CA2158910C - B3-adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia - Google Patents

B3-adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia

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CA2158910C
CA2158910C CA002158910A CA2158910A CA2158910C CA 2158910 C CA2158910 C CA 2158910C CA 002158910 A CA002158910 A CA 002158910A CA 2158910 A CA2158910 A CA 2158910A CA 2158910 C CA2158910 C CA 2158910C
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halo atoms
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CA2158910A1 (en
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David K. Kreutter
Robert L. Dow
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Pfizer Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/343—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Disclosed are pharmaceutical compositions for treat- ing or preventing intestinal motility disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis), gastrointestinal ulcerations, depression, prostate disease, neurogenetic inflammation and dyslipidemia comprising a .beta.3- adrenoceptor antagonist or agonist, which may for example be a compound of the formula: <IMG> <IMG> (wherein R1 is phenyl, (CH2)n-O-phenyl or thiazolyl, each optionally substituted, R2 is hydrogen or alkyl, R3 is hydrogen or substituent, R4 is, for example, (CH2)n-CN, R5 is hydrogen or alkyl, X is bond, O or S, Z is C or N, and Y is O, N or S).

Description

215891~ --1-- ~3-ADRENOCEPTOR AGONISTS A~D ANTAGONISTS FOR THE TREAT~ENT OF INTESTINAL MOTILITY DISORDERS, DEPRES5ION, PRO5TATE DISEASE AND DYSLIPIDEMIA Background of the Invention This invention relates to pharmaceutical compositions for treating or preventing intestinal motility disorders, depression, prostate disease and dyslipidemia comprising a ~3- adrenoceptor antagonist or agonist. ~ -Adrenergic receptors have been categorized into ~ 2 and ~3-subtypes. Agonists of ~-receptors promote the activation of adenylyl cyclase. Activation of ~l-receptors invokes increases in heart rate while activation of ~2-receptors induces relaxation of skeletal muscle tissue which produces a drop in blood pressure and the onset of smooth muscle tremors. Activation of ~3-receptors is known to stimulate lipolysis (the breakdown of adipose tissue triglycerides to glycerol and free fatty acids), and thereby promote the loss of fat mass. Compounds that stimulate ~3-receptors are therefore useful as antiobesity agents. In addition, compound which are ~3- adrenoceptor agonists have hypoglycemic or antidia~eticactivity, but the mechanism of this effect is unknown. Until recently, ~3-adrenoceptors were thought to be found predominately in adipose tissue. ~3-Receptors are now known to be located in such diverse tissues as the intestine and the brain. J. Clin. Invest., 91, 344 (1993). Stimulation of the ~3-receptor has been demonstrated to cause relaxation of smooth muscle in colon and trachea. Life 64680-813 2158910 Sciences, 44, 19, 1411 (1989); Br. J. Pharm., 112, 55 (1994). For example, stimulation of ~3-receptors has been found to induce relaxation of histamine-contracted guinea pig ileum, J. Pharm. Exp. Ther., 260, 1, 192 (1992). It has now been found that there is expression of the ~3-receptor in human prostate. Antagonism or agonism of these receptors should result in relaxation of prostate smooth muscle and that ~3-agonists and antagonists should be useful for the treatment or prevention of prostate disease. Administration of N-[(2S)-7-carbethoxymethoxy-1,2,3,4- tetrahydronaphth-2-yl]-(2R)-2-hydroxy-2-(3-chlorophenyl)- eth~n~m;ne hydrochloride, a ~3-agonist, has been reported to demonstrate activity in rodent models of depression, Europ. J. Pharm., 2 , 193 (1992). N-[2-(4-Carbomethoxymethoxyphenyl)-l-methylethyl]- 2-hydroxy-2-(3-chlorophenyl)-eth~n~m;ne reduces plasma triglycerides and fatty acids in genetic animal models of obesity and diabetes and therefore will be useful for the treatment and prevention of dyslipidemia. United States Patent 4,338,333, issued July 6, 1982, refers to eth~n~m;ne derivatives including the compound of formula K, described below, which possess antiobesity and antihyperglycaemic activity. United States Patent 5,061,727~ issued October 29, 1991, refers to substituted 5-(2-(2-aryl-2-hydroxyethyl)- amino)-propyl)-1,3-benzodioxoles including the compound of formula J, described below, which possess antidiabetic, anti- 64680-813 ~158910 --3-- hyperglycemic and antiobesity properties. European Patent Publication 516,349, published December 2, 1992, refers to 2-hydroxyphenethyl amines including the compound of formula L, described below, which possess antiobesity, hypoglycemic and related utilities. Summary of the Invention This invention relates to a pharmaceutical composi- tion for treating or preventing prostate disease in a mammal, preferably a human, comprising an amount of a ~3-adrencceptor antagonist or agonist effective in antagonizing or agonizing the ~3-andrenoceptor, or a pharmaceutically acceptable salt or prodrug thereof, and a pharmaceutically acceptable carrier. The present invention relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of intestinal motility disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gastritis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and gastrointestinal ulcerations, depression, prostate disease, neurogenetic inflammation and dyslipidemia in a mammal, preferably a human, comprising, in admixture with a pharmaceutically acceptable carrier, a ~3-adrenoceptor antagonizing or agonizing effective amount of either (a) an amount of a compound of the formula; 64680-813 ~ 21S8910 . -3a- OH H R5 R~ ~X~ yZ~R4 wherein R is phenyl, -(CH2)n-O-phenyl or thiazolyl, wherein said phenyl, the phenyl moiety of said -(CH2)n-O-phenyl and said thiazolyl may optionally be substituted with one or more substituents, preferably from one to three substituents, independently selected from hydrogen, (Cl-C6)alkyl optior.ally substituted with one or more halo atoms, preferably from one to three halo atoms, hydroxy, (Cl-C6)alkoxy optionally substituted with one or more halo atoms, preferably from one to three halo atoms, (Cl-C6)alkylthio, fluoro, chloro, bromo, iodo, nitro and cyano; R is hydrogen or (Cl-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; R3 is hydrogen, -(CH2)n-phenyl, (Cl C10) 1 y , -(cH2)n-NR R8, -(CH2)n-cO2R , ~(CH2)n~C~NR R ~ ~(CH2)n~R -(CH2)n-SO3R , -(CH2)n-SO2-(Cl-C6)alky~, -(CH2)n-SO2NR R , or a heterocycle selected from -(CH2)n-pyridyl, -(CH2)n~ pyrimidyl, -(CH2)n-pyrazinyl, -(CH2)n-isoxazolyl, -(CH2)n- oxazolyl, -(CH2)n-thiazolyl, -(CH2)n~(1,2,4-oxadiazolyl), 64680-813 2158910 -3b- -(CH2)n-imidazolyl, -(CH2)n-triazolyl and -(CH2)n-tetrazolyl, wherein one of the ring nitrogen atoms of said -(CH2)n~ imidazolyl, -(CH2)n-triazolyl or -(CH2)n-tetrazolyl may optionally be substituted by (Cl-C6)alkyl optionally substituted with one or more halo 64680-813 2158910 . atoms, preferably from one to three halo atoms, and wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by (C,-C0)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo O atoms, halo, nitro, cyano, -(CH2)n-NR7R8, -(CH2)n-C02Rl ', -(CH2)n-C-NR'R8, -(CH2)n-ORl ', 5 -(CH2)n-S03Rl 1, -(CH2)n-S02-(Cl -C6)alkyl, or -(CH2)n-So2NR7R8, and wherein the phenyl moiety of said (CH2)n-phenyl may optionally be substituted with one or more substituents, preferably one to three substituents, independently selected from (Cl- C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms, hydroxy, (Cl-C6)alkoxy optionally substituted with one or more halo 10 atoms, preferably from one to three halo atoms, (Cl-C6)alkylthio, fluoro, chloro, bromo, 1l iodo, cyano, nitro, -(CH2)n-NR'R8, -(CH2)n-C02R2, -(CH2)n-C-NR'R8, -(CH2)n-OR", -(CH2)n- S03R", -(CH2)n-S02-(Cl-C6)alkyl, and-(CH2)n-S02NR R; R4 is -(CH2)n-CN, -(CH2)nCO2Rl 1, -(CH2)n-SO3Rl ', -(CH2)n-SO2-(C, -Co)alkyl, -(CH2)n-S02-NR'R3, -(CHJnCH20H optionallysubstituted with asuitr~le protecting group 15 (e.g., benzyl ester and t-butyl ester), -(CH2)n-CH0, -(CH2)n-C(=O)Rl', -(CH2)n- C(=O)NR'R8, or a heterocycle selected from -(CHJn-thia_olyl, -(CH2)n-oxazolyl, -(CH2)n- i,ni'-~olyl,-(CH2)n-triazolyl,-(CH2)n-1,2,4-oxadia_olyl,-(CH2)n-isoxazolyl,-(CH2)n-tetrazolyl and -(CH2)n-pyrazolyl; wherein one of the ring nitrogen atoms of said -(CH2)n-i,ni~olyl, -(CH2)n-triazolyl and -(CH2)n-tetrazolyl may optionally be substituted by (C,-C~)alkyl 20 optionally suhstihlted with one or more halo atoms, preferably from one to three halo atoms; wherein each of said heterocycles may optionally be suhstihlted on one or more of the the ring carbon atoms by hydrogen, (C,-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms, -(CH2)n-NR7R3, -(CH2)n- o C02R", halo, nitro, cyano, -(CH2)n-C-NR7R5, -(CH2)n-ORl 1, -(CH2)n-S03Rl 1, -(CH2)n-S02- 25 (Cl-C6)alkyl, or-(CH2)n-S02NR7R8; R5 is hydrogen or (C,-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; $ 1 2158910 -5- each R7 and each R3 is selected independently of any other R7 and R8 in the same molecule, and is selected from the group consisting of hydrogen, (C,-C~)alkyl, (C1-C8)alkoxy(Cl-C6)alkyl or (C3-C8)cycloalkyl, or R7 and R8, when attached to the same nitrogen atom, together with the nitrogen to which they are attached, form a saturated 5 heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur; Rl', wherever it occurs, is selected independently from any other Rll in the same molecule and is selected from hydrogen and (Cl-C6) alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; n is an integer from zero to six; X is a direct link, oxygen or sulfur; Y is oxygen, nitrogen or sulfur; and Z is carbon or nitrogen; with the proviso that: (i) when Y is oxygen or sulfur, R3 is absent, and (ii) when 15 Z is nitrogen, R5 is absent; or a pharmaceutically acceptable salt or prodrug thereof, that is effective in treating or preventing such condition; (b) an amount of a compound of the formula OH ¦ H ~N~cOxC 2 H Cl J or a pharmaceutically acceptable salt or prodrug thereof, that is effective in lle~ting or preventing such condition; (c) an amount of a compound of the formula 2158910 --6-- OH ~, ",N~3~o~ ~O C H 3 Cl or a pharmaceutically acceptable salt or prodrug thereof, that is effective in treating or preventing such condition with the proviso that the compound of formula K is excluded from the treatment or prevention of dyslipidemia; or (d) an amount of a compound of the formula: OH ~,H C H2 C 2H or a pharmaceutically acceptable salt or prodrug thereof, that is effective in treating or preventing such condition. In preferred embodiments of the present invention, the pharmaceutical compositions contain one or more of the following compounds or pharmaceutically acceptable salts or prodrugs of these compounds: 64680-813 2158910 --7-- 1-(5-(2(2(S)-hydroxy-3-phenoxy-propylamino)-ethoxy)- benzofuran-2-yl)-ethanone, 1-(2-(2-isoxazol-3-yl-benzofuran-5-yloxy)-ethylaminc)- 3-phenoxy-propan-2(S)-ol, 1-(2-(2-(5-methyl-isoxazol-3-yl)-benzofuran-5-yloxy)- ethylamino)-3-phenoxy-propan-2(S)-ol, 1-(2-(2-(2-methyl-thiazol-4-yl)-benzofuran-5-yloxy)- ethylamino)-3-phenoxy-propan-2(S)-ol, 1-(2-(2-(5-methyl-(1,2,4)-oxadiazol-3-yl)-benzofuran- 5-yloxy)-ethylamino)-3-phenoxy-propan-2(S)-ol, 1-(2-(2-(1,2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy)- ethylamino)-3-phenoxy-propan-2(S)-ol, l-benzyl-5-(2(R)-(2-(3-chloro-phenyl)-2(R)-hydroxy- ethylamino)-propyl)-lH-indole-2-carboxylic acid methyl ester, l-benzyl~5-(2(R)-(2-(3-chloro-phenyl)-2(R)-hydroxy- ethylamino)-propyl)-lH-indole-2-carboxylic acid, l-benzyl-5-(2(R,S)-(2(S)-hydroxy-3-phenoxy-propyl- amino)-propyl)-lH-indole-2-carboxylic acid ethyl ester, l-benzyl-5-(2(R,S)-(2tS)-hydroxy-3-phenoxy-propyl- amino)-propyl)-lH-indole-2-carboxylic acid, 5-(2(R,S)-(2-(3-chloro-phenyl)-2(R)-hydroxy-ethyl- amino)-propyl)-l-(4-dimethylsulfamoyl-benzyl)-lH-indole-2- carboxylic acid ethyl ester, 5-(2-(R,S)-(2-(3-chloro-phenyl-2(R\-hydroxy-ethyl- amino)-propyl)-l-(4-dimethylsulfamoyl-benzyl)-lH-indole-2- carboxylic acid, 1-(4-dimethylsulfamoyl-benzyl-5-(2(R,S)-(2(S)- hydroxy-3-phenoxy-propylamino)-propyl)-lH-indole-2-carboxylic 64680-813 ~ 21~8910 --8-- acid ethyl ester, 1-(4-dimethylsulfamoyl-benzyl)-5-(2(R,S)-(2(S)- hydroxy-3-phenoxy-propylamino)-propyl)-lH-indole-2-carboxylic acid, 5-(2(R,S)-(2-(3-chloro-phenyl)-2(R)-hydroxy-ethyl- amino)-propyltl-(4-methanesulfonylamino-benzyl)-lH-indole-2- carboxylic acid ethyl ester, 5-(2(R,S)-(2-(3-chloro-phenyl)-2(R)-hydroxy-ethyl- amino)-propyl)-l-(4-methanesulfonylaminc-benzyl)-lH-indole-2- carboxylic acid, 5-(2(R,S)-(2(S)-hydroxy-3-phenoxy-propylamino)- propyl)-l-(4-methanesulfonylamino-benzyl)-lH-indole-2-carboxylic acid ethyl ester, 5-(2(R,S)-(2(S)-hydroxy-3-phenoxy-propylamino)- propyl)-l-(4-methanesulfonylamino-benzyl)-lH-indole-2-carboxylic acid, 5-(2(R,S)-(2(R,S)-(6-amino-pyridin-3-yl)-2-hydroxy- ethylamino)-propyl)-l-benzyl-lH-indole-2-carboxylic a~id ethyl ester, and 5-(2(R,S)-(2(R,S)-(6-amino-pyridin-3-yl)-2-hydroxy- ethylamino)-propyl)-l-benzyl-lH-indole-2-carboxylic acid. As indicated above, this invention also encompasses pharmaceutical compositions containing prodrugs of compounds of the formula~I, J, K and L. Compounds of formula I, J, K or L having free aminG, amidG, hydroxy or carboxylic groups can be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a polypeptide chain of two or more 64680-813 2158910 - g (e.g., two, three or four) amino acid residues which are covalently joined through peptide bonds to free amino, hydroxy or carboxylic acid groups of compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids commonly designated by three letter symbols and also include 4-hydroxyproline, hydroxylysine, demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid, citrulline homocystein, homoserine, ornithine and methionine sulfone. Prodrugs also include compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently bonded to the above substituents of formula I through the carbonyl carbon prodrug sidechain. Prodrugs also include compounds of formula I in which the secondary amine and its ~-hydroxy when taken together form a group of the formula /U-(CH2) n\ Rl ~ N ~ X XIX wherein n, R , R2 and X are as defined in formula I and U and V are independently carbonyl, methylene, SO2 or SO3, wherein methylene is optionally substituted with hydroxy. Prodrugs also include compounds of formulæ J, K and L which also contain a secondary amine and a ~-hydroxy group that can fGrm an analogous group to formula XIX. 64680-813 2158910 -9a- As indicated above, this invention also encompasses pharmaceutical composition containing pharmaceutically accept- able salts of compounds or prodrugs of formulæ I, J, K and L. The acids that may be used to prepare pharmaceutically accept- able acid addition salts of those compounds of formulae I, J, K and L that are basic in nature are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pomoate [i.e., 1,1'- methylene-bis-(2-hydroxy-3-naphthoate)] salts. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formulae I, J, K and L that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g. t calcium and magnesium), ammonium or water- soluble amine addition salts such as N-methylglucamine- (meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines. The term "halo", as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo. 64680-813 2158910 - -9b- The term "alkyl" as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof. The term "alkoxy", as used herein, includes O-alkyl groups wherein "alkyl" is defined as above. 64680-813 ~r 2158910 -10- ` The term ~one or more substituents," as used herein, includes from one to the maximum number of substituents possible based on the number of available bondingsites. The compounds of the formula 1, J, K and L have chiral centers and therefore S exist in di~ere,lt enantiomeric forms. This invention relates to all optical isomers and all stereoisomers of compounds of the formula 1, J, K or L, and mixtures thereof. 21S8910 Detailed Descri~tion of the Invention The processes and products of the present invention are illustrated in the following reaction schemes. Except where otherwise indicated, in the reaction scheme and ~liscussion that follow, formulas 1, Il, 111, IV, and V, and substituents R', R2, R3, R4, 5 R5, R~, R7, R8, Rl, X and halogen are defined as above. `- 2158910 SCHEME 1 S R~ NH2 R ~f~X~Y\~ R4 IV I I I R5 OH H `~X~ Y~R4 I (~ 2158910 -13- SCHEME 2 ,R5 R~ + H2N`Z~--X~Z`~R4 V II OH H R5 R l/~'N`Z~X~Z\~R 4 ~R3 ~ 2158910 -1 4- SCHEME 3 OH H z/R5 S R l~N1~X~\>~ C O 2H IB R5 OH H l~Nl~X~ CO2R2 I~ ~R5 OH H z l~N~X~ ~C O N R 7 R 8 IC 2158910 SCHEME 4 C H 3 - X ~C \~R 4 X V R3 I IR5 H-X~C\~R4 XVI R3 I R5 R ~ ~R 4 X V I I IR5 ~of-- -@C \~R 4 I I I R3 H2N~X~C \~R4 I I R3 ~ 21~8910 -16- SCHEME 5 R5 S Br~ \~R4 y R3 V I o ~Z\~R 4 I I I 2s H 2 N~X~Z~R 4 ~ ~` 21~8910 -17- SCHEME 6 R5 I W~ \>~,R9 13 R VI I IR5 W~C\>~R9 13 Y R VI I I ~ R 9 IX .~ 21~8910 -18- SCHEME 7 R5 R9 R9 W~Z\>~6 R3 X I Rs W~Z~R 10 R3 Rs R5 R9 20W~\>~\ ~--R9 W~Z N R3 R3 XI I XI I I 215891~ -19- Scheme 1 illustrates the preparation of compounds of the formula I from aldehydes or ketones of formula lll. Referring to Scheme 1, a compound of the formula lll is reacted with a compound of the formula IV to produce a compound of the formula 1. This reaction is 5 typically carried out in the presence of a reducing agent such as sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, hydrogen anda metal catalyst, zinc and hydrochloric acid, or borane dimethyl sulfide followed by treatment with formic acid. It is generally conducted at temperatures from about ~0C to about 50C. Suitable reaction inert solvents for this reaction include lower alcohols 10 (e.g., methanol, ethanol and isopropanol), acetic acid, chlorinated hydrocarbon solvents (e.g., methylene chloride, chloroform, 1,2 dichloroethane) and tetrahydrofuran (THF). Preferably, the solvent is 1,2-dichloroethane, the temperature is about 25C, and the reducing agent is sodium triacetoxyborohydride. Scheme 2 illustrates an alternative method for the preparation of compounds of 15 formula I from amines of formula ll. Referring to Scheme 2, a compound of formula I can be synthesized from compounds of formula ll by reaction with an epoxide of the formula V. This reaction is typically carried out by reacting an amine of formula ll with an epoxide of formula V in a polar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile 20 or a lower alkanol such as ethanol, isopropanol or butanol, at a temperature from about -10C to about 125C. Preferably the solvent is dimethyl sulfoxide and the reaction is run at a temperature from about 0C to about 10C. A preferred modification of the above reaction involves pr~t,eal"~ent of the amine of formula ll with N-(trimethyl-silyl)-acetamide to form a silyated compound of the 25 formula R5 C H 3-S,--N~--X~ R 3 X I V 2158910 -20- This reaction is typically carried out in a polar aprotic solvent such as dimethyl sulfoxide, dimethyl formamide, acetonitrile or a lower alkanol such as ethanol, isopropanol or butanol, at a temperature from about -1 0C to about 1 25C. Preferably, the silyation is carried out at about 25C and the reaction with the epoxide is accomplished at about 60 C. After silyation is complete, the compound of formula XIV is reacted with the epoxide of formula V as described above. Scheme 3 illustrates the preparation of compounds of formulae IB and IC from compounds of formula IA. Compounds of formula IA are compounds of formula I wherein R4 is CO2R2. Compounds of formulae IB and IC are compounds of formula I in which R4 is CO2H and Co2NR7R8, respectively. Compounds of formula IA are prepared by the methods of Schemes 1 and 2. The transformations depicted in scheme 3 may be accomplished by methods well known to those skilled in the art. Referring to Scheme 3, compounds of formula IA can be converted into carboxylic acids of formula IB by treatment with an acid or a base. Examples of s~itA~Ie bases for the reaction are: sodium hydroxide (NaOH), potassium hydroxide (KOH), and lithium hydroxide. Suitable acids for the reaction include: hydrochloric acid (HCI), hydrobromic acid and sulfuric acid. r, efel ~bly, the base is potassium hydroxide. The solvent for the aforesaid process is typically a lower alkanol, hexane, DMF, toluene and/or water. The lower alkanol can be methanol, ethanol, propanol or butanol. The reaction temperature may range from about 0C to about 100C. Preferably, the ter"peralure is about 25C. Compounds of formula IA can be converted into other esters of the formula IA, in which a di~erer,l definition of R2 has been substituted, by transe~terificalion. Transesterification is facilitated by reacting a compound of formula IA with acid or base in an excess of an alcohol of the formula R2OH. SuitA~le acids for the reaction include hydrochloric, hydrobromic, sulfuric and toluene sulfonic acid. Preferably, the acid is hydrochloric acid. The reaction temperature may range from about 0C to about 115C. Suitable solvents include alcohols of formula R2OH, and mixtures thereof with toluene, cyclohexane, DMF and methylene chloride. Alternatively, compounds of formula IA can be converted into amides of formula IC by treatment of the ester of formula IA with an amine of the formula R7R8NH. Usually, a polar protic solvent such as a lower alkanol is used, and the reaction is run at a temperature from about 0C to about 125C for about 0.5 to about 24 hours. 21~8910 -21 - Suitable solvents include lower alcohols, and mixtures thereof with toluene, cyclohexane, DMF and methylene chloride. Preferably, the reaction is conducted in methanol at about 65C for about 3 to about 24 hours. Scheme 4 refers to the preparation of compounds of the formulae ll and lll, 5 wherein X is O or S. Compounds of formulae ll and lll are the starting materials for the synthesis of compounds of formula I in Schemes 1 through 3. Compounds of formulalll, wherein X is O or S, can be used to form compounds of formula I according to the processes of Scheme 1. Compounds of formula ll, wherein X is O or S, can be usedto form compounds of formula I according to the processes of Scheme 2. R~fer,i"g to Scheme 4, compounds of formula ll are made by reductive amination of a compound of formula lll. The conditions for reductive amination are as described above for the conversion of the ketone of formula lll to the compound of formula I in Scheme 1, with the exception that the amine used is ammonia or an acid addition salt thereof, instead of the amine of formula IV. Compounds of formula lll can be made in three steps beginning with compounds of the formula XV. Compounds of the formula XV are first converted to thiols or phenols of the formula XVI by treatment of an ether (when X is O) or a thioether (when X is S) of formula XV with boron tribromide. Suitable solvents for the aforesaid reaction are 20 non-polar aprotic solvents such as methylene chloride, toluene, chloroform, or carbon tetrachloride. Preferably, the solvent is methylene chloride. The temperature of the reaction may range from about -78C to about 20C during the reaction with borontribromide. It is preferably about OC. The thiol or phenol of formula XVI so formed is converted into a ketal or acetal25 of the formula X~ll by treatment with a compound of the formula Rllo Y R110 wherein Y is chloro, bromo or iodo, in the presence of a base. Preferably, the thiol or phenol of formula XVI is first converted into an anion by reaction with a base. 21~8910 -22- Examples of appropriate bases include sodium hydride and potassium t-butoxide. The preferred base is sodium hydride (NaH). Examples of suitable solvents for the aforesaid process include polar aprotic solvents such as dimethyl formamide, dimethylsulfoxide, and sulfolane. Preferably, the solvent is dimethyl formamide.5The temperature for the aforesaid reaction is in the range of about -10C to about 100C. Preferably, the temperature is 30C. The ketal or acetal of formula XVII so formed is converted into the cor, esponding compound of formula lll by reaction with an acid. Typically, this reaction is conducted at a temperature in the range of about 10C to about 100C. Examrles 10of appropriate acids for the aforesaid process are hydrochloric, hydrobromic and sulfuric acids. Preferably, the acid is hydrochloric acid. Suitable solvents for the aforesaid process include polar solvents such as acetone and/or water. Preferably, the solvent is acetone. Scheme 5 refers to the preparation of compounds of the formulae lll and ll 15wherein X is a direct link. Compounds of the formulae lll and ll are starting materials for the synthesis of the compounds of the invention illustrated in Schemes 1 through 3. Compounds of formula lll, wherein X is a direct link, can be used to forrn compounds of formula I according to the processes of Scheme 1. Compounds of the formula ll, wherein X is a direct link, can be used to form 20compounds of the formula I according to the processes of Scheme 2. Referring to Scheme 5, compounds of the formula lll can be converted into compounds of the formula ll by reductive amination of a compound of the formula lll with ammonia as described in Scheme 1. Compounds of the formula lll are prepared from compounds of the formula Vl, 25by treatment of a compound of the formula Vl with a tin reagent of the formulaR2COCH2Sn(CH3CH2CH2CH3)3 in the presence of palladium (Il) acetate and tri-o- tolylphosphine. The tin reagent, R2COCH2Sn(CH3CH2CH2CH3)3, is formed by reactionof tributyltin methoxide with a compound of the formula O 1l CH ~ O CH2~CH2 - 21S8910 Suitable solvents for the aforesaid process include nonpolar solvents such as toluene, benzene and hexane. Preferably, the solvent is toluene. The temperature for the aforesaid process is generally in the range of about 10C to about 150C, and ispreferably about 95C. Scheme 6 refers to the preparation of compounds of formula IX, wherein W is bromo, -OCH3 or -SCH3. Compounds of formula IX wherein W is bromo are compounds of formula Vl in Scheme 5, wherein R4 is a group of the formula f N> R9 wherein each R9 is selected independently from the other R9 and is selected from the group consi~li"g of hydrogen, (C1-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms, -(CH2)n-NR7R3, -(CH2)n-CO2R", halo, o Il nitro, cyano, -(CH2)n-C-NR7R8, -(CH2)n-OR1 1, -(CH2)n-SO3R1 1, -(CH2)n-SO2-(C, -C5)alkyl, and -(CH2)n-SO2NR7R3. Compounds of formula IX wherein W is -OCH3 or -SCH3 are compounds of formula XV in Scheme 4, wherein X is oxygen or sulfur and R4 is a group of the formula ~ ~N> R9 ,~S R 25 wherein each R9 is selected independently from the other R9 and is defined as above. Referring to Scheme 6, a compound of formula IX, wherein R9 is defined as above is formed in two steps beginning with a compound of formula Vll. The compound of formula Vll is reacted with a suitable halogenating agent such as liquid bromine, N-bromosuccinimide, N-chlorosuccinimide or chlorine gas in the presence of 30 light to form an a-haloketone of the formula Vlll wherein Y is chloro, bromo or iodo. This reaction is typically carried out in a solvent such as carbon tetrachloride, 2158910 -24- chloroform or methylene chloride, preferably carbon tetrachloride, at atemperature from about 10C to about 100C, preferably about 30C. The a-haloketone of formula Vlll is converted into the thiazole of formula IX byreaction of the a-haloketone of formula Vlll with a thioamide of the formula S R9-C-NH2. wherein R9 may be a different R9 than the R9 of the a-haloketone and R9 is defined as above. This reaction is typically carried out in a polar protic solvent such as a loweralkanol, DMF, DMSO, or digyJme. Suitable alcohols include methanol, ethanol, propanol and butanol. The reaction temperature may range from about 20C to about 150C. F~efer~bly, the reaction is carried out in ethanol at a temperature of about 80C. Scheme 7 refers to the preparation of compounds of the formulae Xl, Xll and Xlllwherein W is bromo, -OCH3 or -SCH3. Compounds of the formula Xl wherein W is bromo are compounds of formula Vl in Scheme 5 wherein R4 is R9 R9 )~( ~\N/0 and R9 is defined as above and each R9 is selected independently from the other R9. Compounds of formula Xl wherein W is -OCH3 or -SCH3 are compounds of 25 formula XV in Scheme 4 wherein X is oxygen or sulfur and R4 is R9 R9 ~\N/0 and R9 is defined as above and each R9 is selected independently from the other R9. Compounds of formula Xll wherein W is bromo are compounds of formula Vl in Scheme 5 wherein R4 is 2158910 0 N ~\N~--R 9 5 and R9 is defined as above. Compounds of formula Xll wherein W is -OCH3 or -SCH3 are compounds of formula XV in Scheme 4 wherein X is oxygen or sulfur and R4 is 0 N ~N~--R and R9 is defined as above. Compounds of formula Xlll wherein W is bromo are compounds of formula Vl in Scheme 5 wherein R4 is R9 N~ ~N,b 20 and R9 is defined as above. Compounds of formula Xlll wherein W is -OCH3 or -SCH3 are compounds of formula XV in Scheme 4 wherein X is oxygen or sulfur and R4 is R9 N~ ~\N/0 and R9 is defined as above. Referring to Scheme 7, compounds of formula X wherein Rl is -COCH2R9 and 30 R9 and W are defined as above are converted into isoxazoles of formula Xl by a two step process. Compounds of formula X are first converted into oximes of the formula ~158910 R5 ~Cy>~9 XV~ I I by treatment of the ketone of formula X with hydroxylamine in a polar solvent such as a lower alkanol and/or water. Suitable alcohols include methanol, ethanol and isopropanol. The reaction temperature may range from about 20C to about 100C. The oxime of formula XVIII is converted into the isoxazole of formula Xl by reaction with two equivalents of a strong base such as lithium diisopropyl amide, phenyl lithium or N-butyl lithium, followed by addition of an amide of the formula 1 5 R9C-N-(CH3)2 and R9 may be a di~erent R9 than the R9 of the oxime and R9 is defined as above, and subsequent cyclization with hydrochloric acid in dioxane at reflux. Modifications of this 20 process are described in G. N. Barber, Journal of Organic Chemistry, 43, 3015-3021 (1 978). Scheme 7 also describes the synthesis of 3,5-disubstituted-1 ,2,4-ox~ l s of formula Xll from compounds of formula X, wherein R10 is an ester equivalent of formula -COR1', and wherein Rl' is halo or alkoxy. The ester of formula X is reacted with an 25 amidoxime of the formula NOH Il R9~--NH2 30 and R9 is defined as above, to form the oxadiazole of formula Xll, according to the procedure described in Swain et al., J. Med. Chem. 34, 140-151 (1991). Scheme 7 also describes the synthesis of 3,5 disubstituted 1 ,2,4-ox~di~ole6 of formula Xlll. Oxadiazoles of formula Xlll can be synthesized by reacting compounds of formula X, wherein R10 is an amidoxime of the formula - ~158910 -27- NOH ~--N H 2 5 with an ester equivalent (i.e. R9COCI) or a compound of the formula R9C(oR2)3, wherein R9 is defined as above, according to the procedure of Shine et al., J. Heterocyclic Chem., 26, 125-128 (1989). The compounds of formula J can be prepared according to the methods described in United States Patent 5,061,727, which issued on October 29, 1991. The compounds of formula K can be prepared according to the methods described in United States Patent 4,338,333, which issued on July 6, 1 982. The compounds of formula L can be prepared according to the methods described in European Patent Publication 516,349, published December 2, 1992. United States Patents 5,061,727 and 4,338,333 and European patent publication 15 516,349 are all incorporated herein by reference in their entireties. The pharmaceutically-acceptable cation salts of the compounds of the present invention are readily prepared by reacting the acid forms with an appropriate base, usually one eguivalent, in a co-solvent. Typical bases are sodium hydroxide, sodium methoxide, sodium ethoxide, sodium hydride, potassium methoxide, magnesium 20 hydroxide, calcium hydroxide, benzathine, choline, diethanolamine, pi"era~i"e and tromethamine. The salt is isolated by concentration to dryness or by addition of a non- solvent. In many cases, salts are preferably prepared by mixing a solution of the acid with a solution of a di~erent salt of the cation (sodium or potassium ethylhex~1oate, magnesium oleate), employing a solvent (e.g., ethyl acetate) from which the desired 25 cationic salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. The acid addition salts of the compounds of the present invention are readily prepared by reacting the base forms with the appropriate acid. When the salt is of a monobasic acid (e.g., the hydrochloride, the hydrobromide, the p-toluenesulfonate, the 30 acetate), the hydrogen form of a dibasic acid (e.g., the hydrogen sulfate, the succinate) or the dihydrogen form of a tribasic acid (e.g., the dihydrogen phosphate, the citrate), at least one molar equivalent and usually a molar excess of the acid is einrl~ycd. However, when such salts as the sulfate, the hemisuccinate, the hydrogen phosphate 2158910 -28- or the phosphate are desired, the appropriate and exact chemical equivalents of acid will generally be used. The free base and the acid are usually combined in a co-solvent from which the desired salt precipitates, or can be otherwise isolated by concentration and/or addition of a non-solvent. The amino acid prodrugs of this invention may be prepared by conventional peptide coupling reactions coupling a free amino or carboxylic group of the compound of formula I with an amino acid or a polypeptide, e.g. dipeptide, chain. The coupling reaction is generally conducted at a temperature of about -30 to about 80 C., preferably about 0 to about 25C. Suitable coupling reagents are usually presen~, such as dicyclohexylcarbodiimide with hydroxybenzotriazole (HBT), N-3- dimethylami"opr.~pyl-N'-ethylcarbodiimide with HBT, 2-ethoxy-1-ethoxycarbonyl-1,2- dihydroquinoline, carbonyl diimidazole with HBT, or diethylphosphoryl-cyanide. The reaction is generaly conducted in an inert solvent such as acetonitrile, methylene chloride, chloroform, dimethylformamide, dioxane, tetrahydrofuran, dimethoxyethane, or water, or a mixture of two or more such solvents. Ester, carbonate or carbamate prodrugs of this invention may be prepared by reaction of a free hydroxyl or amino group of the compound of formula I with an activated carbonyl containing molecule such as acetyl chloride or ethyl chlon~for",ate. The reaction can be carried out neat or in the presence of a reaction inert solvent such as methylene chloride, at atemperature from about -78 to about 100C. Alcohols can also be reacted with cyanogen chloride in the presence of a Lewis acid to form carbamates. Ester and amide prodrugs of free carboxylic acid groups can be made according to the methods of scheme 3. Prodrugs in which the secondary amine and its B hydroxy, taken together, form a group of the formula /U--( C H2 ) n\ O V R ~ X I X 2158910 -29- are formed by methods analogous to those described in United States Patent 4,593,023 to Beecham issued on June 3, 1986, European Patent Application 170,135A to Beecham published on July 21, 1984 and United States Patent 4,607,033 issued on August 1 9, 1986 to Beecham. When treating or preventing intestinal motility disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gasl,ilis and duodenitis, (including that induced by H. pylori), intestinal ulcerations (including inflammatory bowel ~li,e~se, ~'cerali~/e colitis, Crohn's disease and proctitis) and gastrointestinal ulrer~ons, depression, prostate disease, neurogenetic inflammation and dyslipidemia generally satisfactory results are obtained when the compounds of the formula 1, J, K or L and the pharmaceutically acceptable salts thereof are administered to mammals, including man, via either the oral or the parenteral route. A.l"~i"i~l,alion by the oral route is preferred, being more convenient and avoiding the possible pain and i"ilalion ofinjection. However, in circumstances where the patient cannot swallow the medi~ on, or absorption following oral administration is impaired, as by disease or other abnormality, it is essential that the drug be administered parenterally. By either route, the dosage is in the range of about 0.05 to about 50 mg/kg body weight of the subject per day, preferably about 0.1 to about 10 mg/kg body weight per day, administered singly or as a divided dose. However, the optimum dosage for the individual subject being treated will be determined by the person responsible for the treatment, generally smaller doses being administered initially and thereafter increments made to determine the most suitable dosage. This will vary according to the particular compound employed and with the subject being treated. When treating or preventing i"te~li"al motility disorders, preferable results are 26 obtained when the compounds of the formula 1, J, K or L are admi"i~tered at a daily dos~ge of from about 1 milligram to about 10 milligrams per kilogram of body weight, preferably given in divided doses 4 times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 10 milligrams to about 1000 milligrams, preferably from about 10 milligrams to about 300 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 10 milligrams to about 300 milligrams. This dosage regimen may be adjusted to provide the individual optimal therapeutic response. 2l~89lo -30- When treating or preventing depression, preferable results are obtained when the compounds of the formula 1, J, K or L are administered at a daily dosage of from about 1 milligram to about 10 milligrams per kilogram of animal body weight, pref~r~bly given in divided doses 4 times a day, or in sustained release form. For most large 5 mammals, the total daily dosage is from about 10 milligrams to about 1,000 milligrams, preferably from about 10 milligrams to about 300 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 10 milligrams to about 300 milligrams. This dosage regimen may be adjusted to provide the optimal individual therapeutic response. When treating or preventing prostate disease, preferable results are obtained when the compounds of the formula 1, J, K or L are administered at a daily dosage of from about 1 milligram to about 10 milligrams per kilogram of animal body weight, prefe, ably given in divided doses 4 times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 10 milligrams to about 1000 15 milligrams, pref~rably from about 10 milligrams to about 300 milligrams. In the case of a 70 kg adult human, the total daily dose will generally be from about 10 milligrams to about 300 milligrams. This dosage regimen may be adjusted to provide the optimalindividual therapeutic response. When treating or preventing dyslipdemia, preferable results are obtained when 20 the compounds of the formula 1, J, K or L are administered at a daily dosage of from about 0.1 milligram to about 10 milligrams per kilogram of animal body weight, pl eferably given in divided doses 4 times a day, or in sustained release form. For most large mammals, the total daily dosage is from about 1 milligrams to about 1000 milligrams, preferably from about 1 milligrams to about S0 milligrams. In the case of 25 a 70 kg adult human, the total daily dose will generally be from about 1 milligrams to about 50 milligrams. This dosage regimen may be adjusted to provide thè individual optimal therapeutic response. The compounds of the formula 1, J, K and L are preferably used in co~ aliGn with a pharmaceutically acceptable carrier or diluent. Suit~hle pharmaceutically- 30 acceptable carriers include inert solid fillers or diluents and sterile aqueous or org~1icsolutions. The active compound will be present in such pharmaceutical cor"positions in amounts sufficient to provide the desired dosage amount in the range descriLed above. Thus, for oral admi~ lralion the compounds of then formula 1, J, K or L can be ~1~8910 -31 - combined with a suitable solid or liquid carrier or diluent to form capsules, tablets, powders, syrups, solutions, suspensions and the like. The pharmaceutical compositions may, if desired, contain additional components such as flavorants, sweeteners, excipients and the like. The tablets, pills, capsules, and the like may also contain a binder such as gumtragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a diai"tegr~li"g agent such as corn starch, potato starch, alginic acid; a lubricant such as com starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a swe_teni"g agent such as sucrose, lactose or saccharin. When a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil. Various other materials may be present as coatings or to modify the physical form of the dosage unit. For instance, tablets may be coated with shellac, sugar or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweeter,i"g agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor. These active compounds of formula 1, J, K and L may also be administered parenterally. For parente, al admi"isl, ~lion the compounds 1, J, K or L can be combined with sterile aqueous or organic media to form injectable solutions or suspensions. Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions can also be prepare~d in sesame or peanut oil, ethanol, water, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, vegetable oils, N-methyl glucamine, polyvinylpyrrolidone and mixtures thereof in oils as well as aqueous solutions of water-soluble pharmaceutically acceplable salts of the compounds. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. The injectable solutions prepared in this manner can then be administered intravenously, intraperitoneally, subcutaneously, or intramuscu~rly, with intramuscular administration being the preferled parenteral route in man. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and 215~910 must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The effective dosage of the active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. For practical use, the pharmaceutical composition may be put in commercial package. Such commercial package usually comprises a written matter associated with the composition. The written matter states that the pharmaceutical composition should or can be used for treating or preventing the conditions or disorders mentioned above. Selectivity of a compound for ~3-receptors over ~2 and ~1 receptors may be determined using the following procedures. In vitro selectivity may be determined by measurement of cyclic Adenosine mono-phosphate (cAMP) in Chinese hamster ovary cells. Chinese hamster ovary cells uniquely transfected with the gene for the human ~ 2 or ~3 receptor are grown to confluence in Ham's F12 media containing 10~ fetal bovine serum, 500 ~g/ml Geneticin, 100 U/ml penicillin, 100 ~g/ml streptomycin and 250 ng/ml Fungizone. Compounds are dissolved in Ham'sF12 media, and added to the cells at lO 10 - 10 5 M along with 10~3 M isobutylmethylxanthine to inhibit 64680-813 ~158910 -32a- phosphodiesterase activity. The media and cells are then incubated for 10 minutes at 37C. At the end of this period, the media is aspirated, the cells dissolved in 0.01 N hydro- chloric acid and then the media is neutrali~ed with 1 N sodium hydroxide. The cellular content of cAMP can then be determined by Radioimmuno Assay (RIA) using a kit from New England Nuclear. There is a direct correlation between the cellular content of cAMP and the agonism of the ~3-receptor. In vivo efficacy may be determined by measurement of oxygen consumption in male Sprague-Dawley rats. Whole animal oxygen consumption may be measured using an open circuit, indirect calorimeter (Oxymax , from Columbus Instruments, Columbus, OH). The Oxymax gas sensors are calibrated with nitrogen (N2) gas and gas mixture (0.5% carbon dioxide (CO2), 20.5% oxygen (2)~ 79% N2) before each experiment. Rats (male, Sprague-Dawley, 300-380 g body weight) are placed in sealed chambers (43x43x10 cm) of the calorlmeter and the chambers placed in activity monitors. Air flow rate through the chambers is set at 1.6-1.7 l/min. The Oxymax calorimeter software calculates the oxygen consumption (ml/kg/h) based on the flow rate of air through the chambers and difference in oxygen content at inlet and output ports. The activity monitors have 15 infrared light beams spaced one inch apart on each axis; ambulatory activity is recorded when two consecutive beams are broken 64680-813 2158910 -33- (repeated interruptions of the same beam are not reg~istered) and the results are recorded as counts. Basal oxygen consumption and ambulatory activity can be measured every 10 minutes for 2.5 to 3 hours. At the end of the basal period, the chambers are opened and the test compound (0.01 to 10 mg/kg, prepared in saline)5 or an equivalent volume of saline is administered by oral gavage. Oxygen consumption and ambulatory activity can be measured every 10 minutes for an additional three hours post-dosing. Percent change in oxygen consumption may be c 'c~ ~lated by averaging the post-dosing values for 2.5 hours and dividing by basal oxygen consumption (average of the predosing values except the first hour). Oxygen consumption values 10 obtained during time periods where ambulatory activity exceeded 100 counts are excludecl from the c~lcul~tion. Thus, the values represent % change in resting oxygen consumption. In vivo selectivity for 13l and 132 adrenoceptors may be determined by measu,e",e"ls of heart rate and blood pressure gathered on rats (male, Sprague 15 Dawley, 300-380 g body weight) anesthetized with pentobarbital (50-60 mg/kg, i.p.). The left carotid artery is cannulated with PE50 tubing. The catheter is tunneledsuhcutz~neously, exteriorized at the back of the neck, filled with a solution ofpolyvinylpyrrolidone in heparinized saline, flamc se~'ed and taped. Exl,eriments are performed 7 days after surgery. On the day of the experiment, the catheters are 20 untaped and flushed with saline. After at least 30 minutes, basal values for heart rate and blood pressure were measured by attaching the catheter to a pressure transducer and the results recorded on a Grass Model 7 polygraph. A~ter obtaining basal values, the test compound or vehicle is administered by oral gavage, and b!ood pressure (measure f 132 activity) and heart rate (measure of 131 activity) measurements are taken 25 at 15, 30, 45 and 60 minutes. To determine changes, basal values are subtracted from the average of the post dosing values. All of the compounds of the invention were tested in the in vitro model and showed better than a four fold increase in cAMP levels at a dose of 10 ,uM. Compounds of the formula 1, J, K or L also have the effect of reducing intestinal 30 motility and thus find utility as aiding in the treatment of various gastrointestinal disorders such as irritable bowel syndrome, peptic ulceration, esophagitis, gastritis and duodenitis, (including that induced by H. Pvlori), intestinal ulcerations (including inflammatory bowel disease, ulcerative colitis, Crohn's disease and proctitis) and 2158910 -34- gastrointestinal ulcerations. It has been proposed that the motility of non-sphincteric smooth muscle contraction is mediated by activity as i33 adrenoreceptors. The availability of a 133 specific agonist,with little activity at 131 and B2 receptors will assist in the pharmacologic control of intestinal motility without concurrent cardiovascular effects. In v activity of the compounds of formula I for the treatment or prevention of i"tesli,)al motility disorders can be determined according to the following procedures. Eighteen-hour fasted male Sprague Dawley derived (CD) rats (175-225 grams) are dosed with 0.1, 1.0, or 2.0 mg/kg p.o. of compound or vehicle (distilled water). Thirty minutes after drug administration, the rats are orally dosed with 0.25 ml of a solution of sodium chromate in 0.9% saline containing about 20,000 cpm of 5lCr (speciflc activity 350 mCi/mg Cr). Twenty minutes later, the rats are sacrificed, the gastroesophageal, pyloric, and ileocecal junctions are then ligated, and the stomachs and small intestines removed. The small intestines are then divided into ten equal lengths, and the stomach and each length of intestine assayed for radioactivity with a yarn",a counter. Gastric emptying rate may then be determined for each rat by comparing the amount of radioactivity in the intestine relative to the total in the intestine plus stomach. In addition, the geometric center of the distribution of the radioactive marker is then used as a measure of the overall transit rate through the stomach and intestine. The geometric center is calculated by summing the products of the fractions of 5lCr in each segment times the segment number: geometric center = s ((hactionof 5lCr per seyme,,l) x (segment number)). For these cal~ tions the stomach may be considered segment number 0, and the ten i"te~li"al segments as numbers 1 to 10. Thus, a geometric center of 0.0 would indicate that the entire load of 5lCr had remained in the stomach. Data from two experiments may be pooled, and statistical evaluations were made using Dunnett's multiple comparison test. Altematively, in groups of 8, overnight-fasted male Sprague-Dawley (CD) rats (175-225 grams) may be anesthetized with methoxyflurane. A small abdominal incision is then made, and the pylorus can then be ligated. Immediately after the ligation, a solution of compound or the vehicle (distilled water) is injected into the proximal duodenum. The doses of drug used should be 0.1, 1.0 and 2.0 mg/kg. The incisionscan then be closed and the rats can be allowed to recover from the anesthesia. Two hours after the ligation the rats are sacrificed and the gastric fluid collected and cleared by centrifugation. Total volume of secretion can be determined by weight, and acidity ~158910 -35- can be determined by titration to pH 7.0 with 0.1 N NaOH using an automatic titrator (Radiometer I 1 185). The data from two experiments is then pooled. A group of rats treated with 10 mg/kg of the antisecretory histamine H~-receptor antagonist cimetidine may be included in each experiment as a positive control. Statistical evaluations can 5 be made using Student's t-test. In vitro activity for relaxation of contracted ileum from isolated guinea pig ileum can be determined according to the following procedure. Fresh isolated segments of guinea pig ileum (about 1.5 cm long) are mounted in tissue baths contai"i"g Tyrode's physiological salt solution at 30C and aerated continuously with O2:CO2 (95%:5%). 10 Tissues are then equilibrated for 60-90 minutes under 4.0 gm tension in order to achieve stable baselines. I lista~"ine is then added to the baths in a cumulative fashion in concenl,alions ranging from 1 nM to 10~M. The maximum tension generated aftereach addition of his~ar"ine is recorded on a Grass Physiograph. The tissues are then washed with several changes of Tyrode's solution, basal tension can be re~djusted to 15 4.0 grams, and a stable baseline is then again obtained. Each tissue may then be exposed to a single concentration of test compound (range 1 nM to 10 IJM) or vehicle and after a 30 minute equilibration period, the histamine does response curve may then be repe~ted Results from multiple experiments are standardized (0-100%) to the maximum response of the control tissues and plotted as percent maximum tension 20 versus the log of the histamine concehl,alion in the absence and presence of the drug. In vivo activity of the compounds of formula 1, J, K or L for depression can be determined according to the following procedures. Male CD-1 mice (25-30 g, fasted ovemight) are be randomly assigned to treatment groups and given vehicle or test compound at doses of 32, 10, 3.2, 1.0, 0.32, 25 0.1, or 0.032 mg/kg. The compound of formula I (in 5% Emulphor: 5% ethanol: 90% saline) is administered by oral gavage. Isoproterenol, which should be used as acontrol standard, has poor bioavailability and, for this reason, can be ad"~ini~l~rt:d in saline vehicle by the subcutaneous route. Evaluations should be conducted ~blind~ with changes in overt behavior assessed one half hour, one hour and two hours after drug 30 ad,.,ini:,l,alion using a modification of the quantitive scoring system described by Irwin S., Druq Screeninq and Evaluation of New Compounds in Animals. in: Nodine J.H. Siegler P.E. eds. Pharmacologic Techniques in Drug Evaluation. Chicago: YearbookMedical Publishers, (1964). Briefly, animals should be placed in Plexiglas~ cu~ c'~s ~ 2158910 (dimensions: 15 x 15 x 18 cm) and observations made of undisturbed behavior. Mice may then be transferred to a large observation box and evaluated individually for changes in locomotor activity, reflexes, muscle tone and autonomic nervous system function. Seven behaviors (e.g. convulsions, death, urination/defecation) are scored as present or absent and their frequencies expressed as the percent of animals exhibiting the response. Sixteen other behaviors, such as piloerection, disturbance of gait, ptosis, positional passivity, body position, locomotion, respiration rate, llanster arousal, body/abdominal tone, limb tone, provoked biting, tail pinch, toe pinch, corneal reflex, skin color, inverted screen, pupil size (30xmm), may be scored using a 0 - 8 scale, with values of 0, 2, 4, 6 and 8 representing none, slight, moderate, marked and extreme magnitudes of behavior, respectively. Scores for normal behavior in drug-naive animals may be reported either as 0 (e.g. for disturbance of gait, positional passivity) or 4 (e.g. for body position, locomotion respiration rate and transfer arousal). An inverted screen (scored on a 0 - 2 scale) may be used to assess motor coordination and grip strength. Pupil sizes can be measured using the reticle of a binocular roscope. Following the initial 2 hr obseNation period, animals may be retained for 24 hr to determine the incidence of delayed mortality. Alternatively, compounds of formula I can be assessed for antidepressan~ activity according to the follov~;, Ig procedure. Male CD1 mice weighing between 20 and 25 g, and Sprague-Dawley rats wei~l ,i, lg between 200 and 250 g, may be obtained from Charles River, USA. Hydrochloride salts of compounds of formula I are dissolved in water. The CGm pounds may be administered to mice in a volume of 10 ml kg l, and to rats in a volume 2 ml kg l. Control animals receive the vehicle. Positive test results for the following nine parameters indicate antidepressant activity. I. Effect on basal rectal temperature: Mice are given drug or its vehicle, and their rectal temperatures recorded 30, 60, 90, 120 and 180 min later by means of a thermometer and a thermoelectric probe inserted at a constant depth into the rectum. Il. Antagonism of hypothermia induced bY reserpine: Mice are given reserpine (2.5 mg kg-l i.p. dissolved in 1% citric acid). Their rectal temperatures may be measured 3.5 h later. The mice may then be divided into dif~erent groups so as to obtain the same mean rectal temperature in each group. Half ~ a 8 91 0 an hour later (i.e. 4 h after reserpine), the mice are given the vehicle or test drug. Rectal temperature can be measured again 90 min later (i.e. 5 h 30 after the injection of reserpine) (Bourin et al., The Value of the Reserpine Test in Psychopharmacoloqy, Arzneim. Forsch. 33, 1173, (1983)). 5 Ill. Antagonism of hypothermia induced by aPomorphine: Half an hour after the mice are placed in individual cages, their rectal temper~tures are recorded. The animals should be allocated so as to obtain the same mean rectal temperature in each group. Apomorphine (16 mg kg-l s.c.) can be given 30 min after the test drug or its vehicle. Rectal temperature can be measured again 30 10 min after the apomorphine treatment (Puech et al, Antagonism of HvPothermia And Behavioural Response To APomorphine; A Simple. RaPid And Discriminating Test ForScreening Antidepressants And Neuroleptics, Psychopharmacology 75, 84, (1981)). IV. Potentiation of lethality induced by vohimbine: This test can be performed on groups of 10-20 mice basically as described by 15 Quinton, R.M., The Increase In The Toxicity Of Yohimbine Induced By l")i~.r~ mine And Other Dru~s In Mice, Br. J. Pharmacol. 21, 51 (1963). Test drugs or vehicle can be a.ll nii)istered i.p. 30 min before the administration of yohimbine. Yohimbine hydrochloride can then be admini~tered s.c. at a does of 30 mg kg-l (ex~ressed in terms of the salt) always at the same time of day, between 1.30 and 3.30 p.m. Lethality 20 can be recorded the next morning at 9 a.m. V. Anta~onism of ptosis induced by reserpine: Mice are given the vehicle or drug, and 60 min later injected with reserpine (2 mg kg l i.v., dissolved in dilute ascorbic acid) (Gouret et al., Interaction De Divers Psychotropes Avee Cinq Effects de la Reserpine Chez la Souris Et Chez Le Rat: Ptose Palpébrale, Hypothermie, HvPomotilité, Catalepsie Et Pointes Pontogén-o~llo Occipitales. ~. Pharmacol. (Paris) 8, 333, (1977)). One hour later, the degree of ptosis in each eye can be measured in each mouse as 0 (eye completely open) to 4 (eye full closed). This gives a maximum score of 8 per mouse. Vl. Activity in the behavioral despair test in mice: Sixty minutes after the administration of the test drug or its vehicle, the mice are individually forced to swim in an open cylindrical container (diameter 10 cm, height 25 cm), containing 8.5 cm of water at 22 + 1 C; the total duration of immobility during the last 4 min of a single 6-min test session can be scored. A mouse should be ~ 2158910 considered to be immobile whenever it remained floating in the water in a slightly hunched position, its head just above the surface (Porsolt et al., Pharmacoloqical models of Depression. In: Animal Models in Psychopharmacology. Advances in Pharmacological Science, eds. B. Olivier, J. Mos and J. L. Slangen (Birkhauser Verlag, 5 Berlin) p. 1 37,1 977). Vll. Effect on learned helplessness behavior: This test is performed basically as described by Giral et al. Reversal Of I lel,uless Behaviour In Rats By Putative 5-HT,~ Aqonists. Biol. Psychiat. 23, 237. (1988). Electric footshocks are delivered to male albino Sprague-Dawley rats placed in chambers (20 10 X 10 X 10 cm) with pl~,r-.31~ss walls and covers. The floors are made of stainless-steel grids (1.5 cm mesh). A constant-current shocker is delivered as 60 scrambled, randomized inescapable shocks (15 s duration, 0.8 mA, every 60 + 15 s) to the grid floor. Control rats are then placed in identical chambers for 1 h but no shock is admi, .i:,lered. All preconditioning trials are performed on day 1 between 9 and 11 a.m. 15 Avoidance training is initiated 48 h (day 3) after inescapable shock in automated two- way shuttle-boxes (60 X 21 X 30 cm) with plexiglass walls and a floor consi~li"g of ~tai,.less steel rods spaced 1.0 cm apart in order to evaluate escape deficits. Each shuttle-box is divided into two chambers of equal size by a stainless-steel p~ lition, with a gate providing access to the adjacent compartment through a 7 X 7 cm space. 20 Shuttle-box sessions are performed for 3 consecutive days (days 3, 4 and 5). The animals are placed individually in the shuttle-box and allowed to h~hih~te to the environment for 5 min (for the first session only) and then subjected to 30 trials. The i,lt~il,ial interval should be 30 s. A light signal, used as a conditioned stimulus, is presented during the first 3 s of each trial. Crossing the gate into the other 25 compartment of the box during this 'conditioned-stimulus only' period (refer, ed to as avoidance response) allows the rats to avoid shocks. A period with conditioned stimulus plus electric foot-shock (0.8 mA) may be presented if an avoidance response does not occur. Crossing the gate into the other compartment during this conditioned stimulus plus shock period is refer,ed to as an escape response. Absence of escape 30 response during the 3-s duration conditioned stimulus plus shock should be considered to be an escape failure. The rats (n = 10 per group) should be treated randomly according to one of the fcllowing protocols: the control sample, which receives no shock, and is given vehicle; 2158910 -39- experimental animals with inescapable shock are treated daily with vehicle or drug. Animals should be treated orally over 5 consecutive days, i.e. 6 h after shock pret,eal",ent on day 1, and then twice per day, a half dose in the morning (30 min before shuttle-box session) and a half dose in the afternoon (except on the 5th day). 5 Statistical analysis can be performed on the mean number of escape failures using a two-way analysis of variance (subjects X sessions) followed by Dunnett's test. Vlll. Effect on locomotor activity Locomotor activity of mice is measured by means of photocells in a series of activity cages (Apelex, France), linked to a control unit and printer. The animals are 10 placed singly in activity cages 30 min after treatment and motility was assessed over a period of 30 min (Boissier, J.R. and P. Simon Action De La Caféine Sur La Motilité Spontanéé De La Souris. Arch. Int. Pharmacodyn, 158, 212. (1965)). IX. Evaluation of drug-induced drinking For the determination of drug-induced drinking, rats are placed in individual 15 cages fitted with special water dispensers. The dispensers allow the animal free access to the water bottle nozzle. Vehicle or drug is administered and the water intake may be measured after 3 hours by weighing the water bottle. The volume of fluid drunk may be c~cu~tecl by subtraction, assuming the density of water to be 1.0 g/ml. The animals must be allowed at least 24 h to become accustomed to the novel environment of the individual cage before the experiment is performed (Lehr et al., Copious Drinking And Simultaneous Inhibition Of Urine Flow Elicited By Beta-Adrenergic Stimulation And Contrary Effect Of AlPha-Adrenergic Stimulation. J. Pharmacol. Exp. Ther. 158, 150. (1 967)). In vivo activity of the compounds of formula 1, J, K or L for prostate di~ease can be determined according to the following procedure. Male rabbits (CEGAN) weighing 3 to 4 kg are sacrificed by exsanguination and cervical dislocation. The bladder and urethra are rapidly removed and placed in lukewarm Krebs solution containing bicarbonate. The composition of this Krebs medium is as follows, in mM: sodium chloride (NaCI) 114 potassium chloride; (KCI) 4.7; calcium chloride (CaCI2) 2.5; potassium dihydrogen phosphate (KH2P04) 1.2. magnesium sulfate (MgSO4) 1.2; sodium (~ . 2158910 40- bicarbonate (NaHC03) 25.0; glucose 11.7; ascorbic acid 1.1. Propranolol (1.0 ~M) Ts added into the Krebs medium to block the 13-adrenergic receptors. The bladder is opened transversely and the "trigone~ region of the muscle, located on the dorsal surface of the bladder and between the two ureters, is ~lissectecl 5 out. A 5 mm ring of urethra, from the region situated between the base of the bladder and the prostate, is also prepared. The portions of trigone muscle and urethra are washed under a tension of 1 g in Krebs medium. The contraction-response curve to cumulated concentrations of phenylephrine is determined. Additions of the agonist are performed every 5 min. The tissues are washed until the original tension is reest~l shed, and are then incubated for 30 min. with the active agent. A second response curve to phenylephrine is determined in the presence 15 of the active agent. The lesponse curves to concer,l,alions of phenylephrine in the presence or absence of drug are e~ ressed as a percentage of the maximum response obtained relative to the control curve. By means of clinical studies, it can also be possible to show the efficacy of 20 active agents in patients suffering from dysuria of neurological origin with urethral hypertonia. Five milligrams of drug is injected intravenously continuously for a period of 20 min. Sphil)cterometric measurements are made using an electronic micro-sensor, before and after the injection of the drug, at the bladder neck and at the striated 25 sphincter of the posterior urethra. Compounds of the formula 1, J or L lower triglyceride levels and cholesterol levels and raise high density lipoprotein levels and are therefore of use in cOIll~alill9 medical conditions wherein such lowering (and raising) is thought to be beneficial. Thus they may be used in the treatment of hypertriglyceridaemia, hypercholesterolemia 30 and conditions of low HDL (high density lipoprotein) levels in addition to the treatment of atherosclerotic disease such as of coronary, cerebrovascular and peripheral arteries, cardiovascular disease and related conditions. ~ 2158910 41 - The active compounds may also be combined with other active ingredients known for use in the treatment of atherosclerosis and related conditions, for example fibrates such as clofibrate, bezafibrate and gemfibrozil; inhibitors of choleslerol biosynthesis such as HMG-CoA reductase inhibitors for example lovastatin, simvastatin 5 and pravastatin; inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA;cholesterol acyltransferase) inhibitors for example melinamide; anion exchange resins for example cholestyramine, cole~ .ol or a dialkylaminoalkyl derivatives of a cross-linked dextran; nicotinyl alcohol, nicotinic acid or a salt thereof; vitamin E; and thyromimetics. Activity of compounds of formula 1, J or L for dyslipidemia can be determined according to the following procedure. C57BL/6J ob/ob mice (male, 3040 g body weight, Jackson Lab, Bar Harbor, ME), housed 5 mice per cage in an environmentally CG~ d room, can be dosed once daily for 3 weeks with drug (0.1, 1 or 3 mg/kg, n=15 per group) or vehicle (saline) by oral gavage. Body weight of each mouse can be measured daily and food intake per cage was determined by v.ei~l ,i"g the amount of food left in the trough. At the end of the study, 24h after giving the final dose of compound, the mice may be killed by decapitation and blood collected. Plasma concentrations of glucose, free fatty acids and triglycéride can be determined with the VP Super System Autoanalyzer (Abbott, Irving, TX). Compounds of the formula 1, J, K or L inhibit the release of neuropeplides in certain sensory fibara in the lung. As sensory nerves may play an important role in the neu.ogenic inflammation of airways, including cough, the instant speciRc 133 agonists may be useful in the treatment of neurogenetic inflammation, such as asthma, with minimal effects on the cardiopulmonary system. The present invention is illustrated by the following Examples. I lo~ cr, it should be understood that the invention is not limited to the specific details of these examples. EXAMPLES Procedure A Methyl 5-hvdroxybenzofuran-2-carboxylic acid To a stirred solution of ethyl 5-methoxybenzofuran-2-carboxylic acid (5.0 g, 26 mmol) in ~' ~hloromethane (CH2CI2) (100 mL) at 0C was added boron t.ibrom-~e (8.6 mL, 91 mmol) and the resulting dark solution was allowed to stir at room temperature 215~910 ~2- for 2 hours. The reaction solution was poured over ice, stirred for 30 minutes and extracted with ethyl acetate, (EtOAc). The organic phase was washed with water, saturated aqueous brine, dried over sodium sulfate, (Na2SO4), and concerlt.dled in vacuo to afford 5-hydroxybenzofuran-2-carboxylic acid (4.0 9; m.p. 223-228C). Compounds of the formula 1, J, K or L inhibit the release of neuropeptides in certain sensory fibara in the lung. As sensory nerves may play an important role in the neurogenic inflammation of airways, including cough, the instant specific 133 agonists may be useful in the treatment of neurogenetic inflammation, such as asthma, with minimal effects on the cardiopulmonary system. Gaseous hydrochloric acid was bubbled into a cooled (0C), stirred solution of the above acid in methanol (50 mL) over a 15-min period. The resulting solution was then refluxed for 2.5 hours, and was then cooled and concer,l,ated in vacuo. Theresidue was dissolved in ethyl acetate, washed with water, brine, dried (Na2SO4) and concen~,~ted in vacuo. The resulting solids were flash chro,.,atographed on silica gel (40% ethyl acetate:hexanes) to afford the title compound as a yellow solid, (3.3 9; m.p. 164-166C. Analytical calculated for CloH8O4 C, 62.52; H, 4.20. Found: C, 62.47;H, 4.09). Procedure B Methyl 5-(2,2-dimethoxvethyloxy)benzofuran-2-carboxylic acid To a stirred slurry of sodium hydride (0.11 g of 60% in oil, 2.7 mmol) in p-dioxane (10 mL) was added methyl 5-hydroxybenzofuran-2-carboxylic acid (0.5 g,2.6 mmol) and the resulting green slurry was stirred at room tempe,cll-lre for 15 min. To this slurry was added a solution of bromoacetaldehyde dimethyl acetal (0.5 g, 3.0 mmol) in dimethylformamide (DMF) (10 mL) and the resulting solution was heated at reflux for 15 hours. The reaction mixture was poured into ethyl acetate, washed with water, brine, the organic phased dried (Na2SO4) and concer,l,ated in vacuo. The resulting oil was flash chrollldtographed on silica gel (25% ethyl acetate:hexanes) to afford the title compound as a colorless solid, (0.16 g; m.p. 74-74C). Procedure C Methyl 5-(ethanal-2-oxv)benzofuran-2-carboxylic acid A solution of methyl 5-(2,2-dimethoxyethyloxy)benzofuran-2-carboxylic acid (0.16g, 0.6 mmol) in acetone (4 mL) and 2 N aqueous hydrochloric acid (0.3 mL) was refluxed for 3.5 hours. The reaction solution was concenl,-ated in vacuo, J;ssolved in 21a8910 ~3- ethyl acetate, washed with water, brine, dried (Na2SO4) and concentrated in vacuo to afford the title compound as a colorless solid, (0.14 9; m.p. 112-115C). Procedure D Methyl 5-rpropan-2-one-vl)benzofuran-2-carboxylic acid A solution of methyl 5-bromobenzofuran-2-carboxylic acid (2.4 g, 9.3 mmol), tributyltin methoxide (4.0 mL, 14 mmol), isopropenyl acetate (1.4 mL, 14 mmol), palladium (Il) acetate (0.1 9, 0.5 mmol) and tri-o-tolylphosphine (0.3 9, 1 mmol) in toluene (6 mL) were heated at 95C for 2 hours. The reaction solution was concer,l,ated in vacuo and subjected to flash chromatography on silica gel (25% ethyl acetate:hexanes) to afford the title compound as a colorless solid, (1.8 g; m.p.77-79C, Analytical c~cu'~tedforC13Hl204: C, 67.25; H, 5.21. Found: C,67.12; H, 4.95). Procedure E 5-Methoxy-2-(2-methyl-thiazol4-yl)-benzofuran A solution of 2-bromo-1 -(5-methoxy-benzofuran-2-yl)-ethanone (0.6 9,2.2 mmol) and thioaceta",ide (0.4 9, 5.1 mmol) in ethanol (15 mL) were refluxed for 1 hour. The reaction mixture was concentrated in vacuo and subjected to flash chromatographyon silica gel (14% ethyl acetate:hexanes) to afford the title compound as a solid, (0.47 g; m.p. 136-137C). Example 1 Methyl 5-(2-(2(S)-hvdroxy-3-phenoxy-Propylamino)ethoxy)-benzofuran- 2-carboxylic acid To a solution of methyl 5-(ethanal-2-oxy)benzofuran-2-carboxylic acid (0.13 9, 0.56 mmol) and 1 -amino-3-phenoxypropan-2(S)-ol (0.10 9,0.61 mmol) in dichloroethane (3 mL) was added glacial acetic acid (0.05 mL) and sodium triacetoxyborohydride (0.18 9, 0.83 mmol). After 2 hours, the reaction mixture was diluted into ethyl acetate, washed with saturated sodium bicarbonate, brine, the organic layer was dried (Na2S04) and concentrated in vacuo. The resulting oil was subjected to flash chromatography (silica gel, 5% methanol: chloroform) to afford the title compound as an off-white solid. (0.10 9; m.p. 115-119C, Analytical calculated for C2lH23NO6-0.25H20: C, 64.70; H, 6.08; N, 3.59. Found: C, 64.89; H, 6.15; N, 3.51). 21~8910 ~4- Example 2 Methyl 5-(2(R)-(2-(2-trifluoromethvl-thiazol~-yl)-2(R)-hydroxyethyl-amino)- propvl)-benzofuran-2-carboxylic acid A solution of (R)-(2-trifluoromethyl-thiæol-4-yl)-ethylene oxide (0.20 g,1.03 mmol) 5 and methyl 5-(2(R)-2-aminopropyl)-benzofuran-2-carboxylic acid (0.20 9, 0.86 mmol) in isopropyl alcohol (1 ml) was refluxed for 1.5 hours. After cooling, the reaction solution was concer,t,aled in vacuo and the resulting oil was flash chromatographed (silica gel, 2% methanol:chloroform) to afford the title compound as an off-white solid (0.09 9); m.p. 99-100C. Example 3 5-(2-(2(S)-Hydroxv-3-phenoxy-proPylamino)ethoxy)-benzofuran-2-carboxvliacid To a stirred solution of methyl 5-(2-(2(S)-hydroxy-3-phenoxy-propylamino)- ethoxy)-benzofuran-2-carboxylic acid (0.10 9,0.25 mmol) in methanol (5 mL) was added a solution of potassium hydroxide (42 mg, 0.75 mmol) in water (0.4 mL). After 15 hours, the reaction solution was concenl,ated in vacuo! the residue reJissolved in water (4 mL) and the pH adjusted to between 5.0 and 5.5. The resulting solids were collPct~:l washed with water, diethyl ether and dried in vacuo to afford the title co",pound as an off-white solid. (78 mg; m.p. 128-133C. AnalyticaHc~ ted for C2oH2lN0~-1.25H2O: C, 60.99; H, 6.02; N, 3.56. Found: C, 60.75; H, 5.86; N, 3.30). Example 4 5-(2-(2(S)-Hydroxy-3-phenoxy-propylamino)ethoxv)-benzofuran-2-carboxylic acid, (2-methoxy-ethvl)-amide A solution of methyl 5-(2-(2(S)-hydroxy-3-phenoxy-propyl-amino)ethoxy)- benzofuran-2-carboxylic acid (0.10 g, 0.26 mmol) and 2-methoxyethyl-amine (0.6 mL) in methanol (3 mL) were maintained at reflux temperature for 18 h. The re&_tiGn solution was concenl,ated in vacuo and flash chromatographed on silica gel (5% methanol:chloroform) to afford the title compound as a colorless solid. (92 mg; m.p. 95-96C. Analytical calculated for C23H28N2O"-0.25H20: C, 63.79; H, 6.63; N, 6.47. Found: C, 63.59; H, 6.39; N, 6.34.) 2158910 45- Example 5 IsoproPyi 5-(2-(2(S)-hydroxv-3-phenoxy-propylamino)ethoxy)-benzofuran- 2-carboxvlic acid Gaseous hydrogen chloride was slowly bubbled into a cooled (0C), stirred solution of methyl 5-(2-(2(S)-hydroxy-3-phenoxy-propylamino)ethoxy)-benzofuran-2- carboxylic acid (0.1 9, 0.25 mmol) in 2-propanol (5 ml) over a 5 minute period. The resulting solution was then refluxed for 16 hours, cooled and flash chromatographed (silica gel, 5% methanol:chloroform) to afford the title compound as a colorless solid. (0.09 9; m.p. 105-106C. Analytical calculated for C23H27NO6: C, 66.09; H, 6.63; N, 3.35. Found: C, 66.04; H, 6.38; N, 3.31.) Example 6 2-Bromo-1 -(5-methoxy-benzofuran-2-yl)ethanone To a cooled (OC), stirred solution of 5-methoxy-benzofuran-2-oyl chloride (prepared by treatment of 5-methoxy-benzofuran-2-carboxylic acid in refluxing thionyl chloride)(4.6 9, 22 mmol) in diethyl ether (20 ml) and dichloromethane (5 ml) was added a solution of diazomethane (66 mmol) in diethyl ether (45 ml). After 15 minutes gaseous hydrogen bromide was slowly bubbled in over a 20 minute period. After anadditional 30 minutes, the reaction mixture was diluted with ethyl acetate, washed with saturated aqueous brine, the organic layer dried over magnesium sulfate (MgSO4) and conce"llated in vacuo. The resultant red oil was flash chromatographed (silica gel, 10% ethyl acetate:hexanes) to afford the title compound as a light-yellow colore d solid. 2.89. M.p. 86-87C. Example 7 Methyl 5-(2-(2(S)-hvdroxy-3-(2-chlorophenoxy)-propylamino)ethoxy~- benzofuran-2-carboxylic acid The title compound was prepared by a procedure similar to that desc,i6ed in Example 1. M.p. 126-126.5C. Analytical c~c~ ted for C2lH22CINO6: C, 60.07; H, 5.28; N, 3.34. Found: C, 59.89; H, 5.22 N, 3.25. 21~8910 -46- Example 8 Methyl 6-(2-(2(S)-hydroxy-3-phenoxy-Propylamino)ethoxy)-benzofuran- 2-carboxylic acid The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 110-111C. Analytical calculated for C2lH23N06: C, 65.36; H, 5.86; N, 3.94. Found: C, 65.44; H, 6.02; N, 3.63. Example 9 1 0 6-(2-(2(S)-Hvdroxv-3-phenoxy-proPylamino)ethoxy)-benzofuran-2-carboxvlic acid The title compound was prepared by a procedure similar to that described in Example 1. M.p. 214-217C. Analytical c~lcu'-ted for C2oH2lNO6.0.25H2O: C,63.90; H,5.76; N,3.72. Found: C, 63.53; H, 5.66; N, 3.61. Example 10 Methyl 5-(2-(2-(3-chloro-phenyl)-2(R)-hydroxy-ethvlamino)-ethoxv)-benzofuran- 2-carboxylic acid The title compound was prepared by a procedure similar to that descriL,ed in Example 1. M.p. 104-106C. Analytical calculated for C20H20CIN05: C, 61.62; H, 5.17; N, 3.59. Found: C, 61.44; H, 4.96; N, 3.56. ExamPle 11 5-(2-(2-(3-Chloro-phenyl)-2(R)-hydroxy-ethylamino)-ethoxv)-benzofuran- 2-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 1. M.p. 145-153C. 8 9 1 0 Example 12 Methyl 6-(2-(2-(3-chloro-phenyl)-2(R)-hvdroxy-ethylamino)-ethoxv)-benzofuran- 2-carboxylic acid The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 102-103C. Analytical cr'cul~ted for C2oH2oclNo5-o~17H2o C, 61.14; H, 5.22; N, 3.56. Found: C, 61.02; H, 5.39; N, 3.31. Example 13 Methyl 5-(2-(2-(2-trifluoromethyl-thiazol4-yl)-2(R)-hydroxy-ethylamino)-ethoxy)-benzofuran-2-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 1. M.p. 128-131C. Analytical c~lcl~sted for C,8H17F3N2O5S: C, 50.24; H, 3.98; N, 6.51. Found: C, 50.06; H, 3.87; N, 6.28. Example 14 5-(2-(2-(2-Trifluoromethyl-thiazol-4-Yl)-2(R)-hydroxy-ethylamino)-ethoxy) benzofuran-2-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 3. M.p. 155-1 63C. Analytical c~lculsted for Cl7H15F3N2O5S.2.25H2O: C, 44.70; H 4.30; N, 6.13. Found: C, 44.45; H, 4.30; N, 6.13. Example 15 1-(5-(2(2(S)-Hydroxy-3-Phenoxy-propvlamino)-ethoxv)-benzofuran-2-yl)-ethanone The title compound was prepared by a procedure similar to that described in Example 1. M.p. 122-123C. Analytical cr'~ 'qted for C2l H23NO5-0.2H20: C, 67.62; H, 6.32; N, 3.75. Found: C, 67.83; H, 6.10; N, 3.73. 2158910 48- Example 16 1 -(5-(2(2(S)-Hydroxy-3-phenoxy-propylamino)-ethoxy)-benzofuran-2-yl)-butanone The title compound was prepared by a procedure similar to that described in Example 1. M.p. 99-100C. Analytical calculated for C23H27NO5-0.14H2O: C, 69.05; H, 6.87; N, 3.50. Found: C, 69.08; H, 6.76; N, 3.34. Example 17 1 -(2-(2-lsoxazol-3-yl-benzofuran-5-yloxy)-ethvlamino)-3-phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 107-110C. Analytical cr'cul~ted for C22H22N2O5: C, 66.99; H, 5.62; N, 7.10. Found: C, 66.94; H, 5.42; N, 7.00. Example 18 1-(2-(2-lsoxaz`ol-3-yl-benzofuran-5-yloxy)-ethylamino)-3-(2-chloro-phenoxy)- 15 propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 93-96C. Analytical cr'culated for C22H21CIN2O5-0.25H20: C, 60.97; H, 5.00; N, 6.46. 20 Found: C, 60.99; H, 5.26; N, 5.60. Example 19 1 -(2-(2-(5-Methyl-isoxazol-3-yl)-benzofuran-5-yloxy)-ethvlamino)-3- phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in 25 Example 1. M.p. 144-146C (acetone). Analytical calculated for C23H24N2O5: C, 67.63; H, 5.92; N, 6.86. Found: C, 67.65; H, 5.85; N, 6.73. Example 20 - 30 1-(2-(2-(5-Methyl-isoxazol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3- (2-chloro-phenoxy)-proPan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. ` 2158910 -49- M.p. 102-106C. Analytical calculated for C23H23CIN2O5: C, 62.37; H, 5.23; N, 6.32. Found: C, 62.12; H, 5.58; N, 6.01. Example 21 1-(2-(2-(5-Methyl-isoxazol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3- (2-fluoro-phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 118-121C. Analytical calculated for C23H23FN2O5: C, 64.78; H, 5.44; N, 6.57. Found: C, 64.97; H, 5.38; N, 6.22. Example 22 1 -(2-(2-lsoxazol-3-yl-benzofuran-5-yloxy)-ethylamino)-3-(2- trifluoromethyl-phenoxy)-propan-2(S) -ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 90-91 C. Analytical calculated for C23H2tF3N2O5: C, 59.74; H, 4.58; N, 6.06. Found: C, 59.62; H, 4.49; N, 5.66. Example 23 1 -(2-(2-lsoxazol-3-yl-benzofuran-5-yloxy)-ethylamino)-3-(2-cyano- phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 94-95C. Analytical calculated for C23H2l N3O5-0.5H2O: C,64.57; H,5.18; N, 9.81. Found: C, 64.26; H, 5.16; N, 9.35. Example 24 1 -(2-(2-lsoxazol-3-yl-benzofuran-5-vloxy)-ethylamino)-3-(2-fluoro- phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 109-110C. 2158910 -50- Analytical c~lcu'qted for C22H2lFN2O5: C, 64.07; H, 5.13; N, 6.79. Found: C, 63.89; H, 4.98; N, 6.39. Example 25 1 (R)-(3-Chloro-Phenyl)-2-(2-(2-isoxazol-3-yl-benzofuran-5-yloxy)- 5 ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 112-120C. Analytical cr'cul~tedforC21H1gClN2O4: C, 63.24; H, 4.57; N, 7.02. Found: C, 10 62.94; H, 5.13; N, 5.96. Example 26 1 (R)-(3-Trifluoromethyl-phenyl)-2-(2-(2-isoxazol-3-yl-benzofuran-5- yloxv)-ethylamino)-ethanol The title compound was prepared by a proceJure similar to that desc,il,ed in 15 Example 1. M.p. 113-114C. Analytical c-'_u'~tedforC22H19F3N2o4: C, 61.11; H, 4.43; N, 6.48. Found: C, 61.48; H, 4.75; N, 5.79. Example 27 1 (R)-(3-Chloro-phenyl)-2-(2-(2-(5-methyl-isoxazol-3-vl)-benzofuran- 5-yloxv)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 108-110C. Example 28 1 (R)-(3-Trifluoromethyl-phenyl)-2-(2-(2-(5-methyl-isoxazol-3-yl)- benzofuran-5-yloxv)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 126-127C. Analyticalc '~ul~tedforC23H2lF3N2O4: C,61.88;H,4.74;N,6.27. Found: C, 61.75; H, 4.87; N, 6.20. 2158910 ExamPle 29 1 -(2-(2-(2-Methyl-thiazol-4-vl)-benzofuran-5-yloxv)-ethylamino)-3- phenoxy-propan-2(S~-ol; The title compound was prepared by a procedure similar to that described in Example 1. M.p. 150-152C. Example 30 1 (R)-(3-Chloro-phenyl)-2-(2-(2-(2-methyl-thiazol-4-yl)-benzofuran- 5-yloxy)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 127-129C. Analytical calcul~ted for C22H2lCIN2O3S: C, 61.60; H, 4.93; N, 6.53. Found: C, 61.54; H, 4.85; N, 6.27. Example 31 1 -(2-(2-(5-Methyl-(1.2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3- phenox~l-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 112-114 C. Analytical cAIcul~ted for C22H23N3O5: C, 64.53; H, 5.66; N, 10.26. Found: C, 64.48; H, 5.24; N, 9.97. Example 32 1 -(2-(2-(5-Methvl-(1.2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3- 25 (2-chloro-phenoxy)-ProPan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 106-108C. Analytical cAlculAted for C22H22CIN3O5-0.2H20: C, 59.04; H, 5.04; N, 9.39. 30 Found: C, 58.79; H, 4.93; N, 9.18. 21~8910 -52- Example 33 1 -(2-(2-(5-Methyl-(1,2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy~-ethylamino)-3- (2-fluoro-phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 102.5-103.5C. Analytical calculated for C22H22FN30s: C, 61.82; H, 5.19; N, 9.83. Found: C, 61.60; H, 5.21; N, 9.52. Example 34 1-(2-(2-(5-Trifluoromethyl-(1,2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy)- ethvlamino)-3-phenoxv-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 108-113C. ExamPle 35 1 -(2-(2-(5-Trifluoromethyl-(1,2,4)-oxadiazol-3-yl)-benzofuran-5-vloxv)- ethylamino)-3-(2-chloro-phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 112-115C. Analytical calculated for C22HlgF3ClN3O5: C, 53.08; H, 3.85; N, 8.44. Found: C, 53.65; H, 4.08; N, 8.36. Example 36 1 -(2-(2-(5-Trifluoromethyl-(1,2,4)-ox~di~7O1-3-yl)-benzofuran-5-yloxy)- 25 ethylamino)-3-(2-fluoro-phenoxy)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 117-119C. Analytical calculated for C22H19F4N30s: C, 54.89; H, 3.98; N, 8.73. Found: C, 30 54.51; H, 3.84; N, 8.38. 2 ~S8910 -53- ExamPle 37 1 -(2-(2-(5-Ethyl-(1.2,41-oxadiazol-3-vl)-benzofuran-5-yloxy)-ethvlamino)-3- phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 97-98C. HRMS Calcd for C23H25N3O5: 423.1788. Found: 423.1843. Example 38 1 -(2-(2-(5-(2-Propyl)-(1,2,4)-oxadiazol-3-yl)-benzofuran-5-yloxy)-ethylamino)- 1 0 3-phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 111-112C. Analytical c~lcu~qted for C24H27N3O5: C, 65.89; H, 6.22; N, 9.60. Found: C, 15 65.61; H,6.15; N,9.24. Example 39 1 -(2-(2-(5-(2-Phenyl)-(1,2,4)-ox~di~ol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3-phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in 20 Exarnple 1. M.p. 149-151 C. Analytical c-'-ul~ted for C2,H25N3O5: C, 68.78; H, 5.34; N, 8.91. Found: C, _n no. 1~ e l~n. 1~1 0 Q~ VO.~v~ ~.c~ 1~, v.vc. Example 40 1-(2-(2-(5-(2-(3-Pyridyl))-(1.2.4)-oxadiazol-3-yl)-benzofuran-5-yloxy)- ethylamino)-3-phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 150-155C. 21S8910 -54- Example 41 1 -(2-(2-(1 ,2,4)-Oxadiazol-3-yl)-benzofuran-5-yloxy)-ethylamino)-3- phenoxy-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 118-119C. Analytical c~lcul~ted forC2lH2lN3O5: C, 63.79; H, 5.35; N, 10.63. Found: C, 63.79; H, 5.34; N, 10.62. Found: C, 63.79; H, 5.35; N, 10.63. Example 42 1-(2(2-(1,2,4)-Oxadiazol-3-yl)-benzofuran-5-vloxv)-ethylamino)-3-(2-chloro- phenoxv)-propan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 102-104C. Analytical c~cul~ted for C2lH2oClN3O5-0.5H2O: C, 57.46; H, 4.82; N, 9.57, Found: C, 57.65; H, 4.71; N, 9.07. ExamPle 43 1 -(2-(2-(1 ,2,4)-Oxadiazol-3-yl)-benzofuran-5-yloxy)-ethvlamino)-3-(2-fluoro- phenoxy)-proPan-2(S)-ol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 98-101 C. Analytical c~lc~ ted for C2lH20FN3O5: C, 61.01; H, 4.88; N, 10.16. Found: C, 61.39; H, 4.80; N, 9.01. ExamPle 44 1 (R)-(3-Chloro-phenyl)-2-(2-(2-(5-methyl-(1 .2,4)-oxadiazol-3-yl)-benzofuran- 5-yloxy)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 88-92C. Analytical calculated for C2l H20CIN3O4: C, 60.94; H, 4.87; N, 10.15. Found: C, 60.95; H, 4.62; N, 9.75. 2158910 -55- Example 45 1 (R)-(3-Trifluoro-phenyl~-2-(2-(2-(5-methyl-(1,2,4)-oxadiazol-3- yl)-benzofuran-5-yloxy)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in 5 Example 1. M.p. 96-98C. Analytical calculated for C22H20F3N3O4: C, 59.06; H, 4.51; N, 9.39. Found: C, 58.78; H, 4.34; N, 9.17. Example 46 1 (R)-(2-Trifluoromethvl-thiazol-4-yl)-2-(2-t2-(5-methyl-(1,2,4)-oxadiazol-3- yl)-benzofuran-5-yloxy)-ethvlamino)-ethanol The title compound was prepared by a procedure similar to that descriLed in Example 1. M.p. 143-146C. Analytical calculated for C19H17F3N4O4S: C, 50.22; H, 3.77; N, 12.33. Found: C, 50.77; H, 3.60; N, 11.67. Example 47 1 (R)-(3-Chloro-phenvl)-2-(2-(2-(5-trifluoromethyl-(1,2,4)-oxadiazol-3-yl)- benzofuran-5-yloxy)-ethylamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 108-111C. Analytical c~lcul,qted for C21H17F3CIN304: C, 53.92; H, 3.66; N, 8.98. Found: C, 53.93; H, 3.79; N, 8.75. Example 48 1 (R)-(3-Chloro-phenyl)-2-(2-(2-(5-(2-proPyl)-(1,2,4)-ox~ 7OI-3-yl)- benzofuran-5-yloxy)-ethvlamino)-ethanol The title compound was prepared by a procedure similar to that described in Example 1. M.p. 84-87C. Analytical calculated for C23H24CIN3O4: C, 62.51; H, 5.47; N, 9.51. Found: C, 62.34; H, 5.35; N, 9.34. ~ 2158910 -56- Example 49 1 (R)-(3-Chloro-phenyl)-2-(2-(2-(1,2,4)-oxadiazol-3-yl-benzofuran-5-yloxy)- ethylamino)- ethanol The title compound was prepared by a procedure similar to that descriLed in Example 1. M.p. 103-105C. Analytical calculated for C20H,8CIN3O4: C, 60.08; H, 4.54; N,10.51. Found: C, 60.19; H, 4.42; N, 9.58. Example 50 5-(2-(2(S)-Hydroxy-3-phenoxy-Propylamino)ethoxy)-benzofuran-2-carboxylic acid, 1-proPvl-amide The title compound was prepared by a procedure similar to that described in Example 4. M.p. 127-128C. Example 51 (5-(2-(2(S)-Hydroxy-3-phenoxv-propylamino)ethoxy)-benzofuran-2-vl)-Pyrrolidin- 1-vl-methanone The title co",pound was prepared by a procedure similar to that desc-riLed in Example 4. M.p. 117-118C. Analytical c-'.,u~ted for C24H28N205-0.2H20: C, 67.34; H, 6.69; N, 6.54. Found: C, 67.11; H, 6.24; N, 6.40. Example 52 (5-(2-(2(S~-Hydroxy-3-(2-chloro-phenoxy)-propylamino)ethoxy)-benzofuran-2-yl)- 25 pyrrolidin-1-yl-methanone The title compound was prepared by a procedure similar to that described in Example 4. M.p. 89-90C. Analytical calculated for C24H27CIN2O5: C, 62.80; H, 5.93; N, 6.11. Found: C, 30 62.59; H, 5.80; N, 5.94. `~ 21~8910 -57- Example 53 (5-(2-(2(S)-Hydroxy-3-phenoxy-propylamino)ethoxy)-indol-2-yl)-pyrrolidin-1 - yl-methanone The title compound was prepared by a procedure similar to that described in Example 4. M.p. 110-115C. Example 54 (1 -Methyl-5-(2-(2(S)-hydroxv~Phenoxy-propylamino)ethoxy)-indol-2-yl)-pyrrolidin- 1-vl-methanone The title compound was prepared by a procedure similar to that described in Example 4. M.p. 130-131C. Analytical calculated for C25H31 N3O4-0.5H2O: C, 67.23; H, 7.22; N, 9.41. Found:C, 67.55; H, 6.98; N, 9.15. Example 55 5-(2-(2-(3-Chloro-phenyl)-2(R)-hydroxy-ethylamino)-ethoxy)-benzofuran-2-yl)- pyrrolidin-1 -yl-methanone The title compound was prepared by a procedure similar to that described in Example 4. M.p. 96-98C. Analytical c?'cul~ted for C23H25CIN2O4: C, 64.41; H, 5.88; N, 6.53. Found: C, 64.41; H, 5.73; N, 6.19. Example 56 5-(2(R.S)-(2-(2-Trifluoromethyl-thiazol4-vl)-2(S)-hydroxy-ethylamino)-proPvl)- 25 benzofuran-2-carboxylic acid The title compound was prepared by a procedure similar to that described in Example 3. M.p. 145-163C. Analytical calculated for Cl8H17F3N2O4S-1.25H2O: C, 49.48; H, 4.50; N, 6.41. 30 Found: C, 49.38; H, 4.56; N, 6.23. 215~91~ -58- Example 57 5-(2(R)-(2-(2-Trifluoromethyl-thiazol-4-yl)-2(S)-hydroxy-ethylamino)-propYI)- benzofuran-2-carboxylic acid The title compound was prepared by a procedure similar to that described in 5 Example 3. M.p. 168-171C. Analytical cnlcu'ated for C18H17F3N204S-1.5H20: C, 48.98; H, 4.57; N, 6.35. Found: C, 49.04; H, 4.47; N, 6.06. Example 58 4-(2(R,S)-(2-(2-Trifluoromethyl-thiazol-4-yl)-2(S)-hydroxy-ethylamino~- propvl)-benzo-furan-2-carboxylic acid The title compound was prepared by a procedure similar to that descril.ed in Example 3. M.p. 158-176C. AnalyticaHc~lc~ ted for Cl8Hl7F3N204S-1.25H20: C, 48.98; H, 4.57; N, 6.35. Found: C, 48.87; H, 4.31; N, 6.27.

Claims (16)

  1. - 59 - THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS: 1. A pharmaceutical composition for treating or prevent- ing prostate disease in a mammal comprising an amount of a .beta.3-adrenoceptor antagonist or agonist effective in antagonizing or agonizing the .beta.3-adrenoceptor, or a pharmaceutically acceptable salt or prodrug thereof; and a pharmaceutically acceptable carrier.
  2. 2. A pharmaceutical composition for treating or prevent- ing a condition selected from the group consisting of intestinal motility disorders, intestinal ulcerations, gastrointestinal ulcerations, depression, prostate disease, neurogenetic inflammation and dyslipidemia in a mammal, which comprises, in admixture with a pharmaceutically acceptable carrier, (a) an amount of a compound of formula: <IMG> I wherein R1 is phenyl, -(CH2)n-O-phenyl or thiazolyl, wherein said phenyl, the phenyl moiety of said -(CH2)n-O-phenyl and said thiazolyl may optionally be substituted with one or more substituents, preferably one to three substituents, independ- ently selected from hydrogen, (C1-C6)alkyl optionally - 59a - substituted with one or more halo atoms, preferably from one to three halo atoms, hydroxy, (C1-C6)alkoxy optionally substituted with one or more halo atoms, preferably from one to three halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, nitro and cyano; -60- R2 is hydrogen or (C1-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; R3 is hydrogen, -(CH2)n-phenyl, -(C1-C10)alkyl, -(CH2)n-NR7R8, -(CH2)n-CO2R11, <IMG> , -(CH2)n-OR11, -(CH2)n-SO3R11, -(CH2)n-SO2-(C1-C6)alkyl, -(CH2)n- SO2NR7R8, or a heterocycle selected from -(CH2)n-pyridyl, -(CH2)n-pyrimidyl, -(CH2)n- pyrazinyl, -(CH2)n-isoxazolyl, -(CH2)n-oxazolyl, -(CH2)n-thiazolyl, -(CH2)n-(1,2,4- oxadiazolyl), -(CH2)n-imidazolyl, -(CH2)n-triazolyl and -(CH2)n-tetrazolyl, wherein one of the ring nitrogen atoms of said -(CH2)n-imidazolyl, -(CH2)n-triazolyl or -(CH2)n-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally substituted with one or more halo atoms, and wherein each of said heterocycles may optionally be substituted on one or more of the ring carbon atoms by (C1-C6)alkyl optionally substituted with one or <IMG> more halo atoms halo,nitro, cyano, -(CH2)n-NR7R8, -(CH2)n-CO2R11, -(CH2)n-OR11, -(CH2)n-SO2R11, -(CH2)n-SO2-(C1-C6)alkyl, or -(CH2)n-SO2NR7R8, andwherein the phenyl moiety of said (CH2)n-phenyl may optionally be substituted with one or more substituents, preferably one to three substituents, independently selected from (C1-C6)alkyl optionally substituted with one or more halo atoms hydroxy, (C1-C6)alkoxy optionally substituted with one or more halo atoms, (C1-C6)alkylthio, fluoro, chloro, bromo, iodo, cyano, nitro, -(CH2)n- <IMG> NR7R8, -(CH2)n-CO2R11, -(CH2)n-OR11, -(CH2)n-SO3R11, -(CH2)n-SO2-(C1- C6)alkyl, and -(CH2)n-SO2NR7R8; R4 is -(CH2)n-CN, -(CH2)nCO2R11, -(CH2)n-SO3R11, -(CH2)n-SO2-(C1-C6)alkyl, -(CH2)n-SO2-NR7R8, -(CH2)nCH2OH optionally substituted with a suitable protecting group, -(CH2)n-CHO, -(CH2)n-C(=O)R11, -(CH2)n-C(=O)NR7R8, or a heterocycle selected from -(CH2)n-thiazolyl, -(CH2)n-oxazolyl, -(CH2)n-imidazolyl, -(CH2)n-triazolyl, -(CH2)n-1,2,4- oxadiazolyl, -(CH2)n-isoxazolyl, -(CH2)n-tetrzolyl and -(CH2)n-pyrazolyl; wherein one of the ring nitrogen atoms of said -(CH2)n-imidazolyl, -(CH2)n-triazolyl and -(CH2)n-tetrazolyl may optionally be substituted by (C1-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; wherein each of said heterocycles -61 - may optionally be substituted on any of the the ring carbon atoms by hydrogen, (C1- C8)alkyl optionally substituted with one or more halo atoms, preferably from one to <IMG> three halo atoms, -(CH2)n-NR7R8, -(CH2)n-CO2R2, halo, nitro, cyano, -(CH2)n-OR11, -(CH2)n-SO3R11, -(CH2)n-SO2-(C1-C6)alkyl, or -(CH2)n-SO2NR7R8; R5 is hydrogen or (Cl-C6)alkyl optionally substituted with one or more halo atoms, preferably from one to three halo atoms; each R7 and each R8 is selected independently of any other R7 or R8 in the same molecule, and is selected from the group consisting of hydrogen, (C1-C6)alkyl, (C1- C8)alkoxy(C1-C6)alkyl and (C3-C8)cycloalkyl, or R7 and R8, when attached to the same nitrogen atom, together with the nitrogen to which they are attached, form a saturated heterocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms may optionally be replaced by oxygen, nitrogen or sulfur; R11, wherever it occurs, is selected independently from any other R11 in the same molecule and is hydrogen or (C1-C6) alkyl optionally substituted with one or more halo atoms; n is an integer from zero to six; X is a direct link, oxygen or sulfur; Y is oxygen, nitrogen or sulfur; and Z is carbon or nitrogen; with the proviso that: (i) when Y is oxygen or sulfur, R3 is absent, and (ii) when Z is nitrogen, R5 is absent; or a pharmaceutically acceptable prodrug of such compound or a pharmaceutically acceptable salt of such compound or prodrug thereof, that is effective in treating or preventing such condition; b) an amount of a compound of the formula -62- <IMG> J or a pharmaceutically acceptable prodrug of such compound or a pharmaceutically acceptable salt of such compound or prodrug thereof, that is effective in treating or preventing such condition; c) an amount of a compound of the formula <IMG> K or a pharmaceutically acceptable prodrug of such compound or a pharmaceutically acceptable salt of such compound or prodrug thereof, that is effective in treating or preventing such condition with the proviso that the compound of formula K is excluded from the treatment or prevention of dyslipidemia; or d) an amount of a compound of the formula -63- <IMG> L or a pharmaceutically acceptable prodrug of such compound, or a pharmaceutically acceptable salt of such compound or prodrug thereof, that is effective in treating or preventing such condition.
  3. 3. A composition according to claim 2 for treating or preventing intestinal motility disorders in a mammal and being adapted such that 10 to 1,000 milligrams of the compound are administered daily.
  4. 4. A composition according to claim 3, wherein the intestinal motility disorders are irritable bowel syndrome.
  5. 5. A composition according to claim 3, wherein the intestinal motility disorders are peptic ulceration.
  6. 6. A composition according to claim 3, wherein the intestinal motility disorders are esophagitis.
  7. 7. A composition according to claim 3, wherein the intestinal motility disorders are gastritis.
  8. 8. A composition according to claim 3, wherein the intestinal motility disorders are duodenitis. -64-
  9. 9. A composition according to claim 2, for treating or preventing intestinal ulceration.
  10. 10. A composition according to claim 2 r for treating or preventing gastrointestinal ulceration.
  11. 11. A composition according to claim 2 for treating or preventing depression in a mammal and being adapted such that 10 to 1,000 milligrams of the compound are administered daily.
  12. 12. A composition according to claim 2 for treating or preventing prostate disease in a mammal and being adapted such that 10 to 1,000 milligrams of the compound are administered daily.
  13. 13. A composition according to claim 2 for treating or preventing dyslipidemia in a mammal and being adapted such that 1 to 50 milligrams of the compound are administered daily.
  14. 14. A composition according to claim 2 for treating or preventing neurogenetic inflammation in a mammal.
  15. 15. A commercial package which comprises the composition as defined in claim 1 and a written matter associated there- with, wherein the written matter states that the composition should or can be used for treating or preventing prostate disease in a mammal. -65-
  16. 16. A commercial package which comprises the composition as defined in claim 2 and a written matter associated there- with, wherein the written matter states that the composition should or can be used for treating or preventing the condition defined in claim 2.
CA002158910A 1994-09-26 1995-09-22 B3-adrenoceptor agonists and antagonists for the treatment of intestinal motility disorders, depression, prostate disease and dyslipidemia Expired - Fee Related CA2158910C (en)

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