United States Patent [19] [11] Patent Number: 5,576,332 Bodor [45] Date of Patent: Nov

US005576332A United States Patent [19] [11] Patent Number: 5,576,332 Bodor [45] Date of Patent: Nov. 19, 1996

[54] SOFT B-DRENEGIC BLOCKING AGENTS 4,578,403 3/1986 Matier ...... 514/522 4,703,057 10/1987 Marchand et a1...... 514/432 [76] Inventor: Nicholas S. Bodor, 7211 SW. 97th La., FOREIGN PATENT DOCUMENTS Gainesville, Fla. 32608 0041491 12/1981 European Pat. Off. . 59-118746 7/1984 Japan . [21] Appl. No.: 454,946 8201869 6/1982 WIPO . [22] Filed: May 31, 1995 8301772 5/1983 WIPO . OTHER PUBLICATIONS Related US. Application Data Bodor et al, Pharmaceutical Research, 1984, N0. 3, [62] Division of Ser. No. 239,414, May 6, 1994, Pat. No. 5,482, 120—125. 961, which is a division of Ser. No. 997,248, Dec. 28, 1992, Erhardt et al, J. Med. Chem, 1982, vol. 25, No. 12, Pat. No. 5,334,601, which is a division of Ser. No. 822,127, 1408-1412. Ian. 17, 1992, Pat. No. 5,202,347, which is a division of Ser. No. 692,260, Apr. 26, 1991, Pat. No. 5,135,926, which is a Primary Examiner-Bernard Dentz continuation of Ser. No. 286,879, Dec. 20, 1988, abandoned, which is a division of Ser. No. 922,462, Oct. 23, 1986, Pat. Attorney, Agent, or Firm—Burns, Doane, Swecker & No. 4,829,086, which is a continuation of Ser. No. 741,846,‘ Mathis, L.L.P. ?led as PCT/US85/00322, Feb. 28, 1985, abandoned, which is a continuation-in-part of Ser. No. 589,359, Mar. 14, 1984, [57] ABSTRACT abandoned. New soft B-adrenergic blocking agents, useful in the treat [30] Foreign Application Priority Data ment or prevention of cardiovascular disorders and in the treatment of glaucoma, have the formula Mar. 13, 1985 [CA] Canada ...... 07/476391 [51] Int. Cl.6 ...... A61K 31/215; CO7C 69/616 [52] US. Cl...... 514/312; 514/415; 514/470; ROCt’ — CHHZH — Ar — OCHZCHCHZNHR]e 514/534; 546/158; 548/481; 549/467; 549/471; wherein n is an integer from 0 to 10; R is C6—C12 cycloalkyl 560/42 CpH2p—, C6-C18 polycycloa1kyl-CpH2p—, C6-C1!‘ polycy [58] Field of Search ...... 546/158; 548/481; cloalkcnyl-CpH2p—- or C6—C12 cycloalkenyl-CpH2p-— 549/467, 471; 560/42; 514/312, 415, 470, (wherein p is 0, 1, 2 or 3), or together with the adjacent 534 0 [56] References Cited ll U.S. PATENT DOCUMENTS group represents a variety of other complex ester groupings; 3,663,607 5/1972 Barrett et a1...... 260/5011 R1 is C1—C7 alkyl; and Ar is a divalent radical containing at 3,836,671 9/1974 Barrett et a1...... 424/324 4,287,194 9/1981 Kosa ct a1. 424/248.51 least one aromatic nucleus. The corresponding pharmaceu~ 4,387,103 6/1983 Erhardt et a1...... 424/309 tically acceptable acid addition salts are also described. 4,438,128 3/1984 Wiedemann et a1. 424/273 N 4,454,154 6/1984 Matier ...... 424/309 11 Claims, 4 Drawing Sheets U.S. Patent Nov. 19,1996 Sheet 1 0f 4 5,576,332

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24m: 82(20 000.52 wmammwtm a:2.... 5,576,332 1 2 SOFT B-DRENEGIC BLOCKING AGENTS (3) Design the structure and metabolism of the new soft compound in such a way as to yield the starting inactive metabolite in one step without going through toxic interme CROSS-REFERENCE TO RELATED diates. APPLICATION (4) Control transport and binding properties as well as the rate of metabolism and pharmacokinetics by molecular This application is a division of application Ser. No. manipulations in the activation stage. - 08/239,414, ?led May 6, 1994, now U.S. Pat. No. 5,482,961 However, it is not necessary to wait for an inactive which is a division of application Ser. No. 07/997,248, ?led metabolite to be isolated; it may be possible to design the Dec. 28, 1992, now U.S. Pat. No. 5,334,601; which is a 10 inactive metabolite during the general drug design process division of application Ser. No. 07/822,127, ?led Jan. 17, based on knowledge of structural requirements for activity 1992, now U.S. Pat. No. 5,202,347; which is a division of as well as elimination and enzymatic cleavage. application Ser. No. 07/692,260, ?led Apr. 26, 1991, now US. Pat. No. 5,135,926; which is a continuation of appli Recently, several patent publications have described vari cation Ser. No. 06/286,879, ?led Dec. 20, 1988, now aban ous series of short acting B-adrenergic blocking compounds doned; which is a division of application Ser. No. 06/922, containing ester moieties which are structurally related to 462, ?led Oct. 23, 1986, now U.S. Pat. No. 4,829,086; which some of the compounds of the present invention. Thus, is a continuation of application Ser. No. 06/741,846, ?led as Matier US. Pat. No. 4,454,154, issued Jun. 12, 1984, PCT/US85/0O322, Feb. 28, 1985, now abandoned; which is describes a method of treating glaucoma by topical admin a continuation-in-part of my earlier application Ser. No. 20 istration of selected B~blockers. Lower alkyl (C1—C,0) and 589,359, ?led Mar. 14, 1984, now abandoned incorporated lower cycloalkyl (C3-C5) esters are among the compounds by reference herein in its entirety and relied upon. generically disclosed by Matier, but only alkyl esters are speci?cally described. See also related Erhardt et al U.S. Pat. No. 4,387,103, issued Jun. 7, 1983 and American Hospital Supply Corportion’s corresponding International Applica FIELD OF THE INVENTION 25 tion No. PCT/US8l/0l5l4 published under International The present invention provides novel compounds con Publication No. WO82/01869 on Jun. 10, 1982; again, lower taining at least one aromatic nucleus which are soft B-adr alkyl and lower cycloalkyl esters are generically disclosed, energic blocking agents, useful in the treatment or preven but of these only the lower alkyl esters are speci?cally described. The Erhardt et al patent and its PCT counterpart tion of cardiovascular disorders and in the treatment of 30 glaucoma. provide a method for the treatment or prophylaxis of cardiac disorders. A related series of short acting B-blockers is described in Aktiebolaget Hassle’s European Patent Appli BACKGROUND OF THE INVENTION cation No. 818500951, published on Dec. 9, 1981 under European Publication No. 0041491. The Hassle application Many B~adrenergic blocking agents are known and used; 35 generically discloses lower alkyl (C1—C7) and lower unfortunately, however, these agents are generally subject to cycloalkyl (C3—C6) esters, among others, but again does not facile oxidative metabolic degradations. Many of the speci?cally describe any cycloalkyl esters. Moreover, none metabolites also possess signi?cant B-blocking activity and, of these publications appear to address the problem due to their dilferent pharmacokinetic properties, make addressed by the present invention, i.e. how to design dosing and optimization of therapy di?icult. The metabolites B-blockers which would be metabolized in one simple, of bufuralol, for example, have longer biological half-lives predictable, controllable step to an inactive metabolite than the parent drug. Francis et al, Biomed. Mass, Spec which avoiding oxidative metabolism; moreover, the esters trometry, 3,281-285 (1976). Consequently, it is di?icult to of the publications are generally less complex structurally determine an adequate dose of the known B-blockers for than those described hereinbelow. See also Erhardt et al, J. administration, especially when administering them thera Med, Chem, 25, 1408-1412 (1982). Similar simple alkyl peutically to patients suifering from angina pectoris, hyper esters were described much earlier, e.g. Barrett et al US. Pat. tension or unexpected arrhythrrrias during surgical opera No. 3,663,607, issued May 16, 1972. tions. It would be most desirable to design [it-blockers which would be metabolized in a simple, predictable and control 50 SUMMARY AND OBJECTS OF THE lable manner in one step to an inactive metabolite, regardless INVENTION of the conditions of the patient and other drugs used. This would necessitate, however, avoiding oxidative metabolism. In view of the foregoing, it is an object of this invention The present inventor has previously devised a general soft to provide a new class of B-adrenergic agents which will be metabolized in a simple, predictable and controllable man drug approach having such objectives, one speci?c aspect of 55 that approach being the inactive metabolite method. Bodor, ner in one step to an inactive metabolite. It is another object in Proceedings of the 2nd IUPAC-IUPHAR Symposium on of the present invention to provide new B-adrenergic agents Strategy in Drug Research, Noordwijkerhout, J. A. Kever which are not subject to signi?cant oxidative metabolism. It ling Buisman (ed), Elsevier Scienti?c Publishing Company, is another object of this invention to apply the present Amsterdam, 1982; Bodor, Belgian Patent No. 889,563, Nov. inventor’s general inactive metabolite approach to the 3, 1981; Chem. Abstr. 97:6651n (1982). The principles of design of novel soft B-blockers. the inactive metabolite approach are: These and other objects of the present invention are (1) Start the design process with a known inactive achieved by providing compounds of the formula metabolite of a drug. OH (1) (2) Alter the metabolite to obtain a structure that 65 resembles (isosteric and/or isoelectronic) the starting or an ROC — CHI-I2" —— Ar — OCH;Cl-ICI-I2NHR1 analogous drug. wherein: 5,576,332 3 4 n is an integer from O to 10 inclusive; the phenylacetic acid derivative, i.e. the compound of the R is (1) C6—C12 cycloalkyl~CpH2p— wherein p is 0, 1, 2 formula or 3; (2) C6—C18 polycycloalkyl-CpH2p— wherein p is de?ned as above; (3) C6—C18 polycycloalkenyl-CpH2p— CH3 OH wherein p is de?ned as above; (4) C6—C12 cycloalkenyl CPHZP wherein p is de?ned as above; (5) —CH2—X—R2 wherein X is S, S0 or S02 and R2 is C1-C7 alkyl or C3—C12 cycloalkyl, CH3 which is an inactive metabolite of metoprolol and the major —CH2—+s—RZ (6) metabolite found in the urine. [See, for example, Borg et al, CH3 Acta Pharrnacol. Toxicol., 36 (Suppl. V), 125-135 (1975).] wherein R2 is de?ned as above; The rate of hydrolysis deactivation may be controlled by the structure of the esters. lllr (7) Accordingly, the compounds of the present Invention —cn—x—R4 exhibit excellent B-blocking e?icacy without adverse side wherein X is de?ned as above, and wherein R3 is C1—C7 effects for a certain duration, dependent only on the hydro alkyl and R4 is C1—C7 alkyl or wherein R3 and R4 taken lytic metabolism rate. As a consequence, it is easy to control together represent -(CH2)m— wherein m is 3 or 4 and and maintain adequate therapeutic action with a desirable —(CH2)m— is optionally substituted by one to three C1—C7 onset time using the present compounds. The onset time is alkyl; 20 usually short compared with conventional B-adrenergic blocking agents; therefore, the instant compounds are 1'15 (3) expected to be of particular use in the treatment of arrhyth —CI—I—OCOR6 rnias, ischemic heart disease and hypertension, possibly attending surgical operations. The instant compounds are wherein R5 is hydrogen or C1—C7 alkyl and R6 is unsubsti 25 tuted or substituted C1—C7 alkyl, C3—C12 cycloalkyl, Cj—C12 also expected to be of special value when used in the cycloalkenyl or C2—C8 alkenyl, the substituents being treatment of glaucoma, since they will not only reduce selected from the group consisting of halo, CrCq alkoxy, intraocular pressure when applied locally to the eye, but CFQ alkylthio, C1—-C7 alkylsul?nyl, C1—C7 alkylsulfonyl, because of their “soft” nature will deactivate during absorp tion and thus avoid the typical B-blocker systemic side 30 effects which attend use of known [fa-blockers for this purpose.

alkyl), or R6 is unsubstituted or substituted phenyl or benzyl, the substituents being selected from the group consisting of 35 BRIEF DESCRIPTION OF THE DRAWINGS C1—Cq alkyl, C1-C7 alkoxy, halo, carbamoyl, C2—C8 alkoxy FIG. 1 is a graph plotting the mean change in heart rate carbonyl, C2—C8 alkanoyloxy, C1—C7 haloalkyl, (beats/minute) with time following subcutaneous adminis mono(C1—C7 alkyl)amino, di(C1-C7 alkyl)amino, tration of 25 g/kg of isoproterenol to groups of rats pre mono(C1—C7 alkyl)carbamoyl, di(C1-(‘,, alkyl(carbarnoyl, treated 60 minutes prior to isoproterenol administration with C1-C7 alkylthio, C1—C7 alkylsul?nyl and C1—C7 alkylsul fonyl; 6 mg/kg of test compound or control vehicle; FIG. 2 is a graph plotting the mean change in heart rate response (beats/minute) with time in groups of rats pre Ills (9) treated with control vehicle or with test compound at 15, 60 —crr--cooR6 45 or 90 minutes prior to administration of isoproterenol (25 wherein R5 and R6 are de?ned as above; or pg/kg s.i.) at time zero; FIG. 3 is a graph plotting the mean change in blood R5 (10) pressure response (mm Hg) with time following subcutane —él-l—CONR7Rg ous administration of 25 pg/kg of isoproterenol to groups of wherein R5 is de?ned as above, and R7 and R8, which can 50 rats pretreated 60 minutes prior to isoproterenol administra be the same or different, are each hydrogen, C1—C7 alkyl, tion with 6 mg/kg of test compound or control vehicle; and C3—C12 cycloalkyl, phenyl or benzyl, or R7 and R8 are FIG. 4 is a graph plotting the B-adrenergic blocking combined such that —NR7R8 represents the residue of a activities of selected test compounds on the heart rate of saturated monocyclic secondary amine; dogs. 55 and Ar is a divalent radical containing at least one aromatic nucleus. ~ DETAILED DESCRIPTION OF THE The compounds of the present invention avoid the disad INVENTION vantages of many known B-blockers resulting from their active metabolites. The compounds of formula (I) are ratio 60 With respect to the various groups encompassed by the nally designed so that when administered to a mammal they generic terms used in this speci?cation, the following de? are subjected to an enzymatic hydrolytic (i.e. esterase) nitions and explanations are applicable: process which is much faster than oxidative metabolism and The divalent radicals containing at least one aromatic which leads to hydrolyzed metabolites which possess very nucleus which are represented by Ar can be unsubstituted or little or no B-adrenergic activity. Thus, for example, in the 65 substituted monocyclic or polycyclic ring systems and may case of a group of preferred metoprolol derivatives of the include hetero ring atoms, particularly N and O. Illustrative invention, such are designed to hydrolytically deactivate to divalent radicals represented by Ar include the following: 5,576,332 5 6 (l) phenylene, i.e. a radical of the formula (3) divalent aryl‘alkylene-aryl systems, e.g. phenylene C1—C3 alkylene-phenyl radicals such

especially 1,4-phenylene and 1,3-phenylene, optionally bearing one or more substituents such as C1—C7 alkyl, e.g. CH3CH2— or CH3—; C1—C7 aJkyl-—O—C1—Cq alky lene—, e.g. CH3OCH2CH2—; C2—C8 alkenyl, e.g. CH2=CH——CH2—; CFC7 alkyl-—-S—, e.g. CH3—S—; C2-C8 alkenyl—0—, e.g. CH2CH=CH2—O—; C3—C12 CH3 cycloalkyl, e.g. cyclopentyl; CFC, alkyl—-CONH—, e.g. CH3CHZCH2CONH— or CH3CONH—; C1—C7 alkyl 15 Preferably, the divalent radical represented by Ar is selected —CO—~, e.g. CH3CO—; and/or H2NCO—C1—C7 alky lene—-; e.g. H2NCO—CH2—~; Such that the (2) divalent fused ring systems containing two or three rings, optionally containing one or two N, S or O ring atoms, such as:

, especially ; (a)

O O

(b) , especially ;

O 0 (c) OH, especially OH;

0H OH

H H (d) N N

H H (e) '

N - . 0, especially Q1“)% O, and

(i) m or @ , especially

0 ll ROC—-C,,Hz,,—— grouping in formula (I) either simply replaces a hydrogen atom on the corresponding ring of a known [i-blocker or replaces a non-critical ring substituent on the corresponding ring of a known B-blocker, e.g. a lower alkyl, lower alkyl— 0- lower alkylene—, lower alkyl —CONH— or H2NCO—lower alkylene- substituent. Particularly pre and ferred compounds of the invention bear such a structural 5,576,332 7 8 relationship to metoprolol, bufuralol, alprenolol, bunolol, -continued xipranolol, nadolol, tiprenolol, oxprenolol, penbutolol, pin alkyl dolol, carteolol, propranolol, acebutolol, atenolol and prac tolol. Analogues of metoprolol are especially preferred. It should be emphasized that the divalent radicals represented alkyl by Ar must contain at least one true aromatic nucleus, i.e. at respectively, wherein alkyl is as hereinbefore de?ned and least one benzene ring. Thus, a ring system such as exempli?ed. | l The halo substituents can be chloro, bromo, iodo or ?uoro. The haloalkyl substituents can be monohaloalkyl or N N polyhaloalkyl, straight or branched-chain, substituted with f S K from 1 to 3 halogen atoms, the term “halogen” as used herein including chlorine, bromine, iodine or ?uorine. Speci?c is not within the meaning of An as de?ned herein. Hereto examples of the contemplated monohaloalkyl and polyha _loalkyl groups include chloromethyl, dichloromethyl, atoms may be present, however, when located In a ring or trtchloromethyl, bromomethyl, ?uoromethyl, di?uorom rings fused or appended to a benzene ring, e.g. as in (2) (a), ethyl, tri?uoromethyl, l-?uoroethyl, l-chloroethyl, 2-chlo (d) and (e) above. roethyl, 2,2,2-trichloroethyl, 2,2,2-tri?uoroethyl, 1,2-dichlo The alkyl, alkenyl and alkylene groupings encompassed roethyl, l-chloropropyl, 3-chloropropyl, l-chlorobutyl, by any of the structural variables in formula (I) can be l-chloropentyl, 2-chlorohexyl, 4-chlorobutyl and the like. straight or branched-chain groups containing the indicated 20 When R in formula (I) is C6—C12 cycloalkyl—CpH2p—, number of carbon atoms. The term “lower” used in con the cycloalkyl groups contain 6 to 8 ring atoms and may junction with such radicals indicates that they may contain optionally bear one or more, preferably one to four, alkyl up to 7 carbon atoms. substituents, Exemplary such cycloalkyl groups are cyclo Speci?c examples of alkyl radicals encompassed by for hexyl, 2,6-dimethylcyclohexyl, 3,3,5,5-tetramethylcyclo mula (1), whether as speci?c values for R1 or as a portion of 25 hexyl, 2-methylcyclohexyl, 2-ethylcyclohexyl, 4-propylcy an R or Ar group, include methyl, ethyl, propyl, butyl, clohexyl, S-butylcyclohexyl, 2,3-dimethylcyclohexyl, 2,4 pentyl, hexyl and heptyl and their branched-chain isomers, dimethylcyclohexyl, 2,5dimethylcyclohexyl, 2,3,4~ e.g. isopropyl, isobutyl and tert-butyl. Preferred values for tiimethylcyclohexyl, 2,3-dimethyl-5-ethylcyclohexyl, 2,5 R1 are isopropyl and tert-butyl. dimethyl-6-propylcyclohexyl, 2,4-dimethyl-3 The alkenyl radicals encompassed by various R and Ar 30 butylcyclohexyl, 2,2,4,4-tetrarnethylcyclohexyl, 3,3,6,6 values can be exempli?ed by vinyl, propenyl and butenyl tetramethylcyclohexyl, 3,3,4,5,S-pentarnethylcyclohexyl, and the branched-chain groups having 3 or more carbon 3,3,4,5,5,6-hexamethylcyclohexyl, 3,3,5-trimethyl-4-ethyl atoms. cyclohexyl, 3,4,4-trimethyl-5-propylcyclohexyl, cyclohep The alkylene moieties encompassed by CHHZH (when n is tyl, 3-methylcycloheptyl, S-propylcycloheptyl, 6-butylclo other than zero) as well as those encompassed by various 35 heptyl, 7-methylcycloheptyl, cyclooctyl, values for R and Ar are typi?ed by methylene, ethylene, 2-methylcyclooctyl, 3-ethylcyclooctyl, 3,3,4-trimethylcy trimethylene, 2-methyltrimethylene, 2,2-dimethylt1imethyl clooctyl, 3,3,5,5-tetramethylcyclooctyl and the like. Among ene, l-methyltrimethylene, methylmethylene, ethylmethyl the presently preferred cycloalkyl—CpH2p— groups repre ene, tetramethylene, pentamethylene, hexamethylene and sented by R are cyclohexyl, 2,6-dimethylcyclohexyl and the like. 3,3,5,5-tetramethylcyclohexyl. Thus, when R is The alkoxy, alkylthio, alkylsul?nyl, alkylsulfonyl, cycloalky1—CpH2p—, p is preferably zero or one, most alkoxycarbonyl, alkanoyloxy, monoalkylarnino, dialky preferably zero. Even more preferred are cycloalkyl—— larnino, monoalkylcarbamoyl and dialkylcarbamoyl group CpH2p— groups containing at least eight carbon atoms in the ings are of the type cycloalkyl portion. Most especially preferred are 45 cycloalkyl—CpH2p— groups wherein the cycloalkyl portion contains 6 to 8 ring atoms and bears at least two alkyl substituents on the ring (e.g. 2,6-dimethylcyclohexyl and 3,3,5,5-tetramethylcyclohexyl). When a cycloalkyl radical is present in formula (1) as a 50 portion of Ar or as a different portion of R (e.g. when R is —CH2—X—R2 wherein R2 is C3—C12 cycloalkyl), then such a cycloalkyl radical can contain 3 to 8 ring atoms and may optinally bear one or more, preferably one to four, alkyl substituents. Examples of such cycloalkyl groups include 55 the examples of C6—C12 cycloalkyl radicals recited above as well as the lower homologues, e.g. cyclopropyl, Z-methyl cyclopropyl, 3-ethylcyclopropyl, 2-butylcyclopropyl, 3-pentylcyclopropyl, 2-hexylcyclopropyl, cyclobutyl, 2-me thylcyclobutyl, 2,3-dimethylcyclobutyl, 3-butylcyclobutyl, 60 4-hexylcyclobutyl, 2,3,3-trimethylcyclobutyl, 3,3,4,4-tet ramethylcyclobutyl, cyclopentyl, Z-methylcyclopentyl, 3-ethylcyclopentyl, 4-butylcyclopentyl, methylcyclopentyl, B-pentylcyclopentyl, 4-hexylcyclopentyl, 2,3-dimethylcy clopentyl, 2,2,5,S-Ietramethylcyclopentyl, 2,3,4-trimethyl 65 cyclopentyl, 2,4-dimethyl-3-ethy1cyclopentyl, 2,2,3,4,4 O pentamethylcyclopentyl, 2,3-dimethyl-3-propylcyclopentyl and the like. When a cycloalkenyl radical is present in 5,576,332 9 10 formula (I) as a portion of R, corresponding unsaturated conducted at a temperature from about room temperature to radicals such as cyclopentenyl and cyclohexenyl and the about 200° C. (preferably from about 60° to 120° C.), for a like, including alkyl-substituted cycloalkenyl radicals, are period of time from about 30 minutes to 24 hours. Suitable contemplated (depending, of course, on the carbon atom inert solvents include ethers such as dioxane, tetrahydrofu limitations in the generic de?nitions). Again, when R is ran and ethylene glycol monomethyl ether; aromatic hydro’ C5—C12 cycloalkenyl—-C,,H2P—, p is preferably zero or one, carbons such as benzene, toluene or xylene; lower alcohols most preferably zero. An exemplary C6—C12 cycloalkenyl—— such as methanol, ethanol and isopropanol; and esters such CPH2p—— grouping is 3,5,5-trimethyl-2-cyclohexen-l-yl. as ethyl acetate, dimethylformamide and dimethylsulfoxide. The polycycloalkyl—CpH2p— radicals represented by R The process is frequently carried out in the presence of a basic compound, for example an inorganic base such as are bridged or fused saturated alicyclic hydrocarbon systems 10 consisting of two or more rings, optionally bearing one or m sodium carbonate, sodium hydroxide, sodium bicarbonate, ore alkyl substituents and having a total of 6 to 18 carbon sodium amide or sodium hydride; or an organic base such as atoms in the ring portion. The corresponding bridged or triethylamine, tripropylarnine, pyridine, quinoline, DBN fused unsaturated alicyclic hydrocarbon systems are (l,5-diazabiscyclo[4.3.0]non-5-ene), DBU (1,8-diazabi intended by the term “C6—C18 polycycloalkenyl—CpH2p— cyclo[5.4.0]undec~7-ene) or Dabco (1,4-diazabicyclo Such polycycloalkyl and polycycloalkenyl radicals con [2.2.2.]octane or triethylenediamine). The ratio of the stitute especially preferred embodiments of this invention, amounts of reactants used can be selected over a wide range. most especially the bridged entities. These polycyclic It is, however, generally desirable for the amine of formula groups represented by R are exempli?ed by adarnantyl (1H) to be used in an equimolar quantity or in an excess (especially 1- or 2- adamantyl), adarnantylmethyl (espe amount, preferably from an equimolar quantity to about seven times the molar quantity. cially l-adamantylmethyl), adamantylethyl (especially The starting materials of formula (H) can be conveniently l-adamantylethyl), bomyl, norbornyl (e.g. exo-norbornyl or prepared by reacting the corresponding compounds of the endonorbornyl), norbornenyl (e.g. 5-norbomen-2-yl), nor bomylmethyl (e. g. 2-norbomylmethyl), norbomylethyl (e.g. formula 2-norbomylethyl), decahydronaphthyl (e.g. eis or trans decahydronaphth-Z-yl ), 6,6-dimethylbicyclo[3. l . l ]hept-2 25 en-2-ethyl, (+)-(3—methylnorbom-2-yl)methyl, 1,3,3-trim ethyl —2-norbornyl and 5-norbomene-2-methyl. Thus, in the wherein R, n and Ar are de?ned as before, with an epiha~ case of polycyclic radicals, p is preferably 0, 1 or 2. logenohydrin of the formula When R in formula (I) is 30

wherein Hal is a halogen atom, especially Cl or Br. This process can be carried out in the presence of a suitable basic compound, for example an inorganic base such as sodium wherein —NR7R8 represents the residue of a saturated 35 monocyclic secondary amine, such monocycles preferably hydroxide, potassium hydroxide, sodium carbonate, potas have 5 to 7 ring atoms optionally containing another hetero sium carbonate, sodium methoxide, sodium ethoxide, atom (—O—, ——S— or —N-—) in addition to the indicated sodium hydride, sodium metal, potassium metal or sodium nitrogen atom, and optionally bear one or more substituents amide, or an organic basic compound such as piperidine, such as phenyl, benzyl and methyl. Illustrative of residues of pyridine, triethylarnine, DBN, DBU or Dabco, in the pres saturated monocyclic secondary amines which are encom ence or absence of a solvent. Suitable solvents are, for example, a lower alcohol such as methanol, ethanol or passed by the -—NR7R3 term are morpholino, l-pyrrolidinyl, isopropanol; a ketone such as acetone; an ether such as 4-benzyl—l'piperazinyl, perhydro-1,2,4~oxathiazin-4-yl, l dioxane, tetrahydrofuran or ethylene glycol monomethyl or 4- piperazinyl, 4~methyl-l-piperazinyl, piperidino, hex ether; or an aromatic hydrocarbon such as benzene, toluene amethyleneimino, 4-phenylpiperidino, 2-methyl-l-pyrazo 45 or xylene. In this reaction, the epihalogenohydrin of formula lidinyl, 1- or 2-pyrazolidinyl, S-methyl -1-imidazolidinyl, l (V) ordinarily can be used in an equimolar to excess or 3-imidazolidinyl, 4-benzylpiperidino and 4-phenyl-lpip quantity, preferably about 5 to 15 times the molar quantity erazinyl. of the formula (IV) starting material. The process can be The compounds of formula (I) can be prepared by react conducted at a temperature between about 0° and 150° C., ing a starting material of the formula 50 preferably at from about 50° to about 100° C. Usually, the reaction product is a mixture of the corresponding (2,3 (II) epoxy)propoxy and 3-halogeno—2-hydroxypropoxy com ROC—C,.H2,,—Ar—OCl-l2-—Z pounds encompassed by formula (II) and can be used as such wherein, R, n and Ar are de?ned as above and Z is to prepare the formula (I) compounds. 55 The starting materials of formula (IV) can be prepared by esteri?cation of carboxylic acids of the formula

H0OC—C,,H2,,—-Ar—Ol-l (VI) wherein Hal is a halogen atom, especially C1 or Br, with a primary amine of the formula wherein n and Ar are de?ned as before, or the corresponding acid chlorides or acid anhydrides, by reaction with an NH2R1 (III) alochol of the formula

wherein R1 is de?ned as above. This process is preferably ROH (V111) carried out in the presence of an inert solvent, although it can 65 be canied out in the absence of solvent. While time and wherein R is de?ned as before. Reaction conditions, solvents temperature are not critical factors, the reaction is generally and the like vary with the particular reactants employed. 5,576,332 11 12 Generally speaking, when an acid of formula (VI) is utilized as the starting material, the process is conducted in the OH (X) presence of a conventional esteri?cation catalyst, e.g. an inorganic acid such as hydrogen chloride gas, concentrated HOOC—C,,H2,,—Ar—OCH2|CHCH;NI-IR1 sulfuric acid, phosphoric acid, polyphosphoric acid, boron wherein n, Ar and R1 are de?ned as above, under conditions tri?uoride or hypochlorous acid, or an organic acid such as similar to the esteri?cation of a compound of formula (VI) tri?uoroacetic acid, tri?uoromethanesulfonic acid, naphtha as described above. lenesulfonic acid, p-toluenesulfonic acid, benzenesulfonic Equivalent to the compounds of formula (I) for the acid, ethanesulfonic acid, tri?uoromethanesulfonic acid purposes of this invention are the corresponding acid addi anhydride, thionyl chloride, acetone dimethyl acetal and the tion salts formed with pharmaceutically acceptable acids. like. A cation exchange resin may also be used as the Illustrative of such acids are inorganic acids such as hydro catalyst. The reaction can be canied out In the presence or chloric acid, sulfuric acid, hydrobrornic acid and the like; absence of solvent, at a temperature between about —20° to and organic acids such as acetic acid, oxalic acid, succinic about 200° C., preferably between about 0° and about 150° acid, maleic acid, fumaric acid, malic acid, tartaric acid, C., for a period of time from about 10 minutes to about 20 citric acid, malonic acid, methanesulfonic acid, benzoic acid and the like. hours. If a solvent is employed, an inert solvent is desirable, for example, an aromatic hydrocarbon such as benzene, The compounds prepared by the procedures detailed toluene or xylene; a halogenated hydrocarbon such as chlo above can easily be isolated and puri?ed by usual separation roform, dichloromethane, dichloroethane or carbon tetra means, e.g. solvent extraction, dilution, recrystallization, chloride; or an ether such as diethyl ether, tetrahydrofuran, column chromatography or preparative thin-layer chroma dioxane or ethylene glcol monomethyl ether. The ratio of 20 tography. amount of a compound of formula (VI) to an alcohol of the The compounds of the present invention also includes fonnula ROH is not subject to any speci?c restriction and their optical isomers. may be suitably selected from a wide range. While usually For therapeutic use, e. g. in the treatment of angina pec it is desirable that the latter is used in an excess quantity in toris and arrhythmias, a compound of formula (I) or its salt the absence of the solvent, in the presence of the solvent it 25 can be conveniently administered in the form of a pharma is desirable that the latter is used in an equimolar to 5 times ceutical composition containing the formula (1) compound the molar quantity of the former, more preferably an or its salt and a phannaceutically acceptable carrier therefor. equimolar to 2 times the molar quantity of the former. This Suitable carriers vary with the desired fonn of the pharma reaction can advantageously be effected by using a drying _ ceutical composition and may include diluents or excipients agent such as anhydrous calcium chloride, anhydrous cupric 30 such as ?llers, binders, wetting agents, disintegrators, sur sulfate, anhydrous calcium sulfate, phosphorus pentoxide or face-active agents, lubricants and the like. the like. The compound of the invention or its salt may be formu Altemtively, an acid of formula (VI) can be converted to lated together with the carrier into any desired unit dosage the corresponding salt of the type form. Typical unit dosage forms include tablets, pills, pow 35 ders, solutions, suspensions, emulsions, granules, capsules, M*-00C-C,H2,,_Ar~—0r»r (vnr) suppositories; injectable solutions and suspensions are par ticularly preferred. where n and Ar are de?ned as before and M+ is Na+ or the In the preparation of tablets, carriers which are widely like; that salt can then be reacted with a halide of the formula used in this ?eld can be employed, e.g. excipients such as 40 lactose, sucrose, sodium chloride, glucose solution, urea, R—Hal (IX) starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid; binding agents such as water, ethanol, propanol, where R is de?ned as before and Hal is halogen, preferably simple syrup, glucose, starch solution, gelatin solution, C1 or Br, to afford the corresponding starting material of carboxymethyl cellulose, shellac, methyl cellulose, calcium formula (IV). 45 phosphate and polyvinylpyrrolidone; disintegrators such as The compounds of the invention which contain a sul?nyl dried starch, sodium alginate, agar-agar powder, larninalia (S0) or sulfonyl (S02) group can be prepared by oxidation powder, sodium bicarbonate, calcium carbonate, Tweens, of the corresponding sulfur-containing compounds of the sodium lauryl sulfate, stearic acid monoglyceride, starch and invention. Thus, for example, a compound of formula (I) lactose; disintegration inhibitors such as sucrose, stearin, wherein R is —CH2—X——R2 wherein X is S can be treated coconut butter and hydrogenated oil; absorption accelerators with one equivalent of m-chloroperbenzoic acid to afford the such as quaternary ammonium bases and sodium lauryl corresponding sul?nyl derivative, while treatment of the thio sulfate; wetting agents such glycerin and starch; adsorbing compound with two equivalents of m-chloroperbenzoic acid agents such as starch, lactose, kaolin, bentonite and colloidal yields the corresponding sulfonyl derivative. Thus, the com silicic acid; and lubricants such as puri?ed talc, stearic acid pounds of formula (I) wherein R contains a sulfur atom, e.g. 55 salts, boric acid powder, Macrogol and solid polyethylene the compounds in which R is —CH2—X——R2 or glycol. In the preparations of pills, carriers which are known and widely used in this ?eld can also be used, for example, excipients such as glucose, lactose, starch, coconut buter, 60 hydrogenated vegetable oils, kaolin and talc; binders such as wherein X is S and R2, R3 and R4 are de?ned above, are of powdered gum arabic, powdered tragacanth, gelatin and value not only as soft B-adrenergic agents but also as ethanol; and disintegrators such as larninaria and agar-agar. chemical intermediates to the corresponding soft drugs in In the case of tablets, they can be ?rrther coated with the which X is S0 or S02. usual coating materials to make sugar-coated tablets, gelatin The compounds of the present invention can also be 65 ?lm-coated tablets, tablets coated with enteric coatings, prepared by esteri?cation of the corresponding acid of the tablets coated with ?lms or double-layered tablets and formula multi-layer tablets. 5,576,332 13 14 In order to form suppositories, carriers which are known present. Host preferably, the ophthalmic composition is a and widely used in this ?eld can also be used, for example, sterile, isotonic, buffered aqueous solution. Generally speaké polyethylene glycols, coconut butter, higher alcohols, esters ing, the ophthalmic composition containing the instant of higher alochols, gelatin and semisynthesized glycerides. ?-blockers may be prepared and may contain the various In order to prepare formulations suitable for injection, inert ingredients or carriers as previously described in the solutions and suspensions are sterilized and are preferably patent or non-patent literature as being suitable for oph isotonic to blood. In making injectable preparations, carriers which are commonly used in this ?eld can aso be used, for thalmic compositions comprising known B-blockers such as example, water, ethyl alcohol, propylene glycol, ethoxylated timolol and labetolol. The amount of the [Yr-blocker of this isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxy invention which will be present in the ophthalmic compo ethylene sorbitol and sorbitate esters. In these instances, sition will of course vary with the particular B-blocker adequate amounts of sodium chloride, glucose or glycerin employed and the type of formulation selected. Generally can be added to make the preparations isotonic. speaking, the composition will contain 0.01 to 5% of a Furthermore, the usual dissolving agents, buffers, analge~ compound of formula (1), preferably 0.25 to 2.5%; in other sic agents and preservatives can be added, as well as words, each mL of solution will contain 0.1 to 50 mg, coloring materials, perfumes, seasoning agents, sweetening preferably 2.5 to 25 mg, of the free base. The dose admin agents and other medicines, to the pharmaceutical compo istered ophthalmically will be selected according to the sitions, if necessary or if desired. ' particular compound employed and the size and condition of The amount of a compound of formula (I) or its acid addition salt to be present in the pharmaceutical composi 20 the patient, but in any event will be a quantity su?icient to tion, e. g. for use in treatment of angina pectoris and arrhyth cause a signi?cant reduction in intraocular pressure. mias, can suitably be selected from a wide range, but usually In order to further illustrate the present invention and the 1 to 70% by weight of the total composition is preferable. advantages thereof, speci?c examples of compounds of As to the route of administration, e. g. for angina pectoris, formula (I) are given below, it being understood that these same will vary with the particular composition used. For 25 examples are intended only as illustrative and are not in any example, tablets, pills, solutions, suspensions, emulsions, way limitative. Also exempli?ed below are the preparation granules and capsules can be administered orally; and inject of selected starting materials and the preparation of struc able preparations can be administered intravenously, either turally related esters which are not claimed herein (e.g. the alone or mixed with injection transfusions such as glucose lower alkyl esters whose syntheses are given in EXAMPLE solutions and amino acid solutions. If necessary, the inject 30 able preparations can be administered separately, by the 5 below and which are homologues of the ethyl ester intramuscular, intracutaneous, subcutaneous or intraperito~ speci?cally described by Barrett et al, U.S. Pat. No. 3,663, neal route. 607, issued May 16, 1972). The dosage of the compounds of the present invention is In the examples to follow, all melting points are uncor selected according to the usage, purpose and conditions of 35 rected and were obtained by using electrothermal capillary symptoms. For example, when these compounds are admin melting point apparatus. istered therapeutically to patients suffering from angina pectoris, hypertension, or unexpected arrhythrnias during surgical operation, usually 0.5-6.0 mg/kg of the compound EXAMPLE 1 of general formula (I) or its acid addition salt may be administered. Cyclohexyl alcohol (6 g), 4-hydroxyphenylacetic acid The present compounds also may be continuously admin (7.6 g), p-toluenesulfonic acid (1 g) and benzene (300 mL) istered at suitable intervals, including 30 minutes to 60 were refluxed with continuous water separation for 8 hours. minutes. The mixture was cooled and washed with a 10% NaZCO3 The compounds of the present invention and their salts 45 reduce intraocular pressure when applied topically/locally to solution, then with water. Drying over MgSO4 and evapo the eye, thus are of particlar use in the treatment of patients ration of the solvent in vacuo gave 12.24 g of cyclohexyl with glaucoma or in the treatment of other patients who 4~hydroxyphenyl acetate. That compound can be repre require lowering of ocular pressure (such as patients with sented by the formula: elevated intraocular pressure who may be at risk of devel oping glaucoma). The instant compounds and their salts can be conveniently administered for these purposes by formu lating the selected B-blocker, in an effective intraocular pressure lowering amount, together with a non-toxic oph thalmically acceptable carrier therefor. Suitable carriers will 55 be apparent to those skilled in the art of ophthalmic formu lations. Obviously, the choice of suitable carriers will depend on the exact nature of the particular dosage form EXAMPLE 2 desired, e. g. whether the li-blocker is to be formulated into A mixture of 2,6-dimethylcyclohexyl alcohol (11.4 g), an ophthalmic solution or suspension (typically for use as 60 eye drops), an ophthalmic ointment or cream or an oph 4-hydroxyphenylacetic acid (9.12 g), p-toluenesulfonic acid thalmic gel. Preferred dosage forms are solutions, which (1 g) and benzene (300 mL) was re?uxed with continuous contain a major amount of water in addition to the active water separation for 20 hours. The mixture was ?ltered and Ingredient. Minor amounts of other ingredients such as pH the ?ltrate was washed with a 10% NaQCO3 solution, then adjusters (e.g. a base such as NaOH) emulsi?ers or dispers 65 with water. Drying over MgSO4 and evaporation in vacuo ing agents, buffering agents, preservatives, wetting agents afforded 8.02 g of 2,6-dimethylcyclohexyl 4-hydroxyphenyl and jelling agents (e.g. methylcellulose) may also be acetate. That product has the structural formula: 5,576,332 1 5

H3C 0 I | OC — CH1 OH.

H3C The above method was used with minor modi?cations for the synthesis of a number of other esters, i.e.: Isopropyl 4-(2-hydroxy-3-isopropylamino)propoxyphe EXAMPLE 3 nylacetate, crystallized from petroleum ether, melting at A mixture of 4-hydroxyphenylacetic acid (6.08 g), 3,3,5, 59°—60° C.; I S-tetramethylcyclohexyl alcohol (6.24 g), p-toluenesulfonic n-Butyl 4-(2-hydroxy-3-isopropylamino)propoxypheny acid (1 g) and benzene (300 mL) was re?uxed for 8 hours lacetate, crystallized from a mixture of chloroform and with continuous water separation. The mixture was cool ed hexane, melting at 48°—49° C.; and and washed with Na2CO3, then with water. Drying over Benzyl 4-(2-hydroxy-3-isopropylamino)propoxypheny MgSO4 and evaporation in vacuo yielded 12.3 g of 3,3,5, lacetate, crystallized from a mixture of chloroform and S-tetramethylcyclohexyl 4-hydroxyphenylacetate. That hexane, melting at 73°—74° C. product, which can be represented by the structural formula n-Butyl 4-(2-hydroxy-3-tert-butylamino)propoxypheny 20 lacetate was prepared similarly to the n-butyl ester described H3C CH3 above, replacing the isopropylamine starting material in the 0 last step with tert-butylamine. The crude ester was dissolved | l in dimethyl carbonate and a solution of oxalic acid in OC-CH; 0H, dimethyl carbonate was added. The crystals were removed 25 by ?ltration and recrystallized from acetone to yield 9 H3C CH3 g(25%) of n-butyl 4-(2-hydroxy-3-tert-butylamino)pro poxyphenylacetate oxalate hydrate, melting at 112°~114° C. is characterized by the following NMR (CDCl3, TMS, ppm): All ?nal products prepared above gave satisfactory 7.00(d, J=BHz, 2H), 6.60(d, J=8 Hz, 2H), 5.00(br0ad, 1H), elementary analysis i0.4% C, H, N.‘ NMR and ir spectra 3.40(s, 2H) and 1.8—0.80(m, 18H). were consistent with structure. EXAMPLE 4 EXAMPLE 6 A mixture of ethyl 4-(2-hydroxy-3-isopropylarnino)pro poxyphenylacetate (29.5 g), 1N NaOH solution (200 mL), Cyclohexyl 4-hydroxyphenylacetate (9.18 g) in epichlo_ 35 rohydrin (50 mL) was re?uxed for 2 hours in the presence and ethanol (200 mL) was re?uxed for I hour, and then of DBU (1 mL). The mixture was evaporated in vacuo, and evaporated in vacuo. The residue was dissolved with water the residue was re?uxed with isopropylamine (20 mL) in (200 mL). The insoluble material was removed by ?ltration. To the ?ltrate was added dilute hydrochloric acid, and the acetonitrile (100 mL) for 4 hours, then evaporated in vacuo. A solution of oxalic acid in acetone was added to a solution crystals were ?ltered, washed with water, dried and recrys of the residue in acetone. The crystals were removed by tallized from water to yield 20 g of 4-(2-hydroxy-3-isopro ?ltration and recrystallized from acetone to yield 6.05 g of pylarnino)propoxyphenylacetic acid, as colorless needles melting at 2l2°—213° C. That compound has the structural cyclohexyl 4-(2-hydroxy-3-isopropyl amino)propoxyphe formula: nylacetate oxalate 3/4 hydrate, melting at 131°-l 32° C. Elementary analysis and NMR and ir spectra were consistent 0 OH with structure. The free base has the formula: H |

50 CH3 EXAMPLE 5 A mixture of 4-hydroxyphenylacetic acid (9.12 g, 0.06 mol), n-propanol (40 mL) and SOCl2 (2 mL, 0.028 mol) was EXAMPLE 7 re?uxed for 3 hours, then evaporated in vacuo. The residue 55 2,6-Dimethylcyclohexyl 4-hydroxyphenylacetate (8.00 g) was extracted with ethyl acetate (200 mL), washed with 10% was re?uxed with epichlorohydrin (50 mL) in the presence Na2CO3, then water dried (MgSO4), and evaporated in of DBU (1 mL) for 2 hours, and evaporated in vacuo. The vacuo to give n-propyl 4-hydroxyphenylacetate as an oil. A residue was re?uxed with isopropylamine (20 mL) in aceto solution of n-propyl 4-hydroxyphenylacetate (5.8 g, 0.03 nitrile (100 mL) for 4 hours, then evaporated to dryness in mol) in epichlorohydrin (50 mL) was re?uxed in the pres 60 vacuo. To a solution of the residue was added a solution of ence of DBU (2 mL, 0.014 mol) for 2 hours. After the excess oxalic acid in acetone, and the crystals were removed by epichlorohydrin was removed, the residue was re?uxed with ?ltration, washed with acetone,‘ and recrystallized from isopropylamine (20 mL, 0.23 mol) in n-propanol (50 mL), acetone to yield 6.4 g of 2,6-dimethylcyclohexyl 4-(2 for 4 hours, then was evaporated in vacuo. The residue was hydroxy-3-isopropylamino)propoxyphenylacetate oxalate crystallized from n-hexane to yield 3.8 g (41%) of n-propyl 65 hydrate, melting at 89°—91° C. Elementary analysis and 4-(2-hydroxy-3-isopropylamino)propoxyphenylacetate, NMR and ir spectra were consistent with structure. The free melting at 61°—62° C. and having the structural formula: base has the structural formula: 5,576,332 17 18 EXAMPLE 9 H3 C if in 1H3 A solution of 4-(2'hydroxy~3-isopropylamino)pro OCCHZ OCH2CHCH1NH— (13H. poxyphenyl acetic acid (13.4 g) in cyclohexyl alcohol (50 mL) was saturated with hydrogen chloride gas under cool CH3 ing, then was heated at 70° C. for 4 hours. Excess cyclohexyl H3C alcohol was evaporated in vacuo. The residue was dissolved in water (200 mL) and adjusted to pH 9 with 10% NaQCO3 EXAMPLE 8 solution. The oily material was extracted with chloroform 3,3,5,5-Tetramethylcyclohexyl 4-hydroxyphenylacetate (200 mL), washed with water, dried, and evaporated in (10.86 g) was dissolved in 8% methanolic KOH solution (20 vacuo. The residue was dissolved in acetone (100 mL) and m L), and evaporated to dryness in vacuo. Epichlorohydrin (500 mL) was added to the residue, and the mixture was adjusted to pH 5 with 10% oxalic acid in acetone. The re?uxed for 2 hours, then evaporated in vacuo. The residue crystals were removed by ?ltration, washed with acetone, was extracted with benzene (200 mL), washed, dried, evapo dried and recrystallized from acetone to yield 11.8 g of rated in vacuo, and re?uxed with isopropyl amine (20 mL) in acetonitrile for 8 hours, then evaporated in vacuo. A cyclohexyl 4-(2-hydroxy-3-isopropylamino)propoxypheny solution of oxalic acid in acetone was added to a solution of 20 lacetate oxalate % hydrate, melting at 131°—l32° C. the residue in acetone. The crystals were removed by ?ltration and recrystallized from acetone to yield 8.06 g of 3,3,5,5-tetrarnethylcyclohexyl 4-(2-hydroxy-3-isopropy EXAMPLE 10 lamino)propoxyphenylacetate oxalate % hydrate, melting at 96°—97° C. Elementary analysis and NMR and ir spectra 25 Use of the starting materials indicated below in the were consistent with structure. The free base has the struc tural formula: general esteri?cation procedure described in EXAMPLE 1 affords the indicated products:

0 OH CH; OBICH; OCHZCiII-ICHZNH—ICH . ‘CH. H3C CH3