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WO2003004027A1 - Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch - Google Patents

Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch Download PDF

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Publication number
WO2003004027A1
WO2003004027A1 PCT/US2002/021063 US0221063W WO03004027A1 WO 2003004027 A1 WO2003004027 A1 WO 2003004027A1 US 0221063 W US0221063 W US 0221063W WO 03004027 A1 WO03004027 A1 WO 03004027A1
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WO
WIPO (PCT)
Prior art keywords
compound
phenyl
branched
alkyl
mmol
Prior art date
Application number
PCT/US2002/021063
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English (en)
Inventor
Mohammad R. Marzabadi
John Wetzel
John E. Deleon
Yu Jiang
Chien-An Chen
Kai Lu
Bharat Lagu
Original Assignee
Synaptic Pharmaceutical Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to UA2004010518A priority Critical patent/UA75416C2/uk
Priority to MXPA03011886A priority patent/MXPA03011886A/es
Priority to BR0210869-0A priority patent/BR0210869A/pt
Priority to HU0401880A priority patent/HUP0401880A2/hu
Priority to EP02746843A priority patent/EP1411942A4/fr
Priority to AU2002316531A priority patent/AU2002316531B8/en
Priority to EA200400146A priority patent/EA005934B1/ru
Priority to NZ530221A priority patent/NZ530221A/xx
Application filed by Synaptic Pharmaceutical Corporation filed Critical Synaptic Pharmaceutical Corporation
Priority to JP2003510038A priority patent/JP2004536104A/ja
Priority to IL15969702A priority patent/IL159697A0/xx
Priority to KR10-2004-7000087A priority patent/KR20040027870A/ko
Priority to CA002454613A priority patent/CA2454613A1/fr
Priority to US10/345,063 priority patent/US7105544B2/en
Publication of WO2003004027A1 publication Critical patent/WO2003004027A1/fr
Priority to IS7085A priority patent/IS7085A/is
Priority to NO20040028A priority patent/NO20040028L/no
Priority to US10/753,057 priority patent/US7199135B2/en

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Definitions

  • MCH Melanin-concentrating hormone
  • MCH (teleost fish) pituitaries (Kawauchi et al . , 1983). In fish the 17 amino acid peptide causes aggregation of melanin within the melanophores and inhibits the release of ACTH, acting as a functional antagonist of ⁇ -MSH.
  • Mammalian MCH (19 amino acids) is highly conserved between rat, mouse, and human, exhibiting 100% amino acid identity, but its physiological roles are less clear. MCH has been reported to participate in a variety of processes including feeding, water balance, energy metabolism, general arousal/attention state, memory and cognitive functions, and psychiatric disorders (for reviews, see Baker, 1991; Baker, 1994; Nahon, 1994; Knigge et al . , 1996).
  • MCH is overexpressed in the hypothalamus of oh/oh mice compared with ob/+ mice, and that fasting further increased MCH mR ⁇ A in both obese and normal mice during fasting.
  • MCH also stimulated feeding in normal rats when injected into the lateral ventricles (Rossi et al . , 1997) .
  • MCH also has been reported to functionally antagonize the behavioral effects of ⁇ -MSH (Miller et al., 1993; Gonzalez et al, 1996; Sanchez et al .
  • MCH may serve as an integrative neuropeptide involved in the reaction to stress, as well as in the regulation of feeding and sexual activity (Baker, 1991; Knigge et al . , 1996) .
  • the ligand retained biological activity and exhibited specific binding to a variety of cell lines including mouse melanoma (B16-F1, G4F, and G4F-7) , PC12, and COS cells.
  • mouse melanoma B16-F1, G4F, and G4F-7)
  • PC12 PC12
  • COS cells C12
  • MCH methylcellulose
  • lateral hypothalamus a brain area implicated in the regulation of thirst and hunger
  • orexins A and B which are potent orexigenic agents, have been shown to have very similar localization to MCH in the lateral hypothalamus (Sakurai et al . , 1998).
  • MCH mRNA levels in this brain region are increased in rats after 24 hours of food-deprivation (Herve and Fellman, 1997) ; after insulin injection, a significant increase in the abundance and staining intensity of MCH immunoreactive perikarya and fibres was observed concurrent with a significant increase in the level of MCH mRNA
  • MCH appears to act as a functional antagonist of the melanocortin system in its effects on food intake and on hormone secretion within the HPA (hypothalamopituitary/adrenal axis) (Ludwig et al . , 1998). Together these data suggest a role for endogenous MCH in the regulation of energy balance and response to stress, and provide a rationale for the development of specific compounds acting at MCH receptors for use in the treatment of obesity and stress-related disorders.
  • the MCH cell group occupies a rather constant location in those areas of the lateral hypothalamus and subthalamus where they lie and may be a part of some of the so-called "extrapyramidal" motor circuits. These involve substantial striato- and pallidofugal pathways involving the thalamus and cerebral cortex, hypothalamic areas, and reciprocal connections to subthalamic nucleus, substantia nigra, and mid-brain centers (Bittencourt et al . , 1992). In their location, the MCH cell group may offer a bridge or mechanism for expressing hypothalamic visceral activity with appropriate and coordinated motor activity. Clinically it may be of some value to consider the involvement of this MCH system in movement disorders, such as Parkinson's disease and Huntingdon's Chorea in which extrapyr midal circuits are known to be involved.
  • the MCH gene may represent a good candidate for
  • MCH may regulate reproductive functions in male and female rats.
  • MCH transcripts and MCH peptide were found within germ cells in -testes of adult rats, suggesting that MCH may participate in stem cell renewal and/or differentiation of early spermatocytes (Hervieu et al . , 1996) .
  • MCH injected directly into the medial preoptic area (MPOA) or ventromedial nucleus (VMN) stimulated sexual activity in female rats (Gonzalez et al . , 1996) .
  • MCH stimulated luteinizing hormone
  • anti- MCH antiserum inhibited LH release (Gonzalez et al . , 1997) .
  • the zona incerta which contains a large population of MCH cell bodies, has previously been identified as a regulatory site for the pre-ovulatory LH surge (MacKenzie et al . , 1984).
  • MCH has been reported to influence release of pituitary hormones including ACTH and oxytocin.
  • MCH analogues may also be useful, in treating epilepsy.
  • MCH has also been observed to affect behavioral correlates of cognitive functions. MCH treatment hastened extinction of the passive avoidance response in rats (McBride et al . , 1994), raising the possibility that MCH receptor antagonists may be beneficial for memory storage, and/or retention. A possible role for MCH in the modulation or perception of pain is supported by the dense innervation of the periaqueductal grey (PAG) by MCH-positive fibers. Finally, MCH may participate in the regulation of fluid intake. ICV infusion of MCH in conscious sheep produced diuretic, natriuretic, and kaliuretic changes in response to increased plasma volume (Parkes, 1996) .
  • MCH may be an important peptide involved in the central control of fluid homeostasis in mammals.
  • MCH-1 G-protein coupled receptor
  • MCH-1 knockout mice Two groups have shown independently (Marsh et al, 2002; Chen et al, 2002) that the targeted disruption of the MCH-1 receptor gene (MCH-1 knockout) in mice results in animals that are hyperphagic but are lean and have decreased body mass relative to wild-type littermates. The decrease in body mass is attributed to an increase in metabolism. Each group demonstrated that the MCH-1 knockout mice are resistant to diet-induced obesity, and generally exhibit weights similar to. littermates maintained on regular chow.
  • MCHl antagonists are useful to treat obesity, depression, anxiety, as well as urinary disorders .
  • the term "antagonist” refers to a compound which binds to, and decreases the activity of, a receptor in the presence of an agonist.
  • activation may be measured using any appropriate second messenger system which is coupled to the receptor in a cell or tissue in which the receptor is expressed.
  • second messenger systems are adenylate cyclase, intracellular calcium mobilization, ion channel activation, guanylate cyclase and inositol phospholipid hydrolysis.
  • the term "agonist” refers to a compound which binds to, and increases activity of, a receptor as compared • with the activity of the receptor in the absence of any agonist.
  • MCHl human melanin-concentrating hormone-1
  • the synthesis of novel compounds which bind selectively to the cloned human melanin-concentrating hormone-1 (MCHl) receptor, compared to other cloned G-protein coupled receptors, and inhibit the activation of the cloned receptors as measured in in vi tro assays is disclosed.
  • the in vi tro receptor binding assays described hereinafter were performed using various cultured cell lines, each transfected with and expressing only a single cloned receptor.
  • the compounds of the present invention may also be used to treat abnormal conditions such as feeding disorders (obesity, bulimia and bulimia nervosa) , sexual/reproductive disorders, depression, anxiety, depression and anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleep disturbances, or any condition in which antagonism of an MCHl receptor may be beneficial.
  • feeding disorders ovalbumina, bulimia and bulimia nervosa
  • sexual/reproductive disorders depression, anxiety, depression and anxiety
  • epileptic seizure hypertension
  • cerebral hemorrhage congestive heart failure
  • sleep disturbances sleep disturbances
  • the compounds of the present invention may be used to reduce the body mass of a subject.
  • the compounds of the present invention may be used to treat urinary disorders .
  • This invention provides a compound having the structure:
  • Ri is hydrogen, straight chained or branched
  • R is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl ;
  • R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , straight chained or branched C -C alkyl;
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , -C0R 3 , -C0 2 R 3 , straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • X is O or NH
  • R is aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -COR 2 ,
  • R 3 is phenyl
  • A is H
  • R 2 is isopropyl
  • the compound has the structure:
  • compound has the structure:
  • Ri is hydrogen, straight chained or branched C ⁇ -C 7 alkyl; and wherein R 3 is aryl.
  • R 2 is isopropyl; and A is hydrogen.
  • the compound has the structure
  • the compound has the structure:
  • the present invention also provides a compound having the structure :
  • Ri is aryl or heteroaryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -OCH 3 , phenoxy, fused cyclopentanyl, straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • R 2 is straight-chained or branched C ⁇ -C 4 alkyl or cyclopropyl; wherein A is -H, -F, -Cl, - Br, -CN, -N0 2 , straight chained or branched C ⁇ -C- 7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
  • n is an integer from 1 to 5 inclusive.
  • Ri is aryl optionally substituted with one or more -F, -Cl, -Br, -I or straight chained or branched C ⁇ -C 4 alkyl;
  • R 2 is isopropyl
  • n 2
  • the compound has the structure:
  • the compound has the structure
  • the compound has the structure:
  • Ri is thienyl; and wherein A is H.
  • R 2 is isopropyl
  • the compound has the structure:
  • the invention provides a compound having the structure:
  • each R is independently hydrogen, methyl or ethyl ; wherein R 2 is straight- chained or branched C 3 -C 4 alkyl or cyclopropyl;
  • R 3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -H, -F, -Cl, -Br, -I, -CN, -N0 2 , straight chained or branched C ⁇ C 7 alkyl.
  • each A is independently -H, -F, -Cl, -Br, -CN, -N0 2 , -COR 3 , -C0 2 R 3 , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • X is 0, NR 3 , CO or may be absent;
  • Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2/ straight chained or branched Q. -C ⁇ alkyl.
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 2 is isopropyl.
  • the compound has the structure:
  • the compound has the structure:
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is -H, -F, -Cl, -Br.
  • R 2 is isopropyl; and A is hydrogen.
  • the compound has the structure:
  • This invention provides a compound having the structure:
  • Ri is hydrogen, straight chained or branched C ⁇ -C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -OCH 3 , -C0 2 CH 3 , -CF 3 , phenyl, straight chained or branched C 1 -C 7 alkyl;
  • R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl ;
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , -CORi, -C0 2 R ⁇ , straight chained or branched C 1. -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl .
  • each B is independently -H, -F, -Cl, -Br, -I, -CN, -N0 2 , -CORi, -C0 2 R ⁇ , - OCH 3 , -OCF 3 , -CF 3 , straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl or aryl, phenoxy or benzyloxy, wherein the aryl, phenoxy or benzyloxy is optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -C0R ⁇ , -C0 2 R ⁇ ,
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R x is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , straight chained or branched -0-j alkyl.
  • R 2 is isopropyl
  • the compound has the structure:
  • the compound has the structure:
  • This invention provides a compound having the structure:
  • Ri is hydrogen, straight chained or branched C ⁇ -C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -CF 3 , -OCH 3 , straight chained or branched C ⁇ -C 3 alkyl;
  • R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl ;
  • R 3 is -H, -F, -Cl, -Br, -I, -CN, -N0 2 , -CF 3 ,
  • R 4 is hydrogen or aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -CF 3 , straight chained or branched -0 3 alkyl; wherein A is -H, -F, -Cl, -Br, -CN, -N0 2 , straight- chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; and
  • n is an integer from 2 to 4 inclusive.
  • R 3 is -H, -F, -Cl, -Br, -I, -CN, -N0 2 , -OCF 3 or -0CH 3 ;
  • R 4 is hydrogen or phenyl optionally substituted with one or more -F, -Cl or -CF 3 .
  • R x is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 ,
  • R 2 is isopropyl
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure
  • This invention provides a compound having the structure:
  • each Ri is independently hydrogen or CH 3 ;
  • R 2 is straight-chained or branched C ⁇ -C 4 alkyl or cyclopropyl ;
  • R 3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl ; wherein A is -H, -F, -Cl, - Br, -CN, -N0 2 , straight chained or branched Cx-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl ;
  • X is (CH 2 ) 2 , COCH 2 or CONH;
  • R 3 is phenyl optionally' substituted with one or more -F;
  • X is CONH.
  • R 2 is methyl
  • the compound has the structure:
  • the compound has the structure:
  • each Y is independently hydrogen or -F.
  • the compound has the structure:
  • the compound has the structure:
  • R 3 is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl .
  • the compound has the structure:
  • each Y is independently hydrogen or -F.
  • the compound has the structure:
  • the compound is enantiomerically pure .
  • the compound is diastereomerically pure.
  • the compound is enantiomerically and diastereomerically pure.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is from about 0.0lmg to about 500mg.
  • the amount of the compound is from about 0. lmg to about 60mg ' .
  • the amount of the compound is from about lmg to about 20mg.
  • the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
  • the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet.
  • the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
  • the invention also provides a process for making a pharmaceutical composition comprising admixing a therapeutically effective amount of the compound of any of the invention and a pharmaceutically acceptable carrier.
  • This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
  • the therapeutically effective amount is between about 0.30 and about 300 mg per day.
  • the therapeutically effective amount is between about 1.0 and about 100 mg per day. In one embodiment, the disorder is depression.
  • the disorder is anxiety.
  • the disorder is obesity.
  • the disorder is urge incontinence.
  • the invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
  • the invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject's depression.
  • the invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
  • the invention provides the method of alleviating urge urinary incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject's urge urinary incontinence .
  • the invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
  • the invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
  • the invention provides the method of treating overactive bladder in a subject, which comprises administering to the subject an amount of a compound of any of the invention effective to treat the subject's overactive bladder.
  • the invention provides the method of treating a disorder in a subject, wherein the symptoms of the subject can be alleviated by treatment with an MCHl antagonist, wherein the MCHl antagonist is the compound of the invention.
  • the invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount of an MCHl antagonist effective to alleviate the symptoms, wherein the MCHl antagonist is the compound of the invention.
  • This invention provides a compound having the structure:
  • each V is independently phthalimide, aryl, phenoxy or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 5 ; C0 2 R 5 ; -OCOR 5 ; -CON(R 5 ) 2 ; -N(R 5 )COR 5 ; CN; -N0 2 ; -N(R 5 ) 2 ; -OR 5 ; -SR 5 ; (CH 2 ) q OR 5 ; (CH 2 ) q R 5 ; (CH 2 ) q SR 5 ; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl ; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; aryl; phenoxy; C 3
  • each W is independently aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted ith one or more F; Cl; Br; I; COR 3 ; -OCOR 3 ; C0 2 R 3 ; -CON(R 3 ) 2 ; -N(R 3 )COR 3 ; CN; -N0 2 ; -N(R 3 ) 2 ; -OR 3 ; -SR 3 ; (CH 2 ) q 0R 3 ; (CH 2 ) q SR 3 ; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, C 2 -C 7 alkynyl; aryl; phenoxy; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluor
  • each R is independently -H; -F; straight chained or branched C x -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; -N(R 3 ) 2 ; -N0 2 ; -CN; -C0 2 R 3 ; -OCOR 3 ; -OR 3 ; or -N(R 3 )COR 3 ; -CON(R 3 ) 2 ;
  • each R 3 is independently -H; straight chained or branched C ⁇ -C-j alkyl, monofluoroalkyl or polyfluoroalkyl ; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl;
  • each R 5 is -H; -N0 2 ; -N 3 ; -CN; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -0R 3 ; -(CH 2 ) p OR 3 ; -COR 3 ; -C0 2 R 3 ;
  • R 6 is. -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C-C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; -C0R 3 ; -C0 2 R 3 ; -0C0R 3 ; -CON(R 3 ) 2 ; -N(R 3 )COR 3 ; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -OCOR 3 ; -CON(R 3 ) 2 ; -N(R 3 )
  • Z is CO, S0 2 or S0 2 NR 6 ;
  • each m is independently an integer from 0 to 3 inclusive;
  • n is independently an integer from 0 to 5 inclusive;
  • each p is independently an integer from 1 to 7 inclusive;
  • q is an integer from 1 to 3 inclusive
  • cycloalkyl includes C 3 -C 7 cycloalky moities which may be substituted with one or more of the following: F; CN; -N0 ; straight chained or branched C x -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched Ci-C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 ' polyfluorocycloalkyl, C 5 -C cycloalkenyl, -N(R 3 ) 2 ; -OR 3 ; -NCOR 3 ; -C0R 3 ;
  • cycloalkenyl includes C 5 -C 7 cycloalkenyl moities which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -N0 2 ; straight chained or branched C ⁇ -C- 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C-j polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 7 cycloalkenyl, -N (R 3 ) 2 ; -OR 3 ; -NCOR 3 ;
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazzolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl .
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl , benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2, 1-b] thiazolyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1, 8-naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2,1,3 -benzothiazolyl .
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F; -Cl; -Br, -I; CN; -N0 2 ; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C 1 -C7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 7 cycloalkenyl, -N(R 3 ) 2 ,• -0R 3 ; -NC0R 3 ; -COR 3 ; -
  • the compound has the structure:
  • R 6 is straight chained or branched C ⁇ -C 7 alkyl; C 3 -C 7 cycloalkyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p OR 3 ; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; -OR 3 ; -(CH 2 ) q OR 3 ; or straight chained or branched Ci-C 7 alkyl.
  • the compound has the structure:
  • At least one V is phenyl optionally substituted with one or more F; Cl ; Br; -OR 3 ; (CH 2 ) q OR 3 ; straight chained or branched Ci-C 7 alkyl; Cx-C? polyfluoroalkyl; or phenoxy.
  • the compound is :
  • the compound is;
  • the compound is:
  • the compound has the structure:
  • At least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3 ; (CH 2 ) q OR 3 ; straight chained or branched C ⁇ -C 7 alkyl; C ⁇ -C 7 polyfluoroalkyl; or phenoxy.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound has the structure:
  • At least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3 ; -C0R 3 ; (CH 2 ) q OR 3 ; straight chained or branched C ⁇ -C 7 alkyl; C ⁇ -C 7 polyfluoroalkyl; aryl or phenox .
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • the compound has the structure:
  • At least one V is phenyl optionally substituted with one or more F; Cl; Br; -OR 3 ; (CH 2 ) q OR 3 ; straight chained or branched C 1 -C 7 alkyl; C 1 -C 7 polyfluoroalkyl; or phenoxy.
  • the compound is
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure
  • the compound has the structure :
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • Y is hydrogen and V is phthalimide.
  • R 6 is straight chained or branched Ci-C 7 alkyl; C 3 -C 7 cycloalkyl; -N(R 3 ) 2 ; -OR 3 ; -(CH 2 ) p 0R 3 ; aryl, benzyl or heteroaryl, optionally substituted with one or more F; Cl ; Br; I; -OR 3 ; -(CH 2 ) q OR 3 ; or straight chained or branched C 1 -C 7 alkyl.
  • the compound is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound has the structure:
  • At least one V is phenyl or heteroaryl optionally substituted with one or more F; Cl ; Br; I; R 5 ; -OR 5 ; - (CH 2 ) q OR 5 ; -(CH 2 ) q R 5 ; straight chained or branched C ⁇ -C 7 alkyl; C ⁇ -C 7 monoflouroalkyl or polyflouroalkyl; or phenoxy.
  • the compound has the structure:
  • the compound has the structure:
  • V is phenyl which is optionally substituted with one or more F; Cl; Br; -0R 5 ; -(CH 2 ) q OR 5 ; -(CH 2 ) q R 5 ; straight chained or branched alkyl; C ⁇ -C 7 monoflouroalkyl or polyflouroalkyl ; or phenoxy.
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure
  • R 5 is straight chained or branched C ⁇ -C 7 alkyl; C 3 -C 7 cycloalkyl;
  • the compound has the structure:
  • the compound has the structure:
  • X is hydrogen and Y is carbazole optionally substituted with one or more F; Cl; Br; R 5 ; -0R 5 ; - (CH 2 ) q OR 5 ; -(CH 2 ) q R 5 ; straight chained or branched Ci - C 7 alkyl; or C 1 -C 7 monoflouroalkyl or poly louroalkyl; or phenoxy.
  • the compound has the structure :
  • the compound has the structure:
  • Y is hydrogen
  • V is an indole, which can be optionally substituted with one or more F; Cl; Br; R 5 ; -C0 2 R 5 ; -OR s ; -(CH 2 ) q 0R 5 ; -
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure':
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the present invention provides a compond having the srucuture :
  • each X is independently O or S;
  • each R is independently H; -(CH 2 ) t XR 3 ;
  • each t is independently an integer from 1 to 4 inclusive;
  • each R 3 is independently H; straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl ; wherein R 4 is aryl, heteroaryl, C ⁇ -C 7 alkyl substituted with one or two aryl, or C 1 -C7 alkyl substituted with one or two heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I,
  • n independently is an integer from 0 to 7 inclusive;
  • R 5 is H; aryl, C ⁇ -C 7 alkyl substituted with aryl, heteroaryl, or C -C alkyl substituted with heteroaryl; wherein the aryl or heteroaryl may be substituted with one or more of F, Cl, Br, I, -CN, -N0 2 , -N(R 3 ) 2 , -COR 3 , - (CH 2 ) n XR3, - (CH 2 ) n C(X)NR 3 , - (CH 2 ) n C0 2 R 3 , straight chained or branched C 1 -C7 alkyl, monofluoroalkyl, polyfluoroalkyl or carboxamidoalkyl, or straight chained or branched C 2 -C 7 aminoalkyl, alkenyl or alkynyl, or C 3 -C 7 cycloalkyl or C ⁇ -C 7 cycloalkenyl;
  • R 5 and one R 2 on adjacent carbon atoms together may form aryl, heteroaryl, indane or tetrahydronaphthyl, C 3 - C 7 cycloalkyl, or heterocycloalkyl wherein one or two heteroatoms may be 0, N or S;
  • each V is independently aryl, phenoxy .or heteroaryl, wherein the aryl, phenoxy or heteroaryl is optionally substituted with one or more F; Cl; Br; I; COR 5 ; C0 2 R 5 ; ' -OCOR 5 ; -CON(R 5 ) 2 ; -N(R 5 )COR 5 ; CN; -N0 2 ; - N(R 5 ) 2 ; -OR 5 ; -SR 5 ; (CH 2 ) q OR 5 ; (CH 2 ) q SR 5 ; straight chained or branched C 1 -C 7 alkyl optionally substituted with - CON(R 5 ) 2 , -N(R 5 )C(0)R 3 or N(R 3 ) 2 , straight chained or branched monofluoroalkyl or polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, C 2 -
  • each R 6 is independently H; (CH 2 ) t XR 3 ; (CH 2 ) t C(X)NR 3 ; (CH 2 ) t N (R 3 ) C (X) R 3 ; (CH 2 ) t C0 2 R 3 ; (CH 2 ) t OCOR 3 ; straight chained or branched C ⁇ -C ⁇ alkyl optionally substituted with -CON(R 3 ) 2 or -NC(0)R 3 ; straight chained or branched C 2 -C 7 alkyl substituted with -N(R 3 ) 2 ; straight chained or branched C 2 -C 7 alkenyl or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C cycloalkenyl;
  • each R 7 is independently H; F; Cl; Br; I; -COR 3 ; - C0 2 R 3 ; -(CH 2 ) n XR 3 ; - (CH 2 ) n N (R 3 ) C (0) R 3 ; (CH 2 ) n C (X) N (R 3 ) 2 ; - (CH 2 ) ' n C0 2 R 3 ; -CN; -N0 2 ; -N(R 3 ) 2 ; straight chained or branched C x -C 7 alkyl, hydroxyalkyl , aminoalkyl, carboxamidoalkyl, alkoxyalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C ⁇ alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or C 5 -
  • B is CO, S0 2 or S0 2 NR 6 ;
  • R 8 is -H; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C 2 -C 7 alkenyl or alkynyl; C 3 -C 7 cycloalkyl, monofluorocycloalkyl, polyfluorocycloalkyl or cycloalkenyl; -N(R 3 ) 2 ; -NR 3 C(0)R 3 ; -0R 3 ; -(CH 2 ) p 0R 3 ; - COR 3 ; -C0 2 R 3 ; -OCOR 3 ; -CON(R 3 ) 2 ; aryl or heteroaryl, optionally substituted with one or more F; Cl; Br; I; COR 3 ; C0 2 R 3 ; -OCOR 3 ; -NR 3 C(0)R 3 ; -C0N(R 3 ) 2 ; CN;
  • each m independently is an integer from 0 to 3 inclusive;
  • C 2 -C 7 alkenyl wherein the C 2 -C 7 alkenyl may be unsubstituted or substituted with one or more Rg groups;
  • each R 9 is independently H; F; Cl; Br; I; • - (CH 2 ) m XR 3 ; (CH 2 ) m C(X)NR 3 ; (CH 2 ) m C0 2 R 3 ; straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl, polyfluoroalkyl, aminoalkyl, or carboxamidoalkyl; straight chained or branched C 2 -C 7 alkenyl, or alkynyl; or C 3 -C 7 cycloalkyl or C 5 -C 7 cycloalkenyl; wherein R 10 is H; (CH 2 ) t XR 3 ; (CH 2 ) t C (X)NR 3 ; (CH 2 ) t C0 2 R 3 ; straight chained or branched C - 7 alkyl, carboxamidoalkyl; straight chained or branched C 2 -C 7 aminoalkyl
  • Y is S, O, or NR i0 ;
  • each p is independently an integer from 1 to 7 inclusive;
  • the compound has the following structure:
  • the compound has the structure :
  • the compound has the structure :
  • Z is:
  • Z is:
  • the compound has the structure:
  • the compound has the strucuture:
  • This invention provides a compound having the structure:
  • Ri is hydrogen, straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -CH 3 , -CF 3 , -COCH 3 , -C0 2 R 2 , phenyl, phenoxy or straight chained or branched C ⁇ -C 7 alkyl;
  • R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl
  • R 3 is aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , -COR 3 , -C0 2 R 3 , straight chained or branched C 1. -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • X is 0 or NH
  • n is an integer from 0 to 5 inclusive
  • R is aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -COCH 3 , -C0 2 R 2 , straight chained or branched C ⁇ -C 7 alkyl;
  • R 3 is phenyl
  • A is H
  • R 2 is isopropyl
  • X is NH
  • Ri is alkyl
  • n is 1 or 2.
  • X is O
  • R is 3 -acetyl phenyl
  • R 2 is isopropyl
  • R 3 is phenyl
  • n is 1.
  • the compound has the structure:
  • compound has the structure:
  • Ri is hydrogen, straight chained or branched C--C 7 alkyl; and wherein R 3 is aryl.
  • R 2 isopropyl
  • A is hydrogen
  • the compound has the structure:
  • the compound has the structure:
  • the present invention also provides a compound having the structure:
  • R x is aryl or heteroaryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -OCH 3 , phenoxy, fused cyclopentanyl, straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl; wherein R 2 is straight-chained or branched C ⁇ -C 4 alkyl or cyclopropyl ;
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , straight chained or branched C ⁇ C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • n is an integer from 1 to 5 inclusive.
  • R 3. is aryl optionally substituted with one or more -F, -Cl, -Br, -I or straight chained or branched C ⁇ -C 4 alkyl;
  • R 2 is isopropyl
  • n 2
  • n is 2 and R 2 is isopropyl.
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • R is thienyl; and wherein A is H.
  • R 2 is isopropyl
  • the compound has the structure:
  • the invention provides a compound having the structure:
  • each Ri is independently hydrogen, methyl or ethyl ;
  • R 2 is straight-chained or branched C 3 -C 4 alkyl or wherein R 2 is straight- chained or branched C 3 -C 4 alkyl or cyclopropyl;
  • R 3 is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -H, -F, -Cl, -Br, -I, -CN, -N0 2 , straight chained or branched C ! -C 7 alkyl.
  • each A is independently -H, -F, -Cl, -Br, -CN, -N0 2 -COR 3 , -C0 2 R 3 , straight chained or branched Cx-C 6 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • X is 0, NR 3 , CO or may be absent;
  • Y is hydrogen, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , straight chained or branched ⁇ -0 7 alkyl.
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • R 2 is isopropyl.
  • the compound has the structure;
  • the compound has the structure:
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • A is -H, -F, -Cl, -Br.
  • R 2 is isopropyl; and A is hydrogen.
  • the compound has the structure:
  • This invention provides a compound having the structure:
  • R ⁇ is hydrogen, straight chained or branched C ⁇ -C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -OCH 3 , -C0 2 CH 3 , -CF 3 , phenyl, straight chained or branched C 1 -C 7 alkyl;
  • R 2 is straight-chained or branched C 3 -C alkyl or cyclopropyl
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , -CORi, -C0 2 R ⁇ , straight chained or branched C 1 -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl or phenyl.
  • each B is independently -H, -F, -Cl, -Br, -I,
  • W is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-phenyl
  • Ri is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , straight chained or branched C 1 -C 7 alkyl.
  • R 2 is isopropyl
  • the compound has the structure:
  • the compound has the structure:
  • This invention provides a compound having the structure:
  • R x is hydrogen, straight chained or branched C ⁇ -C 7 alkyl, aryl or heteroaryl, wherein the aryl or heteroaryl is optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -CF 3 , -OCH 3 , straight chained or branched C ⁇ -C 3 alkyl;
  • R 2 is straight-chained or branched C 3 -C 4 alkyl or cyclopropyl ;
  • R 3 is -H, -F, -Cl, -Br, -I, -CN, -N0 2 , -CF 3 , -OCH 3 , or straight chained or branched C ⁇ -C 3 alkyl, monofluoroalkyl ' or polyfluoroalkyl , or a phenyl ring fused to C ⁇ and C 7 of the indole moiety;
  • R is hydrogen or aryl optionally substituted with one or more -F, -Cl, -Br, -I, -CN, -N0 2 , -CF 3 , straight chained or branched C ⁇ -C 3 alkyl;
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • R 3 is - H, -F, -Cl, -Br, -I, -CN,
  • R 4 is hydrogen or phenyl optionally substituted with one or more -F, -Cl or -CF 3 .
  • R x is hydrogen or phenyl optionally substituted with one or more -F, -Cl, -Br, -CN, -N0 2 , -CF 3 , -OCH 3 or straight chained or branched C ⁇ -C 3 alkyl;
  • R 2 is isopropyl
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • This invention provides a compound having the structure:
  • each Ri is independently hydrogen or CH 3 ;
  • R 2 is straight-chained or branched C ⁇ -C 4 alkyl or cyclopropyl; wherein R 3 is benzyl or phenyl, wherein the benzyl or phenyl is optionally substituted with a methylenenedioxy group or one or more -F or -Cl;
  • A is -H, -F, -Cl, -Br, -CN, -N0 2 , straight chained or branched C ⁇ -C 7 alkyl, monofluoroalkyl or polyfluoroalkyl;
  • X is (CH 2 ) 2 , COCH 2 or CONH;
  • R 3 is phenyl optionally substituted with one or more -F.
  • X is CONH.
  • R 2 is methyl
  • the compound has the structure:
  • the compound has the structure:
  • each Y is independently hydrogen or -F .
  • the compound has the structure:
  • the compound has the structure:
  • R 3 is benzyl optionally substituted with a methylenedioxy group or one or more -F or -Cl .
  • the compound has the structure:
  • each Y is independently hydrogen or -F.
  • the compound has the structure:
  • the compound is enantiomerically pure.
  • the compound is diastereomerically pure.
  • the compound is enantiomerically and diastereomerically pure.
  • This invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically amount of a compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is from about 0.0lmg to ahout 500mg.
  • the amount of the compound is from about 0. lmg to about 60mg.
  • the amount of the compound is from about lmg to about 20mg.
  • the pharmaceutical composition consists of a carrier which is a liquid and the composition is a solution.
  • the pharmaceutical composition consists of a carrier which is a solid and the composition is a tablet .
  • the pharmaceutical composition consists of a carrier which is a gel and the composition is a suppository.
  • This invention also provides the method of treating a subject suffering from a disorder selected from the group consisting of depression, anxiety, urge incontinence, or obesity comprising administering to the subject a therapeutically effective amount of the compound of the invention.
  • the therapeutically effective amount is between about 0.03 and about 1000 mg per day.
  • the therapeutically effective amount is between about 0.30 and about 300 mg per day.
  • the therapeutically effective amount is between about 1.0 and about 100 mg per day.
  • the disorder is depression. _
  • the disorder is anxiety.
  • the disorder is obesity.
  • the disorder is urge incontinence.
  • the invention provides the method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
  • the invention provides the method of treating a subject suffering from depression, which comprises administering to the subject an amount of a compound of any of claims of the invention effective to treat the subject's depression.
  • the invention provides the method of treating a subject suffering from anxiety, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
  • the 'invention provides the method of alleviating urge urinary ' incontinence in a subject suffering from an overactive bladder, which comprises administering to the subject an amount of the compound of the invention effective to alleviate the subject's urge urinary incontinence.
  • the invention provides the method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
  • the invention provides the method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
  • the invention provides the method of treating overactive bladder in a subject, which comprises administering to the subj ect an amount of a compound of any of the invention effective to treat the subject'.s overactive bladder .
  • the invention provides the method of treating a disorder in a subj ect , wherein the symptoms of the subj ect can be alleviated by treatment with an MCHl antagonist, wherein the MCHl antagonist is the compound of the invention.
  • the invention provides the method of alleviating the symptoms of a disor4der in a subject, which comprises administering to the subject an amount . of an MCHl antagonist effective to alleviate the symptoms, ' wherein the MCHl antagonist is the compound of the invention
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, carbazole, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroatoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl , benzo [b] thiophenyl , indazolyl , benzimidazolyl, purinyl, benzoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo [2, 1-b] thiazolyl,.
  • heteroaryl also includes those chemical moieties recited above which may be substituted with one or more of the following: -F, -Cl, -Br, -I, CN, -N0 2 , straight chained or branched C ⁇ -C 7 alkyl, straight chained or branched C ⁇ -C 7 monofluoroalkyl, straight chained or branched C ⁇ -C 7 polyfluoroalkyl, straight chained or branched C 2 -C 7 alkenyl, straight chained or branched C 2 -C 7 alkynyl; C 3 -C 7 cycloalkyl, C 3 -C 7 monofluorocycloalkyl, C 3 -C 7 polyfluorocycloalkyl, C 5 -C 7 cycloalkenyl,
  • heteroaryl further includes the N-oxides of those chemical moieties recited above which include at least one nitrogen atom.
  • aryl is phenyl or naphthyl .
  • stereoisomers may include enantiomers, diastereomers, or E or Z alkene or imine isomers.
  • the invention also provides for stereoisomeric " mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures.
  • Stereoisomers can be synthesized in pure form (N ⁇ gradi-,- M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 ⁇ B 5, (1983) Academic Press, Editor Morrison, J.) or they' can be resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, J. ; Collet, A. ; ilen, S.; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, Vol.
  • the compounds of the present invention may be present as enantiomers, diasteriomers, isomers or two or- more of the ' compounds may be present to form a racemic or diastereomeric mixture.
  • the compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure. Included in this invention are pharmaceutically acceptable salts and complexes of all of the compounds described herein.
  • the acids and bases from which these salts are prepared include but are not limited to ' the acids and bases listed herein.
  • the acids include, but are not limited to, the following inorganic acids: hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and boric acid.
  • the acids include > but are not limited to, the following organic acids: acetic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, benzoic acid, glycolic acid, lactic acid and mandelic acid.
  • the bases include, but are not limited to ammonia, methylamine, ethylamine, propylamine, dimethylamine, diethylamine , trimethylamine, triethylamine, ethylenediamine, hydroxyethylamine, morpholine, piperazine and guanidine . This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
  • the present invention includes within its scope prodrugs of the compounds of the invention.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
  • administering shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after . administration to
  • the present invention further includes metabolites of the compounds of the present invention.
  • Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • This invention further provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of the compound of the invention and a pharmaceutically acceptable carrier.
  • the amount of the compound is from about 0.01 mg to about 800 mg. In another embodiment, the amount of the compound is from about 0.01 mg to about 500 mg. In yet another embodiment, the amount of the compound is from about 0.1 mg to about 250 mg. In another embodiment, the amount of the compound is from about 0.1 mg to about 60 mg. In yet another embodiment, the amount of the compound is from about 1 mg to about 20 mg.
  • the carrier is a liquid and the composition is a solution. In another embodiment,- the carrier is a solid and the composition is a tablet. In another embodiment, the carrier is a gel and the composition is a capsule, suppository or a cream. In
  • the compound may be formulated as a part of a pharmaceutically acceptable transdermal patch.
  • the compound may be delivered to. ' 'the ' subject by means of a spray or inhalant .
  • This invention also provides a pharmaceutical composition made by combining a therapeutically effective amount of the compound of this invention and a pharmaceuticall acceptable, carrier.
  • This -invention- provides a process for making a pharmaceutical ' composition comprising combining - a - therapeutically ' e fective amount of the compound of . this - invention and a pharmaceutically acceptable carrier.
  • - -solid carrier can include one or more substances which may also act as .endogenous carriers (e.g. nutrient or micronutrient carriers), flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is lh admixture with the finely divided active ingredient.
  • ⁇ In tablets, - the active ingredient is mixed with a carrier -having the necessary compression properties in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in ' a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, coloring agents, viscosity regulators, stabilizers or osmoregulators .
  • suitable examples of liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives/ preferably sodium carboxymethyl cellulose solution) , alcohols (including onohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils
  • the carrier can also be an oily ester such as ethyl oleate or isopropyl myristate.
  • Sterile liquid carriers are useful in sterile liquid form compositions for parenteral administration.
  • The- liquid carrier for pressurized compositions can be a halogenated hydrocarbon or other pharmaceutically acceptable propellent.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by for example,- intramuscular, intrathecal, epidural, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously.
  • the compounds may be prepared as a sterile solid composition which may be dissolved or suspended at the time of administration using sterile water, saline, or other appropriate sterile injectable medium.
  • Carriers are intended to include , necessary and inert binders, suspending agents, lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.
  • the compound can be administered orally in- the form of a s$£ lile - solution ; ⁇ - or suspension, containing other solutes or suspending agents (for example, enough - saline or glucose to make the solution isotonic) , bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleate esters of sorbitol and its anhydrides copolymerized with ethylene oxide) and the like.
  • solutes or suspending agents for example, enough - saline or glucose to make the solution isotonic
  • bile salts for example, enough - saline or glucose to make the solution isotonic
  • bile salts for example, enough - saline or glucose to make the solution isotonic
  • bile salts for example, enough - saline or glucose to make the solution isotonic
  • bile salts for example, enough - saline or glucose to
  • compositions suitable for oral administration include solid forms, such as pills, capsules, granu ⁇ s., tablets, and powders, and liquid forms, such as solutions, syrups, elixirs, and suspensions.
  • forms useful for parenteral administration include "sterile solutions, emulsions, and suspenions .
  • Optimal dosages to be administered may be determined by those skilled in the art, and will vary with the particular compound in use, the strength of the preparation, the mode of administration, and the advancement of the disease condition. Additional factors depending on the particular subject being treated will result i ⁇ a need to adjust dosages, including subject age, weight, gender, diet, and time of administration.
  • a "therapeutically effective amount” is any amount of a compound which, when administered to a subject suffering from a disease against which the compounds are effective, causes reduction, remission, or regression of the disease.
  • a "subject” is a vertebrate, a mammal or a human.
  • depressive and anxiety disorders is for the purpose of illustrating the utility of the compounds of this invention.
  • the definitions of depressive and anxiety disorders given below are those listed in Diagnostic and Statistical Manual of Mental Disorders. 4th ed. (DSM-IV; American Psychiatric Association, 1994a) or Diagnostic and Statistical Manual of Mental Disorders. 3rd ed. Revised (DSM-III-R; American Psychiatric Association, 1987) . Additional information regarding these disorders can be found in this reference, as well as the others cited below, all of which are incorporated herein by reference.
  • Depressive disorders include major depressive disorder and dysthymic disorder (American Psychiatric Association, 1994a; American Psychiatric Association, 1994b) .
  • Major depressive disorder is characterized by the occurrence of one or more major depressive episodes without manic or hypomanic episodes.
  • a major depressive episode is defined as a prominent and relatively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks) ; it should include at least 4 of the following 8 symptoms: change in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and a suicide attempt or suicidal ideation (Medical Economics Company, 2002) .
  • Dysthymic disorder involves a type of depression that is not severe enough to be called a major depressive episode, but that lasts much longer than major depressive disorder, without high phases.
  • HDRS Harmonic Scale
  • CGI Global Impressions
  • the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as the HDRS subfactor scores, including the depressed mood item, sleep disturbance factor and anxiety factor, and the CGI-Severity of Illness rating. It is also contemplated that the compounds of this invention will be effective in preventing relapse of major depressive episodes.
  • Anxiety disorders include panic disorder, agoraphobia with or without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder and generalized anxiety disorder. It is ⁇ contemplated that the compounds of this invention will be effective in treating any of all of these disorders in patients who have been diagnosed with these disorders.
  • Obsessive compulsive disorder is characterized by recurrent and persistent ideas, thoughts, impulses or images (obsessions) that are ego-dystonic and/or repetitive, purposeful and intentional behaviors (compulsions) that are recognized by the person as excessive or unreasonable (American Psychiatric
  • the compounds of this invention will be effective in treating obsessions and compulsions in patients who have been diagnosed with obsessive compulsive disorder by administration of appropriate tests, which may include, but are not limited to any of the following: Yale Brown Obsessive Compulsive Scale (YBOCS) (Goodman, 1989) (for adults) , National Institute of Mental Health Global OCD Scale (NIMH GOCS) , CGI- Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these tests, such as a reduction of several points in the YBOCS total score. It is also contemplated that the compounds of this- invention will be effective in preventing relapse of obsessive compulsive disorder.
  • YBOCS Yale Brown Obsessive Compulsive Scale
  • NIMH GOCS National Institute of Mental Health Global OCD Scale
  • CGI- Severity of Illness scale CGI- Severity of Illness
  • Panic disorder is characterized by recurrent unexpected panic attacks and associated concern about having additional attacks, worry about the implications or consequences of the attacks, and/or a significant change in behavior related to the attacks (American Psychiatric Association, 1994a) .
  • a panic attack is defined as a discrete period of intense fear or discomfort in which four (or more) of the following symptoms develop abruptly and reach a peak within 10 minutes: (1) palpitations, pounding heart, or accelerated heart rate; (2) sweating; (3) trembling or shaking; (4) sensations of shortness of breath or smothering; (5) feeling of choking; (6) chest pain or discomfort; (7) nausea or abdominal distress; (8) feeling dizzy, unsteady, lightheaded, or faint; (9) derealization (feelings of unreality) or depersonalization (being detached from oneself) ; fear of losing control; (11) fear of dying;
  • Panic disorder may or may not be associated with agoraphobia, or an irrational and often disabling fear of being out in public.
  • the compounds of this invention will be effective in treating panic disorder in patients who have been diagnosed with panic disorder on the basis of frequency of occurrence of panic attacks, or by means of the CGI-Severity of Illness scale. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain of the factors measured in these evaluations, such- as a reduction in frequency or elimination of panic attacks, an improvement in the CGI-Severity of Illness scale or a CGI-Global Improvement score of 1 (very much improved) , 2 (much improved) or 3 (minimally improved)-. It is also contemplated that the compounds of this invention will be effective in preventing relapse of panic disorder.
  • Social anxiety disorder also known as social phobia, is characterized by a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others (American Psychiatric Association,
  • the compounds of this invention will be effective in treating social anxiety disorder in patients who have been diagnosed with social anxiety disorder by administration of any of the following tests: the Liebowitz Social Anxiety Scale (LSAS) , the CGI-Severity of Illness scale, the Hamilton Rating Scale for Anxiety (HAM-A) , the Hamilton Rating Scale for Depression (HAM-D) , the axis V Social and Occupational Functioning Assessment Scale of DSM-IV, the axis II
  • Generalized anxiety disorder is characterized by excessive anxiety and worry (apprehensive expectation) that is persistent for at least 6 months and which the person finds difficult to control (American Psychiatric
  • the compounds of this invention will be effective in treating generalized anxiety disorder in patients who have been diagnosed with this disorder according to the diagnostic criteria described in DSM-IV. It is further contemplated that the compounds of the invention will be effective in reducing symptoms of this disorder, such as the following: excessive worry and anxiety, difficulty controlling worry, restlessness or feeling keyed up or on edge, being easily fatigued, difficulty concentrating or mind going blank, irritability, muscle tension, or sleep disturbance . It is also contemplated that the compounds of this invention will be effective in preventing relapse of general anxiety disorder.
  • Post-traumatic stress disorder (PTSD) , as defined by DSM-III-R/IV (American Psychiatric Association, 1987, American Psychiatric Association, 1994a) , requires exposure to a traumatic event that involved actual or threatened death or serious injury, or threat to the physical integrity of self or others, and a response which involves intense fear, helplessness, or horror.
  • DSM-III-R/IV American Psychiatric Association, 1987, American Psychiatric Association, 1994a
  • Symptoms that occur as a result of exposure to the traumatic event include re-experiencing of the event in the form of -intrusive thoughts, flashbacks or dreams, and intense psychological distress and physiological reactivity on exposure to cues to the event; avoidance of situations reminiscent of the traumatic event, inability to recall details of the event, and/or numbing of general responsiveness manifested as diminished interest in significant activities, estrangement from others, restricted range of affect, or sense of foreshortened future; and symptoms of autonomic arousal including hypervigilance, exaggerated startle response, sleep disturbance, impaired concentration, and irritability or outbursts of anger.
  • a PTSD diagnosis requires that the symptoms are present for at least a month and that they cause clinically significant distress or impairment in social, occupational, or other important areas of functioning.
  • the compounds of this invention will be effective in treating PTSD in patients who have been diagnosed with PTSD by administration of any of the following tests: Clinician-Administered PTSD Scale Part 2 (CAPS) , the patient-rated Impact of Event Scale (IES)
  • the compounds of the invention will be effective in inducing improvements in the scores of the CAPS, IES, CGI-Severity of Illness or CGI-Global Improvement tests. It is also contemplated that the compounds of this invention will be effective in preventing relapse of PTSD.
  • the subject invention provides a method of treatment or management of the following indications: depressive disorders, anxiety disorders, eating/body weight disorders, and urinary disorders.
  • depressive disorders are major depressive disorder or dysthymic disorder.
  • anxiety disorders are panic disorder, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post- traumatic stress disorder, acute stress disorder or generalized anxiety disorder.
  • eating/body weight disorders are obesity, weight gain, bulimia, bulimia nervosa or anorexia nervosa.
  • urinary disorders include, but are not limited to urinary incontinence overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis.
  • Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
  • This invention provides a method of modifying the feeding behavior of a subject, which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
  • This invention also provides a method of treating an eating disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the eating disorder.
  • the eating disorder is obesity, bulimia, bulimia nervosa or anorexia nervosa.
  • the present invention further provides a method of reducing the body mass of a subject, which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subject.
  • This invention also provides a method of managing obesity in a subject in need of weight loss, which comprises administering to the subject an amount of a compound of the invention effective to induce weight loss in the subject.
  • This invention also provides a method of managing obesity in a subject who has experienced weight loss, which comprises administering to the subject an amount of a compound of the invention effective to maintain such weight loss in the subject.
  • the present invention also provides a method of treating depression in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression.
  • This invention also provides a method of treating anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's anxiety.
  • This invention also provides a method of treating depression and anxiety in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's depression and anxiety.
  • This invention also provides a method of treating major depressive disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's major depressive disorder. This invention also provides .
  • a method of treating dysthymic disorder in a subject which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's dysthymic disorder.
  • This invention also provides a method of treating obsessions and compulsions in a subject with obsessive compulsive disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's obsessions and compulsions.
  • This invention also provides a method of treating panic disorder, with or without agoraphobia, in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's panic disorder.
  • This invention also provides a method of treating social anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat , the subject's social anxiety disorder.
  • This invention also provides a method of treating generalized anxiety disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's generalized anxiety disorder.
  • This invention also provides a method of treating post-traumatic stress disorder in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's post-traumatic stress disorder.
  • the compounds of this invention will be effective in treating obesity, including weight loss and maintenance of weight loss in patients, who have been diagnosed with obesity by the one or more of the following measurements: an increased body mass index, increased waist circumference (an indicator of intra-adominal fat) , Dual Energy X-Ray Absorptiometry (DEXA) and nestal (android) fat mass. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
  • the compounds of this invention will be effective in treating urinary disorders in patients who have urge or mixed (with a predominance of urge) incontinence as evidenced by the number of unnecessary episodes per week, the number of unnecessary micturitions per day and a low volume voided per micturition. It is further contemplated that the compounds of the invention will be effective in inducing improvements in certain factors measured in these tests.
  • the present invention also provides a method of treating a subject suffering from bipolar I or II disorder, schizoaffective disorder, a cognitive disorder with depressed mood, a personality disorder, insomnia, hypersomnia, narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder or sleepwalking disorder.
  • the present invention provides a method of treating overactive bladder with symptoms of urge urinary incontinence, urgency and/or frequency in a subject, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's overactive bladder.
  • This invention also provides a method of alleviating urge urinary incontinence in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urge urinary incontinence.
  • This invention further provides a method of alleviating urinary urgency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary urgency.
  • this invention provides a method of alleviating urinary frequency in a subject suffering from overactive bladder, which comprises administering to the subject an amount of a compound of the invention effective to alleviate the subject's urinary frequency.
  • the present invention also provides a method of treating a subject suffering from a urinary disorder, which comprises administering to the subject an amount of a compound of the invention effective to treat the subject's urinary disorder.
  • the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia or enuresis.
  • the present invention provides a method of alleviating the symptoms of a disorder in a subject, which comprises administering to the subject an amount of an MCHl antagonist effective to alleviate the symptoms, wherein the MCHl antagonist is any of the compounds of the invention.
  • the subject is a vertebrate, a mammal, a human or a canine.
  • the compound is administered orally.
  • the compound is administered in combination with food.
  • the subject invention provides a method of treatment for the following indications: depression, anxiety, eating/body weight disorders, and urinary disorders.
  • eating/body weight disorders are obesity, bulimia, or bulimia nervosa.
  • urinary disorders include, but are not limited to, urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis. Overactive bladder and urinary urgency may or may not be associated with benign prostatic hyperplasia.
  • This invention provides, a method of modifying the feeding behavior of a subject which comprises administering to the subject an amount of a compound of the invention effective to decrease the consumption of food by the subject.
  • This invention also provides a method of treating an eating disorder in a subject which comprises administering to the subject an amount of a compound of this invention effective to decrease the consumption of food by the subject.
  • the eating disorder is bulimia, obesity or bulimia nervosa.
  • the subject is a vertebrate, a mammal, a human or a canine .
  • the compound is administered in combination with food.
  • the present invention further provides a method of reducing the body mass of a subject which comprises administering to the subject an amount of a compound of the invention effective to reduce the body mass of the subj ect .
  • the present invention also provides a method of treating a subject suffering from depression which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression.
  • the present invention further provides a method of treating a subject suffering from anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's anxiety.
  • the present invention also provides a method of treating a subject suffering from depression and anxiety which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's depression and anxiety.
  • the present invention also provides a method of treating a subject suffering from major depressive disorder, dysthymic disorder, bipolar I and II disorders, schizoaffective disorder, cognitive disorders with depressed mood, personality disorders, insomnia, hypersomnia, . narcolepsy, circadian rhythm sleep disorder, nightmare disorder, sleep terror disorder, sleepwalking disorder, obsessive-compulsive disorder, panic disorder, with or without agoraphobia, posttraumatic stress disorder, social anxiety disorder, social phobia and generalized anxiety disorder.
  • the present invention also provides a method of treating a subject suffering from a urinary disorder which comprises administering to the subject an amount of a compound of this invention effective to treat the subject's a urinary disorder.
  • the urinary disorder is urinary incontinence, overactive bladder, urge incontinence, urinary frequency, urinary urgency, nocturia, or enuresis.
  • reaction mixture was cooled to -78 °C and tert-butyl 4-oxo-l-piperidinecarboxylate (Aldrich Chemical Company, 40.0 mmol) in THF (40 mL) was added dropwise to the reaction mixture and stirred for 30 minutes.
  • Tf 2 NPh (42.0 mmol, 15.0 g) in THF (40 mL) was added dropwise to the reaction mixture and stirred at °C overnight.
  • the reaction mixture was concentrated in vacuo, re-dissolved in hexanes : EtOAc (9:1), passed through a plug of alumina and the alumina plug was washed with hexanes : EtOAc (9:1). The combined extracts were concentrated to yield 16.5 g of the desired product that was contaminated with some starting Tf 2 NPh.
  • TERT-BUTYL N- (3- ⁇ 4- [3- (ACETYLAMINO) PHENYL] -1,2,3, 6-TETRAHYDRO-l-PYRIDINYL ⁇ PROPYL)
  • CARBAMATE A solution of Nl - [3- (l,2,3,6-tetrahydro-4- pyridinyl) phenyl] acetamide. HCl (8.24 mmol), tert-butyl N- (3 -bromopropyl) carbamate and potassium carbonate (33 mmol) in dry dioxane (30 mL) was heated at reflux temperature overnight.
  • PIPERIDINECARBOXYLATE A mixture tert-butyl 4- [3- (acetylamino)phenyl] -1, 2, 3 , 6-tetrahydro-l- pyridinecarboxylate (710 mg) and 5% Pd/C (100 mg) in EtOH (10 mL) was hydrogenated (balloon technique) at room temperature overnight. The reaction mixture was passed through a pad of Celite 545 and the pad of Celite was washed with ethanol.
  • Nl- [3- (4-PIPERIDYL) PHENYL] CETAMIDE A solution of HCl in dioxane (4N, 5 mL) was added to tert-butyl 4- [3- (acetylamino) phenyl] -1-piperidinecarboxylate (660 mg) in dry dichloromethane (15 mL) . The reaction mixture was stirred at room temperature overnight and concentrated in vacuo, giving the desired product. (550 mg) : mp 102-104 °C; X ⁇ .
  • TERT-BUTYL N- (3- ⁇ 4- [3- (ACETYLAMINO) PHENYL] PIPERIDIN ⁇ PROPYL)
  • CARBAMATE A solution of Nl - [3- (4-piperidyl) phenyl] acetamide (550 mg, 0.210 mmol), tert-butyl N- (3 -bromopropyl) carbamate (550 mg, 0.230 mmol), K 2 C0 3 (1.10 g, 0.890 mmol), diisopropylethyl amine (1.50 mL) and a few crystals of KI in dioxane (20 mL) was heated at reflux temperature for 2 days.
  • PYRIDINECARBOXYLATE According to the procedure used for the synthesis of tert-butyl 4- [3- (amino) phenyl] -1, 2, 3 , 6- tetrahydro-l-pyridinecarboxylate,a mixture of 2 M aqueous Na 2 C0 3 solution (2.2 mL) , tert-butyl 4- ⁇ [ (trifluoromethyl) sulfonyl] oxy ⁇ -1, 2, 3 , 6-tetrahydro-l- pyridine-carboxylate (0.5.00 g, 1.51 mmol), 3-nitrophenylboronic acid (0.353 g, 2.11 mmol), lithium chloride (0.191 g, 4.50 mmol) and tetrakis- triphenylphosphine palladium (0) (0.080 g, 0.075 mmol) in dimethoxyethane (5 mL) afforded 0.380g of the desired product .
  • TERT-BUTYL 3- (4- (3-NITR0PHENYL) -3 , 6-DIHYDR0-1 (2H) - PYRIDINYDPROPYLCARBAMATE: A mixture of 2.80 g (14.0 mmol) of 1, 2 , 3 , 6-tetrahydro-4- (3 -nitrophenyl) pyridine, 3.60 g (15.0 mmol) of tert-butyl
  • N- (3 -bromopropyl) carbamate 11.6 g (84.0 mmol) of K 2 C0 3 , 14.6 mL (84.0 mmol) of diisopropylethylamine and 0.78 g (2.00 mmol) of tetrabutylammonium iodide in 250 mL of 1,4-dioxane was heated at reflux temperature for 14 hours .
  • the reaction mixture was filtered and concentrated in vacuo.
  • the residue was dissolved in 100 mL of ethyl acetate and washed 3 X 50 mL of 5% aqueous NaOH solution, the organic layer was dried (MgS0 4 ) and concentrated in vacuo .
  • the residue was dissolved in 100 mL of anhydrous ethanol containing 0.50 g 10% Pd/C and the reaction mixture was stirred under a hydrogen balloon for 24 hours.
  • the reaction mixture was passed through a column of Celite 545 filtering agent, washed with ethanol, the filtrate was dried (MgS0 4 ) and concentrated in vacuo .
  • PYRIDINECARBOXYLATE To a 25-mL RB flask, equipped with a condensor, was added tert-butyl 4- ⁇ [ (trifluoromethyl) sulfonyl] oxy ⁇ -3, 6-dihydro-l (2H) - pyridinecarboxylate (1.0 g) , 4-nitrophenylboronic acid (0.71 g) , sodium carbonate (0.430 mL of 2M solution), lithium chloride (0.382 g) , tetrakis (friphenylphosphine) - palladium (0) (0.173 g) and ethylene glycol dimethyl ether (10 mL) . The reaction mixture was flushed with Argon three times, then the reaction mixture was heated to 100 °C for 3 hrs.
  • reaction mixture was diluted with methylene chloride (30 mL) and water
  • Nitrophenyl) -1, 2 , 3 , 6-tetrahydropyridine was prepared by a similar procedure to that used for the preparation of 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide using HCl gas and tert-Butyl 4- (4-Nitrophenyl) -3 , 6-dihydro- 1 (2H) -pyridinecarboxylate (130 mg) in dioxane (5.0 mL) at room temperature. The reaction -mixture was concentrated in vacuo to give the crude product (69.8 mg) which used in the next reaction without further purification.
  • 2-AMINO-2- (3, 4-DIFLUOROPHENYL) -ETHANOL Into a well- stirred suspension of LiAlH 4 (4.7 g, 0.125 mol) in THF (120 mL) in a 3-necked round bottom flask fitted with a condenser and a dropping funnel, was added a solution of amino- (3, 4-difluorophenyl) -acetic acid methyl ester (10.0 g, 0.05 mol) in THF (100 mL) dropwise at 0 °C. The resulting greenish brown suspension was heated at reflux temperature for 2 h.
  • the reaction mixture was cooled to 0 °C and then carefully quenched sequentially with 5 mL of water, 5 mL .of 3N NaOH followed by 15 mL of water.
  • the resulting suspension was filtered through a fritted glass funnel. To the filter cake was added 100 mL Et 2 0 and the suspension was heated at reflux temperature for 20 min. The suspension was filtered and the combined filtrates were dried over MgS0 4 , filtered and the solvent was removed in vacuo. 2 - Amino-2- (3, 4-difluorophenyl) -ethanol was obtained as a yellow glassy syrup which was used in the next step without further purification.
  • (+) -4- (3, 4-DIFLUOROPHENYL) -OXAZOLIDIN-2-ONE Into a well-stirred suspension of NaH (1.1 g, 45.8 mmol) in THF (40 mL) at R.T. was added a solution of [l-(3,5- difluorophenyl) -2-hydroxy- ethyl] -carbamic acid- tert- butyl ester (5.0 g, 18.3 mmol) in THF (20 mL) via a dropping funnel at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with 10 mL of water.
  • the ether layer was separated and the aqueous layer was extracted with more ether (4 X 200 mL) .
  • the combined extracts were dried with magnesium sulfate and the solvent evaporated.
  • the crude product was purified by column chromatography on silica gel using chloroform/methanol/2M ammonia in methanol (1000:20:10, 1000:40:20, 1000:80:40) as the eluent to give the product as an oil (6.5 g, 62% yield) which was used in the next step without further purification.
  • 1,3-OXAZOLIDINE-3-CARBOXYLATE Into a stirred suspension of sodium hydride (60% suspension in paraffin 203 mg,
  • the relative configurations of the cis and trans isomers were assigned on the basis of E NMR analysis of the respective p-nitrophenyloxycarbonyl derivatives.
  • For the trans isomer an NOE was observed between the protons of the C-5 methyl group and the proton at C-4. No NOE was observed between the protons at the C-4 and C-5 positions of this isomer, which was thus assigned trans stereochemistry.
  • For the cis isomer no NOE was observed between the protons of the C-5 methyl group and the proton at C-4. However, a NOE was observed between the protons at the C-4 and C-5 positions, leading us to assign this isomer cis stereochemistry.
  • Enantiomers of the diastereomers were separated by HPLC by using a Chiralcel OD column (20 x 250 mm) with 80% hexane/20% isopropyl alcohol/ 0.1 % diethylamine as the eluting system (12 mL/min) under isocratic conditions (U.V. 254 nm) .
  • (+) - tl- (3,4-DIFLUOROBENZYL) -2-HYDROXY-ETHYL] -CARBAMIC ACID-TERT-BUTYL ESTER A solution of di- tert-butyl dicarbonate (0.640 g, 2.90 mmol) in CHC1 3 (10 mL) was added in one portion to a solution of (+) -2-amino-3- (3, 4-difluoro) -phenyl-propan-1-ol (0.500 g, 2.62 mmol) in CHC1 3 (20 mL) at 0 °C and the resulting solution was stirred overnight at room temperature.
  • (+) -4- (3,4-DIFLUORO-BENZYL) -OXAZOLIDIN-2-ONE A solution of (+) - [1- (3, 4-difluorobenzyl) -2-hydroxy-ethyl] -carbamic acid- ert-butyl ester (1.00 g, 4.00 mmol) in THF (10 mL) was added via a dropping funnel to a stirring suspension of ' 95% NaH (0.12 g, 5.0 mmol) in THF (20 mL) at room temperature. The resulting suspension was stirred for 3 h and then quenched carefully with water (10 mL) .
  • PIPERIDINYL ⁇ PHENYL) -2-METHYLPROPANAMIDE A mixture of 0.0500 g (0.200 mmol) of 2-methyl-N- [3- (4- piperidinyl) phenyl] propanamide, 0.100 g (0.480 mmol) of 4-chloro-3' , 4' -dimethylbutyrophenone, 0.080 g (0.600 mmol) of K 2 C0 3 and 0.090 g (0.600 mmol) of Nal in 5 mL of DMF was heated at reflux temperature for 18 hours. The reaction mixture was filtered, the filtrate was poured into 5 mL of water and washed with 3 X 5 mL of ethyl acetate. The combined organic extracts were dried
  • PIPERIDINYL ⁇ PHENYL)METHAN ⁇ SULFONAMIDE Using Method II, the desired product was obtained.
  • X H NMR ' 400 MHz, CDC1 3 ) ⁇ 7.82-7.10 (m, 7H) , 3.41 (s, 3H) , 3.40-2.85 (m, 4H) , 2.82-2.35 (m, 5H) , 2.32 (s, 6H) , 2.22-1.80 (m, -6H) ; ESMS m/e : 429.3 (M + H) + .
  • PIPERIDINYL ⁇ PHENYL)ACETAMIDE Using Method III, the desired product was obtained. ⁇ NMR (400 MHz, CDC1 3 ) 6 7.90-6.80 (m, 8H) , 3.30-J ⁇ -.05 (m, 4H) , 2:70-2.45 (m, 3H) , 2.05 (s, 3H) , 1.98-1.65 (m, 8H) ; ESMS m/e : 444.0 (M + H) + .
  • PIPERIDINYL] PHENYL ⁇ -2-METHYLPROPANAMIDE A mixture of 3- methoxy-3 -phenyl-1-chloropropane (23.1 mg, 0.126 mmol), 2-methyl-N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.126 mmol), diisopropylethylamine (0.50 mL) and catalytic amount of tetrabutylammonium iodide in dioxane
  • PIPERIDINYL]PHENYL ⁇ PROPANAMIDE A mixture of 2-methyl- N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.100 mmol), 4-phenyl-1-chlorobutane (21.1 mg, 0.125 mmol-), diisopropylethylamine (0.50 mL) , catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) was heated at reflux temperature for 3 days. The reaction mixture was concentrated and chromatographed using preparative TLC plates [2.5% of NH 3 (2.0 M in methanol) in CHCI 3 ] afforded the product, 2-methyl-N- ⁇ 3- [1-
  • METHYLPROPANAMIDE A mixture of 2-methyl-N- [3- (4- piperidinyl) phenyl] propanamide (28.3 mg, 0.100 mmol), 3- methoxybenzyl chloride (19.6 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) , catalytic amount of tetrabutylammonium iodide and dioxane (2.0 mL) .
  • PIPERIDINYL ⁇ PHENYL) -2-METHYLPROPANAMIDE A mixture of 2- methyl -N- [3- (4-piperidinyl) phenyl] propanamide (28.3 mg, 0.100 mmol), 3 , 5-bis (trifluoromethyl) benzyl bromide (38.4 mg, 0.125 mmol), diisopropylethylamine (0.50 mL) , catalytic amount of tetrabutylammonium ⁇ iodide and dioxane (2.0 mL) .
  • the residue can either be washed with pentane (x3) and the combined pentane extracts were concentrated and chromatographed (silica with hexanes-EtOAc 8:1 as the eluent) to give the desired product (as described as a general procedure by: Srebnik, M.; Ramachandran, P.V.; Brown, H.C. J. Org. Chem. 1988, 53 , 2916-2920) . This procedure was performed on a smaller scale reaction and only a 40% yield of the product was realized.
  • PIPERIDINYL ⁇ PHENYL PROPANAMIDE: A mixture of N-(3- ⁇ l- [ (3R) -3-hydroxy-3-phenylpropyl] -4-piperidinyl ⁇ phenyl) -2- methylpropanamide (9.53 mg, 0.0250 mmol), phenol (4.70 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.22 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days.
  • PIPERIDINYL ⁇ PHENYL) - 2 -METHYLPROPANAMIDE A mixture of N- (3- ⁇ l- [ (3R) -3-hydroxy-3- phenylpropyl] -4- piperidinyl ⁇ phenyl) -2-methylpropanamide (9.53 mg, 0.0250 mmol), 4-methoxyphenol (6.20 mg, 0.050 mmol), triphenylphosphine (9.80 mg, 0.0375 mmol) and diethyl azodicarboxylate (5.2 mg, 0.0300 mmol) in THF (1.0 mL) was stirred at room temperature for 3 days.
  • reaction mixture was poured into water (50 mL) and the aqueous layer was extracted with methylene chloride (3x20 mL) . The combined organic extracts were washed with brine (20 L) , dried over Na 2 S0 4 and concentrated under reduced pressure.
  • the hydrochloric salt was prepared by addition of a slight excess of 1 N HCl in ether (1.2 eq.) to a solution of the free base in dichloromethane. The solvent was removed under reduced pressure, the residue was washed with ether and dried under reduced pressure Anal. Calc. for C 24 H 32 N 2 O 2 +HCl+0.8H 2 0: C, 66.82; H, 8.08 N, 6.49; Cl, 8.22. Found: C, 66.90; H, 7.78; N, 6.63 Cl, 8.52.
  • PIPERIDINYL ⁇ PHENYL) -2-METHYLPROPANAMIDE A mixture of N- (3- ⁇ l- [ (3R) -3-hydroxy-3-phenylpropyl] -4- piperidinyl ⁇ phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-fluorophenol (100 mg) , triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days.
  • PIPERIDINYL ⁇ PHENYL) -2-METHYLPROPANAMIDE A mixture of N- (3- ⁇ l- [ (3R) -3-hydroxy-3-phenylpropyl] -4- piperidinyl ⁇ phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 4-bromophenol (100 mg) , triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days.
  • N-(3- ⁇ l-[(3S)-3- (3-METHOXYPHENOXY) -3-PHENYLPROPYL] -4- PIPERIDINYL ⁇ PHENYL) -2-METHYLPROPANAMIDE A mixture of N- (3- ⁇ l- [ (3R) -3 -hydroxy-3-phenylpropyl] -4- piperidinyl ⁇ phenyl) -2-methylpropanamide (5.20 mg, 0.0137 mmol), 3 -methoxyphenol (100 mg) , triphenylphosphine (30.0 mg, 0.115 mmol) and diethyl azodicarboxylate (7.42 mg, 0.0426 mmol) in THF (0.50 mL) was stirred at room temperature for 3 days.

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Abstract

L'invention concerne des composés qui constituent des antagonistes sélectifs des récepteurs de l'hormone de concentration de la mélanine 1 (MCH1). L'invention concerne également une composition pharmaceutique contenant une quantité thérapeutiquement efficace du composé selon l'invention, et un excipient pharmaceutiquement acceptable. L'invention concerne en outre une composition pharmaceutique obtenue par combinaison d'une quantité thérapeutiquement efficace du composé selon l'invention et d'un excipient pharmaceutiquement acceptable. L'invention concerne également un procédé pour produire une composition pharmaceutique, ledit procédé consistant à combiner une quantité thérapeutiquement efficace du composé selon l'invention et un excipient pharmaceutiquement acceptable
PCT/US2002/021063 2001-07-05 2002-07-03 Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch WO2003004027A1 (fr)

Priority Applications (16)

Application Number Priority Date Filing Date Title
UA2004010518A UA75416C2 (en) 2002-01-09 2002-03-07 Substituted aniline piperidines as selective antagonists for mch
JP2003510038A JP2004536104A (ja) 2001-07-05 2002-07-03 Ｍｃｈ選択的アンタゴニストとしての置換されたアニリン−ピペリジン誘導体
HU0401880A HUP0401880A2 (hu) 2001-07-05 2002-07-03 Helyettesített anilin-piperidinek mint MCH-szelektív antagonisták, ezeket tartalmazó gyógyszerkészítmények és alkalmazásuk
EP02746843A EP1411942A4 (fr) 2001-07-05 2002-07-03 Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch
AU2002316531A AU2002316531B8 (en) 2001-07-05 2002-07-03 Substituted anilinic piperidines as MCH selective antagonists
EA200400146A EA005934B1 (ru) 2001-07-05 2002-07-03 Замещённые анилиновые пиперидины в качестве селективных антагонистов мсн
NZ530221A NZ530221A (en) 2001-07-05 2002-07-03 Substituted anilinic piperidines as MCH selective antagonists
MXPA03011886A MXPA03011886A (es) 2001-07-05 2002-07-03 Piperidinias anilinicas sustituidas como antagonistas selectivos de mch.
KR10-2004-7000087A KR20040027870A (ko) 2001-07-05 2002-07-03 Ｍｃｈ 선택적인 안타고니스트로서의 치환 아닐린 피페리딘
BR0210869-0A BR0210869A (pt) 2001-07-05 2002-07-03 Composto, composição farmacêutica, processo de preparar uma composição farmacêutica, métodos de tratar um indivìduo que sofre de um distúrbio, de depressão e de ansiedade, obesidade, bexiga hiperativa e um distúrbio em um indivìduo, de reduzir a massa corporal de um indivìduo e de aliviar incontinência de urgência urinária e os sintomas de um distúrbio em um indivìduo
IL15969702A IL159697A0 (en) 2001-07-05 2002-07-03 Substituted anilinic piperidines as mch selective antagonists
CA002454613A CA2454613A1 (fr) 2001-07-05 2002-07-03 Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch
US10/345,063 US7105544B2 (en) 2001-07-05 2003-01-14 Substituted alkyl amido piperidines
IS7085A IS7085A (is) 2001-07-05 2003-12-18 Setin anilinísk píperidín sem MCH kjörvís mótlyf
NO20040028A NO20040028L (no) 2001-07-05 2004-01-05 Substituerte anilinske piperidiner som MCH-selektive antagonister
US10/753,057 US7199135B2 (en) 2001-07-05 2004-01-06 Substituted alkyl amido piperidines

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US89979401A 2001-07-05 2001-07-05
US09/899,794 2001-07-05
US4258202A 2002-01-09 2002-01-09
US10/042,582 2002-01-09

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US10/345,063 Continuation-In-Part US7105544B2 (en) 2001-07-05 2003-01-14 Substituted alkyl amido piperidines
US10/753,057 Continuation-In-Part US7199135B2 (en) 2001-07-05 2004-01-06 Substituted alkyl amido piperidines

Publications (1)

Publication Number Publication Date
WO2003004027A1 true WO2003004027A1 (fr) 2003-01-16

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PCT/US2002/021063 WO2003004027A1 (fr) 2001-07-05 2002-07-03 Piperidines aniliniques substituees, utilisees comme antagonistes selectifs de la mch

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EP (1) EP1411942A4 (fr)
JP (1) JP2004536104A (fr)
KR (1) KR20040027870A (fr)
CN (1) CN1671386A (fr)
CA (1) CA2454613A1 (fr)
CO (1) CO5670352A2 (fr)
EA (1) EA005934B1 (fr)
HU (1) HUP0401880A2 (fr)
IL (1) IL159697A0 (fr)
IS (1) IS7085A (fr)
MX (1) MXPA03011886A (fr)
NO (1) NO20040028L (fr)
NZ (1) NZ530221A (fr)
PL (1) PL366624A1 (fr)
WO (1) WO2003004027A1 (fr)

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