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United States Patent 19 11) Patent Number: 4,644,007 York, Jr

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United States Patent 19 11) Patent Number: 4,644,007 York, Jr United States Patent 19 11) Patent Number: 4,644,007 York, Jr. 45 Date of Patent: * Feb. 17, 1987 54) 3-CHLORO-4-(4,5-DIHYDRO-1H-MIDAZO 2832310 7/1980 Fed. Rep. of Germany. 2-YL)-AMINO-5-ALKYLBENZOIC ACIDS, 2905883 8/1980 Fed. Rep. of Germany . 2949287 11/1981 Fed. Rep. of Germany . ESTERS, SALTS, COMPOSITIONS AND 79.2696 6/1980 South Africa . METHODS 1180766 10/1967 United Kingdom. 75) Inventor: Billie M. York, Jr., Fort Worth, Tex. 1216945 12/1970 United Kingdom. 1279543 6/1972 United Kingdom. 73) Assignee: Alcon Laboratories, Inc., Fort 1279931 6/1972 United Kingdom. Worth, Tex. 15954.12 8/1981 United Kingdom . * Notice: The portion of the term of this patent OTHER PUBLICATIONS subsequent to May 14, 2002 has been disclaimed. DeJonge, Europ. J. of Pharm. 71 (1981) 411-420; “Dis crimination Between Peripheral and Central Alpha-A- 21) Appl. No.: 755,373 drenergic Effects Using Meta-Substituted Imidazo 22 Filed: Jul. 15, 1985 lines'. J. Pharmcol. Methods 6(2) 109-20 (1981)-Stahle et al. Related U.S. Application Data J. Labelled Compa. Radiopharm. 17(1), 35-41 (1980), 63. Continuation of Ser. No. 590,464, Mar. 16, 1984, aban Rouot et al. doned, which is a continuation-in-part of Ser. No. J. Med. Chem. 24, 502-507 (1981)-Pieter et al. 519,791, Aug. 3, 1983, Pat. No. 4,517,199, and Ser. No. Naunyn-Schmiedeberg's Pharmacol. 317(8), 1-12 520,071, Aug. 3, 1983, Pat. No. 4,515,800, which is a (1981), DeJonge et al. continuation-in-part of Ser. No. 323,369, Nov. 20, J. Auton. Pharmac. 1, 377-383 (1981)-DeJonge et al. 1981, abandoned. Brit. J. Pharmac. 71, 5-9 (1980)-Rouot et al. 51) Int. Cl............................................. A61K 31/415 CR Acad. Sci. Paris-286 (1978), Rouot et al. 52 U.S. Cl. ..................................... 514/392; 514/913 Life Science 25, 769-774 (1979)-Rouot et al. 58) Field of Search ................................ 514/392,913 Invest. Ophthal. 17(2), 149-158 (1973), Krieglstein et al., "The Peripheral & Central Neural Action of Cloni 56) References Cited dine'. U.S. PATENT DOCUMENTS Chem. Abst. 92,41944(d)-41946(f)-Stahle et al. (1980). 2,938,038 5/1960 Hirt .................................. 260/309.6 Primary Examiner-Douglas W. Robinson 3,236,857 2/1966 Zeik et al. .... ... 260/309.6 Attorney, Agent, or Firm-Lowe, Price, LeBlanc, 3,468,887 9/1969 Stahle et al. ........................ 260/253 Becker & Shur 3,622,579 11/1971 Stahleet al. ... 424/273 3,636,219 1/1972 Culik et al........ ... 424/265 57 ABSTRACT 3,872,121 3/1975 Kummer et al. ..... ... 424/273 3,931,216 1/1976 Franzmairi ....... ... 260/309.6 3-chloro-4-(4,5-dihydro-1H-imidazao-2-yl)-amino-5- 4,125,620 1 1/1978 Stahle et al. ... 424/273 R alkylbenzoic acid, its pharmaceutically acceptable 4,166,859 9/1979 Stahle et al. .................... 424/273 R metal salts and esters are useful in treating glaucoma by 4,213,995 7/1980 Stahle et al..................... 424/273 R virtue of the effect in lowering intraocular pressure 4,250,186 2/1981 Stahle et al. .................... 424/273 R when administered systemically or topically to the eye. 4,262,005 4/1981 McCarthy ....................... 424/273 R Also disclosed are processes for preparing the com 4,287,201 9/1981 Olson et al. ..................... 424/273 R pounds, pharmaceutical compositions comprising the 4,293,564 10/1981 Stahle et al. .................... 424/273 R disclosed compounds; and methods of treatment com FOREIGN PATENT DOCUMENTS prising administering said compositions when a lower 0035393 9/1981 European Pat. Off. ing of intraocular pressure is indicated. 0043659 1/1982 European Pat. Off. 2831657 1/1980 Fed. Rep. of Germany. 14 Claims, No Drawings 4,644,007 1. 2 wherein R is methyl or ethyl and the pharmaceutically 3-CHLORO-4-(4,5-DIHYDRO-1H-MEDAZO-2-YL)- acceptable salts and esters thereof. AMINO-5-ALKYLBENZOIC ACIDS, ESTERS, DESCRIPTION OF PREFERRED SALTS, COMPOSITIONS AND METHODS EMBODIMENTS CROSS REFERENCE TO RELATED As indicated above, the present invention relates to APPLICATIONS novel substituted 4,5-dihydro-1H-imidazo-2-yl benzoic This application is a continuation of Ser. No. 590,464, acids and derivatives. These compounds may be charac filed Mar. 16, 1984, now abandoned, which is a con terized by the following general formula: tinuation-in-part of both Ser. No. 519,791, filed Aug. 3, 10 1983, now U.S. Pat. No. 4,517,199, and Ser. No. H 520,071, filed Aug. 3, 1983, now U.S. Pat. No. R N 4,515,800, which are continuation-in-parts of Ser. No. 323,369, filed Nov. 20, 1981, now abandoned. N=( 15 N FIELD OF THE INVENTION Cl H The present invention relates to certain substituted dihydro-1H-imidazoyl benzoic acids and esters which wherein R is methyl or ethyl and the pharmaceutically are useful in lowering intraocular pressure, and thus are 20 acceptable esters and salts thereof. The pharmaceuti useful in treating glaucoma. cally acceptable acid addition salts from mineral acids or organic acids are also included with the scope of the BACKGROUND invention. Some medicaments presently available for treating The esters contemplated for the compounds of the glaucoma by lowering the intraocular pressure are not 25 invention include any ester moiety which permits the completely satisfactory because they are ineffective, compound to retain its pharmaceutical use in lowering and/or demonstrate unwanted cardio-vascular-pulmo intraocular pressure, and provides a compound which is nary and CNS activities. Additionally, prior art com safe and effective. Thus the compounds covered by the pounds for this use plague the user with any one or above general formula include the free acid (-COOH), more of the following side effects: obvious vasocon 30 alkali and alkaline earth metal salts (e.g., Na, K, C2, and stricton or vasodilation of the vessels of the sclera; obvi Mg), and esters which may be illustrated by the func ous pupil contraction or dilation; and painful stinging. tional group -COOR". The invention is inclusive of all Accordingly, there is a need in the art for compositions ester radicals, R', known to be effective as pharmaceuti which are effective in lowering intraocular pressure and cally acceptable esters. Lower alkyl esters are espe are devoid of unwanted side effects. Such freedom of 35 cially preferred. The pharmaceutically acceptable salts side effects is particularly desired on topical administra of the compounds of the present invention also include tion to the eye. N-acid addition salts, such as the hydrochloride, hydro bromide, maleate, hydrogen sulfate, and the like. SUMMARY OF THE INVENTION As pointed out, the ester moiety may be any compati It is accordingly one object of the invention to pro 40 ble group. More generally stated, pharmaceutically vide novel 3-chloro-4-(4,5-dihydro-1H-imidazo-2-yl)- acceptable carboxyl derivatives of the present invention amino-5-alkylbenzoic acids and esters, salts and meth are those derived by reacting the free acid or salt deriv ods of preparation. ative with alcohols, phenols, alkylating reagents and the A further object of the invention is to provide novel like. For example, esters of interest from the above pharmaceutical compositions of matter containing these 45 listed starting materials are final products having the benzoic acids and esters as the effective ingredient, and -COOR" group at the ester position, wherein R' is methods for treating glaucoma by administration of alkyl having 1-10 carbon atoms, straight or branched, these novel compositions. such as methyl, ethyl, t-butyl, pentyl, decyl and the like; Other objects and advantages of the present invention aminoalkyl including 2-methylaminoethyl, 2-die will become apparent as the description thereof pro 50 thylaminoethyl, 2-acetamidioethyl, phthalimidomethyl, ceeds. succinimidomethyl; alkoxyalkyl wherein the alkoxy In satisfaction of the foregoing objects and advan portion as 1-10 and preferably 1-6 carbon atoms; but tages, the present invention provides 3-chloro-4-(4,5- can be branched, straight or cyclic, and the alkyl por dihydro-1H-imidazo-2-yl)amino-5-alkylbenzoic acids, tion has 1-6 carbon atoms, such as methoxymethyl, salts and the esters, which are useful in lowering intra 55 ethoxymethyl, isopropoxymethyl, decyloxymethyl, ocular pressure when administered topically or systemi ethoxymethyl, isopropoxymethyl, decyloxymethyl, cally to the eye and, thus, are useful in treating glau ethoxypropyl, decyloxypentyl, cyclohexyloxymethyl coma; the novel compounds being of the following and the like; alkanoloxyalkyl wherein the alkanoyloxy general formula: portion is straight or branched and has 1-6 carbon 60 atoms and the alkyl portion has up to 16 carbon atoms, H such as acetoxymethyl, pivaloyloxymethyl, acetoxy N ethyl, propionyloxyethyl, acetoxypropyl, and the like; haloalkyl wherein halo is chloro, bromo, fluoro, or iodo, and the alkyl portion is straight or branched hav 65 ing 1-6 carbon atoms, e.e., 2,2,2-trichloroethyl, trifluo - N Cl. H roethyl, 2-bromopropyl, diiodomethyl, 2-chloroethyl, 2-bromoethyl, and the like; alkenyl having 1-10 carbon atoms, either straight or branched, e.g., allyl, 2-prope 4,644,007 3 nyl, 3-butenyl, 4-butenyl, 4-pentenyl, 2-butenyl, 3 pentenyl, 3-methyl-3-butenyl, methallyl, 1,4-cyclohex adien-1-yl-methyl, and the like; alkynyl having 1-10 carbon atoms, either straight of branched, e.g., 3-penty nyl, propargyl, ethynyl, 3-butyn-1-yl, and the like; al kanoyl, either straight or branched, having 1-10 carbon atoms, such as pivaloyl, acetyl, propionyl, and the like, where X is halogen, methoxy, lower alkyl, e.g., methyl, aralkyl or heteroaralkyl wherein alkyl has 1-3 carbon and n is an integer of 1 to 5; or arylalkyl of 6-14 carbons, atoms, and hetero means 1-4 hetero-O-atoms, including e.g., benzyl.
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