - chloro - 4 - butyrylphenoxymethyl) - compound and its acid and the analogous 2-substituted esters; (182) 41(3-chlorophenoxy)acetophenone and its semi-carbazone, 4-(3-chlorophenoxy) benzoic acid and methyl ester, methyl 4 - (3 - chloro - 4 - butyryl - phenoxy)benzoate and its acid; (183) 2-(3-chlorophenoxy)benzoic acid and methyl ester, methyl 2-(3-chloro-4-butyrylphenoxy) benzoate and its acid.  Pharmaceutical compositions comprise the compounds of the invention with carriers. Oral and parenteral preparations are described, being useful as diuretic, natriuretic and chlorouretic agents.