ZA200101833B - Dihydrobenzodioxine carboxamide and ketone derivatives as 5-HT4 receptor antagonists. - Google Patents

Description

i -» © WO 00/15636 PCT/EP99/06402

DIHYDROBENZODIOXINE CARBOXAMIDE AND KETONE DERIVATIVES AS 5-HT4 RECEPTOR

ANTAGONISTS

This invention relates to compounds of formula 0

R2 “1

N Y

3 SEH) Sz 0)

I wherein:

R' and R? are each independently in each occurrence hydrogen, (Ci-Cg)alkyl, (C,-Cs)alkoxy, halogen, amino or hydroxy;

X is -NH or -CHjy; mis 2, 3, or 4;

Yis -SO,;

Z is represented by formula (A) or (B):

R3 RS R3 /7\ — Q or —N Q (CHy)n (CH,)n

R* R* (A) (B) wherein:

R% RY, and R’ are each independently in each occurrence hydrogen or (Cy-Ce)alkyl;

Qis 0, S, -NR’ or -CR'R;

Pop/So 21.6.99 nis1or2; wherein:

R® is hydrogen, (Ci-Colalkyl, (Cs-Cg)cycloalkyl, heterocyclyl, heteroaryl, -COR’, -SO,R’, -CONR'R", -SO;NR'*R", or aryl optionally mono- or di-substituted with halogen or (C;-Cg)alkyl;

Ris hydrogen or (C,-Cg)alkyl;

Ris hydrogen, (C,-Cs)alkyl, (C,~Cs)alkoxy, aryloxy, -(CH,),CONR'R", -(CH,),SO.NR'R", -(CH;),NR’COR’, or -(CH,),NR’SO,R’; or

R” and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5- or 6-membered ring optionally independently containing 0 or 1 heteroatom of nitrogen, oxygen, or sulfur; wherein: pis0,1,2,30r4;

R’ is (C,-Cg)alkyl, heteroaryl, heterocyclyl, or aryl optionally mono- or di-substituted with halogen or (Ci-Cg)alkyl; and

R' and RM are each independently hydrogen or (C,-Cg)alkyl; or individual isomers, racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salts or hydrates thereof.

It has been shown that compounds of formula I are 5-HT; receptor antagonists. 5-HT (5-hydroxy-tryptamine), also referred to as serotonin, is a neuro- transmitter with mixed and complex pharmacological characteristics and was first discovered in 1948. Serotonin acts both centrally and peripherally on discrete 5-HT receptors. The 5-HT receptor family is presently delineated into seven major subclassifications, 5-HT;, 5-HT,, 5-HT;, 5-HTy, 5-HTs, 5-HT,, and 5-HT5, each of which may also be heterogeneous.

3 in * WO 00/15636 PCT/EP99/06402

The 5-HT, receptors are widely distributed throughout the body and have various functions. For example, the 5-HT, receptors located on postganglionic parasympathetic autonomic efferent neurons of the urinary bladder mediate facilitation of neurogenic bladder detrusor contractions (see Ford, A.P.D.W. and

Kava, M.S., 5-HT4 Receptors in the Brain and Periphery; Eglen, RM,, Ed., Springer-

Verlag Berlin and R.G. Landes Company Georgetown, TX, 1998, pp 171-193;

Waikar, M.V. et al, Br. J. Pharmacol. 1994, 111, 213-218; Corsi, M. et al., Br. J.

Pharmacol. 1991, 104, 719-725). In the central nervous system, the 5-HT, receptors are found on neurons of the superior and inferior colliculi and in the hippocampus, and are thought to be involved in areas of the central nervous system affecting anxiety, depression, cognition, dependency, schizophrenia, appetite, thermoregulation, and such. In the gastrointestinal tract, the 5-HT} receptors are found on neurons, e.g., myenteric plexus, as well as on smooth muscle and secretory cells, and appear to modulate gastrointestinal motility, evoke secretion in the alimentary tract, and stimulate cholenergic excitatory pathways involved in the peristaltic reflex (see Hegde, S.S., 5-HT4 Receptors in the Brain and

Periphery; Eglen, RM, Ed., Springer-Verlag Berlin and R.G. Landes Company

Georgetown, TX, 1998, pp 150-169). In the cardiovascular system, the 5-HT; receptors mediate 5-HT induced positive inotrophy and chronotropy in atrial myocytes, e.g., bradyarrhythmia or tachyarrhythmia (see Kaumann, A. et al,

Naunyn-Schmiedeberg’s Arch. Pharmacol, 1991, 344, 150-159).

Thus, it is clear that 5-HT, receptor antagonists will offer distinct therapeutic advantages collectively in efficacy and rapidity of onset, particularly in urinary tract disorders related to autonomic mediation of storage and voiding reflexes. Additionally, because the 5-HT, receptors found in other organs, e.g., the heart or gastrointestinal tract, are not essential for basic physiological function, minimal side effects are anticipated with improved tolerability (see Ford, A.P.D.W. and Kava, M.S., supra).

U.S. Patent No. 5,852,014 and PCT Published Application WO 93/18036 (Gaster et al.) refer to certain condensed indole carboxamide derivatives which are disclosed as having 5-HT, receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.

U.S. Patent No. 5,763,458 (Clark et al.) and European Patent EP 0 700 383

B1 refer to certain dihydrobenzodioxine-propan-1-one derivatives which are disclosed as 5-HT} ligands.

U.S. Patent Nos. 5,741,801 and 5,872,134, and PCT Published Application

WO 94/27987 (King et al.) refer to certain dihydrobenzodioxine-propan-1-one derivatives which are disclosed as having 5-HT) receptor antagonist activity useful for treating gastrointestinal, cardiovascular or CNS disorders.

U.S. Patent No. 5,708,174 and PCT Published Application WO 94/08994 (King et al.) refer to certain heterocyclic carboxylate derivatives which are disclosed as having 5-HT, receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.

U.S. Patent No. 5,705,509 and PCT Published Application WO 94/17071 (Gaster et al.) refer to certain heterocyclic carboxylate derivatives which are disclosed as having 5-HT, receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.

U.S. Patent No. 5,705,498 and PCT Published Application WO 94/10174 (Gaster et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as being useful in manufacturing medicaments for 5-HT, receptor antagonists.

U.S. Patent Nos. 5,654,320 and 5,798,367 (Catlow et al.) refer to certain indazole carboxamide derivatives which are disclosed as having 5-HT, receptor partial agonist and antagonist activity.

U.S. Patent Nos. 5,620,992 and 5,786,372, and PCT Published Application

WO 94/05654 (King et al.) refer to certain dihydrobenzodioxine carboxylate derivatives which are disclosed as having 5-HT4 receptor antagonist activity.

U.S. Patent No. 5,580,885 and PCT Published Application WO 93/05038 (King et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having 5-HT), receptor antagonist activity.

U.S. Patent Nos. 5,374,637, 5,521,314, 5,536,733, 5,552,553, 5,554,772, 5,565,582, 5,576,448, 5,602,129, 5,610,157, 5,616,583, 5,616,738, and 5,739,134,

» n * WO 00/15636 PCT/EP99/06402 and European Patent EP 0 389 037 B1, (Van Daele et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having gastrointestinal motility stimulating properties.

U.S. Patent Nos. 5,185,335 and 5,262,418 (Van Daele et al.) refer to certain dihydrobenzodioxine carboxamide derivatives which are disclosed as having gastrointestinal motility stimulating properties.

PCT Published Application WO 98/27058 (Bromidge et al.) refers to certain benzamide derivatives which are disclosed as having 5-HTs receptor activity.

PCT Published Application. WO 96/05166 (assigned to Yamanouchi) refers to certain heterocyclic-substituted alkyl-heterocycloalkylamine derivatives which are disclosed as having 5-HT, receptor agonist activity useful for treating CNS disorders and digestive tract movement.

PCT Published Application WO 94/29298 (Gaster et al.) refer to certain dihydrobenzodioxine carboxylate derivatives which are disclosed as having 5-HT, receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and

CNS disorders.

PCT Published Application WO 94/08995 (Gaster et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HT; receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.

PCT Published Application WO 93/16072 (King et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HTj receptor antagonist activity useful for treating gastrointestinal, cardiovascular, and CNS disorders.

PCT Published Application WO 93/03725 (King et al.) refers to certain heterocyclic carboxamide derivatives which are disclosed as having 5-HT, receptor antagonist activity.

Japanese Patent Application JP 11001472 (assigned to Dainippon Pharm) refers to certain benzamide derivatives which are disclosed as having 5-HT,

receptor antagonist activity useful for the prevention and treatment of digestive disorders.

Japanese Patent Application JP 9241241 (assigned to Morishita Roussel) refers to certain N-(1-substituted-4-piperidyl)benzamide derivatives which are disclosed as being selective 5-HT, receptor inhibitors useful for treating chronic gastritis, CNS disorders and urological diseases.

Clark, R.D., 5-HT4 Receptors in the Brain and Periphery; Eglen, RM., Ed.,

Springer-Verlag Berlin and R.G. Landes Company Georgetown, TX, 1998, pp 1-48, refers to the medicinal chemistry of certain 5-HT4 receptor ligands.

Clark, R.D. et al.,Bioorganic & Medicinal Chem. Letters. 1995, 5(18), 2119- 2122, refers to certain benzodioxanyl ketone derivatives having 5-HT, receptor antagonist activity.

Clark, R.D. et al.,Bioorganic & Medicinal Chem. Letters. 1994, 4(20) 2477-2480, refers to certain benzoate derivatives having 5-HT, partial agonist activity.

Objects of the present invention are novel compounds of formula I, their isomers, racemic or non-racemic mixtures of isomers or pharmaceutically acceptable salts or hydrates thereof, the use in the treatment or prophylaxis of diseases, caused by 5-HT, receptors, the use of these compounds for manufacture of corresponding medicaments, processes for the manufacture of these novel compounds and medicaments, containing them. In detail, this invention relates to pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula I, or individual isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or hydrates thereof, in admixture with one or more suitable carriers. In a preferred embodiment, the pharmaceutical compositions are suitable for administration to a subject having a disease state that is alleviated by treatment with a 5-HT}, receptor antagonist.

In a preferred embodiment, this invention relates to the use in the treatment of urinary tract disorder. Such as overactive bladder, outlet obstruction, outlet insufficiency, or pelvic hypersensitivity; most preferably overactive bladder.

This invention further relates to the use in the treatment of central nervous system (CNS) disorders or gastrointestinal disorders or cardiovascular disorders.

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:

“Alkyl” means a monovalent branched or unbranched saturated hydrocarbon radical consisting solely of carbon and hydrogen atoms, having from one to twenty carbon atoms inclusive, unless otherwise indicated.

Examples of an alkyl radical include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-hexyl, octyl, dodecyl, tetradecyl, eicosyl, and the like.

Particular values of (C;-Cg)alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, n-

hexyl.

“Cycloalkyl” means a monovalent saturated carbocyclic radical consisting of one or more rings, which can optionally be substituted with hydroxy, cyano, alkyl, alkoxy, thioalkyl, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl,

sulfonylamino, and/or trifluoromethyl, unless otherwise indicated.

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

Particular values of (Cs-Cg)cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

“Alkoxy” means a radical -OR wherein R is alkyl as defined above.

Examples of an alkoxy radical include, but are not limited to, methoxy, ethoxy, isopropoxy, sec-butoxy, isobutoxy, and the like.

Particular values of (C,-Cs)alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert- butoxy, pentoxy, isopentoxy, and hexoxy.

“Aryl” means the monovalent monocyclic aromatic hydrocarbon radical consisting of one or more fused rings in which at least one ring is aromatic in nature, which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halogen, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl,

sulfonylamino, and/or trifluoromethyl, unless otherwise indicated.

Examples of aryl radicals include, but are not limited to, phenyl, naphthyl, biphenyl, indany}, anthraquinolyl, and the like.

A particularly preferred aryl includes phenyl.

“Aryloxy” means a radical -OR wherein R is an aryl radical as defined above.

Examples of an aryloxy radical include, but are not limited to, phenoxy and the like. “Heteroaryl” means the monovalent aromatic carbocyclic radical having one or more rings incorporating one, two, or three heteroatoms within the ring (chosen from nitrogen, oxygen, or sulfur) which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino and/or trifluoromethyl, unless otherwise indicated. Examples of heteroaryl radicals include, but are not limited to, imidazolyl, oxazolyl, pyrazinyl, thiophenyl, quinolyl, benzofuryl, pyridiyl, indolyl, pyrrolyl, pyranyl, naphtyridinyl, and the like. "Heterocyclyl" means the monovalent saturated carbocyclic radical, consisting of one or more rings, incorporating one, two, or three heteroatoms (chosen from nitrogen, oxygen or sulfur), which can optionally be substituted with hydroxy, cyano, lower alkyl, lower alkoxy, thioalkyl, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino. alkylamino, dialkylamino, aminocarbonyl, carbonylamino, aminosulfonyl, sulfonylamino and/or trifluoromethyl, unless otherwise indicated. Examples of heterocyclic radicals include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, pyrrolidinyl, tetrahydropyranyl, thiomorpholinyl, and the like. "Halogen" means the radical fluoro, bromo, chloro and/or iodo. “Protective group” has the meaning conventionally associated with it in synthetic organic chemistry, i.e., a group which selectively blocks one reactive site in a multifunctional compound such that a chemical reaction can be carried out selectively at another unprotective reactive site. Certain processes of this invention rely upon the protective groups intended to protect the nitrogen atom against undesirable reactions during synthetic procedures and includes, but is not limited to, acetyl, benzyl, benzyloxycarbonyl (carbobenzyloxy, CBZ), p-methoxy- benzyloxy-carbonyl, N-tert-butoxycarbonyl (BOC), trifluoromethylcarbonyl, p-nitrobenzyloxy-carbonyl, and the like. It is preferred to use BOC or CBZ as the amino-protecting group because of the relative ease of removal, for example by

» » © WO 00/15636 PCT/EP99/06402 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 removed after the selective reaction is completed. Certain protective groups may be preferred over others due to their convenience or relative ease of removal. "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 both single and double bonds. “Inert organic solvent” or “inert solvent” means a solvent inert under the conditions of the reaction being described in conjunction therewith, including for example, benzene, toluene, acetonitrile, tetrahydrofuran, N,N-dimethylformamide, chloroform (CHCl;), methylene chloride or dichloromethane (CHCl), dichloroethane, diethyl ether, ethyl acetate, acetone, methylethyl ketone, methanol, ethanol, propanol, isopropanol, tert-butanol, dioxane, pyridine, and the like.

Unless specified to the contrary, the solvents used in the reactions of the present invention are inert solvents. "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 ( R or

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. (London) 1951, 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.

A "pharmaceutically acceptable carrier" means a carrier that is useful in preparing a pharmaceutical composition that is generally compatible with the other ingredients of the composition, not deleterious to the recipient, and neither biologically nor otherwise undesirable, and includes a carrier that is acceptable for veterinary use as well as human pharmaceutical use. "A pharmaceutically acceptable carrier" as used in the specification and claims includes both one and more than one such carrier.

A "pharmaceutically acceptable salt" of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts, for example, 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, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 2-napthalenesulfonic acid, 4-methylbicyclo- [2.2.2] oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; (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; or coordinates with an organic base. Acceptable organic bases include ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methyl-glucamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, sodium hydroxide, and the like; (3) solvent addition forms or crystal forms of the same acid addition salt which are able to be formed. Such solvent addition forms or crystal forms, for example, include: polymorphs, which are crystal structures in which a compound can crystallize in different crystal packing arrangements, all of which have the same elemental composition. Different polymorphs 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 which are generally a crystal form that contains either stoichiometric or non-stoichiometric amounts of a solvent.

Often, during the process of crystallization some compounds have a tendency to trap a fixed molar ratio of solvent molecules in the crystalline solid state, thus forming a solvate. For example, when the solvent is water, hydrates may be formed; when the solvent is alcohol, alcoholates may be formed, etc. amorphous solids which are noncrystalline materials with no long range order and generally do not give a distinctive powder

X-ray diffraction pattern. (4) internal salts formed when one or several nitrogen atoms of aliphatic or aromatic amines are oxidated to the N-oxide form such as N-oxides, in particular those N-oxides formed upon the oxidation of tertiary cyclic amines to give a chemically stable tertiary cyclic amine N-oxides, e.g, the piperidine N-oxide; or (5) quaternary salts formed when a negatively charged acid radical (the anion) joins a molecular structure which includes a central organic nitrogen atom joined to four organic groups (the cation).

The compounds of Formula I, their pharmaceutically acceptable salts, (including quaternary derivatives and N-oxides) may also form pharmaceutically acceptable solvates, such as hydrates, which are included whenever a compound of

Formula I or a salt thereof is referred to herein. Such hydrates are formed by the combination of one or more molecules of water with one of the compounds, in which the water retains its molecular state as H,0, such combination being able to form one or more than one hydrate. “Subject” means mammals and non-mammals. Examples of mammals include, but are not limited to, any member of the Mammalia class: humans, non- human primates such as chimpanzees and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, 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-mammals include, but are not limited to birds, and the like. The term does not denote a particular age or sex. "Treating" or "treatment" of a disorder includes: \

* ‘a WO 00/15636 PCT/EP99/06402 (1) preventing the disorder, i.e., causing the clinical symptoms of the disorder not to develop in a subject that may be exposed to or predisposed to the disorder but does not yet experience or display symptoms of the disease, (2) inhibiting the disorder, i.e., arresting the development of the disorder or its clinical symptoms, or (3) relieving the disorder, i.e., causing temporary or permanent regression of the disorder or its clinical symptoms. "Pharmacological effect” encompasses effects produced in the subject that achieve the intended purpose of a therapy. In one preferred embodiment, a pharmacological effect means that pain symptoms of the subject being treated are prevented, alleviated, or reduced. For example, a pharmacological effect would be one that results in the reduction of pain in a treated subject. In another preferred embodiment, a pharmacological effect means that disorders or symptoms of the urinary tract 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 incontinence or pelvic hypersensitivity in a treated subject. "Disease state” means any disease, condition, symptom, or indication. "Disorders of the urinary tract” or "uropathy" used interchangeably with "symptoms of the urinary tract" means the pathologic changes in the urinary tract.

Examples of urinary tract disorders include, but are not limited to, incontinence, benign prostatic hypertrophy (BPH), prostatitis, detrusor hyperreflexia, outlet obstruction, urinary frequency, nocturia, urinary urgency, overactive bladder, pelvic hypersensitivity, urge incontinence, urethritis, prostatodynia, cystitis, idiophatic bladder hypersensitivity, and the like. The particularly preferred disorder of the urinary tract includes overactive bladder with symptoms of urinary frequency, urgency, or urge incontinence. "Overactive bladder" or "detrusor hyperactivity" includes, but is not limited to, 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. "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), and 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.

“Disorders of the Central Nervous System (CNS)” or “CNS disorder” means neurological and/or psychiatric changes in the CNS, e.g., brain and spinal cord, which manifest in a variety of symptoms.

Examples of CNS disorders, for example, include migraine headache, anxiety, depression, cerebrovascular deficiency, psychoses including paranoia, schizophrenia, attention deficiency, and autism; obsessive/compulsive disorders including anorexia and bulimia; convulsive disorders including epilepsy and withdrawal from addictive substances; cognitive

: diseases including Parkinson’s disease and dementia; and thermoregulation disorder. “Disorders of the gastrointestinal system” or “GI disorders” means physiological changes in the alimentary tract.

Examples of GI disorders, for example, include dyspepsia, gastric stasis, peptic ulcer, reflux esophagitis, gastritis, pseudo-obstruction syndrome, diverticulitis, irritable bowel syndrome, inflammatory bowel disease, Crohn’s disease, flatulence, diarrhea, and peristaltic disorders including disturbed colonic motility.

“Disorders of the cardiovascular system” or “CV disorders” means a physiological or pathological alteration in the cardiovascular system, in particular, improper cardiac chronotropy or arrhythmia.

Examples of CV disorders, for example include bradyarrhythmia, tachyarrhythmia, supraventricular arrhythmia, atrial fibrillation, atrial flutter, or atrial tachycardia.

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

Oo

RZ 4 3 7 ? 13 2 8 5 N Y 10 3 2

I

The side chains of the Z substituent are numbered as shown below:

R3 RS R3

NT 4Q N— 3 —N1 4 or — 1 4

NEErn NE Eryn

Re R* (A) (B)

In general, the nomenclature used in this application is generally based on

AutoNom, a Beilstein Institute computerized system for the generation of IUPAC systematic nomenclature. However, because a strict adherence to these recommendations would result in the names changing substantially when only a single substituent is changed, compounds have been named in a manner that maintains consistency of nomenclature for the basic molecule.

For example, a compound of Formula I wherein X 1s -NH, Y is -5SO,, m is 3, and Z is represented by formula (A) wherein Q is -NR% nis 1, and R', R% R® and R? are each independently hydrogen, and R°® is methyl, is named 2,3-dihydrobenzo- [1,4]-dioxine-5-carboxylic acid {1-[3-(4-methylpiperazine-1-sulfonyl)propyl] piperidin-4-ylmethyl} amide.

For example, a compound of Formula I wherein X is -CH,, Y is -SO,, m is 3, and Z is represented by formula (A) wherein Q is O, nis 1, and R!, R?, R® and R* are each independently hydrogen, is named 1-(2,3-dihydrobenzo|1,4]dioxin-5-y1)- 3-{1-3-(morpholine-4-sulfonyl)propyl]piperidin-4-yl} propan-1-one.

Among the compounds of the present invention set forth in the Summary of the Invention, certain compounds of Formula I are preferred:

R' and R? are each independently in each occurrence hydrogen, (C,;-Cg)alkyl, (C1-Ce)alkoxy, halogen, amino or hydroxy, more preferably hydrogen or (C1-Ce)alkyl, most preferably hydrogen;

X is -NH or -CHj, more preferably —NH; m is 2, 3, or 4, more preferably 3;

Yis -S0y;

Z is represented by formula (A) or (B), more preferably formula (A):

R3 RS R3 /7\ — Q or —N ~

SCH (CH)

R4 R4 (A) (B) wherein:

R% RY, and R® are each independently in each occurrence hydrogen or (Cy-Ce)alkyl, more preferably hydrogen;

Qis0O,S, -NR® or -CR’R®, more preferably O, -NR®, or -CR’R8, most preferably -NRS; n is 1 or 2; more preferably 1 wherein:

. - © WO 00/15636 PCT/EP99/06402

R® is hydrogen, (C;-Cs)alkyl, (Cs-Cg)cycloalkyl, heterocyclyl, heteroaryl, -COR’, -SO,R’, -CONR'RY, -SO,NR'RY, or aryl optionally mono- or di- substituted with halogen or (C,-Cg)alkyl, more preferably (C,-Cg)alkyl, (Cs-Cg)cycloalkyl, -SO,R’, or aryl optionally mono- or di-substituted with halogen or (C,-Cg)alkyl, most preferably (C,-Cg¢)alkyl;

R’ is hydrogen or (C,-Cs)alkyl, more preferably hydrogen;

R® is hydrogen, (C;-Ce)alkyl, (C,-Cg)alkoxy, aryloxy, -(CH,),CONR'R", -(CH,),SO,NR'R", -(CH,),NR’COR’, or -(CH,),NR’SO,R’; more preferably (C,-Cs)alkyl or (C;-Cg)alkoxy, most preferably (C;-Cs)alkyl; or

R’ and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5- or 6-membered ring optionally independently containing 0 or 1 heteroatom of nitrogen, oxygen, or sulfur, more preferably taken together with the common ring carbon to which they are attached form a monocyclic saturated 5-membered ring optionally independently containing 0 heteroatom; wherein: pis 0, 1, 2, 3 or 4; more preferably 0 or 1, most preferably 0;

R’ is (C,-Cg)alkyl, heteroaryl, heterocyclyl, or aryl optionally mono- or di-substituted with halogen or (C,-Ce)alkyl, more preferably (C;-Ce)alkyl or aryl optionally mono- or di-substituted with halogen or (C;-Cg)alkyl, most preferably aryl optionally mono- or di-substituted with halogen or (C,-Ce)alkyl; and

R'® and R" are each independently hydrogen or (C,-Cg)alkyl, more preferably hydrogen.

Among the compounds of the present invention set forth in the Summary of the Invention, one preferred group of compounds of Formula I, designated “Group A”, are those compounds wherein:

R' and R? are each independently hydrogen; mis 3;

X is -NH; and

Z is formula (A), nis 1, and R® and R” are each independently hydrogen.

A first preferred subgroup among the Group A compounds are those compounds wherein:

Q is -NR® wherein:

R°® is hydrogen, (C,-Cg)alkyl, (Cs-Cs) cycloalkyl, more preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or cyclopentyl; most preferably methyl; or

RC is aryl optionally mono- or di-substituted with halogen or (C,-Cg)alkyl, or -SO,R’% more preferably R® and R® are each independently phenyl, 4-fluorophenyl or 4-chlorophenyl.

A second preferred subgroup among the Group A compounds are those compounds wherein: ~~ ~n7n8 hl -

UIs ~-UK K wherein:

R’ and R® are each independently hydrogen or (C,-Cg)alkyl, more preferably hydrogen, methyl, ethyl, or propyl; or

R’ and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5- or 6-membered ring optionally containing 0, or 1 heteroatom of nitrogen, oxygen, or sulfur; more preferably R” and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5-membered ring containing 0 hetero-atoms.

Another preferred group of compounds of Formula I, designated “Group B”, are those compounds wherein R' and R? are each independently hydrogen; Y is -SO,, and mis 3; X is -CHj; Z is formula (A), nis 1, and R? and R* are each independently hydrogen; and Q is O.

Exemplary particularly preferred compounds include:

0

O

CLO

J Q

0] Nc (a) 3 2,3-dihydrobenzo([1,4]dioxine-5-carboxylic acid {1-[3-(4-methylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 0 0

N S. 0] ~TN N 0. 0 (b) CH, 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid {1-[3-(4-propylpiperidine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 0

O sane

Ne -SN 0 I NY 0. © (Ne 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid {1-[3-(4-propylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 0

Oo saaoly

NSN

0 I NT oJ 0 LN

AS 6

F

2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (1-{3-{4[(4- fluorophenyl)piperazine-1-sulfonyl]-propyl}piperidin-4-ylmethyl) amide; i

Oo

Oo

CLO

Neo ~o-SN 0) I NY oJ o L_nN__-cH © T

CH, 2,3-dihydrobenzo[ 1,4] dioxine-5-carboxylic acid {1-[3-(4-isopropylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide;

O

0

COL

Neo~-Sh 0 I NY oJ o Ln : e, 2,3-dihydrobenzo{1,4]dioxine-5-carboxylic acid {1-[3-(4-cyclopentylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 0] 0]

N Se 6. 0 © 2,3-dihydrobenzo{ 1,4] dioxine-5-carboxylic acid {1-[3-(8-azaspiro[4.5]decane- 8-sulfonyl)propyl]piperidin-4-ylmethyl} amide; 0]

N oO

Ag I

N So F 0 SN NY 0

J LILA

~S (h) J o

2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (1-{3-[4-(4- fluorobenzenesulfonyl)piperazine-1-sulfonyl] propyl} piperidin-4-ylmethyl) amide; 0] 0)

COTO

Nao u-S~ CH 0) I NY 3 oS © PN . CH (i) 3 2,3-dihydrobenzo[1,4}dioxine-5-carboxylic acid {1-{3-(4-isobutylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 0

N 0]

CLO

Neo ~oS~ 0} I NY oJ o L_N_ch 0) 2,3-dihydrobenzo| 1,4]dioxine-5-carboxylic acid {1-[3-(4-ethylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; and

O

O

I

N Se (k) 1-(2,3-dihydrobenzo[1,4])dioxin-5-yl) 3-{1-[3-(morpholine-4-sulfonyl) propyl] piperidin-4-yl} propan-1-one.

The novel compounds of formula I can be prepared by methods known in the art, for example by processes described below, which comprises a) reacting a compound of formula

R2 0]

RQ

N

3 NH

R1 o

S with a compound of formula

L- (CH Y-Z 6 to a compound of formula I, wherein the substituents are described above, or b) deprotecting a compound of formula

R? ?

AQ R3

N Y

0 Ser) SNA

R1 ] ¥ oo Np 7 R to a compound of formula

R2 Oo

BQ y rs fo N(CH) NA

Ro LN ~H

R4

Ia wherein the substituents are described above and P is a suitable protecting group, or c) alkylating a compound of formula

R2 O

AQ v R3 « 0 Ser) SNA

SN YON,

Ta RE with an alkylating agent of formula

RL, to a compound of formula

R2 O

NYY i. oN PAE

R? J (CH): N 0]

YN,

Ib Re wherein the substituents are described above and R® is other than hydrogen and L is a leaving group, or d) reacting a compound of formula

R? Q

N ol NH

R? oJ 4] with a compound of formula

L- (CHM Y~ “> Re

WONG

6b R4 R to a compound of formula

R? 2 aR UI. ~ AI = 3 CHIT SNR 0 SONG

RS

Ib Re wherein the substituents are described above, or e) reducing a compound of formula 0

R2

A

N + o! Achy 2

R? L oJ 14 to a compound of formula 0

R2

N Y

EY 0 N(CH Dz

R oJ

Ic wherein the substituents are given above, f) modifying one or more substituents within the definitions given above, and, if desired, converting the compound obtained into a individual isomer or into a pharmaceutically acceptable salt or hydrate thereof.

In detail, compounds of this invention can be made by the methods depicted in the reaction schemes shown below.

The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co. or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser’s Reagents for Organic Synthesis, Wiley & Sons: New York, 1991, Volumes 1-15; Rodd’s Chemistry of Carbon Compounds,

Elsevier Science Publishers, 1989, Volumes 1-5 and Supplementals; and Organic

Reactions, Wiley & Sons: New York, 1991, Volumes 1-40. These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

The starting materials and the intermediates of the reaction 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 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 conveniently at about room (or ambient) temperature, e.g., about 20 °C.

Schemes A, B, C, and D describe alternative methods to generate the compounds of Formula I.

Scheme A

Scheme A, in general, describes a method of preparing compounds of

Formula I wherein X, Y and Z are as defined in the Summary of the Invention.

R2 0) R2 Oo

OH Step 1 L

A —— 1 0 1 0 "ol "oJ 1 2

R2 Oo

Step 2 “1 2 > 2 ee N o Nop 3 mS P oJ 4

R2 0] 4 Step 3 ARS 0) N\ H

R? o_/

R? 0

Step 4 X 2 Nery ~~

L- (CH) Y-2 ; oO (CH,) pd 6 ol) 5 I

In general, the starting compounds of 2,3-dihydrobenzo[1,4]dioxine-5- carboxylic acid 1, an activated carboxylic acid derivative 2, and a protected (aminomethyl)piperidine 3 wherein P is a suitable protecting group such as benzyl,

tert-butoxycarbonyl (BOC) or carbobenzyloxy (CBZ), preferably BOC, are commercially available or known to or can readily be synthesized by those of ordinary skill in the art. For example, compound 1 can be prepared by the method described in Fuson et al., J. Org. Chem. 1948, 13, 494; compound 3 wherein P is

BOC, can be prepared by the method described in Prugh et al., Synthetic Commun. 1992, 22, 2357.

In step 1, an activated carboxylic acid derivative 2 wherein L is a leaving group such as chloro, is prepared by treating the compound 1 with a suitable chlorinating agent, e.g., thionyl chloride or oxalyl chloride, under conditions well known to one skilled in the art. Suitable solvents for the reaction include aprotic organic solvents such as dichloromethane, chloroform, dichloromethane, 1,2-dichloroethane or tetrahydrofuran, and the like.

In step 2, a protected (piperidin-4-ylmethyl)amide 4 wherein P is a suitable protecting group, preferably BOC, is prepared by reacting compound 2 with a protected (aminomethyl)piperidine 3 under acylating conditions. The reaction proceeds in the presence of base such as triethylamine in a suitable inert organic solvent, for example dichloromethane, 1,2-dichlorethane, chloroform, tetrahydrofuran, and the like.

In step 3, a deprotected (piperidin-4-ylmethyl)amide 5 is prepared by removing the protecting group from compound 4 by methods known to one of ordinary skill in the art. For example, when the protecting group is BOC, the deprotecting reaction proceeds by treatment with a strong organic acid such as trifluroacetic acid in an inert organic solvent such as halogenated hydrocarbons including dichloromethane or 1,2-dichloroethane. For example, the deprotecting reaction may also proceed by warming compound 4 in an 10% ethanolic hydrochloric acid solution.

In step 4, a compound of Formula I is prepared by reacting compound 5 with an alkylating agent 6 wherein L is a leaving group, particularly halogen, under alkylating conditions. The alkylating reaction proceeds in the presence of a base such as triethylamine and a catalyst such as sodium iodide. Suitable solvents for the reaction include aprotic organic solvents such as tetrahydrofuran, /

N,N-dimethylformamide, acetonitrile, dimethyl sulfoxide, 1-methyl-2- pyrrolidinone, and the like.

Exemplary preparations of the following compounds utilizing the reaction conditions described in Scheme A are given. A compound of formula 4 is described in Preparation 2, a compound of formula 5 is described in detail in

Preparation 3A, a compound of formula 6 is described in Preparation 4, and a compound of Formula I is described in Example 1.

. . © WO 00/15636 PCT/EP99/06402

Scheme B

Scheme B describes an alternative method of preparing compounds of

Formula I, in particular wherein X is -NH, Y is as described in the Summary of the

Invention, and Z is represented by formula (A) wherein Q is -NR® and R® is as described in the Summary of the Invention. re 0

Alternative Step 4 N R3 > Te vw 0 N(CH TSN “AN

L- (CHIm =~ 3 RI 2/m

Sa R* P 7 R4

R? Q

N

Step 5 H 0 R3 ———e——————

N o> . Neng SNA o NY

Ta RE

R? Q

Step 6 N = 0 Sera SNA

R? . 0 LN

Ib R¢

Alternatively, a compound of Formula Ia or Ib can be prepared by utilizing the reaction conditions previously described in Scheme A, but substituting step 4 in Scheme A with alternative step 4 in Scheme B, and proceeding as in Scheme B above.

In alternative step 4, a protected piperazine compound 7 wherein Pis a suitable protecting group, is prepared by reacting compound 5 with a protected alkylating agent 6a wherein L is a leaving group, particularly halogen, under alkylating conditions. The alkylating reaction proceeds in the same manner as described in Scheme A, step 4.

In step 5, a compound of Formula Ja is prepared by removing the protecting group from compound 7 by methods known to one of ordinary skill in the art. For example, when the protecting group is BOC, the deprotecting reaction proceeds in the same manner as described in Scheme A, step 3.

Optionally, in step 6, a compound of Formula Ib can be prepared by treating a compound of Formula Ia with an alkylating agent R°L wherein R° is other than hydrogen and L is a leaving group such as halogen, under alkylating conditions, as described in Scheme A, step 4.

Exemplary preparations of the following compounds utilizing the reaction conditions described in Scheme B are given. Exemplary preparations of a compound of formula 6a is described in detail in Preparation 5, a compound of

Formula Ia is described in detail in Example 2, and a compound of Formula Ib is described in Examples 4 and 5.

Scheme C

Scheme C describes an alternative method of preparing compounds of

Formula I, in particular wherein X is -NH, Y is as described in the Summary of the

Invention, and Z is represented by formula (A), and particularly wherein Q is -NR® and R® is hydrogen.

R2 0] R2 0

OH Step 1 N | x o - 0 PA

Ro J “0 R' oJ 8 1 ]

R2 0

Step 2 N = es _ se2 A PE

Le (CH Y~ x F 0} (CH) NA

Ba Rr 10 R4

Step 3 7 Step 4 Ta

The starting compounds of formula 1 and an (aminomethyl)pyridine 8 are commercially available, for example from Aldrich Chemical Company, or known to or can readily be synthesized by those of ordinary skill in the art. 10 In step 1, a (pyridin-4-ylmethyl)amide 9 is prepared by acylating the (pyridin-4-ylmethyl)amine 8 with a carboxylic acid 1 in the presence of a coupling agent such as N,N’-carbonyldiimidazole (CDI), dicylohexyl-carbodiimide (DCC) or 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDCI). Suitable solvents for the reaction include aprotic organic solvents such as tetrahydrofuran,

N,N-dimethylforamide, and the like.

In step 2, a pyridinium salt 10 is prepared by reacting compound 9 with a protected alkylating agent 6a wherein L is a leaving group, particularly halogen, under alkylating conditions previously described in Scheme A, step 4.

In step 3, the piperidinyl compound 7 is prepared by the reduction of compound 10. Suitable pyridinyl reducing conditions include catalytic hydrogenation, for example Raney nickel, or platinum or palladium catalyst, (e.g., PtO; or Pd/C) in a protic organic solvent such as methanol or ethanol.

In step 4, a compound of Formula Ia is prepared from compound 8 utilizing the methods described in Scheme B.

Exemplary preparations of the following compounds utilizing the reaction conditions described in Scheme C are given. Exemplary preparations of a compound of formula 6a is described in detail in Preparation 5, a compound of formula 9 is described in detail in Preparation 7A, and a compound of Formula Ia is described in detail in Example 3.

Scheme D

Scheme D describes an alternative method of preparing compounds of

Formula I, in particular wherein X is -NH, Y is as described in the Summary of the

Invention, and Z is represented by formula (A), and particularly wherein Q is -NR° and R® is other than hydrogen.

R2 0 R2 0

OR Step 1 N | XX

Be ———— EES

RI 0 o H _N

H,N x o._/ TQ RO la 9

R? Q ag

Step 2 9 0 NH

S

Step 3 2 re Ib a3 2m” SN oh gb *

The starting compounds of a carboxylic acid ester 1a and an (aminomethyl)pyridine 8 are commercially available, or known to or can readily be synthesized by those of ordinary skill in the art. For example, the carboxylic acid ester 1a can be prepared by methods known in the art such as by the esterification of the corresponding carboxylic acid, or by the esterification of a 2,3- dihydroxybenzoic acid, and subsequent cyclization of the 2,3-dihydroxy-benzoic acid ester in a suitable solvent such as 1,2-dichloroethane under phase-transfer reaction conditions.

In step 1, a (pyridin-4-ylmethyl)amide 9 is prepared by acylating a (pyridin- 4-ylmethyl)amine 8 with a carboxylic acid ester 1a in the presence a strong base such as sodium methoxide in a suitable protic organic solvent such as methanol.

In step 2, a (piperidin-4-ylmethyl)amide 5 is prepared by reducing the pyridinyl group of compound 9 to a piperidinyl group. Suitable pyridinyl reducing conditions include catalytic hydrogenation, for example Raney nickel, or platinum or palladium catalyst, (e.g., PtO; or Pd/C) in a protic organic solvent such as methanol or ethanol.

Alternatively, a (piperidin-4-ylmethyl)amide 5 can be prepared by treating the carboxylic acid ester 1a with a lithiated (aminomethyl)piperidine (prepared by treating the (aminomethyl)piperidine with an organometallic reagent such as n- butyllitium in an aprotic solvent such as tetrahydrofuran under conditions well known in the art). The reaction proceeds at a temperature of about 25° to 100 °C.

Alternatively, a (piperidin-4-ylmethyl)amide 5 can be prepared by treating the carboxylic acid ester 1a with an (aminomethyl)piperidine in the presence of a strong base such as sodium methoxide in a protic organic solvent such as methanol.

In step 3, a compound of Formula Ib is prepared by treating compound 5 with an alkylating agent 6a wherein L is a leaving group, particularly halogen, under alkylating conditions. The reaction proceeds under phase transfer conditions in the presence of a base such as potassium carbonate, sodium carbonate, sodium hydroxide, or trisodium phosphate, a phase transfer catalyst such as tetra-n-butylammonium bromide, and a reaction enhancer such as potassium bromide. Preferable solvent systems for the reaction include toluene/water and the like.

Exemplary preparations of the following compounds utilizing the reaction conditions described in Scheme D are given. Exemplary preparations of a compound of formula 1a is described in detail in Preparation 1, a compound of formula 5 is described in detail in Preparation 3B, 3C, and 3D, a compound of formula 6b is described in detail in Preparation 6, a compound of formula 9 is described in detail in Preparation 7B, and a compound of Formula Ib is described in detail in Example 6.

Scheme E

Scheme E describes an alternative method of preparing compounds of

Formula I, in particular wherein X is -CH, Y and Z are as described in the

Summary of the Invention. 0) OH

R? R2 ———————————————————

N

Oo OH 0) Z 1 x

Rol he 5 la 10 i 0]

R2

Step 2 = EN n | ZN 0

R? oJ

O

R2

Step 3 x 0)

R? oJ 13 0

R2

XX

13 Step 4 . -y- NJ ~Y

L- CH Im~Y=2 i» 0 LU (CH, z 6 0 14

Oo

R2 14 Step 5 y 0 NS (CH) >2z

R? oJ

Ic

The starting compound of a (2,3-dihydrobenzo[1,4]dioxin-5-yl) ketone 1a can readily be synthesized from 2,3-dihydrobenzo{1,4]dioxine by methods known to one of ordinary skill in the art, for example, by methods similarly described

U.S. Patent No. 5,763,458.

The starting compound of pyridine-4-carboxaldehyde 10 is commercially available, for example, from Aldrich Chemical Company, or known to or can readily be synthesized by those of ordinary skill in the art.

In step 1, a pyridinyl B-hydroxy ketone 11 is prepared by reacting compound 1a with compound 10 under aldol condensation reaction conditions, preferably in the presence of a base such as lithium diisopropylamide. The reaction proceeds at a reduced temperature of about —20° to 0 °C in a suitable aprotic organic solvent such as tetrahydrofuran, diethyl ether, and the like.

In step 2, a pyridinyl enone 12 is prepared by dehydrating the alcohol group of compound 14 to an alkene group under conditions well known to one skilled in the art. The elimination reaction proceeds in the presence of an acid such as sulfuric acid, hydrochloric acid, or a Lewis acid.

In step 3, a pyridinyl ketone 13 is prepared by the hydrogenation of the alkene group of compound 12 to an alkyl group under conditions well known to one skilled in the art. Suitable hydrogenation conditions include catalytic hydrogenation using a platinum or palladium catalyst (e.g., PtO, or Pd/C) in a protic organic solvent such as methanol, ethanol, ethyl acetate, and the like.

In step 4, a pyridinium salt 14 is prepared by reacting compound 13 with an alkylating agent 6 wherein L is a leaving group, particularly halogen, under alkylating conditions previously described in Scheme A, step 4.

In step 5, a compound of Formula Ic is prepared by the reduction of pyridinyl group of compound 14 to a piperidinyl group. Suitable pyridinyl reducing conditions include catalytic hydrogenation, for example Raney nickel or platinum or palladium catalyst (e.g., PtO; or Pd/C) in an alcoholic solvent such as methanol or ethanol.

Exemplary preparations of the following compounds utilizing the reaction conditions described in Scheme E are given. A compound of formula 11 is described in Preparation 8, a compound of formula 12 is described in

Preparation 9, a compound of formula 13 is described in Preparation 10, and a compound of Formula Ic is described in Example 7.

The compounds of Formula I are 5-HT, receptor antagonists and are useful for treating disorders which can be ameliorated by interaction with 5-HT}4 receptors. For example, the compounds of Formula I can block 5-HT, receptor mediated peristalsis and are useful in treating diseases involving hypermotility states, or can block 5-HT, receptor mediated enhancement of neurogenic contractions of detrusor smooth muscle and are useful in the treatment of diseases involving overactive bladder (or detrusor hyperactivity), or can block 5-HT, receptor mediated positive chronotropy and are useful as antiarrhythmic agents.

Thus, the compounds of Formula I are useful for treating a variety of disorders including urinary tract disorders, CNS disorders, gastrointestinal disorders, and cardiovascular disorders.

Particular urinary tract disorders include diseases, conditions, or symptoms which relate directly or indirectly to dysfunction of urinary bladder smooth muscle or its innervation causing disordered urinary storage or voiding control such as overactive bladder, outlet obstruction, outlet insufficiency, and pelvic hypersensitivity (see Ford, A.P.D.W. and Kava, supra). Overactive bladder disorders include, but are not limited to, changes symptomatically manifested as urgency, frequency, reduced bladder capacity, incontinence, detrusor hyperreflexia (neurogenic bladder) or detrusor instability. Additionally, overactive bladder disorders include, but are not limited to changes urodynamically manifested as altered bladder capacity and micturition threshold, unstable bladder contractions, or sphincteric spasticity. Outlet obstruction disorders include, but are not limited to, benign prostatic hyperplasia (BPH), urethral stricture disease, tumors, which are symptomatically manifested as, for example, obstructive (low flow rates, difficulty in initiating urination) or irritative symptoms (urgency, suprapubic pain). Outlet insufficiency disorders include, but are not limited to, urethral hypermobility or intrinsic sphincteric deficiency, and are symptomatically manifested as stress incontinence. Pelvic hypersensitivity disorders include, but are not limited to, changes symptomatically manifested as pelvic pain or discomfort, interstitial cell cystitis, prostadynia, prostatis, vulvadynia, urethritis, orchidalgia, or symptoms related to overactive bladder disorders.

Particular CNS disorders include diseases, conditions, or symptoms which include a variety of neurologic and psychiatric disorders such as cognitive disorders, psychoses, and obsessive/compulsive and anxiety/depression behavior.

Cognitive disorders include attentional or memory deficits, dementia states, cerebral vascular deficiency and Parkinson’s disease. Psychoses which may be treatable with the compounds of this invention include paranoia, schizophrenia and autism. Obsessive/compulsive behavior includes eating disorders, for example bulimia. Anxiety/depressive states include anticipatory anxiety (e.g., prior to surgery, dental work, etc.), depression, mania, seasonal affective disorder (SAD), and the convulsions and anxiety caused by withdrawal from addictive substances such as opiates, benzodiazepines, nicotine, alcohol, cocaine and other drugs of abuse.

Particular gastrointestinal disorders include diseases, conditions, or symptoms which relate directly or indirectly to motility of the stomach, esophagus, and of both the large and small intestines (see Hegde, S.S., supra). Specific disorders include, but are not limited to, dyspepsia, gastric stasis, peptic ulcer, reflux esophagitis, flatulence, bile reflux gastritis, pseudo-obstruction syndrome, irritable colon syndrome, diverticular disease, biliary dysmotility, gastroparesis, irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), Crohn’s disease, and retarded gastric empyting. Other uses include short-term prokinesis to facilitate diagnositic radiology and intestinal intubation, and for treating chronic and acute diarrhea, particularly diarrhea induced by cholera and carcinoid syndrome.

Particular cardiovascular disorders include diseases, conditions, or symptoms which relate directly or indirectly to cardiac arrhythmias (e.g., supraventricular arrhythmia, atrial fibrillation, atrial flutter, atrial tachycardia).

The 5-HT, receptor antagonist activity of the test compounds can be identified by an in vitro assay which utilizes isolated thoracic esophagus muscle in the rat. This assay is well-established as a model for identifying and characterizing compounds that interact with 5-HT, receptors (e.g., see Baxter, G.S. et al., Naunyn-

Schmiedeberg’s Arch.Pharmacol., 1991, 343, 439-446), and is described in more detail in Example 15.

The 5-HT, receptor antagonist properties of the test compounds can be identified by an in vivo assay by determining the inhibitory activity on 5-HT induced heart rate increases in anesthetized and vagotomized Yucatan micropigs (e.g., see Eglen et al, Br. J. Pharmacol. 1993, 108, 376-382) and is described in more detail in Example 16.

The invention includes a pharmaceutical composition comprising a compound of the present invention or individual isomers, racemic or non-racemic mixture of isomers, or pharmaceutically acceptable salts or hydrates thereof, together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients.

In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration

Claims (33)

Claims

1.A compound of formula O R2 13 N Y rR SCH) Nz 0] I wherein: R' and R? are each independently in each occurrence hydrogen, (Cy-Ce)alkyl, (C,-Cg)alkoxy, halogen, amino or hydroxy; X is -NH or -CHj3; mis 2, 3, or 4; Y is -SO3; Z is represented by formula (A) or (B): R3 RS R3 /7\ ! —N Q or —N Q NX Hn (CH )n R4 R#* (A) (B) wherein:

R? R%, and R® are each independently in each occurrence hydrogen or (Cy-Co)alkyl; Qis 0, S, -NR’, or -CR’R%; nis lor2; wherein: R® is hydrogen, (C;-Cs)alkyl, (Cs-Cs)cycloalkyl, heterocyclyl, heteroaryl, -COR’, -SO,R’, -CONR'RY, -SO,NR'’R*, or aryl optionally mono- or di-substituted with halogen or (C,-Cg)alkyl; R’ is hydrogen or (C,-Cg)alkyl; R® is hydrogen, (C;-Ce)alkyl, (C;-C)alkoxy, aryloxy, -(CH,),CONR'R", ~(CH,),SO,NR'’R", -(CH,),NR’COR’, or -(CH,),NR’SO,R’; or R” and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5- or 6-membered ring optionally independently containing 0 or 1 heteroatom of nitrogen, oxygen, or sulfur; wherein: pis0,1,2,3 or4; R’is (C1-Cg)alkyl, heteroaryl, heterocyclyl, or aryl optionally mono- or di-substituted with halogen or (C;-Cq)alkyl; and R' and R" are each independently hydrogen or (C,-Cg)alkyl;

M » WO 00/15636 PCT/EP99/06402 as an individual isomer, racemic or non-racemic mixture of isomers, or a pharmaceutically acceptable salt or hydrate thereof.

2. The compound of Claim 1 wherein R' and R? are each independently hydrogen.

3. The compound of Claim 2 wherein Y is -SO; and m is 3.

4. The compound of Claim 3 wherein X is -NH.

5. The compound of Claim 4 wherein Z is formula (A), nis 1, and R? and R* are each independently hydrogen.

6. The compound of Claim 5 wherein Q is -NR®.

7. The compound of Claim 6 wherein R® is (C;-Cg)alkyl or (Cs-Cg)cycloalkyl.

8. The compound of Claim 7 wherein R° is methyl, ethyl, propyl, isopropyl, butyl, isobutyl, or cyclopentyl.

9. The compound of Claim 8 wherein R® is methyl.

10. The compound of Claim 6 wherein R® is aryl optionally mono- or di- substituted with halogen or (C,-C¢)alkyl, or -SO,R’.

11. The compound of Claim 10 wherein R® and R’ are each independently phenyl, 4-fluorophenyl, or 4-chlorophenyl.

12. The compound of Claim 5 wherein Q is -CR'R®.

13. The compound of Claim 12 wherein R” and R® are each independently hydrogen or (C,-Cs)alkyl.

14. The compound of Claim 13 wherein R” and R® are each independently hydrogen, methy, ethyl, or propyl.

15. The compound of Claim 12 wherein R’ and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5- or 6-membered ring optionally independently containing 0, or 1 heteroatom of nitrogen, oxygen, or sulfur.

Co

16. The compound of Claim 15 wherein R’ and R® taken together with the common ring carbon to which they are attached form a monocyclic saturated 5-membered ring containing 0 heteroatoms.

17. The compound of Claim 3 wherein X is —CH,.

18. The compound of Claim 17 wherein Z is formula (A), n is 1, and R® and R* are each independently hydrogen.

19. The compound of Claim 18 wherein Q is O.

20. The compound of Claim 1 which is 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid {1-[3-(4-methylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid {1-[3-(4-propylpiperidine- 1-sulfonyl)propyl]piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo([1,4]dioxine-5-carboxylic acid {1-[3-(4-propylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl] amide; 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid (1-{3-[4[(4- fluorophenyl)piperazine- 1-sulfonyl]- propyl} piperidin-4-ylmethyl) amide; 2,3-dihydrobenzo|[1,4]dioxine-5-carboxylic acid {1-[3-(4- isopropylpiperazine-1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo[1,4]dioxine-5-carboxylic acid {1-[3-(4- cyclopentylpiperazine-1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo| 1,4] dioxine-5-carboxylic acid {1-[3-(8- azaspiro[4.5]decane-8-sulfonyl) propyl] piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo[ 1,4] dioxine-5-carboxylic acid (1-{3-[4-(4- fluorobenzenesulfonyl)piperazine- 1-sulfonyl] propyl} piperidin-4-ylmethyl) amide; 2,3-dihydrobenzo{1,4]dioxine-5-carboxylic acid {1-[3-(4- isobutylpiperazine-1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; 2,3-dihydrobenzo(1,4] dioxine-5-carboxylic acid {1-[3-(4-ethylpiperazine- 1-sulfonyl)propyl] piperidin-4-ylmethyl} amide; and v ~ © WO 00/15636 PCT/EP99/06402 1-(2,3-dihydrobenzo[1,4)dioxin-5-yl) 3-{1-[3-(morpholine-4-sulfonyl)- propyl] piperidin-4-yl} propan-1-one.

21. The pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Claim 1 in admixture with one or more suitable carriers for the treatment of diseases.

22. The pharmaceutical composition of Claim 21 wherein the compound or compounds are suitable for administration to a subject having a disorder that is alleviated by treatment with a 5-HT), receptor antagonist.

23. A process for preparing a compound of formula I as defined in claim 1, which process comprises a) reacting a compound of formula R2 0] BQ N 2 0) ~H R! oJ 5 with a compound of formula L- (CH) Y-2Z 6 to a compound of formula |, wherein the substituents are described above, or b) deprotectinga compound of formula R2 Q N AQ ‘ R3 R 0 N(CH) > NT oS SN P 7 R* to a compound of formula

Co

R2 Oo N ag § Rs 0 SCH) SNA YEN Ia R* wherein the substituents are described above and P is a suitable protecting group, or c) alkylating a compound of formula R? 0 ag y ro 0 SCH) SNA R? A 0 YN, Ia R* with an alkylating agent of formula RL, to a compound of formula R2 0 AQ y ro 0 “ei SNA we 1 b Re wherein the substituents are described above and R® is other than hydrogen and L is a leaving group, or d) reacting a compound of formula

R? Q N 0 NH R! 0 S with a compound of formula L- (CH)m=Y~ Ra NT RSL re 6b to a compound of formula R2 0) EN y R3 0 Serr SNA R1 on . Ib Re wherein the substituents are described above, or e) reducing a compound of formula 0 R2 ES 0 AN emp 2 R? L 2m oJ 14 to a compound of formula Oo R2 N Y TOG ~ (CH) - ~, oJ Ic oo wherein the substituents are given above, f) modifying one or more substituents within the definitions given above, and, if desired, converting the compound obtained into a individual isomer or into a pharmaceutically acceptable salt or hydrate thereof.

24. A compound according to any one of claims 1-20 whenever prepared by a process as claimed in claim 10 or by an equivalent method.

25. The use of compound in accordance with any one of claims 1-20 for the treatment or prophylaxis of diseases caused by 5-HT, receptor antagonistic activity or for the manufacture of a medicament containing such compound.

26. The invention as hereinbefore described.

PCT/EP99/06402 if desired, converting the compound obtained into a individual isomer or into a pharmaceutically acceptable salt or hydrate thereof.

24. The use of compound in accordance with any one of claims 1-20 for the prophylaxis of diseases caused by 5-HT, receptor antagonistic activity.

25. The use of a compound in accordance with only one of claims 1-20 in the manufacture of a preparation for the treatment or prophylaxis of diseases caused by 5-HT, receptor antagonistic activity.

26. A substance or composition for use in the treatment or prophylaxis, said substance or composition comprising at least one compound of Claim 1, and said method comprising administering a therapeutically effective amount of said substance or composition.

27. A substance or composition for use in a method of treatment or prophylaxis according to Claim 26, wherein the compound or compounds are suitable for administration to a subject having a disorder that is alleviated by treatment with a 5-HT, receptor antagonist.

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

29. A composition according to claim 21, substantially as herein described and illustrated.

30. A process according to claim 23, substantially as herein described and illustrated.

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

32. A substance or composition for use in a method of treatment or prophylaxis according to claim 26 or claim 27, substantially as herein described and illustrated. AMENDED SHEET

PCT/EP99/06402

33. A new compound, a new composition, a process for preparing a compound, use of a compound as claimed in any one of claims 1 to 20, or a substance or composition for a new use in a method of treatment or prophylaxis, substantially as herein described. AMENDED SHEET