United States Patent (19) 11 4,284,646 Vorbriggen et al. 45) Aug. 18, 1981 54). PROSTANOIC ACID DERIVATIVES AND 57 ABSTRACT THER PREPARATION Prostanoic acid derivatives of the formula (75) Inventors: Helmut Vorbriggen; Norbert Schwarz; Olaf Loge; Walter Elger, all of Berlin, Fed. Rep. of Germany / Z wn A1N 1 X4. R2 R4 (73) Assignee: Schering Aktiengesellschaft, Berlin w y Y B-W -N-( and Bergkamen, Fed. Rep. of R3 Germany wherein R1 is an acid, ester, amide or hydroxyalkylene 21 Appl. No.: 69,193 group; R2 and R3 are H or alkyl; R4 and R5 are both 22 Filed: Aug. 24, 1979 CH3 or one is Cl and the other is CH3; A is CH2CH2 or -CH=CH; B is CH2CH2, trans-CH=CH, -C=- C-or Related U.S. Application Data 63 Continuation of Ser. No. 932,823, Aug. 10, 1978, aban doned, which is a continuation-in-part of Ser. No. ". 821,130, Aug. 2, 1977, abandoned. -CH CH (30) Foreign Application Priority Data W is free or functionally modified hydroxyalkylene or Aug. 6, 1976 (DE) Fed. Rep. of Germany ....... 2635985 carbonyl; Z is free or functionally modified hydrox ymethylene or carbonyl; X-Y is either 51) Int. Cl. ............................................ CO7C 177/00 52 U.S.C. ............................. 424/305; 260/340.5 P; 260/340.7; 260/340.9 P; 260/345.7 P; -ch-h- 260/345.8 P; 260/347.3; 260/347.4; 260/410; R12 260/456 R; 260/464; 260/346.22; 542/426; 556/441; 560/118; 560/121; 560/231; 562/500; or, when Z is free or functionally modified hydrox 562/503; 564/98; 564/217; 424/278; 424/318 ymethylene, (58) Field of Search ....................... 560/118, 121, 231; 562/503, 500; 424/305, 278, 318; 260/345.7 P, 345.8 P, 347.3, 347.4, 456 R, 340.5 P, 340.7, I 340.9 P, 410,542/426,556/441 O 56 References Cited or, when Z is free or functionally modified carbonyl, U.S. PATENT DOCUMENTS -CH=CH-, R12 being H, CH3, CN or free or func 3,419,285 11/1975 Axen .................................... 560/121 tionally modified hydroxy; and physiologically accept 3,932,479 11/1976 Bernady ............................... 260/448 able salts thereof when R1 is an acid group, possess 4,220,798 9/1980 Scolastico et al.................... 560/121 pharmacological activity, including abortion triggering activity. Primary Examiner-Robert Gerstl Attorney, Agent, or Firm-Millen & White 11 Claims, No Drawings 4,284,646 1 2 either of which can be free or functionally modified; PROSTANOIC ACID DERVATIVES AND THEIR X Y is either PREPARATION This is a continuation or application Ser. No. 932,823 -ch-h- or -CH-i- filed Aug. 10, 1978 which in turn is a continuation-in R12 O part of Ser. No. 821,130 filed Aug. 2, 1977, both now abandoned. when Z is a free or functionally modified hydrox ymethylene group, or is either BACKGRUND OF THE INVENTION 10 This invention relates to novel prostanoic acid deriv atives and to processes for their production and use. -ch-h- R2 SUMMARY OF THE INVENTION In a composition aspect, this invention relates to 15 or -CH=CH-, when Z is a free or functionally modi novel prostanoic acid derivatives of general Formula I fied carbonyl group, wherein R12 is a hydrogen atom, methyl, a cyanide group (-CN), or a free or function ally modified hydroxy; R2 is a hydrogen atom or alkyl; R3 is a hydrogen atom or alkyl; R4 and R5 each are 20 methyl or one of R4 and R5 is a chlorine atom and the X./ NA-1N1N2 R4 other is methyl; and, when Ré is hydroxy, the physio logically acceptable salts thereof with bases. v---w-N- In another composition aspect, this invention relates to pharmaceutical compositions comprising a novel wherein R1 is 25 compound of this invention. In process aspects, this invention relates to methods -C-R6 or -C-OR9, of making and using the novel compounds of this inven I / N tion. O R7 R8 30 DETAILED DISCUSSION wherein R6 is hydroxy; a straightchain or branched Contemplated classes of compounds within the scope alkoxy of 1-10 carbon atoms; aryloxy; O-CH2-U-V of Formula I include those wherein: wherein U is a direct bond, carbonyl or carbonyloxy (a) Ré is OH; and V is a phenyl ring substituted by one or more of (b) Ré is alkoxy; phenyl, alkoxy of 1-2 carbon atoms, or halogen atoms, 35 (c) R6 is aryloxy; preferably bromine atoms; or -NHR10 wherein R10 is (d) Ré is -O-CH2-V; alkyl, aryl or the acyl radical of an organic carboxylic (e) Resis or sulfonic acid of 1-15 carbon atoms; and wherein R7 and R8 each are hydrogen atoms or alkyl of 1-4 carbon atoms and R9 is the acyl radical of an organic carboxylic or sulfonic acid of 1-15 carbon atoms or of an inorganic acid or is (f) Ré is -C-NHRio, 45 O R10 is the values given above; A is -CH2-CH2- or (g) R5 is -NH-alkyl; cis- or trans-CH=CH-; B is -CH2-CH2-, tran 50 (h) R5 is -NH-aryl; s-CH=CH-, -C=C- or (i) Ré is -NH-acyl; (j) B is -CH2CH2 or trans-CH=CH-, including -CH-CH those of each of (a) through (i); (k) B is -C=C-, including those of each of (a) 55 through (i); (1) B is wherein the methylene group can be in the a- or (3-posi tion; W is free or functionally modified hydroxymethy lene, a free or functionally modified carbonyl, or - ck 7th -, 60 CH2 R including those of each of (a) through (i); -C- (m) W is hydroxymethylene, including those of each of (a) through (); 65 (n) W is alkoxymethylene, including those of each of wherein Rii is alkyl of 1-5 carbon atoms and the OH (a) through (l); group can be in the a- or 6-position and can be func (o)W is acyloxymethylene, including those of each of tionally modified; Z is carbonyl or hydroxymethylene, (a) through (l); 4,284,646 3 4. (p) W is carbonyl, including those of each of (a) The alkyl groups R10 can optionally be mono- or through (l); polysubstituted by halogen atoms, alkoxy groups, op (q) W is dialkyl ketalized carbonyl, including those of tionally substituted aryl groups, dialkyl amines, and each of (a) through (l); trialkyl ammonium. (r) W is arylenedioxy ketalized carbonyl, including 5 Examples of substituents are fluorine, chlorine or those of each of (a) through (l); bromine atoms, phenyl, dimethylamine, diethylamine, (s) W is alkylenedioxy ketalized carbonyl, including methoxy, ethoxy. those of each of (a) through (l); Preferred alkyl groups R10 are methyl, ethyl, propyl, (t) Z is carbonyl, including those of each of (a) isobutyl, butyl, trichloromethyl and trifluoromethyl. through (s); O Cycloalkyl groups R10 are those of 3-8 carbon atoms, (u) Z is dialkyl ketalized carbonyl, including those of such as, for example, cyclopropyl, cyclobutyl, cyclo each of (a) through (s); pentyl, cyclohexyl preferably cyclopropyl. (v) Z is arylenedioxy ketalized carbonyl, including Examples of aryl groups R10 are substituted as well as those of each of (a) through (s); unsubstituted aryl groups and heteroaryl groups, such (w) Z is alkylenedioxy ketalized carbonyl, including 15 as, for example, phenyl, 1-naphthyl, and 2-naphthyl, those of each of (a) through (s); each of which can be substituted by 1-3 halogen atoms, (x) Z is hydroxymethylene, including those of each of one phenyl group, one to three alkyl groups of respec (a) through (s); tively 1-4 carbon atoms, a chloromethyl, fluoromethyl, (y) Z is esterified hydroxymethylene, including those trifluoromethyl or alkoxy group; and thienyl, furyl or of each of (a) through (S); 20 pyridyl. The substitution in the 3- and 4-positions on the (z) Z is etherified hydroxymethylene, including those phenyl ring is preferred, for example, by fluorine, chlo of each of (a) through (s); rine, alkoxy or trifluoromethyl. (aa) X-Y is -CH2CH2-, including those of each Suitable acyl residues R9 and R10, respectively, are of (a) through (z); physiologically compatible acyl residues, e.g., of or (bb) XY is -CH2CHOH-, including those of 25 each of (a) through (z); ganic carboxylic acids and sulfonic acids of 1-15 carbon (cc) XY is -CH2CHCN-, including those of atoms pertaining to the aliphatic, cycloaliphatic, aro each of (a) through (z); matic, aromatic-aliphatic, or heterocyclic series. These (dd) X:... Y is -CH2CCH3-, including those of acids can be saturated, unsaturated and/or polybasic each of (a) through (z); and/or substituted in the usual manner. Examples of (ee) X;Y is -CH2-CO-, including those of substituents are alkyl, hydroxy, alkoxy, oxo or amino each of (a) through (z); groups, or halogen atoms. (f) both R4 and R5 are CH3, including those of each The following carboxylic acids are illustrative: for of (a) through (ee); and mic acid, acetic acid, propionic acid, butyric acid, iso (gg) one of R4 and R5 is Cl, including those of each of 35 butyric acid, valeric acid, isovaleric acid, caproic acid, (a) through (ee). enanthic acid, caprylic acid, pelargonic acid, capric Examples of alkyl groups R2 and R3 are straight-chain acid, undecylic acid, lauric acid, tridecylic acid, myris and branched alkyl residues of 1-5 carbon atoms, such tic acid, pentadecylic acid, trimethylacetic acid, die as, for example, methyl, ethyl, propyl, isopropyl, butyl, thylacetic acid, tert.-butylacetic acid, cyclopentylacetic isobutyl, and pentyl. Preferred are the methyl and ethyl acid, cyclohexylacetic acid, cyclohexanecarboxylic groups.