HHHHHHH USOO5081145A United States Patent (19) 11 Patent Number: 5,081,145 Guindon et al. 45 Date of Patent: Jan. 14, 1992

(54. INDOLE-2-ALKANOIC ACIDS 4,739,073 4/1988 Kathawala ...... 548/414 X COMPOSITIONS OF AND ANT ALLERGIC USE THEREOF FOREIGN PATENT DOCUMENTS 50957 5/1982 European Pat. Off. . (75. Inventors: Yvan Guindon; John W. Gillard, both 454858 6/1968 Switzerland. of Quebec; Christiane Yoakim, 455777 7/1968 Switzerland . Montreal; Thomas R. Jones, 948460 9/1960 United Kingdom . Kirkland; Rejean Fortin, Montreal-Nord, all of Canada OTHER PUBLICATIONS 73) Assignee: Merck Frosst Canada, Inc., Kirkland, Walton, et al., J. Med. Chen., 8, 204 (1965). Canada E. Walton, et al., J. Med. Chem., 11, 1252 (1968). 21 Appl. No.: 473,551 Primary Examiner-David B. Springer Attorney, Agent, or Firm-Gabriel Lopez; Joseph F. 22 Filed: Feb. 1, 1990 DiPrima 51. Int. Cl...... C07D 209/12; A61K 31/405 52 U.S. Cl...... 514/49; 548/492; 57 ABSTRACT 548/494. Indole-2-alkanoic acids are disclosed. The compounds 58 Field of Search ...... 548/494; 514/419 act as and antagonists and 56 References Cited are useful in treating asthma, inflammation, diarrhea, hypertension, angina, platelet aggregation, cerebral U.S. PATENT DOCUMENTS spasm, premature labor, spontaneous abortion and dis 3,196,162 7/1965 Sarett et al...... 260/39 menorrhea and as cytoprotective agents. 3,242,162 3/i966 Sarett et al. 260/21 3,242, 63 3/966 Sarett et al...... 260/21 3,242,193 3/1966 Sarett et al...... 260/319 6 Claims, No Drawings 5,081,145 1. NDOLE-2-ALKANOIC ACIDS COMPOSITIONS OF AND ANT ALLERGIC USE THEREOF CROSS-REFERENCE

This is a continuation of application Ser. No. 197,117 filed Jan. 21, 1988 which is a continuation-in-part of patent application U.S.S.N. 624,173, filed June 25, 1984, pending, both abandoned. 10 SUMMARY OF THE INVENTION This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prosta 15 glandins and prostaglandin biosynthetic intermediates CCC. wherein: These compounds antagonize the actions of contrac R is H or alkyl of 1 to 6 carbons or R1 and R8 taken tile , such as PGF2, PGG2, PGH2, 20 together form a group (CH2), wherein v is 1 to 7; PGD2, and TXA2. The use of agents which act as pros R2 is taglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain pros taglandins, such as PGF2, PGD2, PGG2, and PGH2, are potent contractants of bronchial muscle. Indeed 25 human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF2. wherein: The compounds of the present invention also produce each R8 is independently H, OH, C1 to C4-O-alkyl antithrombotic effects. Thus, they are useful in the 30 or alkyl of 1 to 4 carbons; or an Ri and an R8 taken treatment and/or prevention of thromboembolic dis together form a group (CH2) wherein v is 1 to 7. eases such as arterial thrombosis. R9 is COOR; CH2OH, CHO, tetrazole; NHSOR10 In addition to the involvement of contractile prosta wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, glandins in chronic obstructive lung disease (or asthma), perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substi prostaglandins are known to play a role in other allergic 35 tuted by alkyl or alkoxy groups of 1 to 3 carbons, halo conditions, as well as inflammation, diarrhea, hyperten gen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 Sion, angina, platelet aggregation, cerebral spasm, cere carbons; CONHSO2R10; hydroxymethylketone; CN; or bral ischemia, myocardial ischemia, premature labor, CONGR3)2; spontaneous abortion, dismenorrhea, glomerular ne X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 phritis, and systemic lupus erythematosis. Conse to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the quently, the compounds of this invention will alleviate unit the above mentioned diseases. In addition to the prostaglandin antagonist actions, R1 R8 the compounds of this invention are inhibitors of the 45 C Co synthesis of leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease condi wherein the dotted line represents an optional triple tions such as asthma, psoriasis, inflammation, pain, ul bond and in which the R1 and R8substituents are absent cers and systemic anaphylaxis. Thus inhibition of the when a triple bond is present; synthesis of such compounds will alleviate these disease 50 r and q are each independently 0 to 5 and p is 0 or 1 States. provided that the total of p, q and r is 2 to 6; The compounds of the present invention may be used R is H, alkyl of 1 to 6 carbons; phenyl or phenyl to treat or prevent mammalian (especially, human) dis substituted by R; or C1 to CA alkylphenyl or C1 to C4 ease states such as erosive gastritis; erosive esophagitis; 55 alkylphenyl in which the phenyl is substituted by R.'; inflammatory bowel disease; ethanol-induced hemor R, R, R6 and R7 are each independently selected from: rhagic erosions; hepatic ischemia; noxious agent in (1) hydrogen; duced damage or necrosis of hepatic, pancreatic, renal, (2) alkyl having 1 to 6 carbon atoms; or myocardial tissue; liver parenchymal damage caused (3) alkenyl having 2 to 6 carbon atoms; by hepatoxic agents such as CC14 and D-galactosamine; (4) -(CH2)M wherein n is 0 to 3 and M is ischemic renal failure; disease-induced hepatic damage; a) OR12; bile salt induced pancreatic or gastric damage; trauma b) halogen; or stress-induced cell damage; and glycerol-induced c) CF3; renal failure. 65 d) SR12; The present invention relates to a pharmaceutical e) phenyl or substituted phenyl wherein substituted composition comprising a compound of the Formula I: phenyl is as defined below in the definition of R12; f) COOR13; 5,081, 145 3 4. O (H. || || H. g) C-R1; (-,-,-,-,-,-,-) 5 OH. H. H. CH H CH-CH3 h) tetrazole; H. H. H H. H. H. H. H. O (-,-,-,-,-,-,-,-,-,-). i) -NH-C-R1- is 10 OH CH3 OH H OH CH3 H H wherein R15 is C to C6 alkyl, benzyl or phenyl; H. H. H j)-NR13R13; ----, and the like. k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, H CH3 H O CF3; 15 The alkyl groups referred to above may be straight O chain or branched or may include cycloalkyl groups. 1) -C-CH2OH: As used herein, the term "lower' as applied to alkyl, acyl, alkoxy and the like, unless stated otherwise refers m) -SOR12; 20 to groups having 1 to 6 carbon atoms. Halogen or halo n) -CONR 13R 13; means fluoro, chloro, bromo and/or iodo. o) -SO2NR13R 13; Pharmaceutically acceptable salts of the compounds described herein are included within the scope of the p) -SO2R12; present invention. Such salts may be prepared from q) NO2; 25 pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from O inorganic bases include sodium, potassium, lithium, r) O-C-R14. ammonium, calcium, magnesium, ferrous, zinc, copper, O 30 manganous, aluminum, ferric, manganic salts and the I like. Particularly preferred are the potassium, sodium s) O-C-NR13R 13. calcium and magnesium salts. Salts derived from phar maceutically acceptable organic non-toxic bases include O salts of primary, secondary, and tertiary amines, substi t) O-C-OR5, 35 tuted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, u) CN; such as isopropylamine, tri-methylamine, diethanol each R12 independently is H; C to C6 alkyl; benzyl; amine, diethylamine, triethylamine, tripropylamine, phenyl or substituted phenyl wherein the substituents ethanolamine, 2-dimethylaminoethanol, 2-die are C1 to C3 alkyl, halogen, CN, CF3, COOR, 40 thylaminoethanol, tomethamine, lysine, arginine, histi CH2COOR13, C1 to C3 alkoxy, or C1 to C4 perfluoroal dine, caffeine, procaine, hydrabamine, choline, inidaz kyl; ole, betaine, ethylenediamine, , methylglu camine, theobromine, purines , N,N-diben each R13 is independently H, phenyl or C to C6 alkyl; zylethylenediamine, piperidine, N-ethylpiperidine, nor and pholine, N-ethylmorpholine, polyamine resins and the each R14 independently is H., (CH2)COOR13 45 like. wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or Preferred compositions of the present invention com substituted phenyl wherein substituted phenyl is as de prise compounds of the Formula I wherein: fined above in the definition of R12; or a pharmaceuti each R1 is H or alkyl of 1 to 6 carbons or R1 and R8 cally acceptable salt thereof, and a pharmaceutically taken together form a group (CH2) wherein v is 1 to 7; acceptable carrier. 50 R2 is As used herein, the terms "each independently' or the equivalents thereof are employed to describe a num ber of possible position isomers and/or structural varia tions. For example, as described above, R2 is: 55

R1 R wherein: -(+xi-R each R8 is independently H, OH, C1 to C4-O-alkyl R8 R8 60 or alkyl of 1 to 4 carbons; or an R and an R8 taken together form a group (CH2) wherein v is 1 to 7; - The letters r and q, represent possible alkane chains of R9 is COOR1, CH2OH, CHO, tetrazole; CONH from 0 to 5 carbon atoms, each having the R1 and R8 SO2R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 substituent groups. On each carbon atom of the alkane carbons, perhaloalkyl of 1 to 6 carbons, phenyl or chain, the R and/or R8 substituent may be different. 65 phenyl substituted by alkyl or alkoxy groups of 1 to 3 The above description therefore contemplates struc carbons, halogen, hydroxy, COOH, CN, formyl or acyl tures such as the following for the segments -(CRR8 to 1 to 6 carbons; hydroxymethylketone; CN; or )- and -(CRR)-: CONGR3)2; 5,081,145 5 6 X is O; S; SO; SO2, NR11 wherein R11 is H, alkyl of 1 are C1 to C3 alkyl, halogen, CN, CF3, COOR13, C1 to to 6 carbons, acyl of 1 to 6 carbons, CN; CRR, or the C4 perfluoroalkyl; or CH2COOR13; unit each R13 is independently H, phenyl or C1 to C6 alkyl; and, each R1 is independently H, (CH2)COOR13 Ri R8 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted phenyl is as de fined above in the definition of R12; or a pharmaceuti wherein the dotted line represents an optional triple cally acceptable salt thereof, and a pharmaceutically bond and in which the R and R8substituents are absent O acceptable carrier. when a triple bond is present; More preferred compositions of the present invention r and q are each independently 0 to 5 and p is 0 or 1 comprise compounds of the Formula I wherein: provided that the total of P, q and r is 2 to 4; R1 is H or alkyl of 1 to 6 carbons or R1 and R8 taken R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl together form a group (CH2), wherein v is 1 to 7; substituted by R.; or C1 to C4 alkylphenyl or C1 to C4 15 R2 is alkylphenyl in which the phenyl is substituted by R; R, R5, R6 and R7 are each independently selected from: (l) hydrogen; (2) alkyl having 1 to 6 carbon atoms; 20 (3) alkenyl having 2 to 6 carbon atoms; (4) -(CH2)M wherein n is 0 or 1 and M is wherein: a) OR12; each R8 is independently H, OH, C1 to C4-O-alkyl b) halogen; 25 or alkyl of 1 to 4 carbons; or an R and an R8 taken c) CF3; together form a group (CH2) wherein v is 1 to 7; d) SR12; R9 is COOR1; CH2OH, CHO, tetrazole; hydroxyme e) phenyl or substituted phenyl wherein substituted thylketone; phenyl is as defined below in the definition of R12; X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 f) COOR13; 30 to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the t

g) C-R1, Ri R8 h) tetrazole; 35 wherein the dotted line represents an optional triple O bond and in which the R1 and R8substituents are absent i) -NH-C-R15 when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 wherein R15 is C to C6 alkyl, benzyl or phenyl; provided that the total of P, q and r is 2 to 4; j)-NR13R 13; R is H, alkyl of 1 to 6 carbons; phenyl or phenyl k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, substituted by R; or C1 to C4 alkylphenyl or C1 to C4 or CF3; alkylphenyl in which the phenyl is substituted by R; 45 R, R, R6 and R7 are each independently selected from: (1) hydrogen; 1) -C-CH2OH: (2) alkyl having 1 to 6 carbon atoms; (3) alkenyl having 2 to 6 carbon atoms; m) -SOR12; 50 (4) M wherein M is n) -CONR13R 13; a) OR12; o) -SO2NR13R 13; b) halogen; p) -SO2R12; c) CF3; q) NO2; d) SR12; 55 e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12; O f) COOR13; r) O-C-R14, O s) O-C-NR13R 13; g) C-R1, O h) tetrazole; t) O-C-OR15; 65 u) CN: each R12 is independently H; C to C6 alkyl; benzyl; i) -NH-C-R15 phenyl or substituted phenyl wherein the substituents wherein R1 is C to Cs alkyl, benzyl or phenyl; 5,081,145 7 8 j)-NR13R 13; R3 is alkyl of 1 to 6 carbons, but is not cycloalkyl; k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, R4, R5, R6 and R7 are each independently selected or CF3; from: (1) hydrogen; (2) alkyl having 1 to 6 carbon atoms; (3) M wherein M is 1) -C-CH2OH: a) OR12; b) halogen; m) -SOR12 wherein R12 is as defined above; c) CF3; n) -CONR13R13; O d) SR12; o) -SO2NR13R 13; e) -SOR12; p) -SO2R12; f) -SO2R12; q) NO2; O O 15 g) o-c-R1 r) O-C-R14. wherein R1 is H., (CH2)COOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl s) o-c-NRi3R 13; wherein substituted phenyl is as defined above in 20 the definition of R12; H, C1 to C6 alkyl, CF3, phenyl O or substituted phenyl wherein substituted phenyl is t) O-c-OR15; as defined below in the definition of R12; h) CN; u) CN; 25 each R12 is independently H; C1 to C6 alkyl; benzyl; each R12 is independently H; C to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR3, are C1 to C3 alkyl, halogen, CN, CF3, COOR3, CH2COOR13, wherein R3 is H, phenyl, C1 to C6 alkyl, CH2COOR13, or C1 to C4 perfluoroalkyl; or C to C4 perfluoroalkyl; each R13 is independently H, phenyl or C1 to C6 alkyl; 30 or a pharmaceutically acceptable salt thereof, and a and pharmaceutically acceptable carrier. each R14 is independently H, (CH2)COOR13 The present invention also relates to novel com wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or pounds of Formula I represented by Formula la: substituted phenyl wherein substituted phenyl is as de fined above in the definition of R12; or a pharmaceuti cally acceptable salt thereof, and a pharmaceutically 35 R4 4. Ia acceptable carrier. Most preferred compositions of the present invention comprise compounds of the Formula I wherein: R1 is H or alkyl or 1 to 3 carbons or R1 and R taken together form a group (CH2) wherein v is 1 to 7, with the proviso that R on the benzylic carbon attached to the indole nitrogen is H; R2 is 45 R Rl -(+xyg-R R8 R8 50 wherein: wherein: R1 is H or alkyl of 1 to 6 carbons or R1 and R8 taken each R8 is independently H, or alkyl of 1 to 4 carbons; together form a group (CH2) wherein v is 1 to 7; or an R and an R8 taken together form a group (CH2) R2 is wherein v is 1 to 7. R9 is COOR1, CH2OH, CHO; or tetrazole; 55 R R X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CRR, or the unit wherein: R1 R8 each R8 is independently H, OH, C1 to C4-O-alkyl, or CECne alkyl of 1 to 4 carbons or R1 and R8 taken together form a group (CH2) wherein v is 1 to 7; wherein the dotted line represents an optical triple bond R9 is COOR1; CH2OH, CHO, tetrazole; NHSO2R10 and in which the R1 and R8substituents are absent when 65 wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, a triple bond is present; perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substi r and q are each independently 0 to 5 and p is 0 or 1 tuted by alkyl or alkoxy groups of 1 to 3 carbons, halo provided that the total of p, q and r is 2 to 3; gen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 5,081,145 9 O carbons; CONHSOR10; hydroxymethylketone; CN; or -continued CONGR3)2; O X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the unt u) CN; each R12 is independently H; C to C6 alkyl; benzyl; R1 R8 phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR3, as CEC CH2COOR13 C1 to C3 alkoxy, or C1 to C4 perfluoroal O kyl; wherein the dotted line represents an optical triple bond each R13 is independently H, phenyl or C1 to C6 alkyl; and in which the R1 and R3substituents are absent when each R4 is independently H, (CH2)COOR13 a triple bond is present; wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or r and q are each independently 0 to 5 and p is 0 or 1 substituted phenyl wherein substituted phenyl is as de provided that the total of p, q and r is 2 to 6, with the 15 fined above in the definition of R12; or a pharmaceuti proviso that when R1 and R8 are H, X is CH2, R' is cally acceptable salt thereof. 5-methoxy and R6 is halogen, then the sums of p, q and Preferred novel compounds of the present invention r is 3 to 6; are compounds of the Formula Ia wherein: R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl 20 R1 is H or alkyl of 1 to 6 carbons or R and R8 taken substituted by R; or C1 to C4 alkylphenyl or C1 to C4 together form a group (CH2) wherein v is l to 7; alkylphenyl in which the phenyl is substituted by R; R2 is R*, R5, R6 and R7 are each independently selected from: Ri R (1) hydrogen; 25 (2) alkyl having 1 to 6 carbon atons; -(c)--x(g)-R9 (3) alkenyl having 2 to 6 carbon atoms; R8 R8 (4) -(CH2)M wherein n is 0 to 3 and M is a) OR12; wherein: b) halogen; 30 each R8 is independently H, OH, C to C4-O-alkyl, or c) CF3; alkyl of 1 to 4 carbons or R1 and R8 taken together form d) SR 12; a group (CH2) wherein v is 1 to 7; R9 is COOR1, CH2OH, CHO, tetrazole; CONH e) phenyl or substituted phenyl wherein substituted SOR10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 phenyl is as defined below in the definition of R12; 35 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or f) COOR13; phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; hydroxymethylketone; CN; or g) C-R1. CONCR8); X is O; S; SO; SO2, NR11 wherein R11 is H, alkyl of 1 h) tetrazole; to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the t O Ri R8 i) -NH-c-Riss 45 -CaC wherein R15 is C1 to C6 alkyl, benzyl or phenyl; j)-NR13R 13; wherein the dotted line represents an optional triple k)-NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, bond and in which the R and R8substituents are absent or CF3; 50 when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 4, with the proviso that when R1 and R8 are H, X is CH2, R“ is 1) -C-CHOH; 5-methoxy and R is halogen, then the sums of p, q and 55 r is 3 to 4; m) -SOR12; R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl n) -CONR13Ri3; substituted by R; or C1 to C4 alkylphenyl or C1 to C4 o) -SO2NR13R13; alkylphenyl in which the phenyl is substituted by R“; p) -SO2R12; R“, R5, R6 and R7 are each independently selected 60 from: q) NO2; (1) hydrogen; (2) alkyl having 1 to 6 carbon atons; O (3) alkenyl having 2 to 6 carbon atons; (4) -(CH2)M wherein n is 0 or 1 and M is 65 a) OR12; b) halogen; c) CF3; d) SR12; 5,081,145 11 12 e) phenyl or substituted phenyl wherein substituted R9 is COOR; CH2OH, CHO, tetrazole; hydroxyme phenyl is as defined below in the definition of R12; thylketone; f) COOR 13; X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the O 5 t g) c-R; Ri R8 wherein R1 is H., (CH2)COOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl io as CaC wherein substituted phenyl is as defined below in the definition of R12; wherein the dotted line represents an optional triple h) tetrazole; bond and in which the R and R8substituents are absent when a triple bond is present; r and q are each independently 0 to 5 and p is 0 or 1 15 provided that the total of p, q and r is 2 to 4, with the i) -NH-C-R15 proviso that when R and R8 are H, X is CH2, R' is 5-methoxy and R is halogen, then the sums of p, q and wherein R5 is C1 to C6 alkyl, benzyl or phenyl; r is 3 to 4; j)-NR13R 13; R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl k)-NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, substituted by R; or C1 to C4 alkylphenyl or C1 to C4 or CF3; alkylphenyl in which the phenyl is substituted by R; R“, R5, R6 and R7 are each independently selected from: 1) -C-CH2OH: 25 (l) hydrogen; (2) alkyl having 1 to 6 carbon atoms; m) -SOR12; (3) alkenyl having 2 to 6 carbon atoms; n) -CONR13R 13; (4) M wherein M is o) -SO2NR13R 13; a) OR12; p) -SO2R12; 30 b) halogen; q) NO2; c) CF3; d) SR 12; O e) phenyl or substituted phenyl wherein substituted r) O-C-R1.14 35 phenyl is as defined below in the definition of R12; f) COOR 13; s) o-c-NR13R 13. O g) c-R4, 40 t) O-c-OR15. h) tetrazole; u) CN: each R12 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents 45 are C1 to C3 alkyl, halogen, CN, CF3, COOR3, i) on NH-C-R15 CH2COOR13 C1 to C3 alkoxy C1 to C4 perfluoroalkyl; wherein R15 is C1 to C6 alkyl, benzyl or phenyl; each R13 is independently H, phenyl or C1 to C6 alkyl; j)-NR13R 13; each R4 is independently H, (CH2)COOR3 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or 50 k)-NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, substituted phenyl wherein substituted phenyl is as de or CF3; fined above in the definition of R12; or a pharmaceuti cally acceptable salt thereof. O More preferred novel compounds of the present in 1) -C-CH2OH, vention are compounds of the formula Ia wherein: 55 R1 is H or alkyl of 1 to 6 carbons or R and R8 taken m) -SOR12; together form a group (CH2) wherein v is 1 to 7; n) -CONR13R 13; R2 is o) -SO2NR13R 13; p) -SO2R12; R R1 60 q) NO2; -(c)--x(c)-R9 R8 R8 O r) O-C-R1. wherein: 65 each R8 is independently H, OH, C1 to C4-O-alkyl, or alkyl of 1 to 4 carbons or R1 and R8 taken together form a group (CH2) wherein v is 1 to 7; 5,081,145 13 14 -continued wherein R1 is H, C1 to C6 alkyl, CF3, phenyl or O substituted phenyl wherein substituted phenyl is as defined below in the definition of R12; h) CN; u) CN: each R12 is independently H; C1 to C6 alkyl; benzyl; each R12 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR13, are C1 to C3 alkyl, halogen, CN, CF3, COOR3, CH2COOR3, C1 to C3 alkoxy; or C1 to C4 perfluoroal CH2COOR13, C1 to C3 alkoxy or C1 to C4 perfluoroal 10 kyl; kyl; each R13 is independently H, phenyl or C1 to C6 alkyl; each R13 is independently H, phenyl or C1 to C6 alkyl; or a pharmaceutically acceptable salt thereof. and Most-particularly preferred novel compounds of the each R1 is H, (CH2)COOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein 15 present invention are compounds of the formula Ia substituted phenyl is as defined above in the definition wherein: of R12; or a pharmaceutically acceptable salt thereof. R1 is H or alkyl of 1 to 3 carbons, with the proviso Most preferred novel compounds of the present in that R1 on the benzylic carbon attached to the indole vention are compounds of the formula Ia wherein: nitrogen is H; R1 is H or alkyl of 1 to 3 carbons or R and R8 taken 20 R2 is together form a group (CH2) wherein v is 1 to 7, with the proviso that R on the benzylic carbon attached to the indole nitrogen is H; Ri R1 R2 is -(c)--x(g)-R9 25 R8 R8 R1 R -(+xyg-r' wherein: R8 R8 each R8 is independently H or alkyl of 1 to 4 carbons, 30 with the proviso that at least one of the R1 or R3substit wherein: uents in R2 is not hydrogen; each R8 is independently H, OH, C1 to C4-O-alkyl or R9 is COOH, CH2OH, CHO; or tetrazole; alkyl of 1 to 4 carbons or R and R8 taken together form X is CRR8; a group (CH2), wherein v is 1 to 7; r and q are each independently 0 to 3 and p is 0 or 1 R9 is COOR1, CH2OH: CHO, or tetrazole; 35 provided that the total of p, q and r is 2 to 3; X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 R3 is alkyl of 1 to 6 carbons, but not cycloalkyl; to 6 carbons, acyl of 1 to 6 carbons, CN; CRR8; or the R“, R5, R6 and R7 are each independently selected unit fron: (1) hydrogen; R1 R8 (2) alkyl having 1 to 6 carbon atoms; -CeC (3) M wherein M is a) OR12; wherein the dotted line represents an optional triple b) halogen; bond and in which the R and R8substituents are absent 45 c) CF3; when a triple bond is present; d) SR 12; r and q are each independently 0 to 5 and p is 0 or 1 e) -SOR12; provided that the total of p, q and r is 2 to 3, with the proviso that when R1 and R8 are H, X is CH2, R“ is f) -SO2R12; 5-methoxy and R is halogen, then the sum of r, p and q 50 is 3 to 4; O R3 is alkyl of 1 to 6 carbons, but not cycloalkyl; g) o-c-R4, R“, R5, R6 and R7 are each independently selected fron: (1) hydrogen; 55 wherein R is H, C to C6 alkyl, CF3, phenyl or (2) alkyl having 1 to 6 carbon atoms; substituted phenyl wherein substituted phenyl is as (3) M wherein M is defined below in the definition of R12; a) OR12; h) CN; b) halogen; each R2 is independently H; C1 to C6 alkyl; or benzyl; c) CF3; 60 or a pharmaceutically acceptable salt thereof. d) SR12; Other most-particularly preferred novel compounds e) -SOR12; of the present invention are compounds of the formula f) -SO2R12; Ia wherein: R1 is H or alkyl of 1 to 3 carbons, with the proviso 65 that R on the benzylic carbon attached to the indole g) o-c-R14, nitrogen is H; R2 is 5,081,145 15 16 The following reaction schemes illustrate the prepa ration of the compounds of the present invention:

Scheme I Preparation of Formula I Compounds R4 RS R3 R3

lower N-NH2 -- alkanol R2 R5 O (7 R2 reflux R5 N HC) Rl III R1 R6 R6

R7 R7 II I R5 R

R5 N CH2R3

R R6

R7 Ib

Schene III -(c)--x(c)-R9 Preparation of Hydrazine Derivatives (II) is 7. CHR1 wherein: 40 R4 each R8 is independently H or alkyl of 1 to 4 carbons; R9 is COOH, CH2OH, CHO; or tetrazole; Et3N X is O; S; SO; or SO2: -- -i > r and q are each independently 0 to 3 and p is 1 pro- reflux vided that the total of p, q and r is 2 to 3; 45 NH-NB: , 7 R3 is alkyl of 1 to 6 carbons, but not cycloalkyl; R HCl R R R“, R5, R6 and R7 are each independently selected V V from: R4 (l) hydrogen; (2) alkyl having 1 to 6 carbon atoms; 50 (3) M wherein M is a) OR12; b) halogen; N-NH2 c) CF3; Rs d) SR12; 55 HC e) -SOR12; Rl f) -SO2R12; R6

O g) o-c-R“, I wherein R4 is H, C1 to C6 alkyl, CF3, phenyl or With regard to Scheme I, the alkanol solvent can substituted phenyl wherein substituted phenyl is as have an important effect on the course of the reaction. defined below in the definition of R12; 65 With some of the ketones III, the final product may h) CN; contain a mixture of the isomers I and Ib. Formation of each R12 is independently H; C1 to C6 alkyl; or benzyl; the undesired Ib is minimized by using ispropanol or or a pharmaceutically acceptable salt thereof. tert-butanol in place of methanol or ethanol. 5,081,145 17 18 The sequence described above is an application of the The Bischler Indole Synthesis used in the sequence Fischer Indole Synthesis. Numerous indole syntheses described for the synthesis of compounds of the present are described in reviews, such as, for example "Hetero invention envisages the alkylation of an appropriately cyclic Compounds' Volume 25, Parts I, II, III, W. J. 5 substituted halo or tosyloxy ketone (VII) by an appro Houlihan (Ed.), Interscience, J. Wiley & Sons, N.Y., priately substituted aniline derivative (VI), in an alco 1979. Appropriate manipulations of functional groups holic solvent. The condensation step is effected through the use of a Lewis Acid or mineral acid. The indole using sequences described in such reviews will lead to derivative.so produced (IX) may then be alkylated by the compounds of the present invention. Another useful an aralkylhalide to product I. sequence is shown in Scheme III. The following ketones (1-7) of structure III are known in the art: Schene III Preparation of Indole-2-Alkanoic acids 15 TABLE R4 Ketones of Formula III No. Structure Reference R3 1. Methyl 4-oxohexanoate: -- 2 R2. G B. L. Feringa and O 20 W. Dannenberg, Synth. NH Commun., 3, 509-514 R5 X O COMe (1983). VI VII 2. Ethyl 4-oxohexanoate: D. A. Wehrli and V. Chu, R4 25 Org. Synth., 58, 79-82 (1978). O R3 N 3. 3-Methyl-4-oxohexanoate: ZnCl27, orAise ACl3 A. P. Cowling and J. Mann, J. Chen. Soc., Rs H R2 30 Chem. Commun., 1006-007 VIII H (1978). Methyl 2,2-dimethyl-4- R4 oxohexanoate: R. Scarpati, G. Scherillo, R3 35 F. Imperato and R. A. Nicolaus, Gazz. Chim. Ital, 97, 654–664 (1967). R5 NH R 5. Methyl 5-oxoheptanoate: 40 M. K. Eberle and G. G. Kahle, Tetrahedron Lett. R6 21, 2303-2304 (1980). CH2X 6. 3-Methyl-5-oxoheptanoic + IX-Ge. 45 acid: C. Conti, A. Niccoli and R. Rossi, R7 Chim. Ind. (Milan) 58; 877 (1976). R4 Methyl 6-oxooctanoate: 50 T. Terasawa and T. Okada, R3 Tetrahedron 33, 595-598 (1977).

N R2 Ethyl 2,3-dimethyl-4-oxo R5 55 hexanoate

COOEt R6

60 Examples of Formula I compounds useful in the pharmaceutical compositions of the present invention are tabulated below. The numbers preceding the R, R R, and R7 definitions indicate the substituent position in the structure. Standard abbreviations such as Me for 65 methyl, Et for ethyl, Pr for propyl, Bufor butyl, Ac for X = Cl: Br; o-o-O)-ch acetyl, and Ph for phenyl are used. Compounds 3 to 72 are novel compounds.

5,081,145 23 24 Specific Examples of the Formula I compounds are 3-(1-p-chlorobenzyl-3-methyl-5-methoxyindol-2-yl)- the following, all but the first being novel: 2,2-diethyl propanoic acid; 3-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2- 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)-2,2- yl); diethyl propanoic acid; 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)pro 5 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)-2- pionic acid; ethyl propanoic acid; 3-1-(4-chlorobenzyl)-3,4-dimethylindol-2-yl)propionic 3-1-(4-chlorobenzyl)-3-ethyl-5-fluoroindol-2-yl)-3- acid; methyl propanoic acid; and 4-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2- 3-1-(4-chlorobenzyl-3-methyl-5-methoxy-2-indolyl)- yl)butanoic acid; 10 3-1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2- pentanoic acid. yl)propionic acid; In those instances when asymmetric centers are pres 3-(1-(4-chlorobenzyl)-3-methylindol-2-yl)propionic ent, more than one stereoisoner is possible, and all acid; possible isomeric forms are deemed to be included 3-1-(4-methylthiobenzyl)-3-methyl-5-methoxyindol-2- 15 within the planar structural representations shown. yl)propionic acid; Optically active (R) and (S) isoners may be resolved 3-1-(4-methylthiobenzyl)-3-methyl-5-fluoroindol-2- using conventional techniques known to the skilled yl)propionic acid; artisan. 3-1-(4-methylsulfinylbenzyl)-3-methyl-5-methoxyin The prostaglandin antagonist properties of the com dol-2-yl)propionic acid; pounds of the present invention can be demonstrated by 4-1-(4-methylthiobenzyl)-3-methyl-5-methoxyindol a number of biological assays, one of which, inhibition 2ylbutanoic acid; of platelet aggregation, is described below. 4-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2- yl)butanoic acid; Inhibition of Induced Threshold Aggregation of 1-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2- 25 Human Platelets yl)methoxyacetic acid; Human platelet rich plasma (PRP) is prepared from 3-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl)- venous blood of male volunteers who have taken no 2,2-dimethylpropanoic acid; nedication for ten days prior to test. Blood is trans 3-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl)-3- 30 ferred into plastic centrifuge tubes containing 3.8% methylpropanoic acid; Trisodium Citrate in 0.9% NaCl (in a ratio of blood to 3-methyl-4-1-(4-chlorobenzyl)-5-methoxy-3-methylin anticoagulant of 9:1), mixed by gentle inversion, and dol-2-yl)butanoic acid; 3-methyl-4-1-(4-chlorobenzyl)-5-fluoro-3-methylindol centrifuged at room temperature for ten minutes at 116 2-yl)butanoic acid; g. The supernatant (PRP) is transferred into plastic 3-1-(4-chlorobenzyl)-3-methyl-5-fluoro-2-indolyl)-2,2- 5 tubes. Platelet poor plasma (PPP) is obtained by centri dimethyl propanoic acid. fuging the residual blood cells at 4000 g for ten minutes. Further examples include: PRP is left to stand at least one half hour prior to test 4-1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl)- 1ng. 2,4,3,3-tetramethylbutanoic acid; Platelet Aggregation is measured using a Payton 4-1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl)- Aggregometer and Recorder. Following calibration of 4,3,3-trimethylbutanoic acid; the instrument, a cuvette containing PRP (225 microli 4-1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl)- ters) is incubated for three minutes at 37 C. Drug vehi 2,2,3-trimethylbutanoic acid; cle (control), or a drug concentration is then added in a 4-1-(4-chlorobenzyl-5-fluoro-3-methyl-1H-indol-2-yl)- 45 volume of 0.5 microliter. After one minute, the aggre 2,3,3-trimethyl butanoic acid; gating agent (U44069, 9,11-dideoxy-9a,11a-epoxyme 4-1-(4-chlorobenzyl-5-methoxy-3-methyl-1H-indol-2- thano PGF2g) is added to the cuvette in a volume of 25 yl)-2,2,3-trimethylbutanoic acid; microliters. Recording is continued until the maximal 4-1-(4-chlorobenzyl-5-ethoxy-3-methyl-1H-indol-2-yl)- response is obtained. 2,2,3-trimethylbutanoic acid; 50 The threshold (approximately 20–30% of maximum) 4-1-(4-chlorobenzyl-5-chloro-3-methyl-1H-indol-2-yl)- aggregation concentration of the agonist to be used is 2,2,3-trimethylbutanoic acid; first determined in the presence of the drug vehicle 4-1-(4-chlorobenzyl-3-methyl-5-trifluoromethyl-1H (control). Test compounds are then assayed at 10 or 30 indol-2-yl)-2,4,3,3-tetramethylbutanoic acid; micrograms/ml initially, and if active, are further tested 4-1-(4-chlorobenzyl-3-methyl-5-trifluoromethylthio 55 . 1H-indol-2-yl)-2,4,3,3-tetramethylbutanoic acid; in order to determine the concentration range at which 3-1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2- 20-80% of the threshold aggregatory response is inhib yl)-2,2,3-trimethyl propanoic acid; ited. All drugs are dissolved in dimethylsulfoxide. 3-1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2- The height of the aggregation response (measured in yl)-2,3,3-trimethyl propanoic acid; 60 divisions of the recorder paper, 1 division=2.5 mm) in 3-1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2- the presence of the drug is recorded, and calculated as yl)-2,2,3,3-tetramethyl propanoic acid; percent inhibition of the mean height of the control 3-1-(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2- threshold responses. The ICso (drug concentration yl)-2,2,3-trimethyl propanoic acid; which inhibits 50% of the aggregatory response) is 3-1-(4-chlorobenzyl)-5-fluoro-3-methyl-1H-indol-2-yl)- 65 obtained by regression analysis. 2,2,3-trimethyl propanoic acid; Compounds of Formula I or Ia can be tested using the 3-1-(4-chlorobenzyl)-5-chloro-3-methyl-1H-indol-2- following assay to determine their mammalian leuko yl)-2,2,3-trimethyl propanoic acid; triene biosynthesis inhibiting activity. 5,081,145 25 26 of from about 0.01 mg to about 100 mg per kg body Rat Peritoneal Polymorphonuclear (PMN) weight of a mammal. Leukocyte Assay The exact amount of a compound of Formula I or Ia to be used as a cytoprotective agent will depend on, Rats under ether anesthesia are injected (i.p.) with 8 inter alia, whether it is being administered to heal dam ml of a suspension of sodium caseinate (6 grams in ca. 50 aged cells or to avoid future damage, on the nature of ml water). After 15-24 hr. the rats are sacrificed (CO2) the damaged cells (e.g., gastro-intestinal ulcerations vs. and the cells from the peritoneal cavity are recovered nephrotic necrosis), and on the nature of the causative by lavage with 20 ml of buffer (Eagles MEM containing agent. An example of use of a compound of Formula I 30 mM HEPES adjusted to pH 7.4 with NaOH). The 10 or Ia to avoid future damage is co-administration with a cells are pelleted (350Xg, 5 min.), resuspended in buffer non-steroidal anti-inflammatory drug (for example, in with vigorous shaking, filtered, through lens paper, domethacin). recentrifuged and finally suspended in buffer at a con The effective daily dosage level for compounds of centration of 10 cells/ml. A 500 ul aliquot of PMN Formulae I or Ia inducing cytoprotection in mammals, suspension and test compound are preincubated for 2 15 especially humans, will generally range from about minutes at 37 C., followed by the addition of 10 plM 0.002 mg/kg to about 100 mg/kg, preferably from about A-23187. The suspension is stirred for an additional 4 0.02 mg/kg to about 30 mg/kg. The dosage may be minutes then bioassayed for LTB4 content by adding an administered in single or divided individual doses. aliquot to a second 500 ul portion of the PMN at 37° C. Any suitable route of administration may be en The LTB4 produced in the first incubation causes ag 20 ployed for providing a mammal, especially a human gregation of the second PMN, which is measured as a with an effective dosage of a compound of Formula I or change in light transmission. The size of the assay ali Ia. For example, oral, rectal, transdermal, parenteral, quot is chosen to give a submaximal transmission intramuscular, intravenous and the like may be em change (usually -70%) for the untreated control. The ployed. Dosage forms include tablets, troches, disper percentage inhibition of LTB4 formation is calculated 25 sions, suspensions, solutions, capsules and the like. from the ratio of transmission change in the sample to The pharmaceutical compositions of the present in the transmission change in the compound-free control. vention comprise a compound of Formula I or Ia as an The cytoprotective activity of a compound may be active ingredient or a pharmaceutically acceptable salt observed in both animals and many by noting the in thereof, and may also contain a pharmaceutically ac creased resistance of the gastrointestinal mucosa to the 30 ceptable carrier and optionally other therapeutic ingre noxious effects of strong irritants, for example, the ul dients. The term "pharmaceutically acceptable salts' cerogenic effects of or indomethacin. In addition refers to salts prepared from pharmaceutically accept to lessening the effect of non-steroidal anti-inflamma able non-toxic bases including inorganic bases and or tory drugs on the gastrointestinal tract, animal studies ganic bases. Salts derived from inorganic bases include 35 sodium, potassium, lithium, annonium, calcium, mag show that cytoprotective compounds will prevent gas nesium, ferrous, zinc, copper, manganous, aluminum, tric lesions induced by oral administration of strong ferric, manganic salts and the like. Particularly pre acids, strong bases, ethanol, hypertonic saline solutions ferred are the annonium, potassium, sodium, calcium and the like. and magnesium salts. Salts derived from pharmaceuti Two assays can be used to measure cytoprotective cally acceptable organic non-toxic bases include salts of ability. These assays are; (A) an ethanol-induced lesion primary, secondary, and tertiary amines, substituted assay and (B) an indomethacin-induced ulcer assay. amines including naturally occurring substituted anines, cyclic amines and basic ion exchange resins, A. Ethanol-Induced Gastric Ulcer Assay such as isopropylamine, trimethylamine, diethylamine, Twenty-four hour fasted Sprague-Dawley (S.D.) rats 45 triethylamine, tripropylamine, ethanolamine, 2-dime are perorally (p.o.) dosed with 1.0 ml absolute ethanol. thylaminoethanol, 2-diethylaminoethanol, trometha Fifteen to thirty minutes prior to ethanol administra mine, lysine, arginine, histidine, caffeine, procaine, hy tion, groups of rats each receive either an aqueous vehi drabamine, choline, betaine, ethylenediamine, glucos cle (aqueous methylcellulose 5% wt.) or the test com amine, methylglucamine, theobromine, purines, pipera pound at various doses perorally. One hour later, the 50 zine, piperidine, N-ethylpiperidine, polyamine resins animals are sacrificed and stomach mucosae are exam and the like. The compositions include compositions ined for resulting lesions. suitable for oral, rectal, ophthalmic, pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, B. Indomethacin-Induced Ulcer Assay intramuscular and intravenous) administration, al Indomethacin, 10 mg/kg p.o., is used to induce ulcers 55 though the most suitable route in any given case will in 24 hour fasted S.D. rats. Fifteen minutes prior to depend on the nature and severity of the conditions indomethacin administration, groups of rats each re being treated and on the nature of the active ingredient. ceive either an aqueous vehicle (5% by weight methyl They may be conveniently presented in unit dosage cellulose) or the test compound at various doses per form and prepared by any of the methods well-known orally. Four hours later the animals are sacrificed and in the art of pharmacy. stomach mucosae are examined for resulting ulcers. For use where a composition for intravenous admin The magnitude of a prophylactic or therapeutic dose istration is employed, a suitable dosage range for anti of a compound of Formula I or Ia will, of course, vary asthmatic, anti-inflammatory or anti-allergic use is from with the nature of the severity of the condition to be about 0.01 mg to about 20 mg (preferably from about treated and with the particular compound of Formula I 65 0.1 mg to about 10 mg) of a compound of Formula I or or Ia and its route of administration. In general, the Iaper kg of body weight per day and for cytoprotective daily dose range for anti-asthmatic, anti-allergic, anti-in use from about 0.002 mg to about 100 mg (preferably flammatory, or anti-thrombotic use lies within the range from about 0.02 mg to about 30 mg and more preferably 5,081,145 27 28 from about 0.1 mg to about 10 mg) of a compound of accessory ingredients. Compressed tablets may be pre Formula I or Ia per kg of body weight per day. In the pared by compressing in a suitable machine, the active case where an oral composition is employed, a suitable ingredient in a free-flowing form such as powder or dosage range for anti-asthmatic, anti-inflammatory or granules, optionally mixed with a binder, lubricant, anti-allergic use is, e.g. from about 1 to about 100 mg of 5 inert diluent, lubricating, surface active or dispersing a compound of Formula I or Ia per kg of body weight agent. Molded tablets may be made by molding in a per day, preferably from about 5 mg to about 40 mg per suitable machine, a mixture of the powdered compound kg and for cytoprotective use from about 0.01 mg to moistened with an inert liquid diluent. Desirably, each about 100 mg (preferably from about 0.1 mg to about 30 tablet contains from about 25 mg to about 500 mg of the mg and more preferably from about 0.1 mg to about 10 10 active ingredient and each cachet or capsule contains mg) of a compound of Formula I or Ia per kg of body from about 25 to about 500 mg of the active ingredient. weight per day. The following are examples of representative phar For administration by inhalation, the compounds of maceutical dosage forms for the compounds of Formula the present invention are conveniently delivered in the I or Ia: form of an aerosol spray presentation from pressurized 15 packs or a nebuliser. The preferred composition for niectable Suspension - Ing/ml inhalation is a powder which may be formulated as a Compound of Formula I or Ia 2.0 cartridge from which the powder composition may be Methylcellulose 5.0 inhaled with the aid of a suitable device. In the case of Tween 80 0.5 20 Benzyl alcohol 9.0 a pressurized aerosol, the dosage unit may be deter Methyl paraben 1.8 mined by providing a valve to deliver a metered Propyl paraben 0.2 amount. Water for injection to a total volume of 1 ml In practical use, a compound of Formula I or Ia can Tablet mg/tablet be combined as the active ingredient in intimate admix Compound of Formula I or Ia 25.0 ture with a pharmaceutical carrier according to conven 25 Microcrystalline Cellulose 325.0 Providone 14.0 tional pharmaceutical compounding techniques. The Microcrystalline Cellulose 90.0 carrier may take a wide variety of forms depending on Pregelatinized Starch 43.5 the form of preparation desired for administration, e.g., Magnesium Stearate 2-2.5 oral or intravenous. In preparing the compositions for 500 oral dosage form, any of the usual pharmaceutical 30 Capsule ng/capsule media may be employed, such as, for example, water Compound of Formula 1 or Ia 25.0 glycols, oils, alcohols, flavoring agents, preservatives, Lactose Powder 573.5 coloring agents and the like in the case of oral liquid Magnesium Stearate 1-1.5 preparations, such as, for example, suspensions, elixirs 600 and solutions; or carriers such as starches, sugars, dilu 35 ents, granulating agents, lubricants, binders, disintegrat In addition to the compounds of Formula I or Ia, the ing agents and the like in the case of oral solid prepara pharmaceutical compositions of the present invention tions such as, for example, powders, capsules and tab can also contain other active ingredients, such as non lets. Because of their ease of administration, tablets and steroidal anti-inflammatory drugs (NSAIDs), periph capsules represent the most advantageous oral dosage eral agents such as zonepirac, and unit form, in which case solid pharmaceutical carriers the like, inhibitors, leukotriene antago are obviously employed. If desired, tablets may be sugar nists, leukotriene biosynthesis inhibitors, H2-receptor coated or enteric coated by standard techniques. antagonists, antihistiminic agents, prostaglandin antago In addition to the common dosage forms set out nists, ACE inhibitors, and thromboxane synthetase in above, the compounds of Formula I or a may also be 45 hibitors. The weight ratio of the compound of the For administered by controlled release means and/or deliv mula I or Ia to the second active ingredient may be ery devices such as those described in U.S. Pat. Nos. varied and will depend upon the effective dose of each 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and ingredient. Generally, an effective dose of each will be 4,008,719, the disclosure of which is hereby incorpo used. Thus, for example, when a compound of the For rated herein by reference. 50 mula I or Ia is combined with a second active ingredient Pharmaceutical compositions of the present invention the weight ratio of the compound of the Formula I or Ia suitable for oral administration and by inhalation in the to the second ingredient will generally range from case of asthma therapy may be presented as discrete about 1000:1 to about 1:1000, preferably from 200:1 to units such as capsules, cachets or tablets each contain 1:200. Combinations of a compound of the Formula I or ing a predetermined amount of the active ingredient, as 55 Ia and other active ingredients will generally be within a powder or granules or as a solution or a suspension in the aforementioned range, but in each case, an effective an aqueous liquid, a non-aqueous liquid, an oil-in-water dose of each active ingredient should be used. emulsion or a water-in-oil liquid emulsion. Such compo NSAIDs can be characterized into five groups: sitions may be prepared by any of the methods of phar (1) the propionic acid derivatives; macy but all methods include the step of bringing into (2) the derivatives; association the active ingredient with the carrier which (3) the derivatives; constitutes one or more necessary ingredients. In gen (4) the biphenylcarboxylic acid derivatives; and eral, the compositions are prepared by uniformly and (5) the intimately admixing the active ingredient with liquid or a pharmaceutically acceptable salt thereof. carriers or finely divided solid carriers or both, and 65 The propionic acid derivatives which may be used then, if necessary, shaping the product into the desired comprise: , ibuprufen aluminum, , presentation. For example, a tablet may be prepared by , , , , feno compression or molding, optionally with one or more profen, , ketoprofen, indoprofen, , 5,081,145 29 30 , , , , tioxa which can bear a variety of substituents and in which profen, , , , flu the free -COOH group can be in the form of a pharma profen and bucloxic acid. Structurally related propionic ceutically acceptable salt group, e.g., -COO-Na+. acid derivatives having similar analgesic and anti-in The oxicans which can be used in the present inven flammatory properties are also intended to be included tion comprise: piroxican, Sudoxicam, and 4 in this group. hydroxyl-1,2-benzothiazine 1,1-dioxide 4-(N-phenyl)- Thus, "propionic acid derivatives' as defined herein carboxamide. Structurally related oxicams having simi are non-narcotic /non-steroidal anti-inflam lar analgesic and anti-inflammatory properties are also matory drugs having a free -CH(CH3)COOH or intended to be encompassed by this group. -CH2CH2COOH group (which optionally can be in 10 Thus, "oxicans' as defined herein are non-narcotic the form of a pharmaceutically acceptable salt group, analgesics/non-steroidal anti-inflammatory drugs C-3. -CH(CH3)COO-Na+ Or -CH2CH which have the general formula: 2COONa), typically attached directly or via a car bonyl function to a ring system, preferably to an aro 15 OH matic ring system. O The acetic acid derivatives which may be used com prise: indomethacin, which is a preferred NSAID, sulin C-NH-R diac, , zonepirac, , , al clofenac, ibufenac, isoxepac, furofenac, tiopinac, 20 N zidometacin, , , clidanac, oxpinac, S / CH3 and . Structually related acetic acid deriv (O)2 atives having similar analgesic and antiinflammatory properties are also intended to be encompassed by this wherein R is an aryl or heteroaryl ring system. group. 25 The following NSAIDs may also be used: acemeta Thus, "acetic acid derivatives' as defined herein are cin, alminoprofen, sodium, aminoprofen, ani non-narcotic analgesics/non-steroidal anti-inflamma trazafen, antrafenine, auranofin, lysinate, ben tory drugs having a free -CH2COOH group (which zydamine, beprozin, broperamole, bufezolac, carprofen, optionally can be in the form of a pharmaceutically cinmetacin, ciproguazone, clidanac, cloximate, dazida acceptable salt group, e.g. -CH2COONa), typi 30 mine, deboxamet, delmetacin, detonidine, dexindo cally attached directly to a ring system, preferably to an profen, , di-fisalamine, difenpyramide, emorfa aromatic or heteroaromatic ring system. zone, enfenamic acid, enolicam, epirizole, etersalate, The fenamic acid derivatives which may be used , , fanetizole mesylate, fenclofenac, comprise: , , flufe fenclorac, fendosal, fenflumizole, fentiazac, , namic acid, and . Structur 35 , , , , ally related fenamic acid derivatives having similar fopiirtoline, fosfosal, furcloprofen, furofenac, analgesic and anti-inflammatory properties are also glucanetacin, guaimesal, , isofezolac, iso intended to be encompassed by this group. nixim, isoprofen, isoxepac, isoxicam, lefetamine HCl, Thus, "fenamic acid derivatives' as defined herein leflunomide, lofemizole, calcium, lotifazole, are non-narcotic analgesics/non-steroidal anti-inflam , lysin clonixinate, meclofenamate sodium, matory drugs which contain the basic structure: meseclazone, miroprofen, , nictindole, ninesulide, orpanoxin, , oxapadol, oxapro zin, perisoxal citrate, pineprofen, pimetacin, piproxen, 45 pirazolac, pirfenidone, pirprofen, pranoprofen, pro NH glumetacin maleate, , pyridoxiprofen, sudoxican, suprofen, talmetacin, talniflumate, tenox ican, thiazolinobutazone, thielavin B, tiaprofenic acid, COOH tiaramide HCl, tiflamizole, timegadine, tioxaprofen, 50 tolfenamic acid, tolpadol, tryptamid, ufenamate, and . which can bear a variety of substituents and in which zidometacin. the free -COOH group can be in the form of a pharma The following NSAIDs, designated by company ceutically acceptable salt group, e.g., -COONa. The biphenylcarboxylic acid derivatives which can code number, may also be used: 48.0156S, AA861, be used comprise: diflunisal and flufenisal. Structurally AD1491, AD1590, AFP802, AFP860, AHR6293, 55 AI77B, AP504, AU8001, BAYo8276, BPPC, BW540C, related biphenylcarboxylic acid derivatives having simi BW755C, CHINOIN 127, CN100, CO893XX, CPP, lar analgesic and anti-inflammatory properties are also D10242, DKA9, DV17, EB382, EGYT2829, EL508, intended to be encompassed by this group. F1044, FZ, GP53633, GP650, GV3658, HG/3, ITC, Thus, "biphenylcarboxylic acid derivatives' as de ITF, ITF182, KB1043, KC8973, KCNTEI6090, fined herein are non-narcotic analgesics/non-steroidal KME4, LA2851, LT696, LU20884, M7074, MED15, anti-inflammatory drugs which contain the basic struc MG18311, MR714, MR897, MY309, NO 164, tute: ONO3144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029, RU26559, RUB265, SCR152, SH440, SIR 133, SIR 136, SIR92, SPAS510, SQ27239, 65 ST281, SX1032, SY6001, SaH46798, TA60, TAI901, TEI615, TVX2706, TVX960, TZI615, U60257, ( ) ( ) COOH UR2310, WY23205, WY41770, YMO9561, YM13162, YS1033, and ZK31945. 5,081,145 31 32 Finally, NSAIDs which may also be used include the 1,2,3,4-tetrahydroiso-isoquinoline-3(S)-carboxylic acid; salicylates, specifically aspirin, and the phenylbuta and, 1-carboxymethyl-3(S)-(1(S)-ethoxycarbonyl-3- zones, and pharmaceutically acceptable salts thereof. phenylpropylamino)-2,3,4,5-tetrahydro-lh 1-benzaze Pharmaceutical compositions comprising the For pine-2-one. mula I or a compounds may also contain other inhibi In particular the class of ACE inhibitors which have tors of the biosynthesis of the leukotrienes such as are been found to have a potentiating effect when used in disclosed in EP 138,481 (Apr. 24, 1985), EP 115,394 combination with the Formula I or Ia compounds are (Aug. 8, 1984), EP 136,893 (Apr. 10, 1985), and EP those disclosed in U.S. Pat. No. 4,374,829, which also 140,709 (May 8, 1985), which are hereby incorporated discloses methods for their preparation and which pa herein by reference. O tent is incorporated herein by reference and which The compounds of the Formula I or Ia may also be compounds are generally represented by the Formula used in combination with leukotriene antagonists such XI: as those disclosed in EP 106,565 (Apr. 25, 1984) and EP 104,885 (Apr. 4, 1984), which are hereby incorporated herein by reference and others known in the art such as 15 O R1 R3 R4 R5 O XI those disclosed in European Patent Application Nos. R-C-c-NH-cH-C-N-C-C-R6 56,172 and 61,800; and in U.K. Patent Specification No. 2,058,785, which are hereby incorporated herein by R2 O R7 reference. Pharmaceutical compositions comprising the For 20 wherein mula I or Ia compounds may also contain as the second R and R6 are the same or different and are hydroxy, active ingredient, antihistaminic agents such as bena lower C1-C3 alkoxy; dryl, dramamine, histadyl, phenergan and the like. Al lower C-C8 alkenoxy; ternatively, they may include other prostaglandin an dillower C1-C8 alkylamino lower C1-C8 alkoxy tagonists such as those disclosed in European Patent 25 (dimethylaminoethoxy); Application 11,067 (May 28, 1980) or other thrombox acylamino lower C1-C8 alkoxy (acetylaminoethoxy); ane antagonists such as those disclosed in U.S. Pat. No. acyloxy lower C1-C8 alkoxy (pivaloyloxymethoxy); 4,237,160. They may also contain histidine decarboxy aryloxy, wherein the aryl is C6 or C10 such as phe ase inhibitors such as a-fluoromethyl-histidine, de noxy; scribed in U.S. Pat. No. 4,325,961. The compounds of 30 arlower C1-C8 alkoxy, such as benzyloxy; the Formula I may also be advantageously combined substituted aryloxy or substituted arlower-C1-C8 with an H1 or H2-receptor antagonist, such as for in alkoxy wherein the aryl is C6 or C10 and the substit stance cimetidine, ranitidine, terfenadine, famotidine, uent is methyl, halo or methoxy; aminothiadiazoles disclosed in EP 40,696 (Dec. 2, 1981) anino; and like compounds, such as those disclosed in U.S. Pat. 35 lower C-C8 alkylamino; Nos. 4,283,408; 4,362,736; and 4,394,508. The pharma dillower C1-C8 alkylamino; ceutical compositions may also contain a Kit/H hydroxyamino; ATPase inhibitor such as omeprazole, disclosed in U.S. arlower C1-C8 alkylamino wherein the aryl group is Pat. No. 4,255,431, and the like. Each of the references C6-C10 such as benzylamino; referred to in this paragraph is hereby incorporated 40 R is hydrogen; herein by reference. hydrocarbon of from 1 to 20 carbon atoms which When the second active ingredient in compositions of include branched and unsaturated (such as allyl) this invention is a thromboxane synthetase inhibitor, groups; such inhibitor can be as described in UK 2,038,821 (e.g., C3-C10 cycloalkyl; - UK 37248 and hydrochloride), U.S. Pat. No. 45 substituted lower C1-C8 alkyl wherein the substituent 4,217,357 (e.g., UK 34787), U.S. Pat. No. 4,444,775 can be halo, hydroxy, lower C1-C8 alkoxy, aryloxy (e.g., CGS 13080), U.S. Pat. No. 4,226,878 (e.g., ONO wherein the aryl is C6-C10 such as phenoxy, amino, 046), U.S. Pat. No. 4,495,357 (e.g., U63557A) U.S. Pat. dillower C1-C8 alkylamino, acylamino such as acet No. 4,273,782 (e.g., UK-38485), or EP 98,690 (e.g., amido and benzanido, arylamino wherein the aryl CV-4151). 50 is C6 or C10, guanidino, imidazolyl, indolyl, mer An embodiment of the invention is a cardiovascular composition useful for treating arterial thrombosis capto, lower C1-8 alkylthio, arylthio wherein the which comprises an antithrombotic compound of the aryl is C6 or C10 such as phenylthio, carboxy or Formula I or Ia. carboxamido, carbolower C1-8 alkoxy; A further embodiment of the invention is a cardiovas 55 aryl of C6-C10 such as phenyl or naphthyl; cular composition useful for treating arterial thrombosis substituted aryl of C6-C10 such as phenyl wherein the which comprises: (1) the antithrombotic Formula I or substituent is lower C1-C8 alkyl, lower C1-C3 alk Ia compound defined above; and, (ii) an angiotensin oxy or halo, converting (ACE) inhibitor compound which unsubstituted or substituted arloweralkyl, ar is a member of the group: carboxyalkyl dipeptide deriv loweralkenyl, heteroarlower alkyl, or heteroar atives; captopril 1-(3-mercapto-2-methyl-1-oxopropyl)- lower alkenyl, wherein aryl groups are C6 or C10, L-proline); 2-N-(S)-1-ethoxycarbonyl-3-phenyl the alkyl groups are C2-C8, and the heteroatoms propyl)-S-alanyl)-cis, endo-2-azabicyclo3,3,0octane are one of O, N or S and the substituent(s) is halo, 3(S)-carboxylic acid; N-((S)-1-ethoxycarbonyl-3- dihalo, lower C1-C8 alkyl, hydroxy, lower C1-C8 phenylpropyl)-L-alanyl-N-(2-indanyl)-glycine; 1-(N- 65 alkoxy, amino, aminomethyl, acylamino (S)-1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl)-cis (acetylamino or benzoylamino) dilower C1-C8 syn-octahydro-(H-indole-2-S)-carboxylic acid; 2-(N- alkylamino, lower C1-C8 alkylamino, carboxyl, (S)-1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl)- halolower C1-C8 alkyl, cyano or sulfonamido; 5,081,145 33 34 arlower C1-C8 alkyl or heteroarlower C1-C8 alkyl taining a double bond or an alkylene bridge of from 3 to wherein the aryl group is C6 or C10 and the hetero 4 carbon atoms containing a double bond or an alkylene atom is one of O, N or S, substituted on the alkyl bridge as above substituted with hydroxy, lower alkoxy portion by amino or acylamino (acetylamino or or lower alkyl; benzoylamino); or the pharmaceutically acceptable salts thereof R2 and R7 are the same or different and are hydrogen wherein said aryl is a member selected from the group or lower C1-C8 alkyl; consisting of phenyl or naphthyl and said heteroaryl is a R3 is hydrogen, lower C1-C8 alkyl, phenyl lower member selected from the group consisting of pyridyl, C1-C8 alkyl, aminomethyl phenyl lower C1-C3 alkyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl, or thia hydroxy phenyl lower C1-Cs alkyl, hydroxy lower O zolyl. C1-C8 alkyl, acylamino lower C-C8 alkyl (such as More preferred are those antihypertensive com benzoylamino lower C1-C8 alkyl, acetylamino lower pounds of Formula VI wherein: C1-C8 alkyl), amino lower C1-Cs alkyl, dimethylamino R and R6 can each independently be hydroxy, lower lower C1-C8 alkyl, halo lower C1-C8 alkyl, guanidino alkoxy, lower alkenoxy, arloweralkyloxy, amino, lower C1-Cs alkyl, imidazolyl lower C1-C3 alkyl, indo 15 dilloweralkylamino lower alkoxy, acylamino lower alk lyl lower C1-Cs alkyl, mercapto lower C1-C8 alkyl, oxy or acyloxy lower alkoxy; lower C1-C8 alkyl thio lower C1-C8 alkyl; R1 is alkyl having from 1-8 carbon atoms, substituted R“ is hydrogen or lower C1-Cs alkyl; lower alkyl wherein the alkyl group has 1-5 carbon R is hydrogen, lower C1-Cs alkyl, phenyl, phenyl atoms and the substituent is amino, arylthio, aryloxy or lower C1-C8 alkyl, hydroxy phenyl lower C1-Cs alkyl, 20 arylamino, aralkyl or heteroaralkyl wherein the alkyl hydroxy lower C1-C8 alkyl, amino lower C1-C8 alkyl, portion has 1-3 carbon atoms, substituted aralkyl or guanidino lower C1-Cs alkyl, imidazolyl lower C1-C8 heteroaralkyl wherein the alkyl groups have 1-3 carbon alkyl, indolyl lower C1-C8 alkyl, mercapto lower atoms and the substituent(s) is halo, dihalo, amino, ani C1-C8 alkyl or lower C1-Cs alkyl thio lower C-C8 noalkyl, hydroxy, lower alkoxy or lower alkyl; alkyl; or, 25 R2 and R7 are hydrogen; R4 and R5 may be connected together to form an R3 is lower alkyl or amino lower alkyl; alkylene bridge of from 2 to 4 carbon atoms, an alkylene R and Rican be joined together through the carbon bridge of from 2 to 3 carbon atoms and one sulfur atom, and nitrogen atoms to which they are attached to form an alkylene bridge of from 3 to 4 carbon atoms contain a ring of the formula: ing a double bond or an alkylene bridge as above substi 30 tuted with hydroxy, lower C1-C3 alkoxy, lower C1-C8 alkyl or dilower C1-8 alkyl; - Y and, the pharmaceutically acceptable salts thereof. -N Preferred ACE inhibitor compounds of Formula XI are those wherein: 35 R and R6 can each independently be hydroxy, lower COOR6 alkoxy, lower alkenoxy, arloweralkyloxy, amino, diloweralkylamino lower alkoxy, acylamino lower alk wherein Y is CH2, S, or CH-OCH3 or the pharmaceu oxy or acyloxy lower alkoxy; tically acceptable salts thereof wherein said aryl is a R is hydrogen, member selected from the group consisting of phenyl or alkyl of from 1 to 20 carbon atoms, including naphthyl and said heteroaryl is a member selected from branched, cyclic and unsaturated alkyl groups; the group consisting of pyridyl, thienyl, furyl, indolyl, substituted lower alkyl wherein the substituent is benzthienyl, imidazoyl or thiazolyl. halo, hydroxy, lower alkoxy, aryloxy, amino, Still more preferred antihypertensive compounds of loweralkylamino, dilloweralkylamino, acylamino, 45 Formula XI are those wherein: R and R6 can each inde arylamino, guanidino, imidazoyl, indolyl, mer pendently be hydroxy, lower alkoxy, aralkyloxy; capto, loweralkylthio, arylthio, carboxy, R2 and R7 are hydrogen; carboxanido or carbolower alkoxy; phenyl; R3 is methyl, aminoloweralkyl; substituted phenyl wherein the substituent is lower Rand Rare joined through the carbon and nitrogen alkyl, lower alkoxy or halo; 50 atoms to form proline, 4-thiaproline or 4-methoxypro arloweralkyl or heteroaryloweralkylarloweralkenyl line and; or heteroarloweralkenyl, substituted arloweralkyl, R is alkyl having from 1-8 carbon atoms, substituted substituted heteroarylloweralkyl, substituted ar lower alkyl wherein the alkyl group has 1-5 carbon loweralkenyl or substituted heteroarloweralkenyl; atoms and the substituent is amino, arylthio or aryloxy, wherein the substituent is halo or dihalo lower alkyl, 55 aralkyl or heteroaralkyl wherein the alkyl portion has hydroxy, lower alkoxy, amino, aminomethyl, acyl 1-3 carbon atoms, substituted aralkyl or heteroaralkyl amino, diloweralkylamino, loweralkylamino, car wherein the alkyl groups have 1-3 carbon atoms and boxyl, halo alkyl, cyano or sulfonamido; the substituent(s) is halo, dihalo, amino, aminoalkyl, arloweralkyl or heteroarloweralkyl substituted on hydroxy, lower alkoxy or lower alkyl; the alkyl portion by amino or acylamino; and the pharmaceutically acceptable salts thereof R2 and R7 are hydrogen; wherein said aryl is a member selected from the group R3 is lower alkyl, amino lower alkyl, imidazolyl, consisting of phenyl or naphthyl and said heteroaryl is a lower alkyl, halo lower alkyl; member selected from the group consisting of pyridyl, R“ and R5 are joined to form an alkylene bridge of thienyl, furyl, indolyl, benzthienyl, imidazoyl or thia from 2 to 4 carbon atoms or an alkylene bridge of from 65 zolyl. 2 or 3 carbon atoms and one sulfur atom or an alkylene Examples of Formula I or Ia compounds are set forth bridge of from 2 to 3 carbon atoms and one sulfur atom above on pages 40-43. or an alkylene bridge of from 3 to 4 carbon atoms con Examples of Formula XI compounds are: 5,081,145 35 36 (i) N-(1-carboxy-3-phenylpropyl)-L-alanyl-L-proline; tration. These compositions are formulated similarly to (ii) N-(1-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L- the compositions discussed on pages 46 to 51, above. proline; Treatment dosage for human beings for cardiovascu (iii) N-(1-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L- lar use can be varied as necessary. Generally, daily proline; dosages of the composition of the invention can range (iv) N-(1-carboxy-5-aminopentyl)-L-alanyl-L-proline; from about 6000 to about 10 mg; preferably, from about (v) N-a-(1-carboxy-3-phenylpropyl)-L-lysyl-L-proline; 3000 to about 20 mg. (vi) N-a-(1-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L- The amount of active ingredient that may be com proline; bined with the carrier materials to produce a single (vii) N-a-1-carboxy-3-(3-indolyl)-propyl)-L-lysyl-L- O dosage form for cardiovascular use will vary depending proline; upon the host treated and the particular mode of admin (viii) N-a-(1-carboxy-3-(4-chlorophenyl)-propyl)-L- istration. For example, a formulation intended for oral lysyl-L-proline; administration may contain from 5 mg to 5gm of active (ix) N-a-(1-carboxy-2-phenylthioethyl-L-lysyl-L-pro agents compounded with an appropriate and conve line; 15 nient amount of carrier material which may vary from (x) N-a-(1-carboxy-3-(4-chlorophenyl)-propyl)-L-lysyl about 5 to about 95 percent of the total composition. trans-4-methoxy-L-proline; Dosage unit forms will generally contain between from (xi) N-a-(1-carboxy-5-aminopentyl)-L-lysyl-L-proline; about 20 mg to about 500 mg of active ingredients. (xii) N-a-(1-carboxy-3-phenylpropyl)-L-ornithyl-L- It will be understood, however, that the specific dose proline; 20 level for any particular patient will depend upon a vari (xiii) ethyl N-(1-ethoxycarbonyl-3-phenylpropyl)-L-ala ety of factors including the activity of the specific com nyl-L-prolinate hydrochloride; pound employed, the age, body weight, general health, (xiv) N-1-(ethoxycarbonyl)-3-(4-imidazolyl)propyl)-L- sex, diet, time of administration, route of administration, alanyl-L-proline. rate of , drug combination and the severity of (xv) N-1-carboxy-3-(4-imidazolyl)propyl)-L-lysyl-L- 25 the particular disease undergoing therapy. proline; The composition of this invention inhibits platelet (xvi) N-(1(S)-carboxy-3-phenylpropyl)-L-alanyl-L-pro accumulation at the damaged endothelial surface via the line; Formula I or Ia compound. This inhibitory effect is (xvii) N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L-ala 30 potentiated by the presence of the antihypertensive nyl-L-proline maleate salt; compound. (xviii) N-a-(1 (S)-carboxy-3-phenylpropyl)-L-lysyl-L- Thus, the compositions of the invention are useful in proline; treating thrombosis and are also of value in the manage (xix) ethyl N-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L- ment of acute and chronic congestive heart failure. alanyl-L-prolinate hydrochloride; 35 In vivo testing of the composition of this invention in (xx) N-a-(1(S)-ethoxycarbonyl-3-phenylpropyl)-L- test animals (rabbits) can be used to demonstrate that lysyl-L-proline. this composition is pharmaceutically effective in de The above-described Formula VI compounds, their creasing platelet-related arterial thrombic formation. use and the method of preparation thereof are disclosed To demonstrate the potentiation of the antihyperten in U.S. Pat. No. 4,374,829 the disclosure of which is sive compound on the anti-thrombotic Formula I or Ia hereby incorporated herein by reference. compound comprising the combination composition of The resolution of certain Formula I and Ia com the invention, the effect of these compounds on test pounds into their optically pure enantiomers is as dis animals (rabbits) can be determined separately and then closed in U.S. Pat. Nos. 4,424,355 and 4,435,579 which in combination. The effect of a different class of antihy have been incorporated herein by reference. 45 pertensive agents singly and in combination with the The combination composition of the invention can Formula I or Ia compound of the invention can also be contain varying amounts of the Formula I or Ia (i) anti determined for comparative purposes. The methods thrombotic compound and Formula VI (ii) antihyper employed are described in a copending application, tensive compounds. The weight ratio of (i):(ii) can attorney docket no. 17062, U.S. Ser. No. 617,293, filed range from about 25 to 1; preferably from about 10 to 1. 50 June 4, 1984, which is hereby incorporated herein by In addition to the active ingredients of (i) alone or of (i) reference. and (ii) in combination, the compositions of the inven The following examples illustrate the preparation of tion can also contain other conventional pharmaceuti the compounds of the present invention without, how cally acceptable compounding ingredients, as necessary ever, limiting the same thereto. or desired. Such ingredients are generally referred to as 55 carriers or diluents. Conventional procedures for pre All temperatures are in degrees Celsius. paring such compositions in appropriate dosage forms EXAMPLE 1 can be utilized. Whatever the dosage form, it will con tain a pharmaceutically effective amount of the present A. Preparation of Hydrazine Starting Materials composition. 1-(4-Chlorophenyl)methyl)-1-(4-methylphenyl)hydra The combination compositions can be administered zine orally or other than orally; e.g., parenterally, by insuf A mixture of 10 g of p-tolylhydrazine hydrochloride, flation, topically, rectally, etc.; using appropriate dos 75 ml of toluene and 11.5 ml of triethylamine was age forms; e.g., tablets, capsules, suspensions, solutions, heated at reflux for 60 minutes. Then, 7.1 g of p-chloro and the like, for oral administration; suspension emul 65 benzyl chloride was added. After stirring 16 hours at sions, and the like, for parenteral administration; solu reflux, triethylamine hydrochloride was filtered off and tions for intravenous administration; and ointments, washed with ethyl ether. The filtrate and washing were transdermal patches, and the like, for topical adminis concentrated in vacuo and chromatographed on a silica 5,081,145 37 38 gel column (hexane-ethylacetate, 9:1) to give 6.64 g of EXAMPLE 2 the title compound, (Compound No. 5 in Table 3). 3 (or Other hydrazines, similarly prepared, are also shown Beta)-1-(p-Chlorobenzyl)-5-chloro-3-methyl-2- in Table 3. indolyl-propionic acid TABLE 3 Step 1 Hydrazines To 1.84 g of 1,1-(4-chlorophenyl)methyl)-1-(4- chlorophenyl) hydrazide hydrochloride in 60 cc of 10 tert-butanol was added 868 mg of methyl 4-oxo-hexano ate. The reaction mixture was refluxed under nitrogen for 6 hours. The resulting reaction mixture was then evaporated to dryness and the resulting residue sus pended in CH2Cl2. The solid material was then filtered. 5 The filtrate was washed with water, dried and evapo rated. The resulting syrup was then chromatographed on silica gel to give 1.47 g of indole derivative (65%). NMR: H1NMR (CDCl3): 2.25 ppm (Me, 3H, singlet); 2.43 (CH2, 2H, triplet); 3.01 (CH2, 2H, triplet); 3.64 20 Compound No. Compound Name (OMe, 3H, singlet; 5.29 (CH2 Cl, 2H, singlet); 6.83 C 1-(4-chlorophenyl)- methyl)-1-(4-fluoro 25 phenyl)hydrazine hydro chloride (H-2' and H-6, 2H, d); 7.1 (H-6, and H-7, 2H, multi 2. 3,5-Cl2 Cl 1-(4-chlorophenyl)- plet); 7.25 (H-3' and H-5", 2H); 7.49 (H-4, H, singlet). methyl)-1-(3,5-dichloro phenyl)hydrazine hydro Step 2 chloride 30 To 1.06 g of methyl ester in 350 ml of EtOH was 3. 3-OMe C 1-(4-chlorophenyl)- methyl)-1-(3-methoxy added 169 mg of sodium hydroxide dissolved in 3 ml of phenyl)hydrazine hydro H2O. The resulting solution was stirred at room temper chloride ature for 16 hours. The reaction mixture was then acidi 4. 3-Me Cl 1-(4-chlorophenyl)- 35 fied with HCl (1N) and concentrated. The resulting methyl)-1-(3-methyl solution was then extracted with CH2Cl2 (3 times). The phenyl)hydrazine hydro combined organic layer was washed with brine, dried chloride over MgSO4, and evaporated to give 1 g of solid mate 5. 4-Me C 1-(4-chlorophenyl)- rial (100% yield). An analytical sample of this material methyl-1-(4-methyl was be prepared by triturating the resulting solid mate phenyl)hydrazine hydro rial with hexane followed by a filtration (800 mg). chloride Analysis calculated for C19H17Cl2NO2: C, 62.99; H, 6. 4-Cl Cl 1-(4-chlorophenyl)- methyl)-1-(4-chloro 4.74; N, 19.58. Found: C, 63.19; H, 4.78; N, 19.35. phenyl)hydrazine hydro EXAMPLE 3 chloride 45 Cl 1-(4-chlorophenyl)- 3 (or methyl)-1-(phenyl) Beta)-1-(p-Chlorobenzyl)-3-methyl-5-fluoro-2- hydrazine hydrochloride indolyl-propionic acid 8. 4-Br Cl 1-(4-chlorophenyl)- Following the procedure of Example 2, but using methyl)-1-(4-bromo 50 phenyl)hydrazine hydro 1-(4-chlorophenyl)methyl)-1-(4-fluorophenyl)-hydra chloride zine hydrochloride and methyl 4-oxohexanoate as the 9. 4-OMe SMe 1-(4-methylthiophenyl)- starting materials and ethanol as the solvent, the title methyl)-1-(4-methoxy compound was prepared. phenyl)hydrazine hydro 55 Analysis calculated for C19H17ClFNO2: C, 65.98; H, chloride 4.95; Cl, 10.25. Found: C, 65.56; H, 5.17; Cl, 10.52. 10. 4-OMe C 1-(4-chlorophenyl)- methyl)-1-(4-methoxy EXAMPLE 4 phenyl)hydrazine hydro 3 (or chloride Beta)-1-p-Chlorobenzyl-3-methyl-4,6-dichloro-2- 11. NO2 1-(4-nitrophenyl)- methyl)-1-(4-methoxy indolylpropionic acid phenyl)hydrazine Following the procedure of Example 2, but using hydrochloride 1-(4-chlorophenyl)methyl)-1-(3,5-dichlorophenyl)hy 2. 4.F SMe 1-(4-methylthiophenyl)- drazine hydrochloride and methyl 4-oxohexanoate as methyl)-1-(4-fluoro 65 the starting materials and ethanol as the solvent, the title phenyl)hydrazine hydro compound was prepared. chloride Analysis calculated for C19H16O2Cl3N: C, 57.52; H, 4.06. Found: C, 57.40; H, 4.20. 5,081,145 39 40 EXAMPLE 5 EXAMPLE 10 3 (or 1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-(3-carboxy Beta)-1-(p-Chlorobenzyl)-3-methyl-4-methoxy-2- propyl)indole indolylpropionic acid Following the procedure of Example 2, but using Following the procedure of Example 2, but using 1-(4-chlorophenyl)methyl)-1-(4-methoxyphenyl)hy 1-(4-chlorophenyl)methyl)-1-(3-methoxyphenyl)- drazine hydrochloride and methyl 5-oxoheptanoate as hydrazine hydrochloride and ethyl 4-oxohexanoate as the starting materials and ethanol as the solvent, the title the starting materials and ethanol as the solvent, the title O compound was prepared. compound was prepared. Analysis calculated for C2H22NO3Cl: C, 67.83; H, Analysis calculated for C20H20O3NCl: C, 67.12; H, 5.92; N, 3.76. Found: C, 67.92; H, 5.97; N, 3.84. 5.63. Found: C, 67.40; H, 5.43. EXAMPLE 1 EXAMPLE 6 15 3 (or 3 (or Beta)-1-(p-Chlorobenzyl)-3-methyl-2-indolyl)-pro Beta)-1-(p-chlorobenzyl)-3-methyl-6-methoxy-2- pionic acid indolylpropionic acid Following the procedure of Example 2, but using Following the procedure of Example 2, but using 20 1-(4-chlorophenyl)methyl)-1-(phenyl)hydrazine hy 1-(4-chlorophenyl)methyl)-1-(5-methoxyphenyl)- drochloride and methyl 4-oxohexanoate as the starting hydrazine hydrochloride and methyl 4-oxohexanoate as materials and tert-butanol as the solvent, the title con the starting materials and tert-butanol as the solvent, the pound was prepared. title compound was prepared. Analysis calculated for C19H18O2CIN: C, 67.15; H, Analysis calculated for C20H20O3NCl: C, 67. 12; H, 25 5.33; N, 4.12; Cl, 10.43. Found: C, 67.77; H, 5.42; N, 5.63; N, 3.91; Cl, 9.90. Found: C, 67.08; H, 5.64; N, 4.09. 4.48; Cl, 10.48. EXAMPLE 7 EXAMPLE 2 3 (or 3 (or Beta)-1-(p-Chlorobenzyl)-3,4-dimethyl-2-indolylpro 30 Beta)-1-(p-Chlorobenzyl)-5-bromo-3-methyl-2- pionic acid and 3 (or Beta)-1-(p-chlorobenzyl)-3,6-dimethyl-2-indolyl)pro indolylpropionic acid pionic acid (as a mixture) Following the procedure of Example 2, but using 1-(4-chlorophenyl)methyl)-1-(4-bromophenyl)-hydra Following the procedure of Example 2, but using 35 1-(4-chlorophenyl)methyl)-1-(3-methylphenyl)-hydra zine hydrochloride and methyl 4-oxohexanoate as the zine hydrochloride and methyl 4-oxohexanoate as the starting materials and t-butanol as the solvent, the title starting materials and t-butanol as the solvent, the title compound was prepared. compounds were prepared. Analysis calculated for C19H17ClO2BrN: C, 56.10; H, Analysis calculated for C20H2ONClO2: C, 70.26; H, 4.21; Found: C, 56.07; H, 4.27. 5.89; N, 40.9; Cl, 10.37. Found: C, 70.52; H, 5.57; N, EXAMPLE 3 4.56; Cl, 10.03. 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(2-car EXAMPLE 8 boxyethyl)indole 1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-(4-carbox 45 Following the procedure of Example 2, but using ybutyl)indole 1-(4-methylthiophenyl)methyl)-1-(4-methoxyphenyl)- Following the procedure of Example 2, but using hydrazine hydrochloride and methyl 4-oxohexanoate as 1-(4-chlorophenyl)methyl-1-(4-methoxyphenyl)- the starting materials and tert-butanol as the solvent, the hydrazine hydrochloride and methyl 6-oxooctanoate as 50 title compound was prepared. the starting materials and methanol as the solvent, the Analysis calculated for C2H23NO3S: C, 68.29; H, title compound was prepared. 6.23; N, 3.79. Found: C, 68.03; H, 6.12; N, 3.76. Analysis calculated for C22H24NO3Cl: C, 68.57; H, EXAMPLE 14 6.23; N, 3.63. Found: C, 68.45; H, 6.41; N, 3.35. 55 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(2-car EXAMPLE 9 boxyethyl)indole S-oxide 3 (or Using the methyl ester of the title compound of Ex Beta)-1-(p-Chlorobenzyl)-3,5-dimethyl-2-indolylpro ample 13 as the starting material, 250 mg were dissolved pionic acid in 20 ml of dichloro methane and cooled to 0 C. Meta Following the procedure of Example 2, but using chloroperoxybenzoic acid, 138 mg, was added and the 1-(4-chlorophenyl)methyl)-1-(4-methylphenyl)-hydra reaction stirred at 0° C. for 1 hour. 200 mg anhydrous zine hydrochloride and methyl 4-oxohexanoate as the Ca(OH)2 was added and the reaction filtered and evapo reactants and ethanol as the solvent, the title compound rated to dryness. The methyl ester so obtained was was prepared. 65 hydrolyzed according to the conditions described in Analysis calculated for C20H20O2NCl: C, 70.31; H, Example 2. 5.90, N, 4.1; Cl, 10.37. Found: C, 70.37; H, 5.85; N, 4.10; Analysis calculated for C2H23NO4S: C, 63.45; H, Cl, 10.15. 5.70, N, 3.47. Found: C, 63.55; H, 5.67; N, 3.32. 5,081,145 41 42 Analysis calculated for C22H24O3NCl: C, 68.48; H, EXAMPLE 1.5 6.27; N, 3.63; Cl, 9.19. Found: C, 68.49; H, 6.50, N, 3.55; 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(3-car Cl, 8.93. boxypropyl)indole EXAMPLE 21 Following the method of Example 2, but using 1-(4- 3-Methyl-4-1-p-chlorobenzyl-5-fluoro-3-methylindol methylthiophenyl)methyl)-1-(4-methoxyphenyl)-hydra 2-yl)butanoic acid zine hydrochloride and methyl 4-oxoheptanoate as the Following the method of Example 2, but using 1-(4- starting materials and tert-butanol as the solvent, the chlorophenyl)methyl-1-(4-fluorophenyl)hydrazine hy title compound was prepared. 10 drochloride and 3-methyl-4-oxoheptanoic acid as the Analysis calculated for C22H25NO3S3H2O: C, 67.86; starting materials and isopropanol as the solvent, the H, 6.64; N, 3.50. Found: C, 66.85; H, 6.63; N, 3.31. title compound was prepared. EXAMPLE 6 Analysis calculated for C2H2O2NClF: Calc.: C, 4-1-(p-Chlorobenzyl)-3-methyl-5-fluoro-2-indolyl 15 67.47; H, 5.66; N, 3.75; Cl, 9.48; F, 5.08. Found: C, butanoic acid 67.57; H, 5.90, N, 3.60; C1, 9.44; F, 4.50. Following the method of Example 2, but using 1-(4- EXAMPLE 22 chlorophenyl)methyl-1-(4-fluorophenyl)hydrazine hy 3-(1-p-Chlorobenzyl-3-methyl-5-methoxyindol-2-yl)- drochloride and methyl 5-oxoheptanoate as the starting 2,2-dimethylpropanoic acid 20 materials and tert-butanol as the solvent, the title com Following the method of Example 2, but using 1-(4- pound was prepared. chlorophenyl)methyl)-1-(4-methoxyphenyl)hydrazine Analysis calculated for C20H19ClFNO2: C, 66.76; H, hydrochloride and methyl 2,2-dimethyl-4-oxohexano 5.32; Cl, 9.85. Found: C, 66.89; H, 5.24; Cl, 10.26. ate as the starting materials and tert-butanol as the sol EXAMPLE 17 25 vent, the title compound was prepared. Analysis calculated for C22H24NO3Cl: Calc.: C, 3 (or Beta)-1-(p-Thiomethylbenzyl)-3-methyl-5-fluoro-2- 64.48; H, 6.40; N, 3.63. Found: C, 68.32; H, 6.37; N, 3.53. indolylpropanoic acid EXAMPLE 23 Following the procedure of Example 2, but using 30 3-(1-p-Chlorobenzyl-5-hydroxy-3-methylindol-2-yl)- 1-(4-methylthiophenyl)methyl)-1-(4-fluorophenyl)hy propionic acid drazine hydrochloride and methyl 4-oxohexanoate as Beginning with 3-1-p-chlorobenzyl-5-methoxy-3- the starting materials and tert-butanol as the solvent, the methylindol-2-yl)propionic acid which is described in J. title compound was prepared. Med. Chen., 1252 (1968), (2.7 g) was dissolved in 20 ml Analysis calculated for C20H2002FSN: C, 67.20; H, 35 CH2Cl2 at 0°C. 7.6 ml BBr3 (1M in CH2Cl2) was added 5.64; N, 3.91. Found: C, 67.21; H, 5.91; N, 3.88. dropwise and the reaction stirred for 60 minutes. After 180 minutes at 23 C., another 4 ml BBr3 solution was EXAMPLE 1.8 added. The reaction was stirred for a further 180 min 3 (or utes. The reaction was cooled to -20° C. and 15 ml Beta)-(1-p-Methylsulfoxylbenzyl)-3-methyl-5-fluoro-2- MeOH added. The organic phase was washed with indolyl-propanoic acid NaHCO3 (aqueous), dried with Na2SO4 and chromato graphed on silica gel. Hydrolysis of the methyl ester Using the title compound of Example 17, treated was carried out as described in Example 2 to yield 2.2g according to the procedure described in Example 14, of the title compound. the title compound was obtained. 45 Analysis calculated for C19H18O3CN: C, 66.37; H, Analysis calculated for C20H2OFNO3S: C, 64.32; H, 5.27; N, 4.07; Cl, 10.31. Found: C, 66.54; H, 5.16; N, 5.39; N, 3.75. Found: C, 64.18; H, 5.65; N, 3.48. 3.85; Cl, 10.65. EXAMPLE 19 EXAMPLE 24 3-1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-indolyl)- 50 3-(1-p-Chlorobenzyl-5-acetoxy-3-methylindol-2-yl)- butanoic acid propionic acid Following the method of Example 2, but using 1-(4- Using the title compound of Example 23 as starting chlorophenyl)methyl)-1-(4-methoxyphenyl)-hydrazine material, (1 g) was dissolved in CH2Cl2 (20 ml) at 0° C. hydrochloride and methyl 3-methyl-4-oxohexanoate as and 1 ml pyridine added. 1.8 g acetic anhydride was the starting materials and methanol as the solvent, the 55 added and the reaction let stir at 23 for 16 hours. The title compound was prepared. organic phase was washed with H2O (5x5ml), evapo Analysis calculated for C2H22NO3Cl H2O: C, 64.78; rated and chromatographed. H, 6.13; N, 3.59. Found: C, 65.86; H, 6.12; N, 3.37. Analysis calculated for C2H20O3NCl: Calc.: C, EXAMPLE 2.0 65.37; H, 5.22; N, 3.63; Cl, 9.19. Found: C, 65.35; H, 3-Methyl-4-1-p-chlorobenzyl-5-methoxy-3-methylin 5.09; N, 3.54; Cl, 9.25. dol-2-yl)butanoic acid EXAMPLE 25 Following the method of Example 2, but using 1-(4- 3-4,6-dichloro-1-(4-chlorobenzyl)-3-methyl-1H-indol chlorophenyl)methyl)-1-(4-methoxyphenyl)hydrazine 65 2-yl) propanoic acid hydrochloride and 3-methyl-5-oxoheptanoic acid as the Following the method of Example 2, but using 1-1- starting materials and isopropanol as the solvent, the (chlorophenyl)methyl-1-(3,5-dichlorophenyl) hydra title compound was prepared. zine hydrochloride and methyl 4-oxohexanoate as the 5,081,145 43 44 starting materials, in t-butanol as solvent, the title com EXAMPLE 28 pound was prepared. 3-1-(4-bromobenzyl)-3-methyl-5-methoxyindol-2-yl)- 2,2-dimethylpropanoic acid Analysis calculated for C19H16NCl3O2 Following the method of Example 2, but using 1-4- C H bronobenzyl)-1-(4-methoxy phenyl) hydrazine hydro 57.52 4.06 Calc. chloride and methyl-2,2-dimethyl-4-oxohexanoate as 5740 4.20 Found the starting materials, using t-butanol as the solvent, the 10 title compound was prepared. EXAMPLE 26 M.P. - 170 3-1-(4-chlorobenzyl)-4-methoxy-3-methyl-1H-indol EXAMPLE 29 2-yl) propanoic acid 3-(1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl)2- Following the method of Example 2, but using 1-4- 15 methyl propanoic acid (chlorobenzyl)-1-(3-methoxy phenyl) hydrazine hydro Following the method of Example 2, but using 1-4- chloride and methyl-4-oxohexanoate as the starting chlorobenzyl)-1-(4-chlorophenyl) hydrazine hydro materials in t-butanol as solvent, the title compound was chloride and methyl-3-methyl-4-oxohexanoate as start prepared, m.p. 145 C. 20 ing materials, using t-butanol as solvent, the title com Analysis calculated for C20H2003 NCl: Calc.: C, pound was prepared. 67.12; H, 5.63. Found: C, 67.40; H, 5.43. M.P. - 128 EXAMPLE 27 EXAMPLE 30 1-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)- 25 3-(1-(4-iodobenzyl)-3-methyl-5-methoxyindol-2-yl)-2,2- methoxy acetic acid dimethyl propanoic acid Step 1 Following the method of Example 2, but using 1-4- Methyl iodobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochlo 1-(4-chlorobenzyl)-5-fluoro-3-methylindol-2-carboxy 30 ride and methyl-2,2-dimethyl-4-oxo-hexanoate as start late ing materials, using t-butanol as solvent, the title com Following the procedure of Example 42 Step 1, but pound was prepared. using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)-hydrazine M.P. - 152 in place of 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hy 35 EXAMPLE 31 drazine, there was obtained the title compound of Step 3-(1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl)- 1. 2,2-dimethyl propanol Step 2 700 mg of 3-1-(4-chlorobenzyl)-3-methyl-5-methox 1-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yline yindol-2-yl)-2,2-dimethyl propanoic acid methy ester thanol was dissolved in 20 ml dry tetrahydrofuran. The reac tion was cooled to -78 C. and 2 equivalents di-isobu 1.50 g 1-(4-chlorobenzyl)-3-methyl-5-fluoro-1H tyl aluminium hydride (DIBAL) in THF was added. indole-2-carboxylate Me ester was dissolved in 50 ml The reaction was allowed to warm to room temperature dry THF. Diisobutyl aluminum hydride (1.5M) in tetra 45 and quenched with NH4C (aq). Ethyl acetate was hydrofuran (THF) (2 equivalents) was added at -78 added (75 ml) and the organic phase separated, dried C. The reaction was stirred for 16 hrs., allowed to reach and evaporated. The product was isolated by column room temperature and quenched with NH4Cl (aq). The chromatography. organic phase was separated, dried (Na2SO4) and evap 50 orated to produce 1.32 g of product which was purified M.P. - 100.1 on column chromatography to yield the title compound EXAMPLE 32 of Step 2. 3-1-(4-chlorobenzyl)-3-methoxy-5-hydroxyindol-2-yl)- 2,2-dimethyl propanoic acid Step 3 55 The title compound from Step 2 (1.0 g) was dissolved Following the method of Example 23, but using the in dry dimethylformamide (DMF) (10 ml) at -20° C. product of Example 22 as starting material, the title Potassium hexamethyl disilazane base in toluene compound was prepared. (0.69M) was added (1.1 molar equivalents) and the reac M.P. - 37° tion stored for 1 hr. Ethyl 2-bromo acetate (580 mg) (1.2 EXAMPLE 33 equivalents) was added and the reaction stirred for 16 h 3-1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl)- at 21 C. Water was added (3 ml). The product was propanol isolated after extraction from the aqueous DMF with ether. Following purification on column chromatogra 65 Following the method of Example 31, but using the phy, the title ethyl ester was hydrolysed in 3N NaOH starting material of Example 23, the title compound was according to the procedure in Example 2. prepared. M.P. - 154 M.P.s 118 5,081,145 45 46 ester title compound was isolated from a preparative EXAMPLE 34 plate (SiO2) (hexane 8, ethyl acetate 2) (82 mg) and the 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)-2,2- corresponding acid was obtained from hydrolysis as dimethyl propanoic acid shown in Example 2. Following the method of Example 2, but using 1-4- chlorobenzyl-1-(4-fluorophenyl)hydrazine hydrochlo ride 1.9 g and 2,2-dimethyl-4-oxohexanoic acid (950 Analysis calculated for C22H24O3NC -- 2H2O mg) as starting materials, in t-butanol as solvent, after 16 C H hrs. at reflux, the solvent was removed in vacuo, and 10 62.43 6.06 Calc. the title compound was isolated by crystallization and 62.62 5.73 Found filtration, followed by crystallization from hot ethyl acetate:hexane 9:1. EXAMPLE 39 Analysis for C2H2NO2ClF 15 3-1-(4-chlorobenzyl)-3-methyl-5-prop-2-enoxyindol-2- C H yl)-propanoic acid 67.47 5.62 Calc. Using 845 mg of the product of Example 23 as start 67.53 5.70 Found ing material, diluted in 23 ml of dimethyl ketone, 476 20 mg of potassium carbonate and 225 ul of allyl bromine M.P. - 24 was added. The reaction was refluxed overnight. The EXAMPLE 35 reaction was then diluted with water and the acetone 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)-3- removed in vacuo. Then the reaction was extracted with CH3CO2Et and the organic phase was dried and methyl propanoic acid 25 Following the method of Example 2, but using 1-4- concentrated to yield after flash chromatography (hex chlorobenzyl)-1-(4-fluorophenyl) hydrazine hydrochlo ane 8, ethyl acetate 2) 790 mg of the compound, which ride and methyl 3-methyl-4-oxohexanoate as starting was then hydrolyzed following the procedure of Exam materials, the title compound was prepared. ple 2. M.P. - 143 30 EXAMPLE 36 Analysis calculated for C22H22O3NCl 3-1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2- C H yl)butanoic acid 68.83 5.77 Calc. Following the method of Example 23, but using the 35 68.88 5.89 Found product of Example 19 as starting material, the title compound was prepared. M.P. = 131.2 M.P. - 162 EXAMPLE 40 EXAMPLE 37 Methyl-3-1-(4-chlorobenzyl-3-methyl-5-methoxyindol Methyl 2-yl)-2,2-dimethyl-propanoate 4-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)- butanoate Following the method of Example 45, but using the Following the method of Example 44, but using the product of Example 22 as starting material, the title product of Example 16 as starting materials, the title 45 compound was prepared. compound was prepared. M.P. = 110 EXAMPLE 41 Analysis for C2H2NO2FC 3-1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl)-2- C H 50 methyl-butanoic acid 67.47 S.62 Calc. 67.53 5.70 Found Step 1 Ethyl 2,3-dimethyl-4-oxo-hexanoate EXAMPLE 38 55 To 4.23g ethyl 2-bromopropionate in 50 ml acetoni 3-1-(4-chlorobenzyl)-3-methyl-4-propyl-5-hydroxyin trile was added 2.5 g N-3-(pent-2-enyl)-pyrrolidine. dol-2-yl)-propanoic acid The reaction was refluxed for 6 hr. The solvent was removed in vacuo and the product was isolated by 210 mg of the methyl ester of Example 39 was heated chromatography on silica gel to yield 1.5 g of the title in a Kugelhrohr vacuum distillation apparatus at 200 C. without vacuum for 90 min. The product was then compound which was used as such in the second step. distilled in vacuo at 0.1 mm Hg, 200° C. The liquid Step 2 obtained was chromatographed on a preparative plate (hexane 8, ethyl acetate 2). 125 mg. of 3-1-(4- Following the method of Example 2, but using 1-4- chlorobenzyl)-3-methyl-4-(3-propyl)-5-hydroxyindol-2- 65 chlorobenzyl)-1-(4-fluorophenyl) hydrazine hydrochlo yl)propanoic acid methyl ester was isolated, which was ride and ethyl 2,3-dimethyl-4-oxohexanoate as starting then hydrogenated with 10% palladium on charcoal in materials, the title compound was prepared. 10 ml of MeOH with 40 psi H2 for 3 min. The methyl M.P. - 177 5,081,145 47 48 was dried and concentrated to yield 47 g of the title EXAMPLE 42 methyl ester. 1-(4-chlorobenzyl)-3-methyl-5-methoxy-1H-indole-2- methoxy acetic acid. Analysis calculated for C20H21NO3Cl: Step 1 C H N Cl Methyl Calc.: 67.83 5.96 3.77 9.53 1-(4-chlorobenzyl)-5-methoxy-3-methylindol-2-car Found: 67.67 5.2.1 3.68 9.68 boxylate To a solution of 1 g 2-keto butyric acid in 35 ml O MeOH (to which had previously been added 1 ml EXAMPLE 45 CH3COCl at O' C.) was added 12.82 g N-benzyl-4- 3-1-(4-aminobenzyl)-5-methoxy-3-methyl-1H-indol-2- methoxyphenyl hydrazine hydrochloride. The solution yl)-2,2-dimethyl propanoic acid was refluxed for 1 hr., the methanol distilled off and a 15 crystalline pasty residue triturated with methanol to Step 1 give 2.6 g crystalline material. The crystals were 3-1-(4-nitrobenzyl)-5-methoxy-3-methyl-1H-indol-2- swished with 9:1 hexane:EtOAc overnight to yield 2.0 g yl)-2,2-dimethyl propanoic acid pure product, which was used as such in the next step. Following the method of Example 2, but using 1-(4- Step 2 20 nitrophenyl)methyl-1-(4-methoxyphenyl) hydrazine 1-(4-chlorobenzyl)-3-methyl-5-methoxy-1H-indole-2- hydrochloride and methyl 2,2-dimethyl-4-oxo-hexano methanol. ate as the starting materials and tert-butanol as the sol 1.50 g 1-(4-chlorobenzyl)-3-methyl-5-methoxy-1H vent, the title compound was prepared. indole-2-carboxylate methyl ester was dissolved in 50 25 ml dry THF. Diisobutyl aluminum hydride (1.5M) in Analysis calculated for C22H24Os THF (2 equivalents) was added at -78°C. The reaction C H N was stirred for 16 hrs., allowed to reach room tempera Caic.: 66.67 6.06 7.07 ture and quenched with NH4C (aq). The organic phase Found: 67.00 6.12 7.10 was separated, dried (Na2SO4) and evaporated to pro 30 duce 1.32 g of product which was purified on column chromatography to yield the title compound of Step 2. Step 2 Step 3 500 mg of the product of Step 1 was dissolved in 35 The product from Step 2 above (1.0 g) was dissolved 35 ml of absolute ethanol and 50 mg of 10% palladium on in dry DMF (10 ml) at -20° C. Potassium hexanethyl carbon catalyst added. The suspension was hydroge disilazane base in toluene (0.69M) was added (1.1 molar nated at 50 psi until consumption of 2 mole equivalents equivalents) and the reaction stirred for 1 hr. Ethyl of hydrogen occurred. The catalyst was removed by 2-bromo acetate (580 mg) = 1.2 equivalents was added filtration and the title compound was isolated by vac and the reaction stirred for 16 h at 21 C. Water was uum distilation of the solvent (489 mg). added (3 ml). The product was isolated after extraction M.P. - 173 from the aqueous DMF with ether. Following purifica tion on column chromatography, the title ethyl ester EXAMPLE 46 was hydrolysed in 3N NaOH according to the proce 45 4-1-(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2- dure in Example 2. yl)-2,2-dimethylbutanoic acid M.P. = 128 Following the method of Example 2, but using 1-(4- EXAMPLE 43 chlorobenzyl)-1-(4-methoxyphenyl))hydrazine hydro 3-1-(4-chlorobenzyl)-3-methyl-5-chloroindol-2-yl)-2,2- 50 chloride and methyl 2,2-dimethyl-5-oxoheptanoate as dimethyl-propanoic acid starting materials, the title compound was prepared. Following the method of Example 2, but using 1-4- chlorobenzyl)-1-(4-chlorophenylhydrazine hydrochlo Analysis calculated for C23H25NO3Cl C H N ride and methyl-2,2-dimethyl-4-oxohexanoate in t 55 butanol as solvent, the title compound was prepared. Calc.: 69.28 6.52 3.51 M.P. - 142.5 Found: 69.21 6.93 3.22 EXAMPLE 44 Methyl-3--1-(4-chlorobenzyl)-5-methoxy-3-methyl EXAMPLE 47 1H-indol-2-yl)propanoate 4-(1-(4-chlorobenzyl)-5-fluoro-3-methyl-1H-indol-2-yl)- 3-1-(4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol 2,2-dimethylbutanoic acid 2-yl)propanoic acid (50 g) was dissolved in 400 ml abso lute methanol and cooled to 0 C. Boron trifluoride Following the method of Example 2, but using 1-4- etherate (50 ml) was added slowly over 25 min. The 65 chlorobenzyl)-1-4-fluorophenylhydrazine hydrochlo reaction was quenched after 16 hr. by the addition of ride and methyl-2,2-dimethyl-5-oxoheptanoate as start water/NaHCO3. Upon evaporation, the water was re ing materials, in t-butanol as solvent, the title compound moved by extraction with CH2Cl2. The organic phase was prepared. 5,081,145 49 50 EXAMPLE 52 Analysis calculated for C22H23NO2CIF 3-1-(4-chlorobenzyl)-5-ethoxy-3-methyl-1H-indol-2- C H N yl)-2,2-dimethyl propanoic acid Calc.: 68.13 5.60 3.6 5 The title compound of Example 50 was treated ac Found: . 68.34 5.69 3.41 cording to the method described in Example 39 using ethyl bromide as the alkylating agent. The product was EXAMPLE 48 isolated by chromatography on silica gel (CH2Cl2). 10 M.P. = 148 4-1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2- What is claimed is: yl)-3-methylbutanoic acid 1. A compound of the Formula Ib:

Following the method of Example 23, but using 4-1- (4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl)-3- methylbutanoic acid as starting material, the title con- 15 pound was prepared.

Analysis calculated for C2H22NO3Cl C H N 20 67.3 5.92 3.76 Caic. 68.36 5.69 3.51 Found

25 EXAMPLE 49 4-1-(4-methylthiobenzyl)-5-methoxy-3-methyl-1H indol-2-yl)-3-methylbutanoic acid Following the method of Example 2, but using 1-(4- 30 wherein: methylthiobenzyl-1-(4-methoxyphenylhydrazine hy each R is independently H or alkyl of 1 to 3 carbons; drochloride and methyl-3-methyl-5-oxoheptanoate as R2 is starting materials, in t-butanol as solvent, the title com pound was prepared R R. Rl 35 N (-f 5. C- R9 Analysis calculated for C2H22NO3S R8 R8 R C H N 69.56 6.92 3.52 Calc. with the proviso that at least one of R1 or R8 is not H; 69.85 7.20 3.50 Found 40 R3 is alkyl of 1 to 6 carbons, but not cycloalkyl; R and Rs is each independently: (1) hydrogen; EXAMPLE 50 (2) alkyl having 1 to 6 carbon atoms; or (3) M wherein M is 3-(1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2- 4 a) halogen; yl)-2,2-dimethyl propanoic acid b) CF3; Following the method of Example 23, but using 3-1- c) SR12; (4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl)- d) -SOR12; 2,2-dimethyl propanoic acid as starting material, the e) -SO2R12; title compound was prepared. 50 f) O-C(O)-R14; or M.P. = 110 (decomposition) g) CN; R6 and R7 is each independently: EXAMPLE 51 (1) hydrogen; 3-1-(4-chlorobenzyl)-5-hydroxy-3-methyl-1H-indol-2- 55 (2) alkyl having 1 to 6 carbon atoms; or yl)-3-methyl propanoic acid (3) M wherein M is a) OR12; Following the method of Example 23, but using 3-1- b) halogen; (4-chlorobenzyl)-5-methoxy-3-methyl-1H-indol-2-yl)-3- c) CF3; methyl propanoic acid as starting material, the title 60 d) SR12; compound was prepared. e) -SOR12; f) -SO2R12; g) O-C(O)-R1; or C20H2ONO3Cl C H N h) CN; 65 each R8 is independently H or alkyl of 1 to 4 carbons; 67.3 5.59 3.9 Calc. R9 is COOH, CH2OH, or CHO; 67.22 S.74 3.97 Found each R12 is independently H, C1 to C6 alkyl, or benzyl; each R13 is independently H, phenyl, or C1 to C6 alkyl;