Propanolamine derivatives

A method for the prophylactic and/or therapeutic treatment of dysuria that comprises:

• administering to a human being or an animal an effective amount of a compound, which is a β3 adrenergic receptor agonist, having a general formula selected from the group consisting of formula (IV), (V), (VI), (VII) and (VIII),
• or a salt or prodrug thereof, or for the compound of formula (VII) an ester or amide thereof;
• wherein
• (a) a compound of formula (IV) is represented by the following general formula:
• wherein
• R1 is lower alkyl, aryl or arylakyl;
• R2 is hydrogen, hydroxy, alkoxy, —CH2OH, cyano, —C(O)OR7, —CONH2, tetrazole, —CH2NH2 or halogen;
• R3 is hydrogen, alkyl, heterocycle or
• R4 is hydrogen, alkyl or B;
• R5, R5′, R8, R8′ and R8″ are independently hydrogen, alkoxy, lower alkyl, halogen, —OH, —CN, —(CH2)nNR6COR7, —CON(R6)R6′, —CON(R6)OR6′, —CO2R6, —SR7, —SOR7, —SO2R7, —N(R6)SO2R1, —N(R6)R6′, —NR6COR7, —OCH2CON(R6)R6′, —OCH2CO2R7 or aryl;
• or
• R5 and R5′ or R8 and R8′ may together with the carbon atoms to which they are attached form an aryl or heterocycle;
• R6 and R6′ are independently hydrogen or lower alkyl;
• and
• R7 is lower alkyl;
• R9 and R9′ are independently hydrogen, lower alkyl, alkyl, cycloalkyl, arylalkyl, aryl, heteroaryl;
• or
• R9 and R9′ may together with the nitrogen atom to which they are attached form a heterocycle;
• A is a bond, —(CH2)n— or —CH(B)—, wherein n is an integer of 1, 2 or 3 and B is —CN, —CON(R9)R9′— or —CO2R7;
• with the proviso that when A is a bond or —(CH2)n— and R3 is hydrogen or unsubstituted alkyl, then R4 is B or substituted alkyl;
• (b) a compound of formula (V) is represented by the following general formula:
• wherein
• n is 0 to 5;
• m is 0 or 1;
• r is 0 to 3;
• A is pyridinyl;
• R1 is (1) hydroxy, (2) oxo, (3) halogen, (4) cyano, (5) NR8R8, (6) SR8, (7) trifluoromethyl, (8) C1-C10 alkyl, (9) OR8, (10) SO2R9, (11) OCOR9, (12) NR8COR9, (13) COR9, (14) NR8SO2R9, (15) NR8CO2R8, or (16) C1-C10 alkyl substituted by hydroxy, halogen, cyano, NR8R8, SR8, trifluoromethyl, OR8, C3-C8 cycloalkyl, phenyl, NR8COR9, COR9, SO2R9, OCOR9, NR8SO2R9 or NR8CO2R8;
• R2 and R3 are independently (1) hydrogen, (2) C1-C10 alkyl or (3) C1-C10 alkyl with 1 to 4 substituents selected from hydroxy, C1-C10 alkoxy, or halogen;
• X is (1) —CH2—, (2) —CH2—, (3) —CH═CH— or (4) —CH2O—;
• R4 and R5 are independently (1) hydrogen, (2) C1-C10 alkyl, (3) halogen, (4) NHR8, (5) OR8, (6) SO2R9 or (7) NHSO2R9;
• R6 is (1) hydrogen or (2) C1-C10 alkyl;
• R7 is Z-(R1a)n;
• R1a is (1) R1, (2) C3-C8 cycloalkyl, (3) phenyl optionally substituted with up to 4 groups independently selected from R8, NR8R8, OR8, SR8 or halogen, or (4) 5 or 6-membered heterocycle with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, optionally substituted with up to four groups independently selected from oxo, R8, NR8R8, OR8, SR8, or halogen;
• Z is (1) phenyl, (2) naphthyl, (3) or a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, (4) a benzene ring fused to a cycloalkyl ring, (5) a benzene ring fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, (6) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen fused to a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen, or (7) a 5 or 6-membered heterocyclic ring with from 1 to 4 heteroatoms selected from oxygen, sulfur or nitrogen fused to a C3-C8 cycloalkyl ring;
• R8 is (1) hydrogen, (2) C1-C10alkyl, (3) C3-C8 cycloalkyl, (4) Z optionally having 1 to 4 substituents selected from halogen, nitro, oxo, NR10R10, C1-C10 alkyl, C1-C10 alkoxy, C1-C10 alkylthio, and C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2—C1-C10 alkyl, SO2—C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, or Z optionally substituted by from 1 to 3 halogen, C1-C10 alkyl or C1-C10 alkoxy, or (5) C1-C10 alkyl having 1 to 4 substituents selected from hydroxy, halogen, CO2H, CO2—C1-C10 alkyl, SO2—C1-C10 alkyl, C3-C8 cycloalkyl, C1-C10 alkoxy, C1-C10 alkyl, or Z optionally substituted by from 1 to 4 halogen, C1-C10 alkyl or C1-C10 alkoxy;
• R9 is (1) R8 or (2) NR8R8;
• and
• R10 is (1) C1-C10 alkyl, or (2) two R10 groups together with the N to which they are attached forming a 5 or 6-membered ring optionally substituted with C1-C10 alkyl;
• (c) a compound of formula (VI) is:
• wherein
• X is hydrogen, halogen, trifluoromethyl or lower alkyl, and
• R is hydrogen;
• lower alkyl which may have a suitable substituent selected from the group consisting of cyclo(C3-C7)alkyl, hydroxy, lower alkoxy, carboxy and lower alkoxycarbonyl;
• cyclo(C3-C7)alkyl or lower alkanoyl;
• (d) a compound of formula (VII) is represented by the following general formula:
• wherein
• R1 is a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl, hydroxymethyl, methyl, methoxyl, amino, formamido, acetamido, methylsulphonylamido, nitro, benzyloxy, methylsulphonylmethyl, ureido, trifluoromethyl or p-methoxybenzylamino group;
• R2 is a hydrogen, fluorine, chlorine or bromine atom or a hydroxyl group;
• R3 is a hydrogen, chlorine or bromine atom or a hydroxyl group,
• R4 is a hydrogen atom or a methyl group;
• R5 is a hydrogen atom or a methyl group;
• R6 is a hydrogen, fluorine or chlorine atom or a methyl, methoxyl or hydroxy group;
• X is an oxygen atom or a bond;
• Y is an alkylene group of up to 6 carbon atoms or a bond;
• and
• Z is an alkylene, alkenylene or alkynylene group of up to 10 carbon atoms;
• and
• (e) a compound of formula (VIII) is represented by the following general formula:
• wherein
• R is hydrogen or methyl,
• R1 is hydrogen, halogen, hydroxy, benzyloxy, amino or hydroxymethyl,
• R2 is hydrogen, hydroxymethyl, —NHR3, —SO2NR4R4′ or nitro,
• R3 is hydrogen, methyl, —SO2R5, formyl or —CONHR6′,
• R4 and R4′ are independently hydrogen, lower alkyl or benzyl,
• R5 is lower alkyl, benzyl or —NR4R4′,
• R6 is hydrogen or lower alkyl,
• R6′ is hydrogen or lower alkyl,
• R9 is hydrogen, amino, acetylamino or hydroxy, and
• X is N, O, S or methylene;
• provided that when X is N, O or S,
• then R9 is hydrogen, either R7 or R8 is hydrogen, and the other is hydrogen, amino, acetylamino or hydroxy;
• and
• provided that when X is methylene,
• then both R7 and R8 are hydrogen.