ZA200208895B - Substituted 1-aminoalkyl-lactams and their use as muscarinic receptor antagonists. - Google Patents

Description

, SUBSTITUTED 1-AMINOALKYL-LACTAMS AND THEIR USE AS MUSCARINIC RECEPTOR ANTAGONISTS

This invention relates to compounds the general Formula I

Lou

BR:

N CH,); (CH,), (Con _y

R' | z wherein

R!and R® are independently in each occurrence hydrogen, halogen, (C,.¢)-alkyl, -OR}, -SR’, -NR'R", -SOR/, -SO;R’, -COOR’, -OCOR', -OCONR'R", -OSO;R’, -OSO,NR'R"; -NR'SO,R", -NR'COR", -50, NR'R", -SO,(CH;)1.3CONR'R", -CONR'R", cyano, halogenalkyl or nitro; or

Rand R" are independently in each occurrence hydrogen, (C,.¢)-alkyl, substituted (C,.¢)-alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C,.3)-alkyl, heteroaryl-(C;.3)-alkyl, heterocyclyl-(C,.3)-alkyl, cycloalkyl-alkyl, cycloalkyl, or R' and R" together with the nitrogen they are attached may also form a 5- to 7- membered ring, optionally incorporating one additional ring heteroatom chosen from N, O or S(O).2;

R® is independently in each occurrence (C;.¢)-alkyl, (C;.¢)-alkenyl, (C1.¢)-alkynyl or cycloalkyl; or one of X,YorZ is independently -S-, -O-, or >N-R*, the others are -CH,-;

R* is hydrogen, (Ci.¢)-alkyl, halogenalkyl, aryl-(C,.¢)-alkyl, heteroaryl-(C;)-alkyl, -(Ci)-CR'R'R', -COOR', -SO2R', -C(O)R’, . -SO,(CH3)0.3NR'R", -CONR'R", or -PO(OR')2, wherein R' and R" are as defined above; p is an integer from 1 to 3 inclusive; m is an integer from O to 3 inclusive; n is an integer from 1 to 6 inclusive;

or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof. : It has been surprisingly found that compounds of formula I are M2/M3 selective muscarinic receptor antagonists.

Acetylcholine (Ach) is the principal transmitter of the parasympathetic nervous system. The physiological actions of Ach are mediated by activation of either nicotinic or muscarinic receptors. Both of these receptor classes are heterogeneous: e.g., the muscarinic receptor family comprises five subtypes (M,;, M2, M3, My, and Ms) each encoded by distinct genes and possessing unique pharmacology and distribution.

Almost all smooth muscle tissues express both muscarinic M2 and M3 receptors, both of which have a functional role. M2 receptors outnumber M3 receptors by a proportion of approximately 4 to 1. Generally, M3 receptors mediate the direct contractile effects of acetylcholine in the vast majority of smooth muscle tissues. M2 receptors, on the other hand, cause smooth muscle contraction indirectly by inhibiting sympathetically (B- adrenoreceptor)-mediated relaxation.

Compounds that act as antagonists of muscarinic receptors have been used to treat several disease states associated with improper smooth muscle function. Until recently, most of these compounds have been non-selective for the various muscarinic receptor subtypes, leading to unpleasant anti-cholinergic side-effects such as dry mouth, constipation, blurred vision, or tachycardia. The most common of these side-effects is dry- mouth resulting from muscarinic receptor blockade in the salivary gland. Recently developed M2 or M3 specific antagonists have been shown to have reduced side effects.

Evidence suggests that concurrent blockade of M2 and M3 receptors could be therapeutically effective in the treatment of disease states associated with smooth muscle - disorders.

Few M2/M3 selective antagonists have been developed. The present invention fills this need by providing these types of antagonists useful in the treatment of disease states associated with improper smooth muscle function.

More information about muscarinic receptor subtypes and antagonists thereof can be obtained from the following literature. Certain subtypes of the muscarinic receptor in smooth muscle are described in Ehlert et al., Life Sciences 1997, 61, 1729-1740. Hedge et al.,

Life Sciences 1999, 64, 419-428, refers to muscarinic receptor subtypes modulating smooth muscle contractility in the urinary bladder. Eglen et al., Trends. Pharmacol. Sci. 1994, 15, 114-119, and Eglen et al., Pharmacol. Rev. 1536, 48, 531-565, refer to certain muscarinic receptor subtypes and smooth muscle function. Clinical studies of selective muscarinic antagonists are described in Nilvebrant et al., Life Sciences 1997, 60, 1129-1136; Alabaster,

Life Sciences 1997, 60, 1053-1060; Osayu et al., Drug Res. 1994, 44, 1242-1249, and Homma et al., Neurourology and Urodynamics 1997, 345-346. Selective modulation of muscarinic receptor subtypes is reported in Eglen and Hegde, Emerging Drugs 1998, 3, 67-79. Eglen et al, Curr. Opin. Chem. Biol. 1999, 3, 426-432, refers to muscarinic receptor ligands and ) their therapeutic potential. A certain classification of muscarinic acetylcholine receptors is described in Caulfield et al., Pharmacological Reviews 1998, 50(2), 279-290.

In the following literature compounds related to compounds of general formula I are described. US 5,382,595, US 5,177,089, US 5,047,417and US 5,607,953 assigned to Eisai

Co., Ltd. refer to certain butenoic and propenoic acid derivatives. US 4,748,182 assigned to

Merrell Dow Pharm. Inc. refers to certain aromatic 2-aminoalkyl-1,2-benzoisothiazol- 3(2H)one-1,1-dioxide derivatives and their use as anti-hypertensive and anxiolytic agents.

US 4,880,802,and US 5,298,513 assigned to Bayer AG disclose certain aminotetralin derivatives useful for the treatment of the central nervous system, the cardiovascular system or the intestinal system. US 4,584,293 assigned to Dr. Karl Thomae GmbH refers to certain aminotetralins and their use for lowering the heart rate. Certain aminotetralin derivatives showing dopamine D-2 receptor activity are described in US 5,118,704 assigned to Whitby Research Inc.. US 5,545,755 assigned to Upjohn Co. refers to certain aminotetralin derivatives useful to treat central nervous disorders. WO 99/43657 assigned to F. Hoffmann-La Roche AG refers to certain 2-arylethyl-(piperidin-4-ylmethyl)amine derivatives as muscarinic receptor antagonists. Certain 2-aminotetralin benzamides with ability to bind to Dopamine D2, D3, and Serotonin 5HT-1A Receptors are disclosed in

Homan et al, Bioorg. Med. Chem. 1999, 7(6), 1111-1121. Glennon et al, J. Med. Chem. 1989, 32, 1921-1926, refers to N-Phtalimidoalkyl derivatives a Serotonergic Agents.

All publications, patents, and patent applications cited herein, whether supra or infra, are each hereby incorporated by reference in its entirety.

Objects of the present invention are benzocycloalkylenylamine derivatives of

Formula I, prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, and pharmaceutically acceptable salts or hydrates thereof. The invention further relates to pharmaceutical compositions containing a therapeutically effective amount of at least one ] compound of Formula I, or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, in admixture with at least one suitable carrier. In a more preferred embodiment, the pharmaceutical compositions are suitable for administration to a subject having a disease state which is alleviated by treatment with a muscarinic M2/M3 receptor antagonist.

In another aspect the invention relates to the use of these compounds in the treatment of a subject having a disease state that is alleviated by treatment with a } muscarinic M2/M3 receptor antagonist. In a preferred embodiment, the subject has a disease state comprising smooth muscle disorders; preferably genitourinary tract disorders, } 5 respiratory tract disorders, gastrointestinal tract disorders; more preferably genitourinary tract disorders such as overactive bladder or detrusor hyperactivity and its symptoms, such as the changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like. In another preferred embodiment, the disease comprises respiratory tract disorders such as allergies and asthma. In another preferred embodiment, the disease state comprises gastrointestinal disorders.

In another aspect, the invention relates to a process for preparing a compound of

Formula I, which process comprises reacting a compound having a general formula II oO

Ho_~(CH,) Je hg i TN I nu 0 CH (Cag v

Zz with a compound of general formula III iJ 2

R NH x (CH),

R' to provide a compound of Formula I

R° Q

RY i! CH) PIS (CH,), Cy

R’ z wherein R, R%, R* p,m, n, X,Y, and Z are as defined as described herein.

Unless otherwise stated, the following terms used in this Application, including the specification and claims, have the definitions given below. It must be noted that, as used in the specification and the appended claims, the singular forms "a", "an", and "the" include plural referents unless the context clearly dictates otherwise. ' 5 "Lower alkyl" means the monovalent linear or branched saturated hydrocarbon radical, having from one to six carbon atoms inclusive, unless otherwise indicated.

Examples of lower alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, 1-ethylpropyl, sec-butyl, tert-butyl, n-butyl, n-pentyl, n-hexyl, and the like. "Substituted lower alkyl" means the lower alkyl as defined herein, including one to three substituents, preferably one substituent such as hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro, thiol. These groups may be attached to any carbon atom of the lower alkyl moiety. Examples of substituted lower alkyl radicals include, but are not limited to, 2-methoxyethyl, 2-hydroxy-ethyl, dimethyl-aminocarbonylmethyl, 4- hydroxy-2,2-dimethyl-butyl, trifluoromethyl, trifluorobutyl and the like. "Alkylene" means the divalent linear or branched saturated hydrocarbon radical, having from one to six carbons inclusive, unless otherwise indicated. Examples of alkylene radicals include, but are not limited to, methylene, ethylene, propylene, 2-methyl- propylene, butylene, 2-ethylbutylene, and the like. "Alkenyl" means the monovalent linear or branched unsaturated hydrocarbon radical, containing a double bond and having from two to six carbon atoms inclusive, unless otherwise indicated. Examples of alkenyl radicals include, but are not limited to, ethenyl, allyl, 1-propenyl, 2-butenyl, and the like. "Alkynyl" means the monovalent linear or branched unsaturated hydrocarbon radical, containing a triple bond and having from two to six carbon atoms inclusive, unless otherwise indicated. Examples of alkynyl radicals include, but are not limited to, ethynyl, 1-propynyl, 2-butynyl, propargyl, and the like. "Alkoxy" means the radical -O-R, wherein R is a lower alkyl radical as defined herein. i Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like. "Aryl" means the monovalent aromatic carbocyclic radical consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with one or more, preferably one or two, substituents selected from hydroxy, cyanc, lower a'kyl, lower aikoxy, lower halogenalkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino,

alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, i arylcarbonylamino, unless otherwise indicated.

Alternatively two adjacent atoms of the aryl ring may be substituted with a methylenedioxy or ethylenedioxy group.

Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indanyl, anthraquinolyl, tert-butyl-phenyl, 1,3-benzodioxolyl, and the like.

"Arylalkyl" means the radical R'R"-, wherein R'is an aryl radical as defined herein, and R" is an alkyl radical as defined herein.

Examples of arylalkyl radicals include, but are not limited to, benzyl, phenylethyl, 3-phenylpropyl, and the like.

"Cycloalkyl" means the monovalent saturated carbocyclic radical consisting of one or more rings, preferably one or two rings, of three to eight carbons per ring, which can optionally be substituted with one or more, preferably one or two substitutents, selected from hydroxy, cyano, lower alkyl, lower alkoxy, lower halogenalkoxy, alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl,

arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino , alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.

Examples of cycloalkyl radicals include, but are not limited to, cyclopropyl, cyclobutyl, 3-ethylcyclobutyl, cyclopentyl, cycloheptyl, and the like.

"Cycloalkylalkyl" means the radical R'R"-, wherein R' is a cycloalkyl radical as defined herein, and R" is an alkyl radical as defined herein.

Examples of cycloalkylalkyl radicals include, but are not limited to, cyclopropylmethyl, cyclohexylmethyl, cyclopentylethyl, and the like.

"Heteroaryl" means the monovalent aromatic cyclic radical having one or more rings,

preferably one to three rings, of four to eight atoms per ring, incorporating one or more heteroatoms, preferably one or two, within the ring (chosen from nitrogen, oxygen, or sulfur), which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, cyano, lower alkyl, lower alkoxy, lower halogenalkoxy,

alkylthio, halogen, halogenalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated.

Examples of heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, thiazolyl, pyrazinyl, thienyl, furanyl, pyridinyl , quinolinyl, isoquinolinyl, benzofuryl, benzothiophenyl, benzothiopyranyl, benzimidazolyl,

benzoxazoly!, benzothiazolyl, benzopyranyl, indazolyl, indalyl, iscirdelyl, quinclinyl,

isoquinolinyl, naphthyridinyl, benzenesulfonyl-thiophenyl, and the like.

"Heteroarylalkyl" (or "heteroaralkyl") means the radical of the formula R'R", wherein

R'is a heteroaryl radical as defined herein, and R" is an alkylene radical as defined herein. } Examples of heteroarylalky radicals include, but are not limited to, 2-imidazolylmethyl, 3- pyrrolylethyl, and the like. ' 5 "Heterocyclyl" means the monovalent saturated cyclic radical, consisting of one or more rings, preferably one to two rings, of three to eight atoms per ring, incorporating one or more ring heteroatoms (chosen from N, O or S(O),.2), and which can optionally be substituted with one or more, preferably one or two substituents selected from hydroxy, 0X0, cyano, lower alkyl, lower alkoxy, lower halogenalkoxy, alkylthio, halogen, halogen- alkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkyl- aminocarbonyl, arylaminocarbonyl, alkylcarbonylamino, arylcarbonylamino, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholinyl, quinuclidinyl, and the like. "Heterocycloalkyl" ( or "heterocyclylalkyl") means the radical of the formula RR", wherein R' is a heterocyclic radical as defined herein, and R" is an alkylene radical as defined herein. Examples of heterocycloalkyl radicals include, but are not limited to, 1-piperazinylmethyl, 2-morpholinomethyl, and the like. "Halogen" means the radical fluoro, bromo, chloro, and/or iodo. "Halogenalkyl" means the lower alkyl radical as defined herein substituted in any position with one or more halogen atoms as defined herein. Examples of halogenalkyl radicals include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and the like. ; "Hydroxyalkyl" means the lower alkyl radical as defined herein, substituted with one or more hydroxy groups. Examples of hydroxyalkyl radicals include, but are not limited to, hydroxymethyl, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxy- ‘ ethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl, and 2-(hydroxymethyl)-3-hydroxypropyl, and the like. "Acyloxy" means the radical —-O-C(O)-R, wherein R is a lower alkyl radical as defined herein. Examples of acyloxy radicals include, but are not limited to, acetoxy, propionyloxy, and the like.

"Alkoxycarbonyl" or "alkyl ester" means the radical -C(O)-O-R, wherein R is a lower alkyl radical as defined herein.

Examples of alkoxycarbonyl radicals include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, sec-butoxycarbonyl, isopropyloxycarbonyl, and the like. "Aryloxycarbonyl" or "aryl ester" means the radical -C(O)-O-R, wherein R is an aryl radical as defined herein.

Examples of aryloxycarbonyl radicals include, but are not limited "to phenyl ester, naphthyl ester, and the like.

"Arylalkoxycarbonyl" or "arylalkyl ester” means the radical -C(O)-O-RR', wherein R is a lower alkyl radical and R' is an aryl radical as defined herein.

Examples of aryloxy-

carbonyl radicals include, but are not limited to benzyl ester, phenyl ethyl ester, and the like.

"Alkylcarbonyl" (or "acyl") means the radical R-C(O)-, wherein R is a lower alkyl radical as defined herein.

Examples of alkylcarbonyl radicals include, but are not limited to, acetyl, propionyl, n-butyryl, sec- butyryl, t- butyryl, iso-propionyl and the like.

"Arylcarbonyl" means the radical R-C(O)-, wherein R is an aryl radical as defined herein.

Examples of arylcarbonyl radicals include, but are not limited to, benzoyl, naphthoyl, and the like.

"Arylalkylcarbonyl" (or "aralkylcarbonyl") means the radical R-C(O)-, wherein R is an arylalkyl radical as defined herein.

Examples of arylalkylcarbonyl radicals include, but are not limited to, phenylacetyl, and the like.

"Heteroarylcarbonyl" means the radical R-C(O)-, wherein R is an heteroaryl radical as defined herein.

Examples of heteroarylcarbonyl radicals include, but are not limited to, pyridinoyl, 3-methylisoxazoloyl, isoxazoloyl, thienoyl, furoyl, and the like.

"Heterocyclylcarbonyl" ( or "heterocyclocarbonyl”) means the radical R-C(O)-,

wherein R is an heterocyclyl radical as defined herein.

Examples of heterocyclylcarbonyl radicals include, but are not limited to, piperazinoyl, morpholinoyl, pyrrolindinoyl, and the like.

"Cycloalkylcarbonyl" means the radical R-C(O)-, wherein R is a cycloalkyl radical as defined herein.

Examples of cycloalkylcarbonyl radicals include, but are not limited to,

cyclobutanoyl, cyclopentanoyl, cyclohexanoyl, and the like.

"Alkylaminocarbonyl" means the radical -C(O)NR'R", wherein R' is lower alkyl as defined herein, and R" is hydrogen or lower alkyl as defined herein.

Examples of alkylaminocarbonyl include, but are not limited to methylaminocarbonyl, dimethyl-

aminocarbonyl, t-butylaminocarbonyl, n-butylaminocarbonyl, iso-propylaminocarbonyl and the like.

"Arylaminocarbonyl" means the radical -C(O)-NR'R", wherein R' is aryl as defined herein, and R" is hydrogen or aryl as defined herein.

Examples of arylaminocarbonyl include, but are not limited to phenylaminocarbonyl, methoxyphenylaminocarbonyl, diphenylaminocarbonyl, dimethoxyphenylaminocarbonyl, and the like.

"Heteroarylaminocarbonyl" means the radical -C(O)-NR'R", wherein R'is heteroaryl as defined herein, and R" is hydrogen or heteroaryl as defined herein.

Examples of heteroarylaminocarbonyl include, but are not limited to pyridinylaminocarbonyl,

thienylaminocarbonyl, furanylaminocarbonyl, and the like.

"Alkylcarbonylamino” means the radical -N-C(O)-R', wherein R' is lower alkyl as defined herein.

Examples of alkylcarbonylamino include, but are not limited to methylcarbonylamino, iso-propylcarbonylamino, t-butylcarbonylamino, and the like.

"Arylcarbonylamino" means the radical -N-C(O)-R', wherein R' is aryl as defined herein.

Examples of arylcarbonylamino include, but are not limited to phenylcarbonyl- amino, tosylcarbonylamino, and the like.

"Alkylcarbamoyl" means the radical -O-C(O)-NR'R", wherein R' is lower alkyl as defined herein, and R" is hydrogen or lower alkyl as defined herein.

Examples of alkylcarbamoyl include, but are not limited to methylcarbamoyl, ethylcarbamoyl, and the like.

"Arylcarbamoyl" means the radical -O-C(Q)-NR'R", wherein R' is lower aryl as defined herein, and R" is hydrogen or aryl as defined herein.

Examples of arylcarbamoyl i include, but are not limited to phenylcarbamoyl, naphthylcarbamoyl, and the like.

"Arylalkylcarbamoyl" means the radical -O-C(O)-NHR'R", wherein R' is lower alkyl as defined herein, and R" is aryl as defined herein.

Examples of arylalkylcarbamoyl include, but are not limited to benzylcarbamoyl, phenylethylcarbamoyl, and the like. "Alkylaminosulfonyl" means the radical -S(O),-NR'R", wherein R' is lower alkyl as defined herein, and R" is hydrogen or lower alkyl as defined herein.

Examples of alkylaminosulfonyl include, but are not limited to methylaminosulfonyl, dimethyl- aminosulfonyl, and the like.

"Arylaminosulfonyl” means the radical -S(O),-NR'R", wherein R' is aryl as defined herein, and R" is hydrogen or aryl as defined herein.

Examples of arylaminosulfonyl include, but are not limited to phenylaminosulfonyl, methoxyphenylaminosulfonyl, and the like. i "Heteroarylaminosulfonyl" means the radical -5(0),-NR'R", wherein R' is heteroaryl as defined herein, and R" is hydrogen or heteroaryl as defined herein. Examples of heteroarylaminosulfonyl include, but are not limited to thienylaminosulfonyl, piperidinylaminosulfonyl, furanylaminosulfonyl, imidazolylaminosulfonyl and the like. "Alkylsulfonylamino" means the radical -N-S(O),-R', wherein R' is lower alkyl as defined herein. Examples of alkylsulfonylamino include, but are not limited to methylsulfonylamino, propylsulfonylamino, and the like. "Arylsulfonylamino" means the radical -N-5(0),-R', wherein R' is aryl as defined herein. Examples of arylsulfonylamino include, but are not limited to phenylsulfonylamino, naphthylsulfonylamino, and the like. "Alkylsulfonyl" means the radical -S(O),-R, wherein R is lower alkyl or a substituted lower alkyl as defined herein. Examples of alkylsulfonyl include, but are not limited to methylsulfonyl, trifluoromethylsulfonyl, propylsulfonyl, and the like. “Arylsulfonyl" means the radical -5(O),-R, wherein R is aryl as defined herein.

Examples of arylsulfonyl include, but are not limited to phenylsulfonyl, nitrophenyl- sulfonyl, methoxyphenylsulfonyl, 3,4,5-trimethoxyphenylsulfonyl, and the like. "Heteroarylsulfonyl" means the radical -S(O),-R, wherein R is heteroaryl as defined herein. Examples of heteroarylsulfonyl include, but are not limited to thienylsulfonyl, furanylsulfonyl, imidazolylsulfonyl, N-methylimidazolylsulfonyl and the like. "Heterocyclylsulfonyl" means the radical -S(O),-R, wherein R is heterocyclyl as defined herein. Examples of heterocyclylsulfonyl include, but are not limited to piperidinylsulfonyl, piperazinylsulfonyl, and the like. "Alkylsulfonyloxy" means the radical -O-S(O),-R, wherein R is lower alkyl or substituted lower alkyl as defined herein. Examples of alkylsulfonyloxy include, but are not limited to methylsulfonyloxy, trifluoromethylsulfonyloxy, propylsulfonyloxy, and the like. "Arylsulfonyloxy" means the radical -O-S(0),-R, wherein R is aryl as defined herein.

Examples of arylsulfonyloxy include, but are not limited to benzenesulfonyloxy., 4-chloro- benzenesulfonyloxy, and the like,

"Heteroarylsulfonyloxy" means the radical -O-S(O)2-R, wherein R is heteroaryl as defined herein. Examples of hetroarylsulfonyloxy include, but are not limited to thienylsulfonyloxy, and the like. "Heterocyclylsulfonyloxy" means the radical -O-S(O),-R, wherein R is heterocycyl as : 5 defined herein. Examples of heterocyclylsulfonyloxy include, but are not limited to 3,5,dimethyl-isoxazolesulfonyloxy, pyrrolidinylsulfonyloxy, and the like. "Optional" or "optionally" means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, "optional bond" means that the bond may or may not be present, and that the description includes single, double, or triple bonds. “Leaving group” means the group with the meaning conventionally associated with it in synthetic organic chemistry, i.e. an atom or group displaceable under alkylating conditions. Examples of leaving groups include, but are not limited to, halogen, alkane- or arylsulfonyloxy, such as methanesulfonyloxy, ethanesulfonyloxy, thiomethyl, benzene- sulfonyloxy, tosyloxy, and thienyloxy, dihalogenphosphinoyloxy, optionally substituted benzyloxy, isopropyloxy, acyloxy, and the like. "Protective group” or "protecting group" means the group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotected reactive site in the meaning conventionally associated with it in synthetic chemistry. Certain processes of this invention rely upon the protective groups to block reactive oxygen atoms present in the reactants. Acceptable protective groups for alcoholic or phenolic hydroxyl groups, which may be removed successively and selectively includes groups protected as acetates, halogenalkyl carbonates, : benzyl ethers, alkylsilyl ethers, heterocyclyl ethers, and methyl or alkyl ethers, and the like.

Protective or blocking groups for carboxyl groups are similar to those described for hydroxyl groups, preferably tert-butyl, benzyl or methyl esters. Examples of protecting groups can be found in T.W. Greene et al., Protective Groups in Organic Chemistry, (J.

Wiley, 2" ed. 1991) and Harrison et al., Compendium of Synthetic Organic Methods, Vols. 1-8 (J. Wiley and Sons 1971-1996). "Amino-protecting group” means the protecting group that refers to those organic groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, tert- butoxycarbonyl (BOC), trifluoroacetyl, and the like. It is preferred to use either BOC or

CBZ as the amino-protecting group because of the relative ease of removal, for example by mild acids in the case of BOC, e.g., trifluoroacetic acid or hydrochloric acid in ethyl acetate; or by catalytic hydrogenation in the case of CBZ. "Deprotection” or "deprotecting” means the process by which a protective group is ) 5 removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. Deprotecting reagents for protected hydroxyl or carboxyl groups include potassium or sodium carbonates, lithium hydroxide in alcoholic solutions, zinc in methanol, acetic acid, trifluoroacetic acid, palladium catalysts, or boron tribromide, and the like. "Isomerism" means compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers". Stereoisomers that are not mirror images of one another are termed "diastereoisomers", and stereoisomers that are non-superimposable mirror images are termed "enantiomers", or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a "chiral center". "Chiral isomer" means a compound with one chiral center. It has two enantiomeric forms of opposite chirality and may exist either as an individual enantiomer or as a mixture of enantiomers. A mixture containing equal amounts of individual enantiomeric forms of opposite chirality is termed a "racemic mixture”. A compound that has more than one chiral center has 2"! enantiomeric pairs, where n is the number of chiral centers.

Compounds with more than one chiral center may exist as either an individual diastereomer or as a mixture of diastereomers, termed a "diastereomeric mixture". When one chiral center is present, a stereoisomer may be characterized by the absolute configuration ( Ror S) of that chiral center. Absolute configuration refers to the arrangement in space of the substituents attached to the chiral center. The substituents attached to the chiral center under consideration are ranked in accordance with the

Sequence Rule of Cahn, Ingold and Prelog. (Cahn et al, Angew. Chem. Inter. Edit. 1966, 5, 385; errata 511; Cahn et al., Angew. Chem. 1966, 78, 413; Cahn and Ingold, J. Chem. Soc. 1951 (London), 612; Cahn et al., Experientia 1956, 12, 81; Cahn, J., Chem. Educ. 1964, 41, 116). "Geometric Isomers" means the diastereomers that owe their existence to hindered rotation about double bonds. These configurations are differentiated in their names by the prefixes cis and trans, or Z and E, which indicate that the groups are on the same or opposite side of the double bond in the molecule according to the Cahn-Ingold-Prelog rules.

"Atropic isomers" means the isomers owing their existence to restricted rotation caused by hindrance of rotation of large groups about a central bond. ) "Substantially pure" means at least about 80 mole percent, more preferably at least about 90 mole percent, and most preferably at least about 95 mole percent of the desired enantiomer or stereoisomer is present. "Pharmaceutically acceptable” means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use. "Pharmaceutically acceptable salts" of a compound means salts that are pharmaceutically acceptable, as defined herein, and that possess the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L- tartaric acid, tartaric acid, p-toluenesulfonic acid, trimethylacetic acid, trifluoroacetic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; i or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.

The preferred pharmaceutically acceptable salts are the salts formed from hydrochloric acid, trifluoroacetic acid, dibenzoyl-L-tartaric acid, and phosphoric acid.

It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) as defined herein, of the same acid addition salt.

"Crystal forms" (or polymorphs) means crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different crystal forms usually have different X-ray diffraction patterns, infrared spectra, melting points, density hardness, crystal shape, optical and electrical properties, stability and solubility. Recrystallization solvent, rate of crystallization, storage temperature, and other factors may cause one crystal form to dominate. "Solvates" means solvent addition forms that contain either stoichiometric or non stoichiometric amounts of solvent. Some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. If the solvent is water the solvate formed is a hydrate, when the solvent is alcohol, the solvate formed is an alcoholate. Hydrates are formed by the combination of one or more molecules of water with one of the substances in which the water retains its molecular state as H,O, such combination being able to form one or more hydrate. "Prodrug” means a pharmacologically inactive form of a compound which must be metabolized in vivo, e.g., by biological fluids or enzymes, by a subject after administration into a pharmacologically active form of the compound in order to produce the desired pharmacological effect. The prodrug can be metabolized before absorption, during absorption, after absorption, or at a specific site. Although metabolism occurs for many compounds primarily in the liver, almost all other tissues and organs, especially the lung, are able to carry out varying degrees of metabolism. Prodrug forms of compounds may be utilized, for example, to improve bioavailability, improve subject acceptability such as by masking or reducing unpleasant characteristics such as bitter taste or gastrointestinal irritability, alter solubility such as for intravenous use, provide for prolonged or sustained release or delivery, improve ease of formulation, or provide site-specific delivery of the compound. Prodrugs are described in The Organic Chemistry of Drug Design and Drug _

Action, by Richard B. Silverman, Academic Press, San Diego, 1992, Chapter 8: "Prodrugs and Drug delivery Systems" pp. 352-401; Design of Prodrugs, edited by H. Bundgaard,

Elsevier Science, Amsterdam, 1985; Design of Biopharmaceutical Properties through Prodrugs and Analogs, ed. by E. B. Roche, American Pharmaceutical Association, Washington, 1977; and Drug Delivery Systems, ed. by R.L. Juliano, Oxford Univ. Press, Oxford, 1980. "Subject" means mammals and non-mammals. Mammals means any member of the

Mammalia class including, but not limited to, humans, non-human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, and swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice, and guinea pigs; and the like. Examples of non-mamimals include, but are not limited to, birds, and the like.

"Therapeutically effective amount” means an amount of a compound that, when administered to a subject for treating a disease state, is sufficient to effect such treatment for the disease state.

The "therapeutically effective amount” will vary depending on the compound, and disease state being treated, the severity or the disease treated, the age and relative health of the subject, the route and form of administration, the judgement of the attending medical or veterinary practitioner, and other factors. "Pharmacological effect” as used herein encompasses effects produced in the subject that achieve the intended purpose of a therapy.

In one preferred embodiment, a pharmacological effect means that primary indications of the subject being treated are prevented, alleviated, or reduced.

For example, a pharmacological effect would be one that results in the prevention, alleviation or reduction of primary indications in a treated subject.

In another preferred embodiment, a pharmacological effect means that disorders or symptoms of the primary indications of the subject being treated are prevented, alleviated, or reduced.

For example, a pharmacological effect would be one that results in the prevention or reduction of primary indications in a treated subject. "Disease state" means any disease, condition, symptom, or indication. "Treating" or “treatment” of a disease state includes: (1) preventing the disease state, i.e. causing the clinical symptoms of the disease state not to develop in a subject that may be exposed to or predisposed to the disease state, but does not yet experience or display symptoms of the disease state; (2) inhibiting the disease state, i.e., arresting the development of the disease state or its clinical symptoms; or (3) relieving the disease state , i.e., causing temporary or permanent regression of the disease state or its clinical symptoms. "Antagonist" means a molecule such as a compound, a drug, an enzyme inhibitor, or a hormone, that diminishes or prevents the action of another molecule or receptor site. "Disorders of the urinary tract” or "uropathy” used interchangeably with "symptoms of the urinary tract” means the pathologic changes in the urinary tract.

Symptoms of the : urinary tract include overactive bladder (also known as detrusor hyperactivity), outlet obstruction, outlet insufficiency, and pelvic hypersensitivity. "Overactive bladder" or "Detrusor hyperactivity" includes, but is not limited to, the changes symptomaticaliy manifested as urgency, frequency, reduced bladder capacity, incontinence episodes, and the like; the changes urodynamically manifested as changes in bladder capacity, micturition threshold, unstable bladder contractions, sphincteric spasticity, and the like; and the symptoms usually manifested in detrusor hyperreflexia } (neurogenic bladder), in conditions such as outlet obstruction, outlet insufficency, pelvic hypersensitivity, or in idiopathic conditions such as detrusor instability, and the like. : 5 "Outlet obstruction” includes, but is not limited to, benign prostatic hypertrophy (BPH), urethral stricture disease, tumors and the like. It is usually symptomatically manifested as obstructive (low flow rates, difficulty in initiating urination, and the like), or irritative (urgency, suprapubic pain, and the like). "Outlet insufficiency” includes, but is not limited to, urethral hypermobility, intrinsic sphincteric deficiency, or mixed incontinence. It is usually symptomatically manifested as stress incontinence. "Pelvic Hypersensitivity" includes but is not limited to, pelvic pain, interstitial (cell) cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, and the like. It is symptomatically manifested as pain, inflammation or discomfort referred to the pelvic region, and usually includes symptoms of overactive bladder.

Nomenclature: the naming and numbering of the compounds of this invention is illustrated below: i i

AA

N CH,); ~~ H, Ny I (CHy), Cn _y

R' z

In general, the nomenclature used in this Application is based on AUTONOM™ a ]

Beilstein Institute computerized system for the generation of [UPAC systematic nomenclature. For example, a compound of Formula I wherein R! and R? are methoxy, R® ispropyl, pis2,nis3, mis 2 ,X and Y are -CH;- and Z is >NH is named: 4-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,4]diazepan-5-one.

Among compounds of the present invention set forth in the Summary of the : Invention, certain compounds of Formula I, or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof, are preferred.

R! and R? are independently in each occurrence preferably hydrogen, halogen, (Ci.6)-alkyl, alkoxy, alkylsulfonyl, or alkylsulfonyloxy, and more preferably hydrogen, methoxy, methylsulfonyl, or methylsulfonyloxy.

R’ is independently in each occurrence preferably lower alkyl, lower alkenyl or lower ’ 5 alkynyl, more preferably ethyl, propyl, iso-propyl, allyl or propargyl, and even more preferably ethyl or propyl.

R* is preferably hydrogen. p is preferably 1 to 3, more preferably 1 to 2, and even more preferably 2. m is preferably 0 to 3; more preferably 1 to 2; and even more preferably 2. n is preferably 1 to 6; more preferably 1 to 3; and even more preferably 3.

One of X, Y, or Z is independently in each occurrence preferably -S-, -O-, or >N-R%, most preferably >N-R*, and even more preferably >NH.

Especially preferred are compounds of general Formula I, wherein p is 2.

In another preferred embodiment p is 2, and one of X, Y or Z is >N-R* and the others are -CH,-; in another embodiment p is 2, one of X, Y or Z is >N-R* and the others are -CH,-, wherein R* is hydrogen.

In another preferred embodiment, p is 2 and m is 1; in another preferred embodiment p is 2, mis 1 and Y is >N-R* and the others are -CH,-; in another preferred embodiment p is 2, mis 1 and Y is >NH and the others are -CH,-. In a further preferred embodiment, p is 2, m is 1 and Z is >N-R* and the others are -CH,-; in another preferred embodiment p is 2, mis 1 and Z is >NH and the others are -CH,-. An example for such a compound is 4-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]- butyl}-[1,4]diazepan-5-one.

In another preferred embodiment, p is 2 and m is 2; in another preferred embodiment, p is 2, m is 2, and one of X, Y or Z is >N-R* and the others are -CH,-, and in another preferred embodiment p is 2, m is 2, and one of X, Y or Z is >NH and the others are -CH,-. In a further preferred embodiment p is 2, m is 2 and X is >N-R* and the others are -CH,-.

In another preferred embodiment, p is 2, m is 2 and Y is >N-R* and the others are -

CH:-. The following are examples of such compounds: 1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}-

[1,4]diazepan-2-one; 4-(2-dimethylamino-ethanesulfonyl)- 1-{4-[(7-methoxy-1 »2,3,4-tetrahydro-naphthalen-2- yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one; or 1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-y1)-propyl-amino] -butyl}- [1,4]diazepan-2-one.

In a further preferred embodiment, p is 2, m is 2 and Z is >N-R* and the others are -

CH,-; the following are examples of such compounds: 3,5-dimethyl-isoxazole-4-sulfonic acid 7-{ [4-(7-o0x0-[1,4]diazepan-1-yl)-butyl]-propyl- amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester; or 4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino] -pentyl}- [1,4]diazepan-5-one.

In another preferred embodiment n is 3; in another embodiment n is 3 and one of X,

Y, or Z is >N-R* and the others are -CH,-.

In another embodiment n is 3 and Pp is 2, in another embodiment n is 3, pis 2 and oneofX, Yor Zis >N-R? and the others are -CH>-; in another embodiment n is 3, p is 2 and one of X,Y, or Z is >NH and the others are -CH,-. In another preferred embodiment nis3, pis 2, mis 2 and one of X, Y, or Z is >N-R* and the others are -CH,-; and in another preferred embodiment n is 3, pis 2, mis 2, X is >NH, and Y and Z are -CH,-. In another preferred embodiment n is 3, pis 2, mis 2, Y is >NH and X and Z are -CH,-. In another preferred embodiment nis 3, pis 2, mis 2, Z is >NH and X and Y are -CH,-.

In another preferred embodiment p is 2, mis 2, nis 3, one of X, Y or Z is -O- and the others are -CH,-. The following are examples of such compounds: 3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,3]oxazepan-2-one; or 3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,3]oxazepan-2-one.

Other preferred compounds of the present invention include the pharmaceutically acceptable salts of the compounds of the present invention wherein the pharmaceutically acceptable salts are formed from hydrochloric acid, 2,2,2- trifluoroacetic acid, dibenzoyl-L- tartaric acid, sodium, or phosphoric acid, more preferably the salts are formed from hydrochloric acid, 2,2,2-trifluoroacetic acid.

Compounds of the present invention may be made by the methods depicted in the illustrative synthetic reaction schemes shown and described below. : The starting materials and reagents used in preparing these compounds generally are either available from commercial suppliers, such as Aldrich Chemical Co., or are prepared : 5 by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser, Reagents for Organic Synthesis; Wiley & Sons, New York 1991,

Volumes 1-15; Rodd, Chemistry of Carbon Compounds, Elsevier Science Publishers 1989,

Volumes 1-5 and Supplementals; and Organic Reactions, Wiley & Sons, New York 1991,

Volumes 1-40. The following synthetic reaction schemes are merely illustrative of some methods by which the compounds of the present invention may be synthesized, and various modifications to these synthetic reaction schemes may be made and will be suggested to one skilled in the art having referred to the disclosure contained in this

Application.

The starting materials and the intermediates of the synthetic reaction schemes may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Unless specified to the contrary, the reactions described herein preferably take place at atmospheric pressure over a temperature range from about 78 °C to about 150 °C, more preferably from about 0 °C to about 125 °C, and most preferably and conveniently at about room (or ambient) temperature, e.g., about 20 °C.

In general, the compounds of Formula I can be prepared by processes described in the following reaction schemes.

Scheme A

Scheme A, in general, describes a method of preparing a compound of Formula I wherein X,Y, Z, R', R%, R®, p> m, and n are as described hereinbefore. 0 J 0 reductive RY PI]

NT amination N ACHIN X

CH), CH), o) ( En Y os (CH), ( 2 _Y

RR lo F 1 NH I (CH,),

R

A compound of Formula I can generally be prepared by coupling a carboxaldehyde 1 with a benzocyclylamine 2 under reductive amination conditions. Suitable reducing conditions include sodium triacetoxyborohydride, sodium cyanoborohydride, titanium isopropoxide and sodium cyanoborohydride, hydrogen and a metal catalyst and hydrogen k 5 transfering agents such as cyclohexene, formic acid and its salts, zinc and hydrochloric acid, formic acid, or borane dimethylsulfide followed by treatment with formic acid.

Suitable inert organic solvents for the reaction include dichloromethane, 1,2-dichloro- ethane, tetrahydrofuran, alcohols, or ethyl acetate, and the like. Preferably the reaction is carried out under basic conditions with sodium triacetoxyborohydride in 1,2-dichloro- ethane.

Reductive amination procedures are described in the chemical literature. For example, J. Org. Chem. 1996, 61, 3849 and Tetrahedron Letters 1996, 37, 3977, describe methods utilizing sodium triacetoxyborohydride as a reagent for the reductive amination of aldehydes with a wide variety of amines. For example, J. Am. Chem. Soc. 1971, 93, 2897 and Org. Synth. Coll. 1988, 6, 499 describe methods utilizing sodium cyanoborohydride as reagent for reductive amination of carbonyl compounds.

The conventional starting materials of Scheme A are commercially available or are known to, or can readily be synthesized by those of ordinary skill in the art. For example, the starting carboxaldehyde 1 can readily be synthesized as shown by the following reaction schemes (1), (2), and (3).

Scheme (1) x XL

Oxidation/ . x ACH CH ho | x alkylation ACH: ; | x cleavage "~ In 2m vy NaH 2m vy (CH, )

ZT H,C=CH(CH,)L ~z7 © LY a b 1

A carboxaldehyde 1 wherein X, Y, Z, m, and n are as described hereinbefore can be prepared by reacting the amido group of compound a with an alkylating agent of the formula L(CH;),CH=CH; wherein L is a leaving group such as halogen or methane- sulfonyloxy, preferably chloro, under basic conditions to obtain a compound b. The alkylation reaction is followed by the oxidation/cleavage of the terminal alkene group of compound b to an aldehyde group to obtain a carboxaldehyde 1. Various oxidizing agents used in the oxidation/cleavage of alkenes to aldehydes are described in the chemical literature. For example, J. Org. Chem. 1956, 21, 478 describes methods utilizing osmium tetroxide and sodium (meta)periodate; Syn. Comm. 1982, 12, 1063 describes methods utilizing potassium permanganate and sodium(meta)periodate; J. Org. Chem. 1987, 52,

A ~ 3698, describes methods utilizing potassium permanganate and silica gel; Chem. Rev. 1958, 58, 925 describes methods utilizing ozone; J. Org. Chem. 1986, 51, 3213, describes methods utilizing potassium permanganate alone; J. Org. Chem. 1987, 52, 2875, describes methods utilizing sodium (meta)periodate and catalytic ruthenium. Preferably the reaction is carried out with osmium tetroxide and sodium (meta)periodate or ozone.

Scheme (2)

O 0] o tal oN alkylation RO or AN, hydrolysis H CHa) PIS

CH) | > CH Ng aol

LY root on Clr v 8 CH

T : a OR [4 1

Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n are as described hereinbefore can be prepared by reacting the free amine group of compound a with an alkylating agent of the formula L(CH;),C(OR) wherein R is lower alkyl and L is a leaving group such as halogen, preferably bromo, to obtain a compound c. The alkylation reaction 1s followed by the hydrolysis of the acetal group of compound ¢ under acidic conditions to obtain a carboxaldehyde 1.

Scheme (3) 0)

RO CH,); acylation J ~ 2 TNH, — ONT X-Y-Z-(CH)=L : OR OR d e

Q o i internal CH acetal

OR nv lo) Cre PAY f 1

Alternatively, a carboxaldehyde 1 wherein X, Y, Z, m, and n are as described hereinbefore, can be prepared by treating an aminoacetal d wherein R is lower alkyl with an appropriate acylating agent such as acylating agents of the formula L(CH,),COL', or

L(CH3),OCOL', or L(CH;)nN=C=0 wherein in each instance L' is a leaving group such as halogen, preferably chloro, to obtain compound e. The acylating reaction is followed by the internal N-alkylation of compound ¢, and the subsequent hydrolysis of the acetal group of compound f to cbtain a carboxaldehyde 1.

For example, the starting benzocyclylamine 2 can be synthesized as shown by the following reaction scheme (4).

Scheme (4)

R® : 2 2 ] 3 o R3-NH, R NH —_..:.B=: Rirphibp.Pb (CH,), reductive (CH,),

R' amination R' a 2

A benzocyclylamine 2 wherein R', R?, and R’ are as described hereinbefore may be prepared by treatment of a benzocyclylone g with a primary amine of the formula R’NH, under reductive amination conditions. Various methods for the synthesis of a benzo- cyclylamine 2 are described in the chemical literature, for example in J. Med. Chem. 1980, 23, 745-749; J. Med. Chem. 1981, 24, 429-434; J. Med. Chem. 1989, 32, 2128-2134,

J. Org chem. 1996, 61, 3849-3862,.and Bioorg.Med Chem.Lett. 1997, 15, 1995-1998.

Scheme B

Scheme B, in particular, describes a method of preparing a compound of Formula I wherein X is >N-R%, -O-, or -S-; Y and Z are each -CH,-; and RL R%, R3 RY, p> m, and n are as described hereinbefore. 0 a 0) 2

INA Step 1 [Ray ) —_ a ) tn J tg J 0 2m (CH)

RY NHR® R' ’ 1b IB - (CH,),

R

2

A compound of Formula IB can be prepared by proceeding as described in Scheme

A. Preferably, a compound of Formula IB can be prepared by reacting a carboxaldehyde 1b with a benzocyclylamine 2 under reductive amination conditions as described in Scheme B. : Exemplary preparations of a compound of Formula IB are given in Example 1.

Scheme C

Scheme C, in particular, describes a method of preparing a compound of Formula I wherein X and Z are each -CH,-, Y is >N-R?, -O- or -S-, and R!, R% R3, R%, p> m, and n are as described hereinbefore. ; . 3

NI AN NEN AN

(CH,) or ch

O 2 Os) o) (Ctl _np lc 1d a NHR® reductive . (CH,), amination 2

R NHR® 2 reductive amination (CH,), Re 0

R' Rr? | CH ) 2 ~ 2 Nn

Rr (CH), 3 Ym _np deprotection

R® 0 ) : Aon ) 2IANG N (CH,) (CH) NH

R' op ICa ~~ optional

N-substitution

I. 5? o 7° 0 _ by ie [i Sd n N N

CH.) (CHL), 4

R (CH), Cn ois) . (CH), tn NR

ICc ICb

Compounds of Formulas ICa, ICb or ICc can be prepared by proceeding as described in Scheme C.

Preferably, a compound of Formula I wherein Y is -O- or -S- can be prepared by reacting a carboxaldehyde 1c with a benzocyclylamine 2 under reductive amination conditions as described in Scheme C.

Alternatively, a compound of Formula I wherein Y is >N-R* can also be prepared by coupling a nitrogen-protected carboxaldehyde 1d wherein P is a suitable nitrogen- protecting group with a benzocylcylamine 2 in conditions as described above. This reaction is followed by removing the nitrogen-protecting group of compound 3 under acidic conditions to obtain a compound of Formula ICa wherein Y is >NH. The compound of

Formula I wherein Y is >NH may then be further reacted with an appropriate alkylating agent, acylating agent, or sulfonylating agent by procedures known to one skilled in the art to obtain a compound of Formula ICb wherein Y is >N-R* wherein R* is other than H.

Exemplary preparations of compounds of Formulas ICa, ICb or ICc are given in

Examples 2, 3, and 4.

Scheme D

Scheme D, in particular, describes a method of preparing a compound of Formula I wherein X and Y are each -CH,-, and Z is >N-R*, -O- or -S-, and R', R%, R’, R%, p, m, and n are as described hereinbefore. : . . 5

De NE S 1 or } (CH,) 0 2m (CH) od) © SNP le at

RR NHR® reductive amination 2 R' ;

R NHR? 2 reductive amination (CH), rR? [0]

R' RE ) oH) 2 NP 2 SN

CH deprotection

R® 0] © ~ Ne _AoHy ~ 2 iY (CHp) (CH,) 2)m

R 2/p IDa N optional

N-substitution

R® o r® fo) .

R32 RA A CH ) \ oy, Cn on, Cn i °® A IDb Re

IDc

Compounds of Formulas IDa, IDb or IDc can be prepared by proceeding as described in Scheme D.

Preferably, a compound of Formula IDc wherein Z is -O- or -S- can be prepared by reacting a carboxaldehyde le with a benzocyclylamine 2 under conditions as described in

Scheme D.

Claims (35)

-6l - Claims

1. A compound having the general Formula I . . 5 [25 N CH,); ~~ ~ I (CH,), (Clim _y R' Zz wherein R'andR? are independently in each occurrence hydrogen, halogen, (C,.¢)-alkyl, -OR’, -SR’, -NR'R", -SOR', -SO,R’, -COOR', -OCOR’, -OCONR'R", -OSO;R’, -OSO,NR'R"; -NR'SO,R", -NR'COR", -SO, NR'R", -SO,(CH;)1.3CONR'R", -CONR'R", cyano, halogenalkyl or nitro; or R'and R" are independently in each occurrence hydrogen, (C;.¢)-alkyl, substituted (C,.¢)-alkyl, aryl, heterocyclyl, heteroaryl, aryl-(C,.3)-alkyl, heteroaryl-(C;.3)-alkyl, heterocyclyl-(C;.3)-alkyl, cycloalkyl-alkyl, cycloalkyl, or R' and R" together with the nitrogen they are attached may also form a 5- to 7- membered ring, optionally incorporating one additional ring heteroatom chosen from N, O or S(O)o-2; R is independently in each occurrence (C;.¢)-alkyl, (C;.¢)-alkenyl, (Ci1-)-alkynyl or cycloalkyl; or oneof X,YorZ is independently -S-,-O-, or >N-R*, the others are -CH,-; EE 4 is hydrogen, (Cy.)-alkyl, halogenalkyl, aryl-(C,.¢)-alkyl, UE heteroaryl-(C,_¢)-alkyl, -(C,.4)-CR'RR', -COOR/, -SO2R’, -C(O)R', -SO2(CH3).3NR'R", -CONR'R", or -PO(OR’),, wherein R' and R" are as defined above; p is an integer from 1 to 3 inclusive; m is an integer from 0 to 3 inclusive; n is an integer from 1 to 6 inclusive; or prodrugs, individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof.

~ 2.The compound of claim 1, wherein p is 2.

3. The compound of claim 1 or 2, wherein n is 3.

4. The compound of claim 2 or 3, wherein one of X, Y or Z is >N-R%, and the others are -CH,-

5. The compound of claim 2, wherein one of X,Y or Z is >N-R*, and the others are -CH,-, and wherein R* is hydrogen.

6. The compound of claim 2, wherein one of X, Y or Z is >N-R*, and the others are -CH;-, and wherein m is 1.

7. The compound of claim 6, wherein Y is >N-R*, and X and Z are -CH,-.

8. The compound of claim 6, wherein Z is >N-R* and X and Y are -CH,-.

9. The compound of claim 8, which compound is 4-{4-[(7-methoxy-1,2,3,4- tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,4] diazepan-5-one.

10. The compound of claim 2, wherein m is 2.

11. The compound of claim 10, wherein one of X, Y or Z is >NR* and the others are -CHa-.

12. The compound of claim 11, wherein R* is hydrogen.

13. The compound of claim 10, wherein X is >N-R%, and Y and Z are -CH,-.

14. The compound of claim 10, wherein Y is >N-R*, and X and Z are -CH,-.

15. The compound of claim 14, which compound is selected from the group CTT TTT consisting of Co 1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,4])diazepan-2-one; 4-(2-dimethylamino-ethanesulfonyl)-1-{4-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2- yl)-propyl-amino]-butyl}-[1,4]diazepan-2-one; or 1-{4-[(7-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- [1,4]diazepan-2-one. :

16. The compound of claim 10, wherein Z is >N-R*, and X and Y are -CH,-.

17. The compound of claim 16, which compound is selected from the group consisting of 3,5-dimethyl-isoxazoie-4-suifonic acid 7-{[4-(7-oxo-[1,4]diazepan-1-yl)-butyl]-propyl-

amino}-5,6,7,8-tetrahydro-naphthalen-2-yl ester; or 4-{5-[(7-methoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-pentyl}- [1,4]diazepan-5-one.

18. The compound of claim 2, wherein m is 2, nis 3, and one of X,Y or Z is -O- and ; 5 the others are ~-CH,-.

19. The compound of claim 18, which compound is selected from the group consisting of 3-{4-[(6-bromo-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-amino]-butyl}- (1,3) oxazepan-2-one; or 3-{4-[(6,7-dimethoxy-1,2,3,4-tetrahydro-naphthalen-2-yl)-propyl-aminoj-butyl}- (1,3]oxazepan-2-one.

20. A pharmaceutical composition comprising a therapeutically effective amount of one or more compounds of any of claims 1 to 19 in admixture with a pharmaceutically acceptable carrier.

21. The pharmaceutical composition of Claim 20 wherein the compound is suitable for administration to a subject having a disease state which is alleviated by treatment with a M2/M3 muscarinic receptor antagonist.

22. A process for preparing a compound as claimed in claim 1 which process comprises reacting a compound having a general formula II 0) pO RE 0 Chie, oY ag Co with a compound of general formula III /° 2 R NH aI (CH,), R to provide a compound of Formula I

. \" 64 PCT/EP01/05631 rR’ 'e) OR No ACH) OU SE (CH,) Can R! p ~z wherein Rl RZ, R3 p,m,n, X,Y, and Z are as defined in claim 1.

23. A compound according to any one of claims 1 to 19 whenever prepared by a process as claimed in claim 22 or by an equivalent method.

24. The use of one or more compounds according to any one of claims I to 19 for the treatment or prevention of a disease state.

25. The use of one or more compounds according to any one of claims 1 to 19 for the manufacture of medicaments for the treatment or prevention of a disease state, which is alleviated with a M2/M3 muscarinic antagonist.

26. The use according to claim 25, wherein the disease state is associated with smooth muscle disorders comprising diseases of the genitourinary or gastrointestinal tract, or of respiratory states.

27. A substance or composition for use in a method for the treatment or prevention of a disease state, which is alleviated with a M2/M3 muscarinic antagonist, DE "said substance or composition comprising one or more compounds according to any one of claims 1 to 19, and said method comprising administering said substance or composition.

28. A substance or composition for use in a method of treatment according to claim 27, wherein the disease state is associated with smooth muscle disorders comprising diseases of the genitourinary or gastrointestinal tract, or of respiratory states. AMENDED SHEET

65 PCT/EP01/05631

29. The invention as hereinbefore described.

30. A compound according to claim 1, substantially as herein described and illustrated.

31. A composition according to claim 20, substantially as herein described and illustrated.

32. A substance or composition for use in a method of treatment according to claim 21, or claim 27, substantially as herein described and illustrated.

33. A process according to claim 22, substantially as herein described and illustrated.

34. Use according to claim 24, or claim 25, substantially as herein described and illustrated.

35. A new compound, a new composition, a substance or composition for a new use in a method of treatment, a new process for preparing a compound, or a new use of one or more compounds according to any one of claims 1 to 19, substantially as herein described. AMENDED SHEET