WO2008057543A2 - Uii-modulating compounds and their use - Google Patents

Uii-modulating compounds and their use Download PDF

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WO2008057543A2
WO2008057543A2 PCT/US2007/023383 US2007023383W WO2008057543A2 WO 2008057543 A2 WO2008057543 A2 WO 2008057543A2 US 2007023383 W US2007023383 W US 2007023383W WO 2008057543 A2 WO2008057543 A2 WO 2008057543A2
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optionally substituted
benzamide
chlorophenyl
naphthyl
propyl
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PCT/US2007/023383
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French (fr)
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WO2008057543A3 (en
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Ingrid Kristina Luthman
Fredrik Lehmann
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Acadia Pharmaceuticals Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/125—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/77—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
    • C07C233/78—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton

Definitions

  • This invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry, molecular biology and medicine.
  • it relates to compounds that modulate the activity of the human Urotensin II receptor (UII), and to the use of the compounds for the treatment and prevention of diseases and disorders related to UII.
  • UUII human Urotensin II receptor
  • Compounds that modulate the activity of the human UII receptor have also been described in U.S. Provisional Patent Application No. 60/690,312, entitled “UII-MODULATING COMPOUNDS AND THEIR USE,” filed June 10, 2005, and in U.S. Patent Application No. 1 1/449,411, entitled “UII-MODULATING COMPOUNDS AND THEIR USE,” filed June 8, 2006, the disclosures of which are hereby incorporated by reference in their entirety.
  • Urotensin II is an endogenous peptide agonist for a recently identified human G-protein coupled receptor.
  • the human receptor is homologous to the rat orphan receptor GPRl 4.
  • Urotensin II is a cyclic neuropeptide found to be a potent vasoconstrictor in some systems and a vasodilator in others.
  • the peptide is expressed in the motor neurons of the CNS, smooth muscle cells of the bladder and muscle cells of the heart. Its sequence is highly conserved among species, consisting of 11 amino acids in humans, 12 amino acids in fish, and 13 in frogs, with a fully conserved cyclic region from fish to humans.
  • the natural endogenous ligand, urotensin II has been found to modulate the function of the urotensin II receptor. There is therefore a need in the art for non- endogenous ligands and modulators of the urotensin II receptor at least for use as medicaments.
  • Human urotensin II has been reported as an endothelium-dependent vasodilator in rat small arteries (Br. J. Pharmacol., 130(8); 1865-1870).
  • the human urotensin II peptide acts as a vasoconstrictor of rat and primate aorta, and induced a large increase in peripheral resistance in the circulation of primates along with a dramatic decrease in heart rate (Nature, 401; 282-286).
  • urotensin II peptide induced a decrease in blood pressure (General and Comparative Endocrinology 64; 435-439, Neuroendocrinol. Lett. 14(5); 357-363).
  • Indications are that the physiological role of urotensin II in mammals is strongly tissue dependent.
  • the mRNA for the human urotensin II receptor is widely expressed in human tissue and is most abundant in heart and pancreas.
  • the cardiovascular tissue of the left atrium and ventricle of the heart, and arterial tissue such as in the aorta are especially rich in expression of the urotensin II receptor.
  • the receptor is also distributed within the smooth muscle cells of the bladder, coronary arteries, and the aorta, the endothelial cells of the coronary artery and umbilical vein, and the motor neurons of the spinal cord.
  • the distribution of the pro-pre-urotensin II mRNA in the human central nervous system is restricted primarily to the medulla oblongata of the brain and the spinal cord with the urotensin II-like immunoreactivity localized to motor neurons of the ventral horn.
  • the distribution of the pro-pre-urotensin II mRNA in peripheral tissue is primarily restricted to the adrenal glands, the kidneys and the spleen. Accordingly, the UII receptor has a potential role in diseases such as renal failure, and diabetes. (Douglas, S.; Dhanak, D.; Johns, D. G. From 'gills to pills': urotensin II as a regulator of mammalian cardiorenal function.
  • GPR- 14 the urotensin II receptor
  • G-protein coupled receptor the G-protein coupled receptor
  • the only brain regions which express this mRNA are the pedunculopontine tegmental nucleus (PPT), and the lateral dorsal tegmental nucleus (LDTG). These brain stem nuclei are the source of the ascending acetylcholine projection neurons in mammals, and as such are quite well studied, and have had a number of important physiological roles assigned to them.
  • PPT pedunculopontine tegmental nucleus
  • LDTG lateral dorsal tegmental nucleus
  • the present investigators have identified a class of non-endogenous, low molecular weight non-peptide organic compounds that act as specific modulators of the urotensin II receptor.
  • aspects of the present invention relate to compounds of Formula I, Ia, and Ib, as defined herein, or salts or prodrugs thereof.
  • the compounds may appear as mixtures of isomers or as separated and purified isomers.
  • Other aspects of the present invention relate to a complex between the human urotensin II receptor and a compound of the invention and to a method of preparing a complex between a compound of the invention and human urotensin II receptor comprising combining said compound in an effective concentration with human urotensin II receptor.
  • a further aspect of the invention relates to a use of compound of Formula I, Ia, and Ib, salts thereof, or compositions comprising said compounds, for the preparation of a medicament for the treatment of diseases and disorders for which activation or modulation of the urotensin II receptor produces a beneficial response in said disease or disorder.
  • the diseases and disorders are selected from the group consisting of those associated with CNS function, such as Parkinson's Disease, Alzheimer's Disease, depression, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy; OPCA; ADHD; schizophrenia; sleep disorders such as insomnia and narcolepsy; and autonomic dysfunctions such as Shy Drager syndrome.
  • the diseases or disorders are selected from the group consisting of cardiovascular disorders such as hypertension; hypotensive states related to shock, sepsis, major surgery, congestive heart failure, and pulmonary disorders.
  • the diseases or disorders are selected from ischemia such as heart ischemia, renal disorders, urinary disorders such as incontinence, and tumor growth in cancer.
  • the diseases or disorders are selected from the group consisting of stroke, asthma, and restenosis.
  • a variety of disease states have been suggested to be associated with either an altered functioning of the urotensin II receptor or to an imbalance of urotensin II.
  • alteration of urotensin II and signaling through its cognate receptor may be associated with, amongst other disease-states, both hypertension and hypotension.
  • a further aspect of the invention relates to method of altering the vascular pressure in a mammal, comprising constricting or dilating vascular tissue in said mammal, said constricting or dilating being performed by the activation of urotensin receptor signaling, said activation being performed by the administration of an effective amount of a compound of Formula I, Ia, or Ib.
  • the invention relates to methods of altering the heart rate in a mammal, comprising the modulation of urotensin receptor signaling, said modulation being performed by the administration of an effective amount compound of Formula I, Ia, or Ib.
  • a method of treating diseases or disorders in a mammal comprising administering an effective amount of a compound of Formula I, Ia, or Ib is within the scope of the present invention.
  • the present invention further relates to a method of treating diseases for which modulation of the urotensin II receptor produces a physiologically beneficial response in said disease, such as those associated with CNS function and cardiovascular diseases.
  • the invention further relates to a method of altering the locomotor activity of a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, Ia, or Ib.
  • This alteration of locomotor function may indicate a CNS-mediated response of a compound of Formula I, Ia, or Ib and CNS mediated function of the urotensin II receptor that suggests application in CNS therapeutic areas.
  • a further aspect of the invention relates to the treatment of diseases and disorders associated with CNS function.
  • the distribution of the urotensin II receptor within cardiovascular tissue a further aspect of the invention relates to the treatment of cardiovascular disorders.
  • the present invention relates to a compound of Formula I, Ia, or Ib, or salts or prodrugs thereof, complexed with a human urotensin II receptor,
  • An aspect of the invention is related to a compound of Formula (I):
  • X is selected from the group consisting of: Ci-C 4 alkylene, Ci-C 4 alkenylene, Ci-C 4 alkynylene, - N(Ri)-, and -O-;
  • Y is selected from the group consisting of: Ci-C 4 alkylene, Ci-C 4 alkenylene,
  • W is selected from the group consisting of: Q-Qalkylene, Q ⁇ alkenylene, and d-Gjalkynylene;
  • R 1 and R la are each independently H or selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; Cyi is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl; Cy 2 is
  • R 2 and R 2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R 2 and R 2a can be taken together to form an optionally substituted C 2 -Ci 0 heteroalicyclyl; R 3 , R 3c , R 3c j, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, hydroxyl, nitro
  • R 1 , R l3 and R ⁇ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; or if two R groups selected from the group consisting of R 3> R 33 , R 3 b, R 3 c, R 3 d, R 3 e, and R 3 f are covalently bonded to adjacent atoms, then the two R groups can be taken together to form a optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heteroalicyclyl group.
  • X is -N(Ri)-.
  • R 1 and Ri a are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C 4 alkyl.
  • R 2 and R 23 are each independently selected from the group consisting of hydrogen and optionally substituted CpC 4 alkyl.
  • X is -N(Ri)-
  • Ri and R 13 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C 4 alkyl, and R 2 and R 2a are each independently selected from the group consisting of hydrogen and optionally substituted Cj-C 4 alkyl.
  • X is -N(Ri)-; Y is selected from the group consisting of
  • Ri and R] 3 are each independently selected from the group consisting of hydrogen and C 1 -C 4 alkyl; and R 2 and R 2a are each independently selected from the group consisting of hydrogen and Ci-C 4 alkyl.
  • Cy 1 is an optionally substituted phenyl.
  • X is -N(R 1 )-, Y is selected from the group consisting of -C(O)-, -
  • R 3 , R 3b , R 3c , and R 3d , in Cy 2 are hydrogen and R 3a in Cy 2 is an optionally substituted phenyl or an optionally substituted naphthyl.
  • R 3 , R 3b , R 3c , and R 3 d, in Cy 2 are hydrogen and R 3a in Cy 2 is a 4-substituted phenyl or 2-napthyl.
  • R 3 R 3b , R 3c , and R 3 d, in Cy 2 are hydrogen and R 3 in
  • Cy 2 is a 4-chlorophenyl, 4-methoxyphenyl, or 2-napthyl.
  • X is -N(Ri)-
  • Y is a 4-chlorophenyl, 4-methoxyphenyl, or 2-napthyl.
  • R 3 , R 3a , R 3c , and R 3 d, in Cy 2 are hydrogen and R 3b in Cy 2 is a substituted phenyl or an optionally substituted naphthyl.
  • R 3 , R 3a , R 3c , and R 3d , in Cy 2 are hydroge and R 3 b in Cy 2 is a 4-substituted phenyl or 2-napthyl.
  • R 3 , R 3a , R 3c , and R 3 d, in Cy 2 are hydrogen and R 3b in Cy 2 is a 4-chlorophenyl, 4- methoxyphenyl, or 2-napthyl.
  • X is -N(Ri)-
  • 0R ia , and R 3b in Cy 2 is an substituted phenyl or an optionally substituted [0026]
  • the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-phenylbenzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-chlorophenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-methoxyphenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(2-naphthyl)benzamide;
  • N-[ 1 -(4-Chlorophenyl)-4-dimethylaminobutyl]benzamide as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or polymorph; or as metabolite or a pharmaceutically acceptable salt or prodrug thereof.
  • the compound is N-[3-Dimethylamino-l-(2- naphthyl)propyl]-4-(4-chlorophenyl)benzamide. In an embodiment, the compound is N-[3- Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide.
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide;
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of:
  • the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-chlorophenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-methoxyphenyl)benzamide; N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide; and N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide.
  • Another aspect of the invention relates to a compound of Formula (Ia):
  • (Ia) as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of: Ci-C 4 alkylene, Ci-C 4 alkenylene, Ci-C 4 alkynylene, -N(Ri)-, and -O-; Y is selected from the group consisting of: Ci-C 4 alkylene, Ci-C 4 alkenylene, Ci-C 4 alkynylene, -C( O)-, -
  • W is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, and Ci-C 4 alkynylene;
  • R 1 and R la are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; Cyi is or optionally substituted naphthyl;
  • Cy 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 and R 2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R 2 and R 2a can be taken together to form an optionally substituted C 2 -Ci 0 heteroalicyclyl; and R 3) R 3a> , R 31 ,, R 3c , and R 3 a, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalken
  • Cy 2 is optionally substituted phenyl, and Cyi is an alkyl-substituted phenyl or naphtyl. In an embodiment, Cyi is 4-methylphenyl or 2-naphthyl.
  • the compound is selected from the group consisting of: N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-phenylbenzamide; and N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-phenylbenzamide.
  • Another aspect of the invention relates to a compound of Formula (Ib):
  • Ci-C 4 alkylene Ci-C 4 alkenylene, Ci-C 4 alkynylene, -N(Ri)-, and -O-;
  • Y is 0R ia ;
  • W is selected from the group consisting of: Ci-C 4 alkylene, Ci-C 4 alkenylene, and Ci- C 4 alkynylene;
  • Ri and Ri 3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroalicyclyl; Cyi is
  • Cy 2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
  • R 2 and R 2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R 2 and R 2a can be taken together to form an optionally substituted C 2 -Ci 0 heteroalicyclyl; and R 3 , R 3a ,, R 3 b, R 30 and R 3 d, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted
  • X is -N(Ri)--
  • Cy 2 is optionally substituted phenyl.
  • Ri 3 in Y is alkyl.
  • X is -N(Ri)-
  • Cy 2 is optionally substituted phenyl
  • Rj 3 in Y is alkyl.
  • R] 3 in Y is methyl.
  • the compound is selected from the group consisting of: N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(i?)-2-methoxy-2-phenylacetamide;
  • the compounds described herein particularly the compounds according to the Formulae (I), (Ia), and (Ib), have the carbon atom adjacent to both X and Cyi in the S-configuration.
  • Another aspect of the invention relates to a salt, polymorph, ester, metabolite or prodrug of the compounds according to the Formulae (I), (Ia), and (Ib), and all of their variations.
  • Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable amount of one or more compounds according to the Formulae (I), (Ia), and (Ib).
  • Another aspect of the invention relates to a method of treating or ameliorating a disorder selected from the group consisting of a C ⁇ S disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis,and diabetes comprising identifying a subject in need of said treatment or amelioration and administering to the subject a therapeutically effective amount of one or more compounds according to the Formula (I), (Ia), or (Ib).
  • a disorder selected from the group consisting of a C ⁇ S disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis,and diabetes
  • the C ⁇ S disorder is selected from group consisting of Parkinson's Disease, Alzheimer's Disease, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy, OPCA, ADHD, and schizophrenia.
  • the cardiovascular disorder is selected from the group consisting of heart failure, atherosclerosis, hypertension and hypotensive states related to shock, sepsis, major surgery, congestive heart failure, and pulmonary disorders.
  • the sleep disorder is selected from the group consisting of insomnia and narcolepsy.
  • Another aspect of the invention provides a method of identifying a compound which is an agonist, inverse agonist, or antagonist of a Urotensin II receptor, the method comprising contacting the UII receptor with at least one or more test compounds according to the Formulae (I), (Ia), and (Ib), and determining any increase or decrease in activity level of said UII receptor.
  • Another aspect of the invention provides a use of a compound described herein, paricularly one or more compounds according to the Formulae (I), (Ia), and (Ib), to treat or ameliorate a disorder selected from the group consisting of a CNS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis, and diabetes.
  • a disorder selected from the group consisting of a CNS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis, and diabetes.
  • the compounds of Formula I, Ia, or Ib do not include compounds disclosed in WO 2006/135694, filed on JuIe 8, 2006 and entitled “UII- MODULATING COMPOUNDS AND THEIR USE.”
  • Figure 1 is a comparison of pEC50 values with respect to the position of the biphenyl in amides ⁇ Al - C8 ⁇ .
  • Figure 2 is a summary of the structure activity relationship (SAR) results from this study and those in prior studies.
  • Figure 3 is the agonist profiles at the human UT receptor in a PI hydrolysis assay.
  • R may be "taken together" as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group.
  • RIa and RIb of an NRIa RIb group are indicated to be “taken together,” it means that they are covalently bonded to one another at their terminal atoms to form a ring:
  • An R group of this invention may be substituted or unsubstituted.
  • IC 50 refers to an amount, concentration of dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of GPCR, including Urotensin II receptor, activity, in an assay that measures such response in an assay that measures such response for example but not limited to R-SATTM described herein.
  • EC 50 refers to an dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response for example but not limited to R- SATTM described herein.
  • C m to C n in which "m” and “n” are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from “m” to "n", inclusive, carbon atoms.
  • a "Ci to C 4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, CH 3 CH(CH 3 )-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 CH-. If no "m” and "n” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system that has a fully delocalized pi-electron system.
  • aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, iso
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the heteroaryl group may be optionally fused to a benzene ring.
  • heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine and triazine.
  • a heteroaryl group of this invention may be substituted or unsubstituted.
  • hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NRuRi b and protected amino.
  • substituent group(s) that is(are)
  • alkyl refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group.
  • An alkyl group of this invention may comprise from 1 to 20 carbon atoms.
  • An alkyl group herein may also be of medium size having 1 to 10 carbon atoms. It is presently preferred that an alkyl group of this invention be a lower alkyl having 1 to 4 carbon atoms.
  • alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
  • An alkyl group of this invention may be substituted or unsubstituted.
  • substituent group(s) that is(are) one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -
  • Aralkyl groups are aryl groups connected, as substituents, via an alkylene group.
  • the aryl and alkylene group of an aralkyl group may be substituted or unsubstituted. Examples includes but are not limited to benzyl, substituted benzyl, 2- phenylethyl, 3-phenylpropyl, naphtylalkyl.
  • Heteroaralkyl groups are understood as heteroaryl groups connected, as substituents, via an alkylene group. The heteroaryl and alkylene group of a heteroaralkyl group may be substituted or unsubstituted.
  • Examples includes but are not limited to 2- thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, imidazolylalkyl, and their substituted as well as benzo-fused analogs.
  • alkoxy and “alkylthio” refers to RO- and RS-, in which R is an unsubstituted or substituted alkyl, including a lower alkyl. Examples include but are not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
  • aryloxy and arylthio refers to RO- and RS-, in which R is an unsubstituted or substituted aryl, such as but not limited to phenyl.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • arylalkylidene refers to an group to an alkylidene group in which either R' and R" is an aryl group.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • alkylene refers to an alkyl group, as defined here, which is a biradical and is connected to two other moieties.
  • An alkylene group of this invention may be unsubstituted or substituted.
  • methylene (-CH 2 -), ethylene (-CH 2 CH 2 -), propylene (- CH 2 CH 2 CH 2 -), isopropylene (-CH 2 -CH(CH 3 )-), and isobutylene (-CH 2 -CH(CH 3 )-CH 2 -) are examples, without limitation, of an alkylene group.
  • alkenylene refers to an alkylene group, as defined here, that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • the group is a bivalent radical derived by removing a hydrogen atom from each of the terminal carbon atoms. If only one double bond is present in the hydrocarbon chain is it represented by the formula -(C n H 2n- :)---
  • An alkenylene group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
  • alkynylene refers to an alkylene group, as defined here, that contains in the straight or branched hydrocarbon chain one or more tripple bonds.
  • the group is a bivalent radical derived by removing two hydrogen atoms from each of the terminal carbon atoms. If only one triple bond is present in the hydrocarbon chain is it represented by the formula -(C n H 2n-4 )-.
  • An alkynylene group of this invention may be unsubstituted or substituted.
  • acyl refers to an "RC(O)-" group with R as defined above.
  • cycloalkyl refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. Cycloalkyl groups of this invention may range from C 3 to Ci 0 . In other embodiments it may range from C 3 to C 6 . A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above with regard to substitution of an alkyl group.
  • cycloalkenyl refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl,” as defined herein).
  • a cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the groups disclosed above with regard to alkyl group substitution.
  • heteroalicyclic or “heteroalicyclyl” refers to a stable 3- to 18- membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.
  • the "heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic” or “heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings.
  • Heteroalicyclyl groups of this invention may be unsubstituted or substituted.
  • the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido.
  • heteroalicyclic or “heteroalicyclyl” include but are not limeted to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.
  • the ring systems of the cycloalkyl, heteroalicyclic (heteroalicyclyl) and ccycloalkenyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
  • halo or halogen refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1 -chloro-2-fluoromethyl, 2- fluoroisobutyl.
  • haloalkoxy refers to RO-group in which R is a haloalkyl group.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2-fluoroisobutyoxy.
  • An "O-carboxy” group refers to a "RC(O)O-" group with R as defined above.
  • a "trihalomethanesulfonyl” group refers to an "X 3 CSO 2 -" group wherein X is a halogen.
  • a "cyano" group refers to a "-CN” group.
  • An “isocyanato” group refers to an "-NCO” group.
  • a "thiocyanato" group refers to a "-CNS” group.
  • An "isothiocyanato" group refers to an " -NCS” group.
  • a “sulfonyl” group refers to an “SO 2 R” group with R as defined above.
  • S-sulfonamido refers to a "-SO 2 NRi a Ri b " group with Ri 3 and Rib as defined above.
  • N-sulfonamido refers to a "RSO 2 N(Ri a )-" group with R and Ri a as defined above.
  • a "trihalomethanesulfonamido" group refers to an "X 3 CSO 2 N(R)-" group with X as halogen and R as defined above.
  • N-amido refers to a "RC(O)NR 13 -” group with R and Ru as defined above.
  • Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999).
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • Ci-C 3 alkoxyphenyl may include one or more of the same or different alkoxygroups containing one, two or three atoms.
  • each center may independently be of R-conf ⁇ guration or S-configuration or a mixture thereof.
  • the compounds provided herein may be enatiomerically pure or be stereoisomeric or dia stereomeric mixtures.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound.
  • Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base.
  • Base- formed salts include, without limitation, ammonium salt (NH 4 + ); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine.
  • NH 4 + ammonium salt
  • alkali metal such as, without limitation, sodium or potassium
  • alkaline earth such as, without limitation, calcium or magnesium
  • salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine
  • salts with the amino group of amino acids such as, without limitation, arginine and lysine.
  • Useful acid- based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.
  • solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
  • a "prodrug” refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration.
  • the prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug.
  • Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not.
  • the prodrug may also have better solubility than the active parent drug in pharmaceutical compositions.
  • prodrug a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial.
  • prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound.
  • the term “complement” refers to a oligonucleotide or polynucleotide that hybridizes by base-pairing, adenine to tyrosine and guanine to cytosine, to another oligonucleotide. The hybridized oligonucleotides are then said to be complementary.
  • to "modulate" the activity of UII means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner.
  • a natural binding partner is an endogenous molecule that is an agonist for the receptor.
  • to "detect" changes in the activity of UII or of a UII subtype refers to the process of analyzing the result of an experiment using whatever analytical techniques are best suited to the particular situation. In some cases simple visual observation may suffice, in other cases the use of a microscope, visual or UV light analyzer or specific protein assays may be required. The proper selection of analytical tools and techniques to detect changes in the activity of UII or a UII sub-type are well-known to those skilled in the art.
  • An "agonist” is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
  • partial agonist refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
  • An "inverse agonist” is defined as a compound which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
  • antagonist refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor were unoccupied.
  • An antagonist attenuates the action of an agonist on a receptor.
  • An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
  • a "subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • a "patient” refers to a subject that is being treated by an M. D. or a D. V. M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a "diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • U.S. Patent No. 4,564,641 discloses 2-phenyl-2-(2-phenethyl)-4- dialkylaminobutonoic acids as starting materials for the preparation of l-oxo-2-phenyl-2-(2- alkylaminoehtyl)-l,2,3,4,-tetrahydronaphthalenes, compounds useful for treating depression.
  • U.S. Patent No. 3,880,885 discloses benzamides as starting materials for the preparation of tertiary aminoethyl isochromans and isocoumarins, compounds useful as antihypertensive or diuretic agents.
  • one aspect of the present invention relates to the use of a compound selected from the group comprising a compound of Formula I, Ia, or Ib for the preparation of a medicament for the treatment of diseases and disorders for which activation or modulation of the urotensin II receptor produces a physiologically beneficial response in a given disorder.
  • a further aspect of the invention relates to the use of compound of Formula I, Ia, or Ib for the preparation of a medicament for the treatment of diseases and disorders in a mammal selected from the group consisting of diseases and disorders associated with CNS function, such as Parkinson's Disease, Alzheimer's Disease, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy, OPCA, ADHD, schizophrenia, sleep disorders such as insomnia, and autonomic dysfunctions such as Shy Drager syndrome.
  • compounds of Formula I, Ia, or Ib may be useful as medicaments to treat cardiovascular disorders such as hypertension; hypotensive states related to shock, sepsis, major surgery and congestive heart failure.
  • the present invention further relates to a method of altering the locomotor activity of a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, Ia, or Ib.
  • the decrease in locomotor activity and expression of urotensin II receptor in the brainstem are consistent with action of the compounds of Formula I, Ia, or Ib on the CNS to alter sleep/wake patterns.
  • the PPT and LDTG send ascending projections to the thalamus that are critical mediators of sleep and wakefulness in humans. During the sleep state, thalamocortical activity is dominated by rhythmic oscillations that are abolished during the transition to wakefulness, resulting in a significant increase in neuronal responsiveness.
  • the cholinergic cells groups are one of the primary mediators of this transition, where neuronal activity of the PPT and LDTG neurons increase with wakefulness. (Huitron- Resendiz et al., Journal of Neuroscience (2005) 25:5465-5474.) Therefore, modulators of GPR-14 which can increase the activity of these cells may increase wakefulness in humans, while those that decrease the activity of these neurons may induce sleep. Consistent with these observations are the potential clinical use of modulators of GPR-14 as CNS stimulants and sleep promoting CNS depressants (both perhaps without the addictive and physical dependency properties that limit the use of current agents).
  • potential disease states and therapeutic indications for which compounds of Formula I, Ia, or Ib may be connected to include narcolepsy, non-addictive CNS Stimulant, ADHD and Insomnia
  • narcolepsy non-addictive CNS Stimulant
  • ADHD insomnia
  • another aspect of the invention to the use of compound of Formula I, Ia, or Ib for the preparation of a medicament for sleep disorders such as insomnia.
  • a method of altering the vascular pressure in a mammal comprising constricting or dilating vascular tissue in said mammal, the constricting or dilating is performed by the activation of urotensin receptor signaling, said activation being performed by the administration of an effective amount compound of Formula I, Ia, or Ib is anticipated.
  • method of altering the heart rate in a mammal comprising the activation of a urotensin receptor, said activating being performed by the administration of an effective amount compound of Formula I, Ia, or Ib is also anticipated.
  • terapéuticaally effective amount is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes alleviation of the symptoms of the disease being treated.
  • Another embodiment is a method of identifying a compound which regulates activity of an Urotensin II receptor by culturing cells that express the Urotensin II receptors; incubating the cells with at least one compound of Formula I, Ia, or Ib as defined herein; and determining any change in activity of the Urotensin II receptor so as to identify a compound of Formula I, Ia, or Ib which regulates activity of a Urotensin II receptor.
  • Another embodiment is a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of Formula I, Ia, or Ib as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
  • composition refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration.
  • compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • physiologically acceptable defines a carrier or diluent that does not abrogate the biological activity and properties of the compound.
  • the pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
  • Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above.
  • the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art.
  • Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • suitable coatings may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions may take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or
  • the compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increases the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
  • the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • a suitable vehicle e.g., sterile pyrogen-free water
  • the compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • a common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • VPD co-solvent system which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80TM, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol.
  • the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics.
  • co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80TM; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone.
  • other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity.
  • the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • additional strategies for protein stabilization may be employed.
  • salts may be provided as salts with pharmaceutically compatible counterions.
  • Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
  • compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • the exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety).
  • the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight.
  • the dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
  • the daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day.
  • compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day.
  • the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg.
  • the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
  • Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
  • the effective local concentration of the drug may not be related to plasma concentration.
  • composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Example 1 - Synthesis of the Carboxylic Acids of the Present Invention [0162] General: All chemicals were purchased from Aldrich, Acros, Lancaster or Maybridge and were used without prior purification. 1 H (400 MHz) and 13 C (100 MHz) NMR spectra were recorded in CD 3 OD unless otherwise stated using a JEOL JMN-ECP400 instrument. All reactions were monitored by TLC (Merck silica gel 60 F 254 ) and analyzed under UV (254 nm). Melting points were recorded on a Buchi melting point B-545 apparatus and are uncorrected. HRMS were recorded at Inovacia (Stockholm Sweden) using an Agilent MSD-TOF (G 1969A) connected to an Agilent 1 100 HPLC system. Elemental analyses were performed at Kolbe Analytishe Laboratorium, (M ⁇ lheim an der Ruhr, Germany).
  • the carboxylic acids 2, 4, 6, and 8 were created by the following general procedure: 3- or 4-iodobenzoic acid (1.24 g, 5 mmol), K 2 CO 3 (2.7 g, 20 mmol) and the appropriate boronic acid (4-chlorophenyl (0.89 g, 5.5 mmol) or 2-naphthyl (0.95 g, 5.5 mmol)) were dissolved in a mixture Of H 2 O (7.5 ml) and ethanol (7.5 Ml) and heated to 180 °C for 15 min using microwave heating.
  • R 1 3-I or 4-I 2
  • R 2 3-(4-chlorophenyl) 4
  • R 2 3-(2-naphthyl) 6
  • R 2 4-(4-chlorophenyl) 8
  • R 2 4-(2-naphthyl)
  • Reagents and conditions i) LiAIH 4 , THF. ii) CH 3 CN, H 2 SO 4 , -15 0 C, iii) 6M HCI reflux
  • Ketone II 3 (3.7 g, 14.7 mmol) was dissolved in THF (250 mL). LAH (0.57 g, 15.0 mmol) was added slowly and the mixture was stirred for 18 h. NaOH (1 M) (100 mL) was added dropwise until pH 14. The resulting mixture was extracted twice with EtOAc (150 mL + 100 mL). The organic phases were combined, washed with water (200 mL) and brine (200 mL) and concentrated to afford 13 as a yellow oil (3.7 g, 99%).
  • Ketone 123 (1.5 g, 6.6 mmol) was reacted according to the same procedure as described for 13 to afford 14 as a yellow oil (1.2 g, 80%).
  • the crude oil was dissolved in CH2C12 and applied to a SAX-2 ion-exchange column, washed with CH2C12 and MeOH.
  • the product was eluted using methanolic NH3 (2M), and concentrated.
  • the pure products were converted to the corresponding hydrochloride salts for analysis, storage and biological testing.
  • the salts were hygroscopic and turned into slight yellow oils immediately after isolation.
  • R-SAT-testing R-SATTM assays for pharmacological testing were performed as previously described, with the following modifications.
  • NIH-3T3 cells were grown to 80% confluence in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% bovine calf serum (Hyclone) and 1% penicillin/streptomycin/glutamine (Invitrogen).
  • DMEM Dulbecco's modified Eagle's medium
  • Hyclone bovine calf serum
  • Invitrogen penicillin/streptomycin/glutamine
  • the compounds were incubated at 1 ⁇ M in the presence of human or rat liver microsomes (0.5 mg protein/mL), using a Tecan liquid handling robot (LHR).
  • LHR Tecan liquid handling robot
  • a Tris buffer 100 mM, pH 7.4 at 37 0 C
  • the compound was mixed with microsomes and a five-minute pre-incubation period was allowed.
  • the enzymatic reaction was initiated by addition of NADPH (2.0 mM) and samples were drawn at 0, 5, 10, and 30 min.
  • the reaction was stopped by protein precipitation by dispensing the samples into a deep well plate containing acetonitrile, the deep well plate was then centrifuged offline from the LHR.
  • TsA cells were seeded at 10,000 cells/well in Dulbecco's Modified Eagle Medium (DMEM, Invitrogen) supplemented with 10% fetal calf serum, penicillin (100 units/mL) and streptomycin (100 mg/mL) in a 37 0 C humidified atmosphere containing 5% CO 2 . Eighteen hours later, the cells were transfected with the indicated plasmid DNAs (30 ng/well) using PolyFect (Qiagen) 0.5 ⁇ l/well.
  • DMEM Dulbecco's Modified Eagle Medium
  • DMEM culture medium containing 0.2 ⁇ Ci 2-[ 3 H]-myo-inositol (NETl 14, 37 MBg/mL, PerkinElmer) per well (0.1 mL).
  • the cells were washed and incubated with Hank's Balanced Salt Solutions (Invitrogen) supplemented with CaCl 2 (1 mM), MgCl 2 (1 mM), LiCl (10 mM) and BSA 0.2% for 45 min.
  • the buffer was removed, and the cells were incubated for another 45 min at 37 0 C in the same buffer with the indicated concentrations of freshly made ligands.
  • the reaction was stopped by exchange with ice-cold formic acid (20 mM), and the total [ 3 H]inositol phosphates (IPl, IP2 and IP3) formation was determined by ion-exchange chromatography on 1 mL-minicolumns loaded with 200 ⁇ l of a 50% suspension of AG 1-X8 resin (200-400 mesh, Formate form, Bio-Rad, Hercules, CA). The columns were washed with ammonium hydroxide (1 mL 40 mM, pH 9) after loading the cell extracts and then eluted with ammonium formate (0.4 mL 2M) in formic acid (0.1 M).
  • a colourless block crystal of N-[3-dimethylaminopropyl-l-(2-naphthyl)]- 1 -methoxy-2-phenyl-acetamide HCl (C 24 H ⁇ ClN 2 O 2 ) (-)- ⁇ C9 ⁇ having approximate dimensions of 0.40 x 0.30 x 0.25 mm 3 was mounted with epoxy cement on the tip of a fine glass fiber. All measurements were made on a Nonius CAD4 diffractometer with graphite monochromated Mo-Ka radiation.
  • Efficacy 131 ⁇ 8 Efficacy 83 ⁇ 4 Efficacy 77 ⁇ 3 a Results were determined in R-SAT assays and are expressed as pEC50, the negative of the log EC50 in molarity. Results are the average ⁇ standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. b The % efficacy values are normalized to UII at 100%. cNA No detectable activity.d For experimental details, see ref 1.
  • Results were determined in R-SAT assays and are expressed as pEC50, the negative of the log EC50 in molarity. Results are the average ⁇ standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. bThe % efficacy values are normalized to UII at 100%. cFor experimental details, see ref 1.
  • the agonist has the (S)- configuration as all resolved (5)-enantiomers are more than 10 times more potent than their corresponding (7?)-enantiomers.
  • the linker between the aromatic rings is more sensitive to direction than size as amides, ureas, carbamates and esters are active, but not ethers or sulfonamides. 1 In the amide series different spacers between the carbonyl group and the aromatic ring denoted A in Figure 2 are tolerated such as methylene, ethylene, vinyl and ethynyl.
  • substitution pattern in the aromatic ring denoted B in Figure 2 plays a role for the activity as the 4-chlorophenyl substituted derivatives (Al - A8) show high activities compared to the 4-methylphenyl substituted analogues (Bl - B8). As the size of a methyl group and a chlorine atom is about equal, this difference can be attributed to electronic effects.
  • UII racemic A5 and (+)-(S)-A5 were tested for activity in PI hydrolysis assays, at cells transiently expressing recombinant human UT receptors.
  • UII was shown to be a potent agonist, with a pECso-value of 9.5, approximately 30-100 fold lower than its potency in RSAT, as can be seen in Figure 3 and in Table 6 shown below.

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Abstract

Disclosed herein are novel aromatic-containing compounds and methods for using various aromatic-containing compounds for treatment and prevention of diseases and disorders related to the Urotensin II receptor.

Description

UII-MODULATING COMPOUNDS AND THEIR USE
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional Application No. 60/864,590, filed on November 6, 2006 and entitled, "U-II Modulating Compounds and Their Use," which is herein incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION Field of the Invention
[0002] This invention relates to the fields of organic chemistry, pharmaceutical chemistry, biochemistry, molecular biology and medicine. In particular it relates to compounds that modulate the activity of the human Urotensin II receptor (UII), and to the use of the compounds for the treatment and prevention of diseases and disorders related to UII. Compounds that modulate the activity of the human UII receptor have also been described in U.S. Provisional Patent Application No. 60/690,312, entitled "UII-MODULATING COMPOUNDS AND THEIR USE," filed June 10, 2005, and in U.S. Patent Application No. 1 1/449,411, entitled "UII-MODULATING COMPOUNDS AND THEIR USE," filed June 8, 2006, the disclosures of which are hereby incorporated by reference in their entirety.
Description of the Related Art
[0003] Urotensin II is an endogenous peptide agonist for a recently identified human G-protein coupled receptor. The human receptor is homologous to the rat orphan receptor GPRl 4.
[0004] Urotensin II is a cyclic neuropeptide found to be a potent vasoconstrictor in some systems and a vasodilator in others. The peptide is expressed in the motor neurons of the CNS, smooth muscle cells of the bladder and muscle cells of the heart. Its sequence is highly conserved among species, consisting of 11 amino acids in humans, 12 amino acids in fish, and 13 in frogs, with a fully conserved cyclic region from fish to humans. [0005] The natural endogenous ligand, urotensin II, has been found to modulate the function of the urotensin II receptor. There is therefore a need in the art for non- endogenous ligands and modulators of the urotensin II receptor at least for use as medicaments.
[0006] Several responses to urotensin II have been observed in tissues and animals that may indicate physiological functions for this signaling molecule and its receptor and may indicate therapeutic uses of modulators of this system.
[0007] Human urotensin II has been reported as a potent spasmogen of primate airway smooth muscle and its contractile profile with pulmonary vascular tissue has showed that there were regional differences in its efficacy, with potent contractile activity on pulmonary arteries while having no effect in tissues distal from the atria (Br. J. Pharmacol., 131(1); 10-12).
[0008] Human urotensin II has been reported as an endothelium-dependent vasodilator in rat small arteries (Br. J. Pharmacol., 130(8); 1865-1870). The human urotensin II peptide acts as a vasoconstrictor of rat and primate aorta, and induced a large increase in peripheral resistance in the circulation of primates along with a dramatic decrease in heart rate (Nature, 401; 282-286). In anesthetized rats, urotensin II peptide induced a decrease in blood pressure (General and Comparative Endocrinology 64; 435-439, Neuroendocrinol. Lett. 14(5); 357-363). These results suggest that modulators of urotensin II and its receptor may alter cardiovascular function, particularly heart rate, cardiac output, peripheral resistance and arterial pressure. (Russell, F. D. Emerging roles of urotensin-II in cardiovascular disease. Pharmacol. Therapeut. (2004) 103, 223-243; Kruger, S.; Graf, J.; Kunz, D.; Stickel, T.; Merx, M. W.; Hanrath, P.; Janssens, U. Urotensin II in patients with chronic heart failure. Eur. J. Heart Fail. (2005) 7, 475-478; Bousette, N.; Patel, L.; Douglas, S. A.; Ohlstein, E. H.; Giaid, A. Increased expression of urotensin II and its cognate receptor GPRl 4 in atherosclerotic lesions of the human aorta. Atherosclerosis (2004) 176, 117-123).
[0009] Indications are that the physiological role of urotensin II in mammals is strongly tissue dependent. The mRNA for the human urotensin II receptor is widely expressed in human tissue and is most abundant in heart and pancreas. The cardiovascular tissue of the left atrium and ventricle of the heart, and arterial tissue such as in the aorta are especially rich in expression of the urotensin II receptor. Moreover, the receptor is also distributed within the smooth muscle cells of the bladder, coronary arteries, and the aorta, the endothelial cells of the coronary artery and umbilical vein, and the motor neurons of the spinal cord. The distribution of the pro-pre-urotensin II mRNA in the human central nervous system is restricted primarily to the medulla oblongata of the brain and the spinal cord with the urotensin II-like immunoreactivity localized to motor neurons of the ventral horn. The distribution of the pro-pre-urotensin II mRNA in peripheral tissue is primarily restricted to the adrenal glands, the kidneys and the spleen. Accordingly, the UII receptor has a potential role in diseases such as renal failure, and diabetes. (Douglas, S.; Dhanak, D.; Johns, D. G. From 'gills to pills': urotensin II as a regulator of mammalian cardiorenal function. Trends in Pharmacological sciences (2004) 25, 76 - 85; Wenyi, Z.; Suzuki, S.; Hirai, M.; Hinokio, Y.; Tanizawa, Y.; Matsutani, A.; Satoh, J.; Oka, Y. Role of urotensin II gene in genetic susceptibility to Type 2 diabetes mellitus in Japanese subjects. Diabetologia (2003) 46, 972- 976; and Langham, R. G.; Kelly, D. J.; Gow, R. M.; Zhang, Y.; Dowling, J. K.; Thomson, N. M.; Gilbert, R. E. Increased expression of urotensin II and urotensin II receptor in human diabetic nephropathy. American Journal Of Kidney Diseases: The Official Journal Of The National Kidney Foundation (2004) 44, 826-831).
[0010] The physiological role that GPR- 14 (the urotensin II receptor) serves in the mammalian central nervous system is currently unknown. Important insights into the possible physiological effects mediated by this G-protein coupled receptor can be gained from an understanding of which cells in brain express this gene. Recently, the pattern of expression of the mRNA that encodes this receptor was reported. (Clark SD et al Brain Res. (2001) 923: 120-7; Huitron-Resendiz et al Journal of Neuroscience (2005) 25:5465-5474. The GPR- 14 gene is expressed in a discrete, extremely limited distribution within the mammalian central nervous system. The only brain regions which express this mRNA are the pedunculopontine tegmental nucleus (PPT), and the lateral dorsal tegmental nucleus (LDTG). These brain stem nuclei are the source of the ascending acetylcholine projection neurons in mammals, and as such are quite well studied, and have had a number of important physiological roles assigned to them. The expression of this receptor gene in just these cholinergic neurons provides for a novel mechanism by which these cell groups can be selectively modulated by small organic compounds targeted to GPR- 14.
SUMMARY OF THE INVENTION
[0011] The present investigators have identified a class of non-endogenous, low molecular weight non-peptide organic compounds that act as specific modulators of the urotensin II receptor.
[0012] Aspects of the present invention relate to compounds of Formula I, Ia, and Ib, as defined herein, or salts or prodrugs thereof. The compounds may appear as mixtures of isomers or as separated and purified isomers. Other aspects of the present invention relate to a complex between the human urotensin II receptor and a compound of the invention and to a method of preparing a complex between a compound of the invention and human urotensin II receptor comprising combining said compound in an effective concentration with human urotensin II receptor.
[0013] The present inventors have demonstrated for the first time that compounds of the invention, namely compounds of Formula I, Ia, and Ib, as defined herein, to be potent modulators of the human urotensin II receptor. Correspondingly, a further aspect of the invention relates to a use of compound of Formula I, Ia, and Ib, salts thereof, or compositions comprising said compounds, for the preparation of a medicament for the treatment of diseases and disorders for which activation or modulation of the urotensin II receptor produces a beneficial response in said disease or disorder. The diseases and disorders are selected from the group consisting of those associated with CNS function, such as Parkinson's Disease, Alzheimer's Disease, depression, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy; OPCA; ADHD; schizophrenia; sleep disorders such as insomnia and narcolepsy; and autonomic dysfunctions such as Shy Drager syndrome. Alternatively, the diseases or disorders are selected from the group consisting of cardiovascular disorders such as hypertension; hypotensive states related to shock, sepsis, major surgery, congestive heart failure, and pulmonary disorders. Alternatively, the diseases or disorders are selected from ischemia such as heart ischemia, renal disorders, urinary disorders such as incontinence, and tumor growth in cancer. Alternatively, the diseases or disorders are selected from the group consisting of stroke, asthma, and restenosis.
[0014] As stated, a variety of disease states have been suggested to be associated with either an altered functioning of the urotensin II receptor or to an imbalance of urotensin II. For example, alteration of urotensin II and signaling through its cognate receptor may be associated with, amongst other disease-states, both hypertension and hypotension. Accordingly, a further aspect of the invention relates to method of altering the vascular pressure in a mammal, comprising constricting or dilating vascular tissue in said mammal, said constricting or dilating being performed by the activation of urotensin receptor signaling, said activation being performed by the administration of an effective amount of a compound of Formula I, Ia, or Ib. Similarly, the invention relates to methods of altering the heart rate in a mammal, comprising the modulation of urotensin receptor signaling, said modulation being performed by the administration of an effective amount compound of Formula I, Ia, or Ib.
[0015] Moreover, a method of treating diseases or disorders in a mammal, said diseases or disorders being associated with an altered urotensin II receptor activity or imbalance in urotensin II level or activity compared to urotensin receptor activity or urotensin II levels or activity in a mammal not having said disease or disorder, comprising administering an effective amount of a compound of Formula I, Ia, or Ib is within the scope of the present invention. Accordingly, the present invention further relates to a method of treating diseases for which modulation of the urotensin II receptor produces a physiologically beneficial response in said disease, such as those associated with CNS function and cardiovascular diseases.
[0016] The present investigators have found that, upon administration of compounds of Formula I, Ia, or Ib, the locomotor activity of the animal is altered. Accordingly, the invention further relates to a method of altering the locomotor activity of a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, Ia, or Ib.
[0017] This alteration of locomotor function may indicate a CNS-mediated response of a compound of Formula I, Ia, or Ib and CNS mediated function of the urotensin II receptor that suggests application in CNS therapeutic areas. Thus, a further aspect of the invention relates to the treatment of diseases and disorders associated with CNS function. Given, the distribution of the urotensin II receptor within cardiovascular tissue, a further aspect of the invention relates to the treatment of cardiovascular disorders.
[0018] Thus, in a first aspect, the present invention relates to a compound of Formula I, Ia, or Ib, or salts or prodrugs thereof, complexed with a human urotensin II receptor,
[0019] An aspect of the invention is related to a compound of Formula (I):
Figure imgf000007_0001
(I) as a single isomer, a mixture of isomers, or a racemic mixture of isomers; a solvate or polymorph; a metabolite; or a pharmaceutically acceptable salt or prodrug thereof; wherein X is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, - N(Ri)-, and -O-; Y is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene,
C,-C4alkynylene, -C(=O)-, -C(=O)N(Rla)-, -S(O)2-, -S(O)-, -S(O)2N(R13)-, -S(O)N(R13)-, -
N(R13)-, -C(=O)O-, -CC=O)O-W-,
Figure imgf000007_0002
-CC=O)N(R1,)-, -
C(=0)N(R,a)W-, -S(O)2W-, -S(O)W-, -S(O)2N(R13)W-, -S(O)N(R13)W- and -N(R13)W-; W is selected from the group consisting of: Q-Qalkylene, Q^alkenylene, and d-Gjalkynylene; R1 and Rla are each independently H or selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; Cyi is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl; Cy2 is
Figure imgf000008_0001
R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-Ci0 heteroalicyclyl; R3, R3c, R3cj, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(=O)Ri, -C(=O)ORi, -CC=O)NR1R)3, - C(R,)=NR,a, -NR1Ru,
Figure imgf000008_0002
-S(O)NR1R13, -S(O)2NR1R13, -N(Ri)-S(=O)R,a, -N(R,)-S(=0)2Rla, -OR1, -SR1, and -OC(O)Ri; R3a is hydrogen, an optionally substituted phenyl, or an optionally substituted naphthyl; R3b is hydrogen, a substituted phenyl, or optionally substituted naphthyl; provided that at least one of R3a and R3b is an optionally substituted phenyl or an optionally substituted naphthyl. [0020] In an embodiment, Cy1 is selected from the group consisting of:
Figure imgf000009_0001
wherein R3i R3aj R3b, R3c, R3d, R3e, and R3f are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, halogen, hydroxyl, nitro, optionally substituted sulfenyl, optionally substituted sulfϊnyl, optionally substituted sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(=0)Ri, -C(=0)0Ri, -C(=0)NR,Rla, -C(R,)=NRla, -NR1Ri,, -N=CR1R13, -N(RO-CC=O)R13,
-N(R,)-C(=0)NR,,R,b, -S(O)NR1R18, -S(O)2NR1R13, -N(R0-S(=O)Rla, -N(R,)-S(=0)2Ri., - ORi, -SR1, and -0C(=0)R!; wherein R1, Rl3and R^ are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; or if two R groups selected from the group consisting of R3> R33, R3b, R3c, R3d, R3e, and R3f are covalently bonded to adjacent atoms, then the two R groups can be taken together to form a optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heteroalicyclyl group. [0021] In an embodiment, X is -N(Ri)-. In an embodiment, Y is selected from the group consisting of -C(=O)-, -C(=O)N(Rla)-, -C(O)O-, -C(=O)O-W-, -C(O)W-,
Figure imgf000010_0001
-C(O)N(R13)-, -C(=0)N(R,a)W-, and -N(R13)W-. In an embodiment, R1 and Ria are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C4 alkyl. In an embodiment, R2 and R23 are each independently selected from the group consisting of hydrogen and optionally substituted CpC4 alkyl. In an embodiment,
X is -N(Ri)-, Y is selected from the group consisting of -C(=0)-, -C(=O)N(Ria)-, -C(=0)0-, -
Figure imgf000010_0002
Ri and R13 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C4 alkyl, and R2 and R2a are each independently selected from the group consisting of hydrogen and optionally substituted Cj-C4 alkyl.
[0022] In an embodiment, X is -N(Ri)-; Y is selected from the group consisting of
-C(O)- or
Figure imgf000010_0003
Ri and R]3 are each independently selected from the group consisting of hydrogen and C1-C4 alkyl; and R2 and R2a are each independently selected from the group consisting of hydrogen and Ci-C4 alkyl.
[0023] In an embodiment, Cy1 is an optionally substituted phenyl. In an embodiment, X is -N(R1)-, Y is selected from the group consisting of -C(O)-, -
C(O)N(R13)-, -C(O)O-, -C(O)O-W-, -C(O)W-,
Figure imgf000010_0004
-C(O)N(R13)-, -
C(O)N(R13)W-, and -N(Ri3)W-, and Cy1 is an optionally substituted phenyl. In an embodiment, Cy1 is a halogenated phenyl. [0024] In an embodiment, R3, R3b, R3c, and R3d, in Cy2 are hydrogen and R3a in Cy2 is an optionally substituted phenyl or an optionally substituted naphthyl. In an embodiment, R3, R3b, R3c, and R3d, in Cy2 are hydrogen and R3a in Cy2 is a 4-substituted phenyl or 2-napthyl. In an embodiment, R3 R3b, R3c, and R3d, in Cy2 are hydrogen and R3 in
Cy2 is a 4-chlorophenyl, 4-methoxyphenyl, or 2-napthyl. In an embodiment, X is -N(Ri)-, Y
is from the -C(=O)- or
Figure imgf000011_0001
R3a in Cy2 is an optionally substituted phenyl or an optionally substituted naphthyl.
[0025] In an embodiment, R3, R3a, R3c, and R3d, in Cy2 are hydrogen and R3b in Cy2 is a substituted phenyl or an optionally substituted naphthyl. In an embodiment, R3, R3a, R3c, and R3d, in Cy2 are hydroge and R3b in Cy2 is a 4-substituted phenyl or 2-napthyl. In an embodiment, R3, R3a, R3c, and R3d, in Cy2 are hydrogen and R3b in Cy2 is a 4-chlorophenyl, 4- methoxyphenyl, or 2-napthyl. In an embodiment, X is -N(Ri)-, Y is from the -C(=O)- or
Figure imgf000011_0002
0Ria , and R3b in Cy2 is an substituted phenyl or an optionally substituted [0026] In an embodiment, the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-phenylbenzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-chlorophenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-methoxyphenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(2-naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-phenylbenzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(2-naphthyl)benzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-methoxyphenyl)benzamide;
N-[3-Dimemylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-phenylbenzarnide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(2naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(2-naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]benzamide; and
N-[ 1 -(4-Chlorophenyl)-4-dimethylaminobutyl]benzamide; as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or polymorph; or as metabolite or a pharmaceutically acceptable salt or prodrug thereof.
[0027] In an embodiment, the compound is N-[3-Dimethylamino-l-(2- naphthyl)propyl]-4-(4-chlorophenyl)benzamide. In an embodiment, the compound is N-[3- Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide.
[0028] In an embodiment, the compound is selected from the group consisting of:
N-[I -(4-Chlorophenyl)-3 -dimethylaminopropyl] -3 -phenylbenzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(2-naphthyl)benzamide.
[0029] In an embodiment, the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide.
[0030] In an embodiment, the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide.
[0031] In an embodiment, the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-phenylbenzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(2-naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-phenylbenzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-phenylbenzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-(4-methoxyphenyl)benzamide; N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-(2naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[3 -Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylaminopropyl-(S)-l-(4-chlorophenyl)]-(7?)-2-methoxy-2- phenylacetamide;
N-[3-Dimethylaminopropyl-(S)-l-(4-methylphenyl)]-(Λ)-2-methoxy-2- phenylacetamide;
N-[3-Dimethylaminopropyl-(S)-l-(2-naphthyl)]-(i?)-2-methoxy-2-phenylacetamide;
N-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]-(S)-benzamide; and iV-[l-(4-Chlorophenyl)-4-dimethylaminobutyl]-(S)-benzamide.
[0032] In an embodiment, the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-phenylbenzamide;
N-[ 1 -(4-Chlorophenyl)-3 -dimethylaminopropyl] -(S)-3 -(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(2-naphthyl)benzamide.
[0033] In an embodiment, the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4-chlorophenyl)benzamide;
7V-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide; and iV-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide. [0034] In an embodiment, the compound is selected from the group consisting of: N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-chlorophenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4-methoxyphenyl)benzamide; N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide; and N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4-methoxyphenyl)benzamide. [0035] Another aspect of the invention relates to a compound of Formula (Ia):
Figure imgf000015_0001
(Ia) as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -N(Ri)-, and -O-; Y is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -C(=O)-, -
C(O)N(R,a)-, -S(O)2-, -S(O)-, -S(O)2N(R13)-, -S(O)N(R13)-, -N(R18)-, -C(O)O-, -C(O)O-
W-, -C(=0)W-,
Figure imgf000015_0002
-C(O)N(Ri3)-, -C(O)N(R13)W-, -S(O)2W-, -S(O)W-, -
S(O)2N(R13)W-, -S(O)N(Ri3)W- and -N(Ri3)W-; W is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, and Ci-C4alkynylene; R1 and Rla are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; Cyi is
Figure imgf000016_0001
or optionally substituted naphthyl;
Cy2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-Ci0 heteroalicyclyl; and R3) R3a>, R31,, R3c, and R3a, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(=O)Ri, -C(O)OR1, -C(=0)NR,Rla, -C(R,)=NRla, -NR1R13, -N=CR1R13, -N(R,)-C(O)Rla, -N(R,)-C(O)NRlaRlb, -S(O)NR1R13, -S(O)2NR1R13, -N(R,)-S(=O)Rla, -N(R,)-S(=O)2Rla, - OR1, -SRi, and -0C(=0)Ri; provided that at least one Of R3, R3a,, R3b, R3c, and R3d, is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(O)Ri, -C(O)ORi, -C(O)NR1R13, -C(Ri)=NR13, -NR1R13, -N=CR1R13, -N(Ri)-C(O)Ru,
-N(Ri)-C(O)NR,,Rlb, -S(O)NR1Ri3, -S(O)2NR1R,,, -N(R,)-S(O)R,β, -N(RO-S(O)2R13, -
[0036] In an embodiment, X is -N(R,)- and Y is -C(O)- or
Figure imgf000016_0003
In an embodiment, Cy2 is optionally substituted phenyl. In an embodiment, Cyi is an alkyl- substituted phenyl or naphtyl. In an embodiment, X is -N(Ri)- , Y is -C(=0)- or
Figure imgf000017_0001
Cy2 is optionally substituted phenyl, and Cyi is an alkyl-substituted phenyl or naphtyl. In an embodiment, Cyi is 4-methylphenyl or 2-naphthyl.
[0037] In an embodiment, the compound is selected from the group consisting of: N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-phenylbenzamide; and N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-phenylbenzamide. [0038] Another aspect of the invention relates to a compound of Formula (Ib):
Figure imgf000017_0002
(Ib) as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or a pharmaceutically acceptable salt thereof, wherein X is selected from the group consisting
of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -N(Ri)-, and -O-; Y
Figure imgf000017_0003
is 0Ria ;
W is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, and Ci- C4alkynylene; Ri and Ri3 are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, and heteroalicyclyl; Cyi is
Figure imgf000018_0001
or optionally substituted naphthyl; Cy2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl; R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-Ci0 heteroalicyclyl; and R3, R3a,, R3b, R30 and R3d, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(=O)Ri, -C(=O)OR,, -C(O)NR1R13, -C(Ri)-NR13, -NR1R13, -N=CR1R13, -N(R,)-C(=0)Rl3, -N(R,)-C(=0)NRlβR,b, -S(O)NR1R13, -S(O)2NR1R13, -N(R,)-S(=0)Rla, -N(Rt)-S(O)2R13, - OR1, -SR1, and -OC(=O)Ri; provided that at least one of R3, R33,, R3b, R3c, and R3d, is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(O)R1 , -C(O)OR1, -C(O)NR1R13, -C(R,)=NRla, -NR1R13, -NOR1R13, -N(RO-C(O)R13,
-N(R,)-C(O)NRl3Rlb, -S(O)NR1R13, -S(O)2NR1R13, -N(RO-S(O)R13, -N(R,)-S(O)2Rla, - OR1, -SRi, or -OC(O)Ri.
[0039] In an embodiment, X is -N(Ri)-- In an embodiment, Cy2 is optionally substituted phenyl. In an embodiment, Ri3 in Y is alkyl. In an embodiment, X is -N(Ri)-, Cy2 is optionally substituted phenyl, and Rj3 in Y is alkyl. In an embodiment, R]3 in Y is methyl.
[0040] In an embodiment, the compound is selected from the group consisting of: N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(i?)-2-methoxy-2-phenylacetamide;
(+)-N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(i?)-2-methoxy-2- phenylacetamide;
(-)-N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(^)-2-methoxy-2- phenylacetamide;
N-[3-Dimethylaminopropyl-l-(2-naphthyl)]-(i?)-2-methoxy-2-phenylacetamide;
(+)-N-[3-Dimethylaminopropyl-l-(2-naphthyl)]-(i?)-2-methoxy-2-phenylacetamide; and
(-)-N-[3-Dimethylaminopropyl-l-(2-naphthyl)]-(i?)-2-methoxy-2-phenylacetamide.
[0041] In an embodiment, the compounds described herein, particularly the compounds according to the Formulae (I), (Ia), and (Ib), have the carbon atom adjacent to both X and Cyi in the S-configuration.
[0042] Another aspect of the invention relates to a salt, polymorph, ester, metabolite or prodrug of the compounds according to the Formulae (I), (Ia), and (Ib), and all of their variations. Another aspect of the invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable amount of one or more compounds according to the Formulae (I), (Ia), and (Ib).
[0043] Another aspect of the invention relates to a method of treating or ameliorating a disorder selected from the group consisting of a CΝS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis,and diabetes comprising identifying a subject in need of said treatment or amelioration and administering to the subject a therapeutically effective amount of one or more compounds according to the Formula (I), (Ia), or (Ib). In an embodiment, the CΝS disorder is selected from group consisting of Parkinson's Disease, Alzheimer's Disease, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy, OPCA, ADHD, and schizophrenia. In an embodiment, the cardiovascular disorder is selected from the group consisting of heart failure, atherosclerosis, hypertension and hypotensive states related to shock, sepsis, major surgery, congestive heart failure, and pulmonary disorders. In an embodiment, the sleep disorder is selected from the group consisting of insomnia and narcolepsy.
[0044] Another aspect of the invention provides a method of identifying a compound which is an agonist, inverse agonist, or antagonist of a Urotensin II receptor, the method comprising contacting the UII receptor with at least one or more test compounds according to the Formulae (I), (Ia), and (Ib), and determining any increase or decrease in activity level of said UII receptor.
[0045] Another aspect of the invention provides a use of a compound described herein, paricularly one or more compounds according to the Formulae (I), (Ia), and (Ib), to treat or ameliorate a disorder selected from the group consisting of a CNS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis, and diabetes.
[0046] In an embodiment, the compounds of Formula I, Ia, or Ib do not include compounds disclosed in WO 2006/135694, filed on JuIe 8, 2006 and entitled "UII- MODULATING COMPOUNDS AND THEIR USE."
BRIEF DESCRIPTION OF THE DRAWINGS
[0047] Figure 1 is a comparison of pEC50 values with respect to the position of the biphenyl in amides {Al - C8}.
[0048] Figure 2 is a summary of the structure activity relationship (SAR) results from this study and those in prior studies.
[0049] Figure 3 is the agonist profiles at the human UT receptor in a PI hydrolysis assay.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT Definitions
[0050] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this invention belongs. All patent, applications, published applications and other publications are incorporated by reference in their entirety. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise
[0051] As used herein, any "R" group(s) such as, without limitation, Rl, RIa, RIb, R2, R2a, R3, R3a, R3b, R3c, R3d, R3e, and R3f is(are) independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, aralkyl, -CN, -C(=Z)R1, -C(=Z)OR1, -C(=Z)NRlRla, -C(Rl)=NRIa, -NRlRIa, -N=CRlRIa, -N(Rl)-C(=Z)Rla, -N(Rl)-C(=Z)NRlaRlb, -S(O)NRlRIa, -S(O)2NRlRla, -N(Rl)-S(=O)Rla, -N(Rl)-S(=O)2Rla, -ORl, -SRl, and -OQ=Z)Rl, as these groups are defined herein. If two "R" groups are covalently bonded to the same atom or to adjacent atoms, then they may be "taken together" as defined herein to form a cycloalkyl, aryl, heteroaryl or heteroalicyclyl group. For example, without limitation, if RIa and RIb of an NRIa RIb group are indicated to be "taken together," it means that they are covalently bonded to one another at their terminal atoms to form a ring:
Figure imgf000021_0001
An R group of this invention may be substituted or unsubstituted.
[0052] As used herein, "IC50" refers to an amount, concentration of dosage of a particular test compound that achieves a 50% inhibition of a maximal response, such as modulation of GPCR, including Urotensin II receptor, activity, in an assay that measures such response in an assay that measures such response for example but not limited to R-SAT™ described herein.
[0053] As used herein, "EC50" refers to an dosage, concentration or amount of a particular test compound that elicits a dose-dependent response at 50% of maximal expression of a particular response that is induced, provoked or potentiated by the particular test compound, in an assay that measures such response for example but not limited to R- SAT™ described herein.
[0054] Whenever a group of this invention is described as being "optionally substituted" that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being "unsubstituted or substituted" if substituted, the substituent may be selected from the same group of substituents.
[0055] As used herein, "Cm to Cn" in which "m" and "n" are integers refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group or the number of carbon atoms in the ring of a cycloalkyl or cycloalkenyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl or ring of the cycloalkenyl can contain from "m" to "n", inclusive, carbon atoms. Thus, for example, a "Ci to C4 alkyl" group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, CH3CH(CH3)-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3CH-. If no "m" and "n" are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl or cycloalkenyl group, the broadest range described in these definitions is to be assumed.
[0056] As used herein, "aryl" refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system that has a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group of this invention may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfϊnyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof, unless the substituent groups are otherwise indicated.
[0057] As used herein, "heteroaryl" refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. The heteroaryl group may be optionally fused to a benzene ring. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyran, pyridine, pyridazine, pyrimidine, pyrazine and triazine. A heteroaryl group of this invention may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from alkyl, cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NRuRib and protected amino.
[0058] As used herein, "alkyl" refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group. An alkyl group of this invention may comprise from 1 to 20 carbon atoms. An alkyl group herein may also be of medium size having 1 to 10 carbon atoms. It is presently preferred that an alkyl group of this invention be a lower alkyl having 1 to 4 carbon atoms. Examples of alkyl groups include, without limitation, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, amyl, tert-amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl and dodecyl.
[0059] An alkyl group of this invention may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) independently selected from cycloalkyl, aryl, heteroaryl, heteroalicyclyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, -NR^Rib and protected amino.
[0060] "Aralkyl groups" are aryl groups connected, as substituents, via an alkylene group. The aryl and alkylene group of an aralkyl group may be substituted or unsubstituted. Examples includes but are not limited to benzyl, substituted benzyl, 2- phenylethyl, 3-phenylpropyl, naphtylalkyl. [0061] "Heteroaralkyl groups" are understood as heteroaryl groups connected, as substituents, via an alkylene group. The heteroaryl and alkylene group of a heteroaralkyl group may be substituted or unsubstituted. Examples includes but are not limited to 2- thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, imidazolylalkyl, and their substituted as well as benzo-fused analogs.
[0062] As used herein, "alkoxy" and "alkylthio" refers to RO- and RS-, in which R is an unsubstituted or substituted alkyl, including a lower alkyl. Examples include but are not limited to methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso- butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like.
[0063] As used herein, "aryloxy" and "arylthio" refers to RO- and RS-, in which R is an unsubstituted or substituted aryl, such as but not limited to phenyl.
[0064] As used herein, "alkenyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
[0065] As used herein, "alkylidene" refers to a divalent group, such as =CR'R", which is attached to one carbon of another group, forming a double bond, Alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, "arylalkylidene" refers to an group to an alkylidene group in which either R' and R" is an aryl group.
[0066] As used herein, "alkynyl" refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution.
[0067] The term "alkylene" refers to an alkyl group, as defined here, which is a biradical and is connected to two other moieties. An alkylene group of this invention may be unsubstituted or substituted. Thus, methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-), isopropylene (-CH2-CH(CH3)-), and isobutylene (-CH2-CH(CH3)-CH2-) are examples, without limitation, of an alkylene group. [0068] The term "alkenylene" refers to an alkylene group, as defined here, that contains in the straight or branched hydrocarbon chain one or more double bonds. The group is a bivalent radical derived by removing a hydrogen atom from each of the terminal carbon atoms. If only one double bond is present in the hydrocarbon chain is it represented by the formula -(CnH2n-:)-- An alkenylene group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. Alkenylene groups include, but are not limited to, propenylene -HC=C=CH- and vinylene (ethenylene) -HC=CH-.
[0069] The term "alkynylene" refers to an alkylene group, as defined here, that contains in the straight or branched hydrocarbon chain one or more tripple bonds. The group is a bivalent radical derived by removing two hydrogen atoms from each of the terminal carbon atoms. If only one triple bond is present in the hydrocarbon chain is it represented by the formula -(CnH2n-4)-. An alkynylene group of this invention may be unsubstituted or substituted.
[0070] As used herein, "acyl' refers to an "RC(O)-" group with R as defined above.
[0071] As used herein, "cycloalkyl" refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. Cycloalkyl groups of this invention may range from C3 to Ci0. In other embodiments it may range from C3 to C6. A cycloalkyl group may be unsubstituted or substituted. If substituted, the substituent(s) may be selected from those indicated above with regard to substitution of an alkyl group.
[0072] As used herein, "cycloalkenyl" refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be "aryl," as defined herein). A cycloalkenyl group of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the groups disclosed above with regard to alkyl group substitution.
[0073] As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a stable 3- to 18- membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. For the purpose of this invention, the "heteroalicyclic" or "heteroalicyclyl" may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may include fused or bridged ring systems; and the nitrogen, carbon and sulfur atoms in the "heteroalicyclic" or "heteroalicyclyl" may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system in the rings. Heteroalicyclyl groups of this invention may be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of halogen, hydroxy, protected hydroxy, cyano, nitro, alkyl, alkoxy, acyl, acyloxy, carboxy, protected carboxy, amino, protected amino, carboxamide, protected carboxamide, alkylsulfonamido and trifluoromethanesulfonamido. Examples of such "heteroalicyclic" or "heteroalicyclyl" include but are not limeted to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-Oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.
[0074] The ring systems of the cycloalkyl, heteroalicyclic (heteroalicyclyl) and ccycloalkenyl groups may be composed of one ring or two or more rings which may be joined together in a fused, bridged or spiro-connected fashion.
[0075] As used herein, "halo" or "halogen" refers to F (fluoro), Cl (chloro), Br (bromo) or I (iodo).
[0076] As used herein, "haloalkyl" refers to an alkyl group in which one or more of the hydrogen atoms are replaced by halogen. Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl and 1 -chloro-2-fluoromethyl, 2- fluoroisobutyl.
[0077] As used herein, "haloalkoxy" refers to RO-group in which R is a haloalkyl group. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy and l-chloro-2-fluoromethoxy, 2-fluoroisobutyoxy.
[0078] An "O-carboxy" group refers to a "RC(O)O-" group with R as defined above.
[0079] A "C-carboxy" group refers to a "-C(=O)R" group with R as defined above. [0080] An "acetyl" group refers to a CH3C(=O)- group.
[0081] A "trihalomethanesulfonyl" group refers to an "X3CSO2-" group wherein X is a halogen.
[0082] A "cyano" group refers to a "-CN" group.
[0083] An "isocyanato" group refers to an "-NCO" group.
[0084] A "thiocyanato" group refers to a "-CNS" group.
[0085] An "isothiocyanato" group refers to an " -NCS" group.
[0086] A "sulfmyl" group refers to an "-S(=O)-R" group with R as defined above.
[0087] A "sulfonyl" group refers to an "SO2R" group with R as defined above.
[0088] An "S-sulfonamido" group refers to a "-SO2NRiaRib" group with Ri3 and Rib as defined above.
[0089] An "N-sulfonamido" group refers to a "RSO2N(Ria)-" group with R and Ri a as defined above.
[0090] A "trihalomethanesulfonamido" group refers to an "X3CSO2N(R)-" group with X as halogen and R as defined above.
[0091] An "O-carbamyl" group refers to a "-OC(=O)NRiaRib" group with Ria and Rib as defined above.
[0092] An "N-carbamyl" group refers to an "ROC(=O)NRia -" group with Ru and R as defined above.
[0093] An "O-thiocarbamyl" group refers to a "-OC(=S)-NRiaRib" group with R]a and Rib as defined above.
[0094] An "N-thiocarbamyl" group refers to an "ROC(=S)NRU-" group with Rla and R as defined above.
[0095] A "C-amido" group refers to a "-C(=O)NRlaR!b" group with Rla and Rlb as defined above.
[0096] An "N-amido" group refers to a "RC(O)NR13-" group with R and Ru as defined above.
[0097] As used herein, an "ester" refers to a "-C(=O)OR" group with R as defined above. [0098] As used herein, an "amide" refers to a "-C(=0)NRiaRlb" group with Ri3 and Rib as defined above.
[0099] Any unsubstituted or monosubstituted amine group on a compound herein can be converted to an amide, any hydroxyl group can be converted to an ester and any carboxyl group can be converted to either an amide or ester using techniques well-known to those skilled in the art (see, for example, Greene and Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley & Sons, New York, NY, 1999).
[0100] Where the number of substituents is not specified (e.g. haloalkyl), there may be one or more substituents present. For example "haloalkyl" may include one or more of the same or different halogens. As another example, "Ci-C3 alkoxyphenyl" may include one or more of the same or different alkoxygroups containing one, two or three atoms.
[0101] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).
[0102] As employed herein, the following terms have their accepted meaning in the chemical literature.
AcOH acetic acid anhyd anhydrous
CDI 1 , 1 '-carbonyldiimidazole
DCM dichloromethane
DMF N,N-dimethylformamide
DMSO dimethyl sulfoxide
Et2O diethyl ether
EtOAc ethyl acetate
EtOH Ethanol
MeOH Methanol
NH4OAc ammonium acetate
Pd/C palladium on activated carbon [0103] It is understood that, in any compound of this invention having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of R-confϊguration or S-configuration or a mixture thereof. Thus, the compounds provided herein may be enatiomerically pure or be stereoisomeric or dia stereomeric mixtures. In addition it is understood that, in any compound of this invention having one or more double bond(s) generating geometrical isomers that can be defined as E or Z each double bond may independently be E or Z a mixture thereof. Likewise, all tautomeric forms are also intended to be included.
[0104] As used herein, "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to a patient to which it is administered and does not abrogate the biological activity and properties of the compound. Pharmaceutical salts can be obtained by reaction of a compound disclosed herein with an acid or base. Base- formed salts include, without limitation, ammonium salt (NH4 +); alkali metal, such as, without limitation, sodium or potassium, salts; alkaline earth, such as, without limitation, calcium or magnesium, salts; salts of organic bases such as, without limitation, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine; and salts with the amino group of amino acids such as, without limitation, arginine and lysine. Useful acid- based salts include, without limitation, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, methanesulfonates, ethanesulfonates, p-toluenesulfonates and salicylates.
[0105] Pharmaceutically acceptable solvates and hydrates are complexes of a compound with one or more solvent of water molecules, or 1 to about 100, or 1 to about 10, or one to about 2, 3 or 4, solvent or water molecules.
[0106] As used herein, a "prodrug" refers to a compound that may not be pharmaceutically active but that is converted into an active drug upon in vivo administration. The prodrug may be designed to alter the metabolic stability or the transport characteristics of a drug, to mask side effects or toxicity, to improve the flavor of a drug or to alter other characteristics or properties of a drug. Prodrugs are often useful because they may be easier to administer than the parent drug. They may, for example, be bioavailable by oral administration whereas the parent drug is not. The prodrug may also have better solubility than the active parent drug in pharmaceutical compositions. An example, without limitation, of a prodrug would be a compound disclosed herein, which is administered as an ester (the "prodrug") to facilitate absorption through a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to a carboxylic acid (the active entity) once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized in vivo to release the active parent compound. By virtue of knowledge of pharamcodynamic processes and drug metabolism in vivo, those skilled in the art, once a pharmaceutically active compound is known, can design prodrugs of the compound (see, e.g. Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392).
[0107] As used herein, the term "complement" refers to a oligonucleotide or polynucleotide that hybridizes by base-pairing, adenine to tyrosine and guanine to cytosine, to another oligonucleotide. The hybridized oligonucleotides are then said to be complementary.
[0108] As used herein, to "modulate" the activity of UII means either to activate it, i.e., to increase its cellular function over the base level measured in the particular environment in which it is found, or deactivate it, i.e., decrease its cellular function to less than the measured base level in the environment in which it is found and/or render it unable to perform its cellular function at all, even in the presence of a natural binding partner. A natural binding partner is an endogenous molecule that is an agonist for the receptor.
[0109] As used herein, to "detect" changes in the activity of UII or of a UII subtype refers to the process of analyzing the result of an experiment using whatever analytical techniques are best suited to the particular situation. In some cases simple visual observation may suffice, in other cases the use of a microscope, visual or UV light analyzer or specific protein assays may be required. The proper selection of analytical tools and techniques to detect changes in the activity of UII or a UII sub-type are well-known to those skilled in the art.
[0110] An "agonist" is defined as a compound that increases the basal activity of a receptor (i.e. signal transduction mediated by the receptor).
[0111] As used herein, "partial agonist" refers to a compound that has an affinity for a receptor but, unlike an agonist, when bound to the receptor it elicits only a fractional degree of the pharmacological response normally associated with the receptor even if a large number of receptors are occupied by the compound.
[0112] An "inverse agonist" is defined as a compound which reduces, or suppresses the basal activity of a receptor, such that the compound is not technically an antagonist but, rather, is an agonist with negative intrinsic activity.
[0113] As used herein, "antagonist" refers to a compound that binds to a receptor to form a complex that does not give rise to any response, as if the receptor were unoccupied. An antagonist attenuates the action of an agonist on a receptor. An antagonist may bind reversibly or irreversibly, effectively eliminating the activity of the receptor permanently or at least until the antagonist is metabolized or dissociates or is otherwise removed by a physical or biological process.
[0114] As used herein, a "subject" refers to an animal that is the object of treatment, observation or experiment. "Animal" includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. "Mammal" includes, without limitation, mice; rats; rabbits; guinea pigs; dogs; cats; sheep; goats; cows; horses; primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
[0115] As used herein, a "patient" refers to a subject that is being treated by an M. D. or a D. V. M. to attempt to cure, or at least ameliorate the effects of, a particular disease or disorder or to prevent the disease or disorder from occurring in the first place.
[0116] As used herein, a "carrier" refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0117] As used herein, a "diluent" refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
[0118] As used herein, an "excipient" refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A "diluent" is a type of excipient.
Synthesis
[0119] General synthetic routes to the compounds of this invention are shown in Schemes 1 and 2. The routes shown are illustrative only and are not intended, nor are they to be construed, to limit the scope of this invention in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed synthesis and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of this invention.
Figure imgf000033_0001
i) LAH, THF, 91%. ii) R-CH2-X, PS-DIPEA, CH2CI2, 48 and 78%. iii) R-COOH, EDC, DMAP, CH2CI2, 35-98%. iv) PhCN, H2SO4 27%, v) CH3CN, H2SO4, quant, vi) 6M HCI(aq), >99%. vii) R-NCO, NEt3, THF, 19 - 91%. viii) R-COOH, SOCI2, NEt3, THF, 35 - 98% or R-COOH, EDC, DMAP, CH2CI2, 35-98%. ix) R-SO2-CI, NEt3, THF, quant, x) R-NCO, NEt3, THF, 29 - 98%
Scheme 2
Figure imgf000033_0002
i) PS-DCC 2 eqv, PS-DMAP 0.2 eqv, CH2CI2, rt, 96h, 46 - 98%
[0120] U.S. Patent No. 4,564,641 discloses 2-phenyl-2-(2-phenethyl)-4- dialkylaminobutonoic acids as starting materials for the preparation of l-oxo-2-phenyl-2-(2- alkylaminoehtyl)-l,2,3,4,-tetrahydronaphthalenes, compounds useful for treating depression. U.S. Patent No. 3,880,885 discloses benzamides as starting materials for the preparation of tertiary aminoethyl isochromans and isocoumarins, compounds useful as antihypertensive or diuretic agents. [0121] As stated, one aspect of the present invention relates to the use of a compound selected from the group comprising a compound of Formula I, Ia, or Ib for the preparation of a medicament for the treatment of diseases and disorders for which activation or modulation of the urotensin II receptor produces a physiologically beneficial response in a given disorder.
[0122] A body of literature regarding the role of the pontine cholinergic nuclei and the modulation of cognitive processes has emerged in the last few years. Both basal forebrain and pontine cholinergic cell groups are known to control the activity of the hippocampal and cortical circuits that are critical for human attention, memory, and cognition. As such, the selective modulation of the activity of the PPT and LDTG nuclei present a novel pharmacological means to affect cognition and memory. Potential Disease States and Therapeutic Indications, Alzheimer's Disease and related dementias, schizophrenia and related psychoses.
[0123] In light of the distribution of the urotensin II receptor within the central nervous system and within cardiovascular tissue, it is anticipated that the compounds of Formula I, Ia, and Ib will be useful as medicaments to treat an array of neurodegenerative, neuropsychiatric, neurological and cardiovascular disorders. Accordingly, a further aspect of the invention relates to the use of compound of Formula I, Ia, or Ib for the preparation of a medicament for the treatment of diseases and disorders in a mammal selected from the group consisting of diseases and disorders associated with CNS function, such as Parkinson's Disease, Alzheimer's Disease, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy, OPCA, ADHD, schizophrenia, sleep disorders such as insomnia, and autonomic dysfunctions such as Shy Drager syndrome. In addition, compounds of Formula I, Ia, or Ib may be useful as medicaments to treat cardiovascular disorders such as hypertension; hypotensive states related to shock, sepsis, major surgery and congestive heart failure.
[0124] The present invention further relates to a method of altering the locomotor activity of a mammal, comprising administering to said mammal an effective amount of a compound of Formula I, Ia, or Ib. [0125] The decrease in locomotor activity and expression of urotensin II receptor in the brainstem are consistent with action of the compounds of Formula I, Ia, or Ib on the CNS to alter sleep/wake patterns. The PPT and LDTG send ascending projections to the thalamus that are critical mediators of sleep and wakefulness in humans. During the sleep state, thalamocortical activity is dominated by rhythmic oscillations that are abolished during the transition to wakefulness, resulting in a significant increase in neuronal responsiveness. The cholinergic cells groups are one of the primary mediators of this transition, where neuronal activity of the PPT and LDTG neurons increase with wakefulness. (Huitron- Resendiz et al., Journal of Neuroscience (2005) 25:5465-5474.) Therefore, modulators of GPR-14 which can increase the activity of these cells may increase wakefulness in humans, while those that decrease the activity of these neurons may induce sleep. Consistent with these observations are the potential clinical use of modulators of GPR-14 as CNS stimulants and sleep promoting CNS depressants (both perhaps without the addictive and physical dependency properties that limit the use of current agents).
[0126] Thus, potential disease states and therapeutic indications for which compounds of Formula I, Ia, or Ib may be connected to include narcolepsy, non-addictive CNS Stimulant, ADHD and Insomnia Thus, another aspect of the invention, to the use of compound of Formula I, Ia, or Ib for the preparation of a medicament for sleep disorders such as insomnia.
[0127] In light of the distribution of the receptor in cardiovascular tissue, the use of compound of Formula I, Ia, or Ib for the preparation of a medicament acting through the activation of urotensin receptor II signaling for regulating blood pressure in a mammal is a particularly interesting aspect of the invention as well as the use of compound of Formula I, Ia, or Ib for the preparation of a medicament acting through the activation of urotensin receptor II signaling for altering the heart rate or cardiac output in a mammal. Correspondingly, a method of altering the vascular pressure in a mammal, comprising constricting or dilating vascular tissue in said mammal, the constricting or dilating is performed by the activation of urotensin receptor signaling, said activation being performed by the administration of an effective amount compound of Formula I, Ia, or Ib is anticipated. Moreover, method of altering the heart rate in a mammal, comprising the activation of a urotensin receptor, said activating being performed by the administration of an effective amount compound of Formula I, Ia, or Ib is also anticipated.
[0128] Moreover, the use of compound of Formula I, Ia, or Ib for the preparation of a diuretic agent acting through the activation of urotensin receptor II signaling is also anticipated.
[0129] The term "therapeutically effective amount" is used to indicate an amount of an active compound, or pharmaceutical agent, that elicits the biological or medicinal response indicated. This response may occur in a tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, and includes alleviation of the symptoms of the disease being treated.
[0130] Another embodiment is a method of identifying a compound which regulates activity of an Urotensin II receptor by culturing cells that express the Urotensin II receptors; incubating the cells with at least one compound of Formula I, Ia, or Ib as defined herein; and determining any change in activity of the Urotensin II receptor so as to identify a compound of Formula I, Ia, or Ib which regulates activity of a Urotensin II receptor.
[0131] Another embodiment is a pharmaceutical composition comprising a compound of Formula I, Ia, or Ib as described above, and a physiologically acceptable carrier, diluent, or excipient, or a combination thereof.
[0132] The term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, intramuscular, intraocular, intranasal, intravenous, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid and the like. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0133] The term "physiologically acceptable" defines a carrier or diluent that does not abrogate the biological activity and properties of the compound. [0134] . The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990, which is hereby incorporated by reference in its entirety.
[0135] Suitable routes of administration may, for example, include oral, rectal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, intraocular injections or as an aerosol inhalant.
[0136] Alternately, one may administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the area of pain or inflammation, often in a depot or sustained release formulation. Furthermore, one may administer the drug in a targeted drug delivery system, for example, in a liposome coated with a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the organ.
[0137] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
[0138] Pharmaceutical compositions for use in accordance with the present disclosure thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate processing of the active compounds into preparations, which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., as disclosed in Remington's Pharmaceutical Sciences, cited above.
[0139] For injection, the agents disclosed herein may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hank's solution, Ringer's solution, or physiological saline buffer. For transmucosal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
[0140] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds disclosed herein to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by mixing one or more solid excipient with pharmaceutical combination disclosed herein, optionally grinding the resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
[0141] Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
[0142] Pharmaceutical preparations, which can be used orally, include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. [0143] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.
[0144] For administration by inhalation, the compounds for use according to the present disclosure are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin for use in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.
[0145] The compounds may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
[0146] Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances, which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents, which increases the solubility of the compounds to allow for the preparation of highly, concentrated solutions.
[0147] Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
[0148] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides. [0149] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
[0150] A pharmaceutical carrier for the hydrophobic compounds disclosed herein is a co-solvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common co-solvent system used is the VPD co-solvent system, which is a solution of 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™, and 65% w/v polyethylene glycol 300, made up to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; and other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone. Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.
[0151] Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions. Pharmaceutically compatible salts may be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents than are the corresponding free acids or base forms.
[0152] Pharmaceutical compositions suitable for use in the methods disclosed herein include compositions where the active ingredients are contained in an amount effective to achieve its intended purpose. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
[0153] The exact formulation, route of administration and dosage for the pharmaceutical compositions disclosed herein can be chosen by the individual physician in view of the patient's condition. (See e.g., Fingl et al. 1975, in "The Pharmacological Basis of Therapeutics", Chapter 1, which is hereby incorporated by reference in its entirety). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg/kg of the patient's body weight, or 1 to 500 mg/kg, or 10 to 500 mg/kg, or 50 to 100 mg/kg of the patient's body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. Where no human dosage is established, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.
[0154] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 500 mg of each ingredient, preferably between 1 mg and 250 mg, e.g. 5 to 200 mg or an intravenous, subcutaneous, or intramuscular dose of each ingredient between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg of each ingredient of the pharmaceutical compositions disclosed herein or a pharmaceutically acceptable salt thereof calculated as the free base, the composition being administered 1 to 4 times per day. Alternatively the compositions disclosed herein may be administered by continuous intravenous infusion, preferably at a dose of each ingredient up to 400 mg per day. Thus, the total daily dosage by oral administration of each ingredient will typically be in the range 1 to 2000 mg and the total daily dosage by parenteral administration will typically be in the range 0.1 to 400 mg. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.
[0155] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety, which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.
[0156] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen, which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.
[0157] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
[0158] The amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
[0159] The compositions may, if desired, be presented in a pack or dispenser device, which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound disclosed herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
[0160] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.
EXAMPLES
[0161] Embodiments of the present invention are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the invention.
Example 1 - Synthesis of the Carboxylic Acids of the Present Invention [0162] General: All chemicals were purchased from Aldrich, Acros, Lancaster or Maybridge and were used without prior purification. 1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded in CD3OD unless otherwise stated using a JEOL JMN-ECP400 instrument. All reactions were monitored by TLC (Merck silica gel 60 F254) and analyzed under UV (254 nm). Melting points were recorded on a Buchi melting point B-545 apparatus and are uncorrected. HRMS were recorded at Inovacia (Stockholm Sweden) using an Agilent MSD-TOF (G 1969A) connected to an Agilent 1 100 HPLC system. Elemental analyses were performed at Kolbe Analytishe Laboratorium, (Mϋlheim an der Ruhr, Germany).
[0163] The carboxylic acids 2, 4, 6, and 8 were created by the following general procedure: 3- or 4-iodobenzoic acid (1.24 g, 5 mmol), K2CO3 (2.7 g, 20 mmol) and the appropriate boronic acid (4-chlorophenyl (0.89 g, 5.5 mmol) or 2-naphthyl (0.95 g, 5.5 mmol)) were dissolved in a mixture Of H2O (7.5 ml) and ethanol (7.5 Ml) and heated to 180 °C for 15 min using microwave heating. The reaction mixture was filtered through a plug of Celite®, HCl (IM, 25 mL) was added to the filtrate and the resulting mixture was extracted twice with EtOAc. The organic phases were combined, washed with water (50 mL) and brine (50 mL) and concentrated to yield a crude solid, which was recrystallized from toluene to afford the desired compound as a white solid. Scheme 3 below illustrates the creation of the carboxylic acids. Scheme 3
Figure imgf000044_0001
R1 = 3-I or 4-I 2 R2 = 3-(4-chlorophenyl) 4 R2 = 3-(2-naphthyl) 6 R2 = 4-(4-chlorophenyl) 8 R2 = 4-(2-naphthyl)
Reagents and conditions: i) 10% Pd(C), H2O, Ethanol, 1800C, 15 min (microwave)
3-(4-Chlorophenyl)benzoic acid (2)
Figure imgf000044_0002
[0164] 3-Iodobenzoic acid and 4-chlorophenylboronic acid yielded 1.2 g (99%) of 2. Mp 180.9 - 181.7 0C. IH NMR (DMSO-d6) δ 7.51 (d, 2H, J = 7.7 Hz), 7.58 (dd, IH, J = 7.7, 8.2 Hz), 7.71 (d, 2H, J = 7.7 Hz), 7.88 (d, IH, J = 8.2 Hz), 7.96 (d, IH, J = 7.7 Hz), 8.19 (s, IH). 13C NMR (DMSO-d6) δ 127.8, 128.8, 129.0 (2 C:s), 129.5 (2 C:s), 129.9, 131.4, 132.5, 133.3, 138.6, 139.7, 168.2.
3-(2-Naphthyl)benzoic acid (4)
Figure imgf000044_0003
[0165] 3-Iodobenzoic acid and 2-naphthylboronic acid yielded 1.2 g (99%) of 4. Mp 205.0 - 206.3 0C. IH NMR δ 7.46 - 7.54 (m, 2H), 7.61 (dd, IH, J = 7.7, 8.0 Hz), 7.78 (dd, IH, J = 1.5, 8.4 Hz), 7.87 - 7.99 (m, 4H), 8.10 (s, IH), 8.13 (d, IH, J = 7.7 Hz), 8.49 (s, IH). 13C NMR δ 125.3, 126.2, 126.4, 126.6, 127.8, 128.3, 128.8, 129.1, 129.2, 129.9, 129.8, 132.7, 132.9, 133.7, 137.3, 141.6, 171.0. 4-(4-Chlorophenyl)benzoic acid (6)
Figure imgf000045_0001
[0166] 4-Iodobenzoic acid and 4-chlorophenylboronic acid yielded 1.1 g (95%) of 6. IH NMR (DMSO-d6) δ 7.55 (d, 2H, J = 8.8 Hz), 7.76 (d, 2H, J = 8.8 Hz), 7.80 (d, 2H, J = 8.4 Hz), 8.02 (d, 2H, J = 8.4 Hz). 13C NMR (DMSO-d6) δ 127.4 (2 C:s), 129.3 (2 C:s), 129.6 (2 C:s), 130.6 (2 C:s), 133.8, 138.4, 143.5, 167.6, 170.9.
4-(2-Naphthyl)benzoic acid (8)
Figure imgf000045_0002
[0167] 4-Iodobenzoic acid and 2-naphthylboronic acid yielded 0.8 g (65%) of 8. The low yield in this reaction is due to the product crystallizing in the reaction vessel, encapsulating the palladium catalyst. The product is insoluble in almost everything except to some extent boiling IM NaOH and warm DMSO (app 100°C). This made the filtration of the palladium difficult resulting in loss of product. Once in hand, the product reacted nicely in the amidation step in spite of its insolubility. IH NMR (DMSO-d6) δ 7.51 - 7.55 (m, 2H), 7.77 (dd, IH, J = 1.2, 8.4 Hz), 7.83 (d, 2H, J = 8.4 Hz), 7.87 - 7.97 (m, 3H), 8.10 (s, IH), 8.21 (d, 2H, J = 8.4 Hz).
Example 2 - Synthesis of the Amine Compounds of the Present Invention [0168] The amines A, B, C, D, and E were synthesized from their corresponding alcohols using a Ritter reaction as shown below in Scheme 4. [0169]
Scheme 4
Figure imgf000046_0001
11 n = 1 , R = 1-piperidinyl
12 n = 2, R = N(CH3J2
Figure imgf000046_0002
D n = I 1 R = 1 -piperidinyl, 79% 13 n = 1 , R = 1 -piperidinyl, 99% E n = 2, R = N(CH3);,, 70% 14 n = 2, R = N(CH3)2, 80%
Reagents and conditions: i) LiAIH4, THF. ii) CH3CN, H2SO4, -15 0C, iii) 6M HCI reflux
[0170] Structures for the A, B, and C amines are as follows:
Figure imgf000046_0003
l-(4-Chlorophenyl)-3-(l-piperidinyl)propan-l-oI (13)
Figure imgf000046_0004
[0171] Ketone II3 (3.7 g, 14.7 mmol) was dissolved in THF (250 mL). LAH (0.57 g, 15.0 mmol) was added slowly and the mixture was stirred for 18 h. NaOH (1 M) (100 mL) was added dropwise until pH 14. The resulting mixture was extracted twice with EtOAc (150 mL + 100 mL). The organic phases were combined, washed with water (200 mL) and brine (200 mL) and concentrated to afford 13 as a yellow oil (3.7 g, 99%). 1H NMR (CDCl3) δ 1.43 - 1.50 (m, 2H), 1.60 - 1.68 (m, 4H), 1.77 - 1.81 (m, 2H), 2.45 - 2.67 (m, 6H), 4.91 (dd, IH, J = 3.6, 7.2 Hz), 7.29 (s, 4H). 13C NMR (CDCl3) δ 24.4, 26.3 (2 C:s), 33.8, 54.8, 57.9 (2 C:s), 75.3, 127.2 (2 C:s), 128.5 (2 C:s), 132.5, 143.9.
l-(4-Chlorophenyl)-3-(l-piperidinyl)propan-l-amine (D)
Figure imgf000047_0001
[0172] Compound 13 (3.0 g, 11.8 mmol) was dissolved in acetonitrile (5 mL) and stirred on an ice-salt bath. H2SO4 (15 mL) was added slowly. After 18 h NaOH pellets were added until pH 14. The mixture was extracted with EtOAc (2 x 150 mL). The organic phases were combined and washed with water (200 mL) and brine (200 mL) and concentrated to obtain the corresponding acetamide as a yellow oil. HCl (6 M) (40 mL) was then added and the solution was refluxed for 3 days. H2O (100 mL) and NaOH pellets were added slowly to the mixture until pH 14. The mixture was extracted with EtOAc (2 x 100 mL) and the organic phases were combined and washed with water (100 mL) and brine (100 mL) and concentrated to afford D as a yellow oil (2.35 g, 79%). IH NMR (CDC13) δ 1.35 - 1.42 (m, 2H), 1.51 - 1.59 (m, 4H), 1.70 - 1.81 (m, 3H), 2.19 - 2.40 (m, 5H), 3.96 (t, IH, J = 6.6 Hz), 7.26 (s, 4H). 13C NMR (CDC13) δ 24.6, 26.1 (2 C:s), 36.4, 54.8 (2 C:s), 54.9, 56.8, 127.8 (2 C:s), 128.6 (2 C:s), 132.5, 145.2.
l-(4-Chlorophenyl)-4-dimethylamino-butan-l-ol (14)
Figure imgf000047_0002
[0173] Ketone 123 (1.5 g, 6.6 mmol) was reacted according to the same procedure as described for 13 to afford 14 as a yellow oil (1.2 g, 80%). IH NMR (CDC13) δ 1.65 - 1.78 (m, 3H), 1.89 - 1.99 (m, IH), 2.29 (s, 6H), 2.32 - 2.40 (m, 2H), 4.61 (d, IH, J = 8.8 Hz), 7.22 - 7.31 (m, 4H). 13C NMR (CDC13) δ 24.7, 39.7, 44.9 (2 C:s), 59.8, 72.8, 127.2 (2 C:s), 128.2 (2 C:s), 132.2, 144.6.
l-(4-Chlorophenyl)-4-dimethylamino-butan-l-amine (E)
Figure imgf000048_0001
[0174] Compound 14 (1.25 g, 5.5 mmol) was reacted according to the same procedure as described for 13 to afford E as a yellow oil (0.87 g, 70%). IH NMR (CDC13) δ 1.29 - 1.67 (m, 4H), 2.16 (s, 6H), 2.21 (t, 2H, J = 7.3 Hz), 3.88 (t, IH, J = 6.9 Hz), 7.27 (s, 4H). 13C NMR (CDC13) δ 24.7, 37.4, 45.6 (2 C:s), 55.7, 59.7, 127.8 (2 C:s), 128.6 (2 C:s), 132.5, 145.0.
Example 3 - Synthesis of the Amide Derivatives IAl I - (ElOI [0175] The amides (Al - C8} and {D5, E5, DlO, E10} were synthesized using the procedure shown below in Scheme 5.
Scheme 5
Figure imgf000048_0002
Reagents and conditions: i) NEt3, SOCI2, rt, 41 - 99% For details on structures see Tables 1 and 2.
[0176] The benzoic acid (0.5 mmol) was dissolved in THF (75 mL/g) and triethylamine (0.14 mL, 1 mmol) was added. Under vigorous stirring SOC12 (0.05 mL, 0.6 mmol) was added dropwise and the mixture was stirred at rt for 10 min. A 25 mg/mL solution of the amine (100 mg, 0.44 - 0.50 mmol) in THF was added slowly and the reaction mixture was stirred for another 2 h. The mixture was poured into NaOH (IM) and extracted twice with EtOAc. The combined organic phases were washed (water, brine) and concentrated. The crude oil was dissolved in CH2C12 and applied to a SAX-2 ion-exchange column, washed with CH2C12 and MeOH. The product was eluted using methanolic NH3 (2M), and concentrated. The pure products were converted to the corresponding hydrochloride salts for analysis, storage and biological testing. The salts were hygroscopic and turned into slight yellow oils immediately after isolation.
N-Il^-ChlorophenyO-S-dimethylaminopropyll-S-phenylbenzamide HCl {Al}
Figure imgf000049_0001
[0177] Reaction of 3-phenylbenzoic acid with A yielded 120 mg (65%) {Al} which was converted to the hydrochloride salt. IH NMR δ 2.29 - 2.48 (m, 2H), 2.91 (s, 6H), 3.16 - 3.32 (m, 2H), 5.26 (dd, IH, J = 5.9, 9.9 Hz), 7.34 - 7.49 (m, 7H), 7.55 (t, IH, J = 7.7 Hz), 7.67 (d, 2H, J = 7.3 Hz), 7.80 (d, IH, J = 8.8 Hz), 7.85 (d, IH, J = 7.0 Hz), 8.11 (s, IH). 13C NMR δ 30.3, 42.2, 42.6, 51.1, 55.3, 125.8, 126.2, 126.8 (2 Cs), 127.6, 128.3 (2 C:s), 128.6 (2 C:s), 128.7 (2 C:s), 128.9, 130.2, 133.3, 134.4, 140.1, 140.2, 141.6, 168.6. HRTofMS calcd for C24H25C1N2O (M+) m/z 392.1655, found 392.1663.
N-[l-(4-ChIorophenyl)-3-dimethyIaminopropyl]-3-(4-chlorophenyl)benzamide HCl
{A2}
Figure imgf000050_0001
[0178] Reaction of 3-(4-chlorophenyl)benzoic acid with A yielded 120 mg (60%) {A2} which was converted to the hydrochloride salt. 1H NMR δ 2.29 - 2.38 (m, IH), 2.43 - 2.53 (m, IH), 2.90 (s, 6H), 3.16 - 3.34 (m, 2H), 5.24 (dd, IH, J= 5.5, 9.5 Hz), 7.37 (d, 2H, J = 8.1 Hz), 7.43 (d, 2H, J = 8.1 Hz), 7.49 (d, 2H, J = 8.1 Hz), 7.52 (dd, IH, J= 7.7, 7.9 Hz), 7.66 (d, 2H, J = 8.1 Hz), 7.77 (d, IH, J = 7.7 Hz), 7.87 (d, IH, J= 7.9 Hz), 8.11 (s, IH). 13C NMR δ 30.3, 42.2, 42.5, 51.1, 55.3, 125.7, 126.6, 128.3 (2 C:s), 128.4 (2 C:s), 128.6 (2 C:s), 128.8 (2 C:s), 129.0, 130.0, 133.3, 133.6, 134.5, 138.7, 140.1, 140.2, 168.4. HRTofMS calcd for C24H24Cl2N2O (M+) m/z 426.1266, found 426.1273.
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4-methoxyphenyI)benzamide HCl
{A3}
Figure imgf000050_0002
[0179] Reaction of 3-(4-methoxyphenyl)benzoic acid with A yielded 120 mg (60%) {A3} which was converted to the hydrochloride salt. IH NMR δ 2.28 - 2.49 (m, 2H), 2.90 (s, 6H), 3.16 - 3.29 (m, 2H), 3.82 (s, 3H), 5.26 (dd, IH, J = 5.9, 9.5 Hz), 7.00 (d, 2H, J = 8.8 Hz), 7.39 (d, 2H, J = 8.1 Hz), 7.47 - 7.53 (m, 3H), 7.61 (d, 2H, J = 8.8 Hz), 7.74 - 7.80 (m, 2H), 8.06 (d, IH, J = 1.8 Hz). 13C NMR δ 30.3, 42.2, 42.5, 51.1, 54.5, 55.3, 114.1 (2 C:s), 125.3, 125.5, 127.9 (2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 128.8, 129.7, 132.4, 133.2, 134.3, 140.2, 141.2, 159.8, 168.7. HRTofMS calcd for C25H27C1N2O2 (M+) m/z 422.1761, found 422.1765.
N-fl-^-ChlorophenylJO-dimethylaminopropyllO-^-naphthyObenzamide HCl {A4}
Figure imgf000051_0001
[0180] Reaction of 3-(2-naphthyl)benzoic acid with A yielded 150 mg (72%) {A4} which was converted to the hydrochloride salt. 1H NMR δ 2.28 - 2.38 (m, IH), 2.43 - 2.53 (m, IH), 2.87 (s, 6H), 3.14 - 3.33 (m, 2H), 5.26 (dd, IH, J= 8.1, 13.6 Hz), 7.36 (d, 2H, J = 8.8 Hz), 7.47 - 7.58 (m, 5H), 7.77 - 7.90 (m, 6H), 8.14 (s, IH), 8.27 (s, IH). 13C NMR δ 30.2, 42.1, 42.5, 51.1, 55.4, 124.9, 125.6, 126.0, 126.1, 126.2, 126.4, 127.3, 128.0, 128.3 (2 C:s), 128.4, 128.6 (2 C:s), 129.0, 130.4, 133.0, 133.3, 133.8, 134.4, 137.3, 140.2, 141.3, 168.6. HRTofMS calcd for C28H27ClN2O (M+) m/z 442.1812, found 442.1816.
7V-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-phenylbenzamide HCl {A5}
Figure imgf000051_0002
7V-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-chlorophenyl)benzamide HCl
{A6}
Figure imgf000052_0001
[0181] Reaction of 4-(4-chlorophenyl)benzoic acid with A yielded 130 mg (65%) {A6} which was converted to the hydrochloride salt. 1H NMR δ 2.29 - 2.37 (m, IH), 2.41 - 2.50 (m, IH), 2.91 (s, 6H), 3.17 - 3.33 (m, 2H), 5.23 (dd, IH, J= 5.5, 9.9 Hz), 7.38 (d, 2H, J = 8.4 Hz), 7.44 (d, 2H, J = 8.4 Hz), 7.49 (d, 2H, J = 8.4 Hz), 7.63 (d, 2H, J = 8.4 Hz), 7.70 (d, 2H, J = 8.4 Hz), 7.96 (d, 2H, J = 8.4 Hz). 13C NMR δ 30.3, 42.2, 42.6, 51.0, 55.3, 126.6 (2 C:s), 128.0 (2 C:s), 128.2 (2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 128.8 (2 C:s), 132.7, 133.3, 133.9, 138.4, 140.1, 143.2, 168.3. HRTofMS calcd for C24H24Cl2N2O (M+) m/z 426.1266, found 426.1267.
7V-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4-methoxyphenyl)benzamide HCl
{A7}
Figure imgf000052_0002
[0182] Reaction of 4-(4-methoxyphenyl)benzoic acid with A yielded 120 mg (60%) {A7} which was converted to the hydrochloride salt. 1H NMR δ 2.29 - 2.37 (m, IH), 2.41 - 2.51 (m, IH), 2.90 (s, 6H), 3.17 - 3.33 (m, 2H), 3.78 (s, 3H), 5.24 (dd, IH, J= 5.5, 9.5 Hz), 6.97 (d, 2H, J = 8.8 Hz), 7.36 (d, 2H, J= 8.4 Hz), 7.48 (d, 2H, J= 8.4 Hz), 7.56 (d, 2H, J = 8.8 Hz), 7.64 (d, 2H, J = 8.0 Hz), 7.93 (d, 2H, J= 8.0 Hz). 13C NMR δ 30.4, 42.1, 42.6, 51.0, 54.5, 55.3, 114.1 (2 C:s), 126.1 (2 C:s), 127.9 (2 C:s), 128.0 (2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 131.6, 131.9, 133.2, 140.3, 144.2, 160.0, 168.4. HRTofMS calcd for C25H27ClN2O2 (M+) m/z 422.1761, found 422.1777.
7V-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzainide HCl {A8}
Figure imgf000053_0001
[0183] Reaction of 4-(2-naphthyl)benzoic acid with A yielded 150 mg (72%) {A8} which was converted to the hydrochloride salt. 1H NMR δ 2.29 - 2.38 (m, IH), 2.44 - 2.53 (m, IH), 2.89 (s, 6H), 3.16 - 3.24 (m, 2H), 5.25 (dd, IH, J = 4.8, 9.2 Hz), 7.36 (d, 2H, J = 9.9 Hz), 7.43 - 7.51 (m, 4H), 7.72 (d, IH, J= 8.8 Hz), 7.79 - 7.89 (m, 5H), 8.01 (d, 2H, J = 8.1 Hz), 8.08 (s, IH). 13C NMR δ 30.3, 42.3, 42.6, 51.2, 55.4, 124.7, 125.7, 126.1, 126.3, 126.9 (2 C:s), 127.4, 128.1 (2 C:s), 128.2, 128.3 (2 C:s), 128.4, 128.6 (2 C:s), 132.4, 133.1, 133.2, 133.7, 137.0, 140.3, 144.3, 168.4. HRTofMS calcd for C28H27ClN2O (M+) m/z 442.1812, found 442.1822. N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-phenylbenzamide HCI {Bl}
Figure imgf000054_0001
[0184] Reaction of 3-phenylbenzoic acid with B yielded 120 mg (65%) {Bl} which was converted to the hydrochloride salt. 1H NMR δ 2.19 (s, 3H), 2.20 - 2.28 (m, IH), 2.34 - 2.42 (m, IH), 2.77 (s, 3H), 2.78 (s, 3H), 3.05 - 3.10 (m, IH), 3.15 - 3.1.9 (m, IH), 5.14 (dd, IH, J = 5.6, 9.6 Hz), 7.07 (d, 2H, J = 8.0 Hz), 7.22 - 7.35 (m, 5H), 7.42 (t, IH, J = 7.6 Hz), 7.56 (d, 2H, J = 7.2 Hz), 7.66 (d, IH, J = 8.0 Hz), 7.78 (d, IH, J= 7.6 Hz), 8.04 (s, IH). 13C NMR δ 24.0, 34.6, 46.2, 46.6, 55.5, 59.5, 129.9, 130.3, 130.6 (2 C:s), 130.9 (2 C:s), 131.6, 132.8 (2 C:s), 133.0, 133.3 (2 C:s), 134.1, 138.6, 141.4, 142.5, 144.2, 145.5, 172.6. HRTofMS calcd for C25H28N2O (M+) m/z 372.2202, found 372.2204.
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(4-chlorophenyl)benzamide HCl
{B2}
Figure imgf000054_0002
[0185] Reaction of 3-(4-chlorophenyl)benzoic acid with B yielded 150 mg (74%) {B2} which was converted to the hydrochloride salt. IH NMR δ 2.20 (s, 3H), 2.21 - 2.28 (m, IH), 2.31 - 2.42 (m, IH), 2.80 (s, 6H), 3.05 - 3.10 (m, IH), 3.17 - 3.26 (m, IH), 5.14 (dd, IH, J = 5.6, 9.2 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.32 (d, 2H, J = 8.0 Hz), 7.42 (dd, IH, J = 7.6, 7.8 Hz), 7.54 (d, 2H, J = 8.0 Hz), 7.64 (d, IH, J = 7.6 Hz), 7.78 (d, IH, J = 7.8 Hz), 8.01 (s, IH). 13C NMR δ 24.0, 34.6, 46.2, 46.6, 55.5, 59.6, 129.9, 130.6 (2 C:s), 132.4 (2 C:s), 132.9 (2 C:s), 133.1, 133.3 (2 C:s), 134.0, 137.7, 138.7, 138.8, 141.5, 142.3, 142.8, 144.1, 172.4. HRTofMS calcd for C25H27C1N2O (M+) m/z 406.1812, found 406.1814.
yV-[3-DimethyIamino-l-(4-methylphenyI)propyl]-3-(4-methoxyphenyl)benzamide HCl
{B3}
Figure imgf000055_0001
[0186] Reaction of 3-(4-methoxyphenyl)benzoic acid with B yielded 140 mg (70%) {B3} which was converted to the hydrochloride salt. IH NMR δ 2.20 (s, 3H), 2.21 -
2.27 (m, IH), 2.30 - 2.38 (m, IH), 2.79 (s, 6H), 3.03 - 3.10 (m, IH), 3.15 - 3.21 (m, IH), 3.74 (s, 3H), 5.13 (dd, IH, J = 5.6, 9.4 Hz), 6.89 (d, 2H, J = 8.4 Hz), 7.09 (d, 2H, J = 7.6 Hz),
7.28 (d, 2H, J = 7.6 Hz), 7.39 (dd, IH, J = 7.6, 8.0 Hz), 7.50 (d, 2H, J = 8.4 Hz), 7.63 (d, IH, J = 8.0 Hz), 7.70 (d, IH, J = 7.6 Hz), 7.98 (s, IH). 13C NMR δ 23.9, 34.6, 46.2, 46.7, 55.4, 58.6, 59.6, 118.2 (2 C:s), 129.4, 129.5, 130.6 (2 C:s), 131.9 (2 C:s), 132.9, 133.3 (2 C:s), 133.6, 136.5, 138.6, 141.5, 142.3, 145.2, 163.8, 172.5. HRTofMS calcd for C26H30N2O2 (M+) m/z 402.2307, found 402.2324.
N-[3-DimethyIamino-l-(4-methylphenyl)propyl]-3-(2-naphthyl)benzamide HCl {B4}
Figure imgf000055_0002
[0187] Reaction of 3-(2-naphthyl)benzoic acid with B yielded 180 mg (85%) {B4} which was converted to the hydrochloride salt. IH NMR δ 2.19 (s, 3H), 2.20 - 2.26 (m, IH), 2.35 - 2.44 (m, IH), 2.79 (s, 6H), 3.01 - 3.09 (m, IH), 3.12 - 3.20 (m, IH), 5.16 (dd, IH, J = 6.0, 9.6 Hz), 7.07 (d, 2H, J = 8.0 Hz), 7.30 (d, 2H, J = 8.0 Hz), 7.36 - 7.46 (m, 3H), 7.69 (dd, IH, J = 2.0, 8.4 Hz), 7.73 - 7.82 (m, 5H), 8.05 (s, IH), 8.18 (s, IH). 13C NMR δ 24.0, 34.6, 46.2, 46.6, 55.5, 59.5, 129.0, 129.7, 130.0, 130.1, 130.2, 130.4, 130.6 (2 C:s), 131.4, 132.1, 132.5, 133.0, 133.3 (2 C:s), 134.4, 137.0, 137.9, 138.7, 141.4, 141.5, 142.4, 145.3, 172.6. HRTofMS calcd for C29H30N2O (M+) m/z 422.2358, found 422.2358.
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-phenylbenzamide HCl {B5}
Figure imgf000056_0001
[0188] Reaction of 4-phenylb~enzoic acid with B yielded 140 mg (75%) {B5} which was converted to the hydrochloride salt. 1H NMR δ 2.23 (s, 3H), 2.27 - 2.34 (m, 2H), 2.81 (s, 6H), 3.08 - 3.12 (m, IH), 3.16 - 3.22 (m, IH), 5.15 (dd, IH, J = 5.6, 9.4 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.26 - 7.31 (m, 4H), 7.36 (tt, IH, J = 1.6, 6.8 Hz), 7.70 (d, 2H, J = 8.0 Hz), 7.62 (d, 2H, J = 8.4 Hz), 7.87 (d, 2H, J = 8.4 Hz). 13C NMR δ 23.9, 34.6, 46.2, 46.7, 55.4, 59.6, 130.6 (2 C:s), 130.7 (2 C:s), 130.9 (2 C:s), 131.9, 132.0 (2 C:s), 132.8 (2 C:s), 133.3 (2 C:s), 136.7, 141.5, 142.2, 143.9, 148.6, 172.5. HRTofMS calcd for C25H28N2O (M+) m/z 372.2202, found 372.2218. 7V-[3-Dimethylamino-l-(4-methylphenyI)propyl]-4-(4-chIorophenyl)benzamide HCl
{B6}
Figure imgf000057_0001
[0189] Reaction of 4-(4-chlorophenyl)benzoic acid with B yielded 170 mg (84%) {B6} which was converted to the hydrochloride salt. 1H NMR δ 2.23 (s, 3H), 2.24 - 2.38 (m, 2H), 2.82 (s, 6H), 3.05 - 3.13 (m, IH), 3.16 - 3.22 (m, IH), 5.13 (dd, IH, J = 5.6, 9.2 Hz), 7.11 (d, 2H, J - 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.36 (d, 2H, J = 8.4 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.62 (d, 2H, J= 8.0 Hz), 7.87 (d, 2H, J= 8.0 Hz). 13C NMR δ 23.9, 34.6, 46.2, 46.7, 55.4, 59.6, 130.6 (2 C:s), 130.7 (2 C:s), 132.1 (2 C:s), 132.4 (2 C:s), 132.9 (2 C:s), 133.3 (2 C:s), 137.0, 138.0, 141.5, 142.2, 142.6, 147.1, 172.3. HRTofMS calcd for C25H27ClN2O (M+) m/z 406.1812, found 406.1816.
yV-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4-methoxyphenyl)benzamide HCl
{B7}
Figure imgf000057_0002
[0190] Reaction of 4-(4-methoxyphenyl)benzoic acid with B yielded 140 mg (70%) {B7} which was converted to the hydrochloride salt. IH NMR δ 2.20 (s, 3H), 2.21 - 2.28 (m, IH), 2.30 - 2.41 (m, IH), 2.79 (s, 3H), 2.80 (s, 3H), 3.05 - 3.11 (m, IH), 3.16 - 3.22 (m, IH), 3.71 (s, 3H), 5.13 (dd, IH, J = 5.6, 9.6 Hz), 6.89 (d, 2H, J = 8.8 Hz), 7.08 (d, 2H, J = 8.0 Hz), 7.29 (d, 2H, J = 8.0 Hz), 7.48 (d, 2H, J = 8.8 Hz), 7.55 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.4 Hz). 13C NMR δ 23.9, 34.7, 46.2, 46.6, 55.4, 58.6, 59.6, 118.2 (2 C:s), 130.1 (2 C:s), 130.5 (2 C:s), 131.9 (2 C:s), 132.0 (2 C:s), 133.2 (2 C:s), 135.9, 136.1, 141.4, 142.5, 148.2, 164.1, 172.4. HRTofMS calcd for C26H30N2O2 (M+) m/z 402.2307, found 402.2314.
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide HCl {B8}
Figure imgf000058_0001
[0191] Reaction of 4-(2-naphthyl)benzoic acid with B yielded 130 mg (62%) {B8} which was converted to the hydrochloride salt. IH NMR δ 2.17 (s, 3H), 2.19 - 2.27 (m, IH), 2.30 - 2.38 (m, IH), 2.76 (s, 6H), 3.00 - 3.09 (m, IH), 3.11 - 3.17 (m, IH), 5.10 (dd, IH, J = 5.2, 8.4 Hz), 7.05 (d, 2H, J = 8.0 Hz), 7.26 (d, 2H, J = 8.0 Hz), 7.32 - 7.38 (m, 2H), 7.61 (dd, IH, J = 1.2, 8.4 Hz), 7.66 - 7.77 (m, 5H), 7.87 (d, 2H, J = 6.8 Hz), 7.96 (s, IH). 13C NMR δ 24.0, 34.7, 46.2, 46.7, 55.5, 59.6, 128.8, 129.8, 130.2, 130.3, 130.6 (2 C:s), 131.0 (2 C:s), 131.4, 132.1 (2 C:s), 132.2, 132.5, 133.3 (2 C:s), 136.7, 137.2, 137.8, 141.1, 141.4, 142.5, 148.3, 172.4. HRTofMS calcd for C29H30N2O (M+) m/z 422.2358, found 422.2362. N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-phenylbenzamide HCl {CI}
Figure imgf000059_0001
j [0192] Reaction of 3-phenylbenzoic acid with C yielded 170 mg (95%) {CI} which was converted to the hydrochloride salt. IH NMR δ 2.40 - 2.43 (m, IH), 2.50 - 2.53 (m, IH), 2.82 (s, 6H), 3.13 - 3.17 (m, IH), 3.23 - 3.28 (m, IH), 5.37 (dd, IH, J = 4.8, 7.6 Hz), 7.26 - 7.29 (m, IH), 7.34 - 7.40 (m, 4H), 7.46 (t, IH, J = 6.0 Hz), 7.57 - 7.60 (m, 3H), 7.70 (d, IH, J = 6.0 Hz), 7.75 - 7.84 (m, 4H), 7.90 (s, IH), 8.08 (s, IH). 13C NMR δ 34.4, 46.3, 46.6, 55.9, 59.6, 128.6, 129.5, 129.9, 130.0, 130.2, 130.3, 130.8 (2 C:s), 131.4, 131.6, 131.8, 132.5, 132.8 (2 C:s), 132.9, 134.1, 137.2, 137.6, 138.6, 142.5, 144.2, 145.6, 172.8. HRTofMS calcd for C28H28N2O (M+) m/z 408.2202, found 408.2206.
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-chlorophenyl)benzamide HCl {C2}
Figure imgf000059_0002
[0193] Reaction of 3-(4-chlorophenyl)benzoic acid with C yielded 180 mg (92%) {C2} which was converted to the hydrochloride salt. IH NMR δ 2.36 - 2.51 (m, 2H), 2.81 (s, 6H), 3.10 - 3. 20 (m, 2H), 5.34 (dd, IH, J = 5.6, 10.4 Hz), 7.33 - 7.41 (m, 4H), 7.43 - 7.47 (m, IH), 7.55 - 7.59 (m, 3H), 7.67 - 7.83 (m, 5H), 7.88 (s, IH), 8.05 (s, IH). 13C NMR δ 34.4, 46.2, 46.6, 55.8, 59.5, 128.6, 129.5, 129.8, 130.0, 130.2, 130.6, 131.4, 131.8, 132.4 (2 C:s), 132.6, 132.8 (2 C:s), 133.0, 134.0, 137.2, 137.6, 137.7, 138.7, 142.5, 142.8, 144.2, 172.6. HRTofMS calcd for C28H27C1N2O (M+) m/z 442.1812, found 442.1816.
jV-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-methoxyphenyl)benzamide HCl {C3}
Figure imgf000060_0001
[0194] Reaction of 3-(4-methoxyphenyl)benzoic acid with C yielded 130 mg (67%) {C3} which was converted to the hydrochloride salt. 1H NMR δ 2.32 - 2.51 (m, 2H), 2.80 (s, 6H), 3.08 - 3.11 (m, IH), 3.21 - 3.31 (m, IH), 3.66 (s, 3H), 5.34 (dd, IH, J = 4.2, 7.2 Hz), 6.83 (d, 2H, J= 8.4 Hz), 7.32 - 7.37 (m, 3H), 7.45 - 7.49 (m, 2H), 7.52 - 7.60 (m, 2H), 7.68 - 7.78 (m, 4H), 7.87 (s, IH), 8.02 (s, IH). 13C NMR δ 34.5, 46.3, 46.6, 55.9, 58.6, 59.5, 118.1 (2 C:s), 128.6, 129.4, 129.5, 129.6, 130.0, 130.2, 131.5, 131.8, 132.0 (2 C:s), 132.6, 132.9, 133.7, 136.4, 137.1, 137.5, 138.5, 142.8, 145.1, 163.8, 172.8. HRTofMS calcd for C29H30N2O2 (M+) m/z 438.2307, found 438.2324.
iV-[3-DimethyIamino-l-(2-naphthyl)propyl]-3-(2naphthyl)benzamide HCl {C4}
Figure imgf000060_0002
[0195] Reaction of 3-(2-naphthyl)benzoic acid with C yielded 200 mg (99%) {C4} which was converted to the hydrochloride salt. IH NMR δ 2.34 - 2.40 (m, IH), 2.47 - 2.52 (m, IH), 2.75 (s, 3H), 2.77 (s, 3H), 3.06 - 3.13 (m, IH), 3.20 - 3.32 (m, IH), 5.36 (dd, IH, J = 5.6, 9.6 Hz), 7.32 - 7.39 (m, 4H), 7.41 - 7.45 (m, IH), 7.56 (dd, IH, J = 1.6, 8.4 Hz), 7.65 - 7.78 (m, 7H), 7.80 - 7.84 (m, 2H), 7.88 (s, IH), 8.02 (s, IH), 8.20 (s, IH). 13C NMR δ 34.5, 46.2, 46.6, 55.9, 59.5, 128.6, 129.0, 129.5, 129.7, 129.9, 130.0, 130.1, 130.2 (2 C:s), 130.4, 131.4, 131.5, 131.8, 132.1, 132.4, 132.6, 133.0, 134.4, 137.0, 137.1, 137.6, 137.9, 138.6, 141.4, 142.7, 145.3, 172.6. HRTofMS calcd for C32H30N2O (M+) m/z 458.2358, found 458.2363.
yV-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-phenylbenzamide HCl {C5}
Figure imgf000061_0001
[0196] Reaction of 4-phenylbenzoic acid with C yielded 170 mg (95%) {C5} which was converted to the hydrochloride salt. IH NMR δ 2.33 - 2.40 (m, IH), 2.47 - 2.52 (m, IH), 2.77 (s, 3H), 2.79 (s, 3H), 3.09 - 3.16 (m, 2H), 5.34 (dd, IH, J = 5.6, 9.6 Hz), 7.28 (d, 2H, J = 8.8 Hz), 7.32 - 7.36 (m, 3H), 7.44 (d, 2H, J = 8.8 Hz), 7.52 (d, 2H, J = 8.4 Hz), 7.56 (dd, IH, J = 1.2, 8.4 Hz), 7.68 - 7.77 (m, 3H), 7.88 - 7.92 (m, 3H). 13C NMR δ 34.5, 46.2, 46.6, 55.9, 59.5, 128.6, 129.4, 130.0, 130.2, 130.8 (2 C:s), 130.9 (2 C:s), 131.5, 131.8, 131.9, 132.1 (2 C:s), 132.6, 132.8 (2 C:s), 136.6, 137.1, 137.6, 142.8, 143.8, 148.6, 172.5. HRTofMS calcd for C28H28N2O (M+) m/z 408.2202, found 408.2204. 7V-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide HCl {C6}
Figure imgf000062_0001
[0197] Reaction of 4-(4-chlorophenyl)benzoic acid with C yielded 140 mg (72%) {C6} which was converted to the hydrochloride salt. 1H NMR δ 2.36 - 2.40 (m, IH), 2.48 - 2.52 (m, IH), 2.77 (s, 3H), 2.78 (s, 3H), 3.08 - 3.15 (m, IH), 3.21 - 3.27 (m, IH), 5.34 (dd, IH, J = 5.6, 9.6 Hz), 7.28 (d, 2H, J = 8.4 Hz), 7.31 - 7.36 (m, 2H), 7.44 (d, 2H, J= 8.4 Hz), 7.52 (d, 2H, J= 8.4 Hz), 7.56 (dd, IH, J= 1.2, 8.4 Hz), 7.69 - 7.77 (m, 3H), 7.88 - 7.92 (m, 3H). 13C NMR δ 34.5, 46.2, 46.6, 55.9, 59.5, 128.6, 129.4, 130.0, 130.2, 130.7 (2 C:s), 131.5,
131.8, 132.2 (2 C:s), 132.4 (2 Cs), 132.6, 132.9 (2 Cs), 136.9, 137.1, 137.5, 137.9, 142.4,
142.9, 147.0, 172.3. HRTofMS calcd for C28H27ClN2O (M+) m/z 442.1812, found 442.1818.
7V-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide HCl {C7}
Figure imgf000062_0002
[0198] Reaction of 4-(4-methoxyphenyl)benzoic acid with C yielded 160 mg (83%) {C7} which was converted to the hydrochloride salt. 1H NMR δ 2.35 - 2.39 (m, IH), 2.45 - 2.48 (m, IH), 2.76 (s, 3H), 2.77 (s, 3H), 3.09 - 3.12 (m, IH), 3.18 - 3.22 (m, IH), 3.68 (s, 3H), 5.33 (dd, IH, J = 5.6, 9.4 Hz), 6.82 (d, 2H, J = 8.8 Hz), 7.33 - 7.38 (m, 2H), 7.43 (d, 2H, J= 8.8 Hz), 7.52 - 7.56 (m, 3H), 7.70 - 7.78 (m, 3H), 7.85 - 7.88 (m, 3H). 13C NMR δ 34.5, 46.2, 46.6, 55.8, 58.6, 59.5, 118.2 (2 C:s), 128.6, 129.4, 130.0, 130.2 (2 C:s), 130.3, 131.5, 131.8, 131.9 (2 C:s), 132.1 (2 C:s), 132.6, 135.8, 136.0, 137.1, 137.6, 142.8, 148.2, 164.0, 172.5. HRTofMS calcd for C29H30N2O2 (M+) m/z 438.2307, found 438.2322.
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(2-naphthyl)benzamide HCl {C8}
Figure imgf000063_0001
[0199] Reaction of 4-(2-naphthyl)benzoic acid with C yielded 110 mg (55%) {C8} which was converted to the hydrochloride salt. 1H NMR δ 2.33 - 2.39 (m, IH), 2.42 - 2.56 (m, IH), 2.78 (s, 3H), 2.79 (s, 3H), 3.10 - 3.14 (m, IH), 3.20 - 3.27 (m, IH), 5.35 (dd, IH, J = 5.6, 9.6 Hz), 7.34 - 7.39 (m, 4H), 7.56 (d, IH, J= 8.4 Hz), 7.62 (dd, IH, J= 1.6, 8.8 Hz), 7.70 - 7.79 (m, 8H), 7.88 (s, IH), 7.94 (d, 2H, J = 8.4 Hz), 7.99 (s, IH). 13C NMR δ 34.5, 46.2, 46.6, 55.9, 59.6, 128.6, 128.8, 129.4, 129.8, 130.0, 130.2 (2 C:s), 130.3, 131.0 (2 C:s), 131.4, 131.5, 131.8, 132.2 (3 C:s), 132.5, 132.6, 136.6, 137.1, 137.2, 137.6, 137.8, 141.0, 142.8, 148.4, 172.5. HRTofMS calcd for C32H30N2O (M+) m/z 458.2358, found 458.2362. 7V-[3-Dimethylaminopropyl-l-(4-chlorophenyl)]-(R)-2-methoxy-2-phenylacetamide HCI
(A9)
Figure imgf000064_0001
Figure imgf000064_0002
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(R)-2-methoxy-2-phenylacetainide oxalate (A9)
[0200] Compound A (0.9 g, 4.2 mmol) was dissolved in THF (100 mL). (R)-2- Methoxy-2-phenylacetic acid (0.7 g, 4.2 mmol), EDC (0.9 g, 4.5 mmol) and DMAP (0.12 g, 0.9 mmol) were added and the mixture was stirred for three days. Saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL) were added. The phases were separated and the water phase extracted with EtOAc. The combined organic phases were washed (water, brine) and evaporated. The resulting mixture was purified with flash chromatography using MeOH/CH2Cl2/NEt3 (5/94.9/0.1) to give 1.1 g (67%) of the pure diastereomeric mixture which was separated by repeated flash chromatography using MeOHZCH2Cl2ZNEt3 (5Z94.9Z0.1) until the pure diastereomers were obtained (>99.7%). (+)-(R)-N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(R)-2-methoxy-2- phenylacetamide oxalate ((+)-A9 (R5R))
[0201] Mp 179.2 - 181.0 0C. [α]D +50.0 (c 0.034, MeOH). Anal. (C22H27ClN2O6) C, H, N.
(-)-(5)-7V-[l-(4-ChlorophenyI)-3-dimethylaminopropyl]-(Λ)-2-methoxy-2- phenylacetamide oxalate ((-)-A9 (R5S))
[0202] Mp 163.0 - 163.8 0C. [α]D -111.4 (c 0.044, MeOH). Anal. (C22H27ClN2O6) C, H, N
N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(R)-2-methoxy-2-phenylacetaniide HCI
(B9)
Figure imgf000065_0001
[0203] Compound B (0.55 g, 2.9 mmol) was dissolved in THF (100 mL). (R)-2- Methoxy-2-phenylacetic acid (0.48 g, 2.9 mmol), EDC (0.60 g, 3.2 mmol) and DMAP (35 mg, 0.29 mmol) were added and the mixture was stirred for three days. Saturated aqueous NaHCO3 (100 mL) and EtOAc (100 mL) were added. The phases were separated and the water phase extracted with EtOAc. The combined organic phases were washed (water, brine) and concentrated. The residue was purified with flash chromatography using MeOH/CH2Cl2/NEt3 (5/94.9/0.1) to afford 0.42 g (44%) of the pure diastereomeric mixture which was separated by repeated flash chromatography using MeOH/CH2Cl2/NEt3 (5/94.9/0.1) until the pure diastereomers were obtained (200 mg (+), 220 mg (-)) which were converted to their corresponding hydrochloride salt for analysis, storage and biological testing. (+)-N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(R)-2-methoxy-2-phenylacetamide
HCl ((+)-B9)
Figure imgf000066_0001
[0204] [α]D +9.1 (c 0.72, MeOH). 1H NMR δ 2.13 - 2.19 (m, 5H), 2.62 (s, 3H), 2.65 (s, 3H), 2.83 - 2.87 (m, 2H), 3.21 (s, 3H), 4.60 (s, IH), 4.85 (dd, IH, J = 6.0, 9.2 Hz), 7.01 (d, 2H, J = 8.0 Hz), 7.12 (d, 2H, J = 8.0 Hz), 7.20 - 7.27 (m, 3H), 7.36 (d, 2H, J = 7.2 Hz). 13C NMR δ 24.0, 34.5, 46.1, 46.5, 54.3, 59.3, 60.3, 87.6, 130.4 (2 C:s), 131.1 (2 C:s), 132.5 (3 C:s), 133.2 (2 C:s), 141.5, 141.6, 141.8, 176.0
(-)-N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(R)-2-methoxy-2-phenylacetamide
HCl ((-)-B9)
Figure imgf000066_0002
[0205| [α]D -137.2 (c 0.27, MeOH). 1H NMR δ 2.20 - 2.28 (m, 2H), 2.30 (s, 3H), 2.80 (s, 6H), 3.00 - 3.04 (m, 2H), 3.33 (s, 3H), 4.72 (s, IH), 4.95 (dd, IH, J = 5.9, 9.1 Hz), 7.14 (d, 2H, J = 8.0 Hz), 7.23 (d, 2H, J = 8.0 Hz), 7.31 - 7.39 (m, 5H). 13C NMR δ 19.8, 30.3, 42.3 (2 C:s), 50.4, 55.3, 56.1, 83.4, 126.3 (2 C:s), 127.2 (2 C:s), 128.3 (2 C:s), 128.4, 129.1 (2 C:s), 137.4, 137.5, 137.7, 171.8. N-[3-Dimethylaminopropyl-l-(2-naphthyl)]-(R)-2-methoxy-2-phenylacetamide HCI (C9)
Figure imgf000067_0001
[0206] Compound C (0.70 g, 3.0 mmol) was reacted according to the same procedure as described for B to afford 0.55 g (49%) of the pure diastereomeric mixture of C9 which was separated by repeated flash chromatography using MeOH/CH2C12/NEt3 (5/94.9/0.1) until the pure diastereomers were obtained (250 mg (+), 300 mg (-)). The amines were converted to their corresponding hydrochloride salt for analysis, storage and biological testing.
(+)-iV-[3-DimethyIaminopropyl-l-(2-naphthyl)]-(R)-2-methoxy-2-phenylacetamide HCl
((+)-C9)
Figure imgf000067_0002
[0207] [α]D +26.0 (c 1.5, MeOH). 1H NMR δ 2.23 - 2.29 (m, 2H), 2.64 (s, 6H), 2.87 - 2.93 (m, 2H), 3.21 (s, 3H), 4.62 (s, IH), 5.06 (t, IH, J= 7.6 Hz), 7.21 - 7.27 (m, 3H), 7.32 - 7.39 (m, 5H), 7.65 - 7.72 (m, 4H). 13C NMR δ 32.3, 46.4 (2 C:s), 54.6, 59.3, 60.3, 87.6, 128.4, 129.2, 130.0, 130.2, 131.0 (2 C;s), 131.1, 131.4, 131.7, 132.4 (2 C:s), 132.5, 137.1, 137.5, 141.6, 142.0, 176.2.
(-)-iV-[3-Dimethylaminopropyl-l-(2-naphthyl)]-(R)-2-methoxy-2-phenylacetamide HCl
((-)-C9)
Figure imgf000068_0001
[0208] [α]D -133.5 (c 0.29, MeOH). 1H NMR δ 2.31 - 2.42 (m, 2H), 2.81 (s, 6H), 3.00 - 3.11 (m, 2H), 3.36 (s, 3H), 4.76 (s, IH), 5.16 (dd, IH, J= 7.0, 8.1 Hz), 7.29 - 7.32 (m, 3H), 7.39 - 7.49 (m, 4H), 7.77 - 7.85 (m, 4H). 13C NMR δ 30.1, 42.3 (2 C:s), 50.7, 55.3, 56.1, 83.5, 124.3, 125.1, 125.9, 126.1, 127.1 (2 C:s), 127.3, 127.6, 128.3 (2 C:s), 128.4, 128.5, 133.0, 133.4, 137.4, 137.9, 172.1.
yV-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]-4-phenylbenzamide oxalate (D5)
Figure imgf000068_0002
[0209] Reaction of 4-phenylbenzoic acid with D yielded 1 15 mg (67%) D5 which was converted to the hydrochloride salt. 1H NMR δ 1.15 - 1.23 (m, IH), 1.74 - 1.94 (m, 5H), 2.31 - 2.51 (m, 2H), 2.85 - 2.92 (m, 2H), 3.11 - 3.31 (m, 2H), 3.51 - 3.60 (m, 2H), 5.23 (dd, IH, J= 5.5, 9.5 Hz), 7.35 - 7.40 (m, 3H), 7.43 - 7.49 (m, 4H), 7.64 (d, 2H, J= 7.3 Hz), 7.72 (d, 2H, J = 8.1 Hz), 7.95 (d, 2H, J = 8.1 Hz). 13C NMR δ 21.3, 23.0, 23.1, 29.6, 29.7, 51.1, 53.0, 54.4, 54.6, 126.7 (2 C:s), 126.8 (2 C:s), 127.8, 127.9 (2 C:s), 128.3 (2 C:s), 128.6 (2 C:s), 128.8 (2 C:s), 132.4, 133.3, 139.8, 140.1, 144.7, 168.5. Anal. Calcd for C27H29ClN2O x HCl: C, 69.1; H, 6.4; N, 6.0. Found: C, 69.5; H, 6.5; N, 6.4.
N-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]benzamide oxalate (DlO)
Figure imgf000069_0001
[0210] Reaction of benzoic acid with D yielded 95 mg (67%) DlO which was converted to the hydrochloride salt. 1H NMR δ 1.12 - 1.20 (m, IH), 1.61 - 1.80 (m, 5H), 2.10 - 2.22 (m, 2H), 2.85 - 2.93 (m, 2H), 3.00 - 3.23 (m, 4H), 5.14 (dd, IH, J= 5.6, 9.6 Hz), 7.26 (d, 2H, J = 8.4 Hz), 7.33 - 7.45 (m, 5H), 7.81 (d, 2H, J = 8.4 Hz). 13C NMR δ 25.4, 27.1, 38.9, 52.5, 55.4, 57.4, 58.7, 69.7, 131.5 (2 C:s), 132.3, 132.4 (2 C:s), 132.7 (2 C:s), 135.8 (2 C:s), 137.2, 137.9, 144.6, 170.0. Anal. Calcd for C2iH25ClN2O x HCl: C, 64.1; H, 6.7; N, 7.1. Found: C, 64.5; H, 6.5; N, 7.4. N-[l-(4-Chlorophenyl)-4-dimethylaminobutyl]-4-phenylbenzamide oxalate (E5)
Figure imgf000070_0001
[0211] Reaction of 4-phenylbenzoic acid with E yielded 110 mg (61%) E5 which was converted to the oxalate salt.1H NMR δ 1.72 - 2.06 (m, 4H), 2.87 (s, 6H), 3.16 - 3.21 (m, 2H), 5.18 (dd, IH, J - 5.9, 9.2 Hz), 7.36 - 7.39 (m, 3H), 7.43 - 7.48 (m, 4H), 7.65 (d, 2H, J = 7.3 Hz), 7.72 (d, 2H, J = 8.1 Hz), 7.93 (d, 2H, J = 8.1 Hz). 13C NMR δ 21.7, 32.2, 42.2 (2 C:s), 52.8, 57.2, 126.7 (2 C:s), 126.8 (2 C:s), 127.8, 127.9 (2 C:s), 128.2 (2 C:s), 128.4 (2 C:s), 128.7 (2 C:s), 132.8, 132.9, 139.8, 141.2, 144.5, 168.4. HRTofMS calcd for C25H27ClN2O (M+) m/z 406.9597, found 406.9600.
N-[l-(4-Chlorophenyl)-4-dimethylarninobutyl]benzamide oxalate (ElO)
Figure imgf000070_0002
[0212] Reaction of benzoic acid with E yielded 60 mg (41%) ElO which was converted to the oxalate salt. 1H NMR δ 1.71 - 2.01 (m, 4H), 2.86 (s, 6H), 3.14 - 3.22 (m, 2H), 5.13 (dd, IH, J= 5.8, 9.5 Hz), 7.35 (d, 2H, J= 9.2 Hz), 7.42 (d, 2H, J= 9.2 Hz), 7.45 - 7.47 (m, 2H), 7.53 (tt, IH, J= 1.4, 7.3 Hz), 7.84 (dd, 2H, J= 1.4, 7.3 Hz). 13C NMR δ 21.7, 32.2, 42.1, 42.2, 52.8, 57.2, 127.2 (2 C:s), 128.1 (2 C:s), 128.3 (2 C:s), 128.4 (2 C:s), 131.5, 132.8, 134.1, 141.2, 168.7. HRTofMS calcd for Ci9H23ClN2O (M+) m/z 330.8610, found 330.8613.
Biological activity
[0213] R-SAT-testing: R-SAT™ assays for pharmacological testing were performed as previously described, with the following modifications. NIH-3T3 cells were grown to 80% confluence in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% bovine calf serum (Hyclone) and 1% penicillin/streptomycin/glutamine (Invitrogen). Cells were transfected in rollerbottles for 18 h with the human urotensin II receptor and the β-galactosidase marker. After the 18 h transfection, cells were trypsinized, harvested, and frozen. Aliquots of frozen cell batches were thawed and tested for response to control compound to perform quality control before initiation of pharmacological testing, ensuring the correct pharmacological response and sufficient sensitivity. To initiate the pharmacological assay, cells were thawed rapidly and prepared in DMEM media containing 0.4% calf serum (Hyclone), 30% UltraCulture (Biowhittaker), and 1% penicillin/streptomycin/glutamine (Invitrogen), and then added to half-area 96-well microtiter plates containing either test compounds or reference ligands. After a five day incubation of drug with cells in 5% ambient CO2, media was removed and reporter enzyme activity was measured at 420 nm. Microsomal Assay and clearance calculations
[0214] The compounds were incubated at 1 μM in the presence of human or rat liver microsomes (0.5 mg protein/mL), using a Tecan liquid handling robot (LHR). A Tris buffer (100 mM, pH 7.4 at 37 0C) was used as incubation medium. The compound was mixed with microsomes and a five-minute pre-incubation period was allowed. The enzymatic reaction was initiated by addition of NADPH (2.0 mM) and samples were drawn at 0, 5, 10, and 30 min. The reaction was stopped by protein precipitation by dispensing the samples into a deep well plate containing acetonitrile, the deep well plate was then centrifuged offline from the LHR. The plate was again moved to the LHR and the supernatants were transferred to a second deep well plate for analysis using a liquid chromatography system coupled to a tandem mass spectrometer in the electrospray positive ion mode. The peak areas obtained at the different time points gave the elimination rate constant, from which the intrinsic clearance (CL,nt) was calculated. Phosphatidyl Inositol (PI) hydrolysis assays
[0215] TsA cells were seeded at 10,000 cells/well in Dulbecco's Modified Eagle Medium (DMEM, Invitrogen) supplemented with 10% fetal calf serum, penicillin (100 units/mL) and streptomycin (100 mg/mL) in a 37 0C humidified atmosphere containing 5% CO2. Eighteen hours later, the cells were transfected with the indicated plasmid DNAs (30 ng/well) using PolyFect (Qiagen) 0.5 μl/well. Approximately 18-20 hours post-transfection, the medium was removed, and the cells labeled overnight with DMEM culture medium containing 0.2 μCi 2-[3H]-myo-inositol (NETl 14, 37 MBg/mL, PerkinElmer) per well (0.1 mL). The cells were washed and incubated with Hank's Balanced Salt Solutions (Invitrogen) supplemented with CaCl2 (1 mM), MgCl2 (1 mM), LiCl (10 mM) and BSA 0.2% for 45 min. The buffer was removed, and the cells were incubated for another 45 min at 37 0C in the same buffer with the indicated concentrations of freshly made ligands. The reaction was stopped by exchange with ice-cold formic acid (20 mM), and the total [3H]inositol phosphates (IPl, IP2 and IP3) formation was determined by ion-exchange chromatography on 1 mL-minicolumns loaded with 200 μl of a 50% suspension of AG 1-X8 resin (200-400 mesh, Formate form, Bio-Rad, Hercules, CA). The columns were washed with ammonium hydroxide (1 mL 40 mM, pH 9) after loading the cell extracts and then eluted with ammonium formate (0.4 mL 2M) in formic acid (0.1 M). Eluates (0.1 mL) were loaded on LumaPlate-96 (Yttrium silicate scintillator coated, PerkinElmer) and air-dried overnight and counted on a Microplate Scintillation & Luminescence Counter (TopCount NXT, PerkinElmer). X-Ray Structure Determination
[0216] A colourless block crystal of N-[3-dimethylaminopropyl-l-(2-naphthyl)]- 1 -methoxy-2-phenyl-acetamide HCl (C24H^ClN2O2) (-)-{C9} having approximate dimensions of 0.40 x 0.30 x 0.25 mm3 was mounted with epoxy cement on the tip of a fine glass fiber. All measurements were made on a Nonius CAD4 diffractometer with graphite monochromated Mo-Ka radiation.22 Cell constants and an orientation matrix for data collection corresponded to a primitive monoclinic cell with dimensions: a = 5.4068(11) A α = 90 ° b = 10.174(2) A β = 93.02(2) ° . c = 20.701(6) A ■ γ = 90 °
V = 1137.1(5) A3
[0217] For Z = 2 and F.W. = 412.94, the calculated density is 1.206 mg/m3. The space group was determined to be P21 (#4). The data were collected at a temperature of 298(2) K to a maximum 2Θ value of 51.92 °.
[0218] A total of 2492 reflections including Friedel equivalents were collected of which 2366 were unique and observed (Rint = 0.0113). The linear absorption coefficient, μ, for Mo-Ka radiation is 0.189 mm"1, and no absorption correction was applied. The data were corrected for Lorentz and polarization effects.23
[0219] The structure was solved by direct methods and expanded using Fourier techniques.24'25 The non-hydrogen atoms were refined anisotropically, and hydrogen atoms were treated as idealized contributions. The final cycle of full-matrix least-squares refinement on F was based on 1428 observed reflections (I > 2.00σ(I)) and 265 variable parameters and converged with unweighted and weighted agreement factors of:
2 2 2 2 2 1/2
R = Σ ||Fo| - |Fc|| / Σ |Fo| = 0.0669; Rw = {∑[w (Fo - Fc ) ] / Σ[w(Fo ) ]} = 0.1840 [0220] The maximum and minimum peaks on the final difference Fourier map corresponded to 0.641 and -0.570 e/A respectively. The absolute structure Flack parameter is 0.03(19).26
[0221] Results are summarized in Table 1 below.
Table 1. Yields, activity and efficacy of amides {Al - C8} tested in the R-SAT™ assay.
Figure imgf000074_0001
1 R = 3-phenyl 5 R = 4-phenyl COOH 2 R = 3-(4-chlorophenyl) 6 R = 4-(4-chlorophenyl)
R4 Kj 3 R = 3-(4-methoxyphenyl) 7 R = 4-(4-methoxyphenyl) 4 R = 3-(2-naphthyl) 8 R = 4-(2-naphthyl)
Amines
B
Acids
{Al} {Bl} {CI}
Yield 65% Yield 65% Yield 95% pEC50 6.24 ± pEC50 6.09 ± pECso 6.27 ±
1 J.
0.23 0.07 0.17
Efficacy 92 ± 26 Efficacy 45 ± 4 Efficacy 67 ± 5
{A2} {B2} {C2}
Yield 60% Yield 74% Yield 92% pEC50 6.36 ± pEC50 6.19 ± pEC50 5.96 ±
9
0.21 0.21 0.12
Efficacy 63 ± 13 Efficacy 39 ± 4 Efficacy 45 ± 6
{A3} {B3} {C3}
Yield 60% Yield 70% Yield 67% pECso 6.24 ± pEC50 5.97 ± pEC50 6.19 ±
0.03 0.11 0.10
Efficacy 78 ± 18 Efficacy 69 ± 10 Efficacy 50 ± 16 {A4} {C4}
{B4} Yield 72% Yield 99% Yield 85% pEC506.44 ± pECso 5.46 ±
4 pECso NA 0.09 0.13 Efficacy NA Efficacy 41 ± 14 Efficacy 38 ±9
{A5} {B5} {C5}
Yield 50%d Yield 75% Yield 95% pEC507.11± pEC506.70 ± pEC506.92 ± j <;
0.01 0.17 0.18
Efficacy 116 ±11 Efficacy 114 ±17 Efficacy 111 ± 3
{A6} {B6} {C6}
Yield 65% Yield 84% Yield 72% pEC507.12± pEC506.90 ± pEC507.36± f.
0.04 0.13 0.11
Efficacy 137 ±2 Efficacy 108 ± 8 Efficacy 129 ± 5
{A7} {B7} {C7}
Yield 60% Yield 70% Yield 83% pEC507.13± pEC506.46 ± pEC506.98 ±
7 I
0.31 0.21 0.07
Efficacy 143 ± 24 Efficacy 119 ± 11 Efficacy 111 ± 0
{A8} {B8} {C8}
Yield 72% Yield 62% Yield 55% pEC506.51 ± pEC506.09 ± pEC506.28 ±
O C
0.02 0.03 0.05
Efficacy 131 ±8 Efficacy 83 ± 4 Efficacy 77 ± 3 aResults were determined in R-SAT assays and are expressed as pEC50, the negative of the log EC50 in molarity. Results are the average ± standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. b The % efficacy values are normalized to UII at 100%. cNA = No detectable activity.d For experimental details, see ref 1.
Example 4: Separation of Amine Enantiomers
[0222] To separate the enantiomers of amines A - C, the racemates were reacted with (R)-2-methoxy-2-phenyl-acetic acid (9) in the presence of EDC and DMAP to produce {A9 - C9}, as shown in Scheme 6 below.
Scheme 6
Figure imgf000076_0001
A - C {A9 - C9}
Reagents and conditions: i) EDC, DMAP rt, 44 - 49%
[0223] The diastereomeric amides were separated by flash chromatography to yield (+)- and (-)-A9 - C9 which were subsequently hydrolyzed using refluxing 6M HCI. The amines (+)- and (-)-A - C were reacted with 4-phenylbenzoic acid and 4-(4- chlorophenyl)benzoic acid to afford amides (+)- and (-)-A5 and C6 respectively in good yields using the same method as described above, as shown in Table 2 below.
Table 2. Activity and efficacy of (R)- and (5)-{A5} and {C6} in the R-S AT™ assay.
Figure imgf000076_0002
Cmpd R, R2 pEC5O a Efficacy"
(+)-(5)-{A5}c 4-Ph 4-Cl-Ph 7.49 ± 0.33 1 16 ± 18
(-)-(/?)-{A5}c 4-Ph 4-Cl-Ph 5.84 ± 0.10 96 ± 16
(+MSMC6} 4-(4-Cl-Ph) 2-naphthyl 7.64 ± 0.23 129 ± 4 (-MΛMC6} 4-(4-Cl-Ph) 2-naphthyl 6.34 ± 0.15 53 ± 5 aResults were determined in R-SAT assays and are expressed as pEC50, the negative of the log EC50 in molarity. Results are the average ± standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. bThe % efficacy values are normalized to UII at 100%. cFor experimental details, see ref 1.
Example 5: Pharmacological Testing
[0224] Compounds Al - ElO were tested for their agonistic properties at human
UT receptors using the functional R-SAT™ assay previously described. 17-'20 The results are shown in Tables 1 and 2 above, and also in Tables 3 and 4 below.
Table 3. Activity and efficacy of amides {D5 - El 0} in the R-SAT™ assay.
Figure imgf000077_0001
D5: R = Ph E5: R = Ph D10: R = H E10: R = H
Cmpd pEC5O a Efficacy"
{A5}c 7.11 ± 0.01 116 ± 11
D5 6.50 ± 0.21 91 ± 12
DlO 5.42 10.01 77 ± 23
E5
ElO 5.19 ± 0.07 55 ± 0
Results were determined in R-SAT assays and are expressed as pEC50, the negative of the log EC50 in molarity. Results are the average ± standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. bThe % efficacy values are normalized to UII at 100%. cFor experimental details, see ref 1.
Table 4. Activity and efficacy of enantiomerically pure amides (A9 - C9) in the R-SAT™ assay.
a
Figure imgf000078_0001
of the log EC50 in molarity. Results are the average ± standard deviations of 2-5 determinations of the EC50 where each compound was tested in eight doses in triplicate. bThe % efficacy values are normalized to UII at 100%. cFor experimental details, see ref 1.
[0225] For control of the UT receptor selectivity all compounds were tested against the m3 receptor as a negative control (data not shown). Both the racemate of A5 and pure (S)-A5 were also tested in a phosphatidyl inositol (PI) hydrolysis assay to further characterize their agonistic properties.
Example 6: Metabolism
[0226] Five compounds with different properties were tested for their metabolic stability in human and rat liver microsomal preperations. Two amides (A5 and C6) and one each of ester (15), carbamate (16) and urea (17) derivatives1 were tested, the results are summarized in Table 5. [0227] Since an intrinsic clearance of <25 in human and <45 in rat approximately corresponds to a bioavailability of about 50%, all compounds tested are believed to have good bioavailability in humans. There is however a large difference in clearance between the two species, which can be explained by the higher metabolic oxidation capabilities in rats compared to most other species. The higher clearance of 15 and 16 in rat liver microsomes could thus be a result of the aromatic methyl groups present which are prone to oxidation. However, all the tested compounds have clearance values low enough to suggest that they have a sufficient lifetime in vivo to reach their target receptor.
[0228] Results of the testing are shown in Table 5. Table 5. Clearance of selected derivatives in rat and human liver microsome preparations.
Figure imgf000079_0001
Comp. CL(jnt) Human CL0n.) Rat
15 0 530
16 4 217
17 0 25
{A5} 3 7
{C6} 0 170
Example 7: Structure Activity Relationships
[0229] As is apparent from Table 1 and illustrated in Figure 1 , the positioning of the biphenyl is of vital importance for potency, as all 4-biaryl derivatives (A5 - C8) are significantly more potent than their corresponding 3-biaryl analogues (Al - C4) independent on structure or functionalities in the aromatic ring.
[0230] Within the 3-biaryl series, the substitution pattern in the two rings plays only a minor role for the potency as all but two derivatives (B4 and C4) exhibit ECso-values within 0.5 log units (pECs0 5.96 - 6.44). See Table 1 and Figure 1. Another trend, especially for the 4-biaryl series is that the 4-(2-naphthyl) substituent is the least favourable for activity (A4 - C4 and A8 - C8). For efficacy, substitution in the 4-position is more favourable, as all 4-substituted biaryl derivatives showed higher or much higher efficacies than the corresponding 3-substituted analogues. .See Table 1.
[0231] In our previous study on 3-(4-chloropheny)-3-(2- (dimethylamino)ethyl)isochroman-l-one analogues3 we observed that a prolongation of the distance between the aromatic rings and the amino moiety decreased the activity ca 0.5 log units we also found that larger amino groups than dimethylamino were detrimental to the activity.3 In the present invention, D5 and DlO showed the same decrease (0.5 log units) in activity, as seen in Table 2, compared to the corresponding compounds with unchanged chain length (A5 and 18, respectively)1.
Figure imgf000080_0001
[0232] Furthermore, to test the proposed influence of larger amino groups we synthesized the piperidinyl analogues E5 and ElO. As shown in Table 2, when comparing E5 with A5 the same negative result was obtained. These results indicate that the two different series of agonists bind to the UT-receptor at the same site, which is also in agreement with results from computational studies.1
Example 8: Enantiomers
[0233] In order to verify that compounds in the amide series of UT-agonists preferably have the ^-configuration, the diastereomeric amides A9 - C9 were synthesized, as seen in Table 3. The absolute configuration of (-)-C9 was determined using X-ray crystallography and was found to have the (R, ^-configuration.
[0234] In separate experiments (-) and (+)-C9 were hydrolysed and both enantiomers of C were reacted with acid 6 to yield (+)-{C6} and (-)-{C6}, respectively. As seen in Tables 3 and 4 there is a large difference in activity for the enantiomers, again the S- enantiomer being far more potent than the /?-enantiomer for all pairs except (+)- and (-)-B9 which show equal potencies. [0235] The combination of the results obtained for the benzamides synthesized in the present study and previous results regarding similar systems,1'3 make it possible to conclude the information illustrated in Figure 2. It is beneficial when the agonist has the (S)- configuration as all resolved (5)-enantiomers are more than 10 times more potent than their corresponding (7?)-enantiomers. The linker between the aromatic rings is more sensitive to direction than size as amides, ureas, carbamates and esters are active, but not ethers or sulfonamides.1 In the amide series different spacers between the carbonyl group and the aromatic ring denoted A in Figure 2 are tolerated such as methylene, ethylene, vinyl and ethynyl. The substitution pattern in the aromatic ring denoted B in Figure 2, plays a role for the activity as the 4-chlorophenyl substituted derivatives (Al - A8) show high activities compared to the 4-methylphenyl substituted analogues (Bl - B8). As the size of a methyl group and a chlorine atom is about equal, this difference can be attributed to electronic effects. In the A-ring many diverse functionalities (such as methyl, methoxy, trifluoromethyl, chloro, dioxolane, phenoxy, phenyl and combinations thereof) are well tolerated, but in general lipophilic substituents in the 4-position are most beneficial with the exception for the 4-(2-naphthyl) derivatives (A4 - C4 and A8 - C8) which apparently are too large for optimal receptor interaction.
Example 9: Phosphatidyl inositol (PI) hydrolysis assay
[0236] UII, racemic A5 and (+)-(S)-A5 were tested for activity in PI hydrolysis assays, at cells transiently expressing recombinant human UT receptors. UII was shown to be a potent agonist, with a pECso-value of 9.5, approximately 30-100 fold lower than its potency in RSAT, as can be seen in Figure 3 and in Table 6 shown below.
Table 6. Agonist profiles at the human UT receptor determined in PI hydrolysis assays. a
Ligand pEC 50 Efficacy (%)
(+)-{A5} 5 .9 ± 0. 3 66 ± 19
{A5} 5 .5 ± 0. 4 69 ± 23
UII 9 .5 ± 0. 2 100 ± 2 a)Data represent mean ± S. D. of at least three independent experiments.
[0237] The much higher potency seen in RSAT is consistent with a much higher degree of receptor reserve, a phenomenon we have observed with many other receptors besides the UT-receptor.21 In contrast, (±)-A5 and (+)-(5)-A5 were each partial agonists (pEC50 5.5 and 5.9, and efficacies 69% and 66%, respectively) compared with UII.
[0238] It will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure.
[0239] The disclosures of the following references are hereby incorporated by reference in their entirety:
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Claims

WHAT IS CLAIMED IS:
1. A compound of Formula (I):
Figure imgf000085_0001
(I) as a single isomer, a mixture of isomers, or a racemic mixture of isomers; a solvate or polymorph; a metabolite; or a pharmaceutically acceptable salt or prodrug thereof; wherein:
X is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -N(Ri)-, and -O-;
Y is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene,
C,-C4alkynylene, -C(=O)-, -C(O)N(R la)-, -S(O)2-, -S(O)-, -S(O)2N(R13)-, -
S(O)N(R12)-, -N(R13)-, -C(O)O-, -C(O)O-W-, -C(O)W-,
Figure imgf000085_0002
-
C(O)N(R13)-, -C(O)N(R13)W-, -S(O)2W-, -S(O)W-, -S(O)2N(R13)W-, - S(O)N(R13)W- and -N(Ri3)W-;
W is selected from the group consisting of: d-C4alkylene, d-C4alkenylene, and d-C4alkynylene;
Ri and R13 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl;
Cy1 is selected from the group consisting of an optionally substituted aryl and an optionally substituted heteroaryl;
Cy2 is
Figure imgf000086_0001
R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-CiO heteroalicyclyl;
R3, R3c, R3d, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, halogen, hydroxyl, nitro, sulfenyl, sulfϊnyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(=O)Ri, -C(=O)OR,, -C(O)NR1R,., -C(R,)=NRla, -NR1R13, -N=CR1R13, -N(R,)-C(=0)Rla, -N(R,)-C(O)NR,aRib, -S(O)NR1R13, -S(O)2NR1R13, -N(R,)-S(O)R,., -N(Ri)-S(O)2Ru, -ORi, -SR1, and -OC(O)Ri;
R3a is hydrogen, an optionally substituted phenyl, or an optionally substituted naphthyl;
R3b is hydrogen, a substituted phenyl, or optionally substituted naphthyl; provided that at least one of R3a and R3b is an optionally substituted phenyl or an optionally substituted naphthyl.
2. The compound of Claim 1, wherein Cy1 is selected from the group consisting of:
Figure imgf000087_0001
wherein R3] R3a, R3b, R3c, R3d, R-3e, and R3f are each independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, halogen, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(=O)Ri, -C(=O)ORi, -CC=O)NR1Ru, -C(Ri)=NRi,, - NR1R13, -N=CR1R13, -N(R,)-C(=O)R,a, -N(RO-C(O)NRuR^, -S(O)NR1Ru, - S(O)2NR1R13, -N(RO-S(O)Ri,, -N(RO-S(O)2Ru, -OR,, -SR1, and -OC(O)R1; wherein R)1 Ri3 and Rn, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl; or if two R groups selected from the group consisting of R3, R3a, R3b, R3c, R3d, R3e, and R3f are covalently bonded to adjacent atoms, then the two R groups can be taken together to form an optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted heteroalicyclyl group.
3. The compound according to Claims 1 to 2, wherein: X is -N(RO-;
Y is selected from the group consisting of -C(O)-, -C(=0)N(Ria)-, -C(O)O-,
-C(O)O-W-, -C(O)W-,
Figure imgf000088_0001
, -C(O)N(Rla)-, -C(O)N(R13)W-, and -
N(R13)W-;
Ri and R)3 are each independently selected from the group consisting of hydrogen and optionally substituted Ci -C4 alkyl; and
R2 and R2a are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C4 alkyl.
4. The compound according to Claims 1 to 3, wherein:
X is -N(RO-;
Y is selected from the group consisting of -C(O)- or
Figure imgf000088_0002
Ri and R]3 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C4 alkyl; and
R2 and R23 are each independently selected from the group consisting of hydrogen and optionally substituted Ci-C4 alkyl.
5. The compound according to Claims 1 to 4, wherein Cyi is an optionally substituted phenyl.
6. The compound according to Claims 1 to 5, wherein Cyi is a halogenated phenyl.
7. The compound according to Claims 1 to 6, wherein: R3, R3b, R3c, and R3d> in Cy2 are hydrogen; and
R3a in Cy2 is an optionally substituted phenyl or an optionally substituted naphthyl.
8. The compound according to Claims 1 to 7, wherein: R3, R3b, R3c, and R3d, in Cy2 are hydrogen; and R3a in Cy2 is a 4-substituted phenyl or 2-napthyl.
9. The compound according to Claims 1 to 8, wherein: R3 R3b, R3C, and R3^ in Cy2 are hydrogen; and
R3 in Cy2 is a 4-chlorophenyl, 4-methoxyphenyl, or 2-napthyl.
10. The compound according to Claims 1 to 6, wherein: R3, R3a, R3c, and R3d, in Cy2 are hydrogen; and
R3b in Cy2 is a substituted phenyl or an optionally substituted naphthyl.
11. The compound according to Claims 1 to 7, wherein: R3, R3a, R3c, and R3d] in Cy2 are hydrogen; and
R3b in Cy2 is a 4-substituted phenyl or 2-napthyl.
12. The compound according to Claims 1 to 8, wherein: R3, R3a, R3c, and R34 in Cy2 are hydrogen; and
R3b in Cy2 is a 4-chlorophenyl, 4-methoxyphenyl, or 2-napthyl.
13. The compound of Claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-phenylbenzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4- chlorophenyl)benzamide;
N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4- methoxyphenyl)benzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(2-naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- chlorophenyl)benzam ide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-phenylbenzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(4- chlorophenyl)benzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(4- methoxyphenyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-3-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4- methoxyphenyl)benzamide;
N-[3-Dimemylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-3-phenylbenzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-3-(2naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(2-naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]benzamide; and
N-[l-(4-Chlorophenyl)-4-dimethylaminobutyl]benzamide; as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or polymorph; or as metabolite or a pharmaceutically acceptable salt or prodrug thereof.
14. The compound of Claim 1, wherein the compound is iV-[3-Dimethylamino-l- (2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide.
15. The compound of Claim 1, wherein the compound is N-[3-Dimethylamino-l- (2-naphthyl)propyl]-(S)-4-(4-chlorophenyl)benzamide.
16. The compound of Claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-phenylbenzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-3-(4- methoxyphenyl)benzamide ; N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- chlorophenyl)benzamide ;
N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino- 1 -(4-methylphenyl)propyl]-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4- methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(2-naphthyl)benzamide.
17. The compound of Claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- methoxyphenyl)benzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-(2-naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide.
18. The compound of claim 1, wherein the compound is selected from the group consisting of: N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- chlorophenyl)benzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-4-(4- methoxyphenyl)benzamide ;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-4-(4-methoxyphenyl)benzamide.
19. The compound of claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-phenylbenzamide;
N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(4- chlorophenyl)benzamide;
N-[ 1 -(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(4- methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-(2- naphthyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- methoxyphenyl)benzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2- naphthyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-phenylbenzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(4- methoxyphenyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-3-(2- naphthyl)benzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2- naphthyl)benzamide ;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-phenylbenzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-3-(4- methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-3-(2naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(2-naphthyl)benzamide;
N-[3-Dimethylaminopropyl-(S)-l-(4-chlorophenyl)]-(Λ)-2-methoxy-2- phenylacetamide;
N-[3-Dimethylaminopropyl-(S)-l-(4-methylphenyl)]-(i?)-2-methoxy-2- phenylacetamide ;
N-[3-Dimethylaminopropyl-(S)- 1 -(2-naphthyl)]-(Λ)-2-methoxy-2- phenylacetamide;
N-[l-(4-Chlorophenyl)-3-(l-piperidinyl)-propyl]-(S)-benzamide; and
N-[l-(4-Chlorophenyl)-4-dimethylaminobutyl]-(S)-benzamide.
20. The compound of claim 1, wherein the compound is selected from the group consisting of
7V-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-3-phenylbenzamide;
N-[ 1 -(4-Chlorophenyl)-3 -dimethylaminopropyl] -(S)-3 -(4- methoxyphenyl)benzamide; N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- methoxyphenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2- naphthyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2- naphthyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(2-naphthyl)benzamide.
21. The compound of Claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- methoxyphenyl)benzamide ;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(2- naphthyl)benzamide ;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-(2- naphthyl)benzamide; N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide .
22. The compound of claim 1, wherein the compound is selected from the group consisting of:
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- chlorophenyl)benzamide;
N-[l-(4-Chlorophenyl)-3-dimethylaminopropyl]-(S)-4-(4- methoxyphenyl)benzamide;
N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-(S)-4-(4- chlorophenyl)benzamide; and
N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-(4- methoxyphenyl)benzamide.
23. A compound of Formula (Ia):
Figure imgf000095_0001
(Ia) as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -N(Ri)-, and -O-;
Y is selected from the group consisting of: Ci-C4alkylene, Ci-C4alkenylene,
C1-C4alkynylene, -C(=O)-, -C(=O)N(R,,)-, -S(O)2-, -S(O)-, -S(O)2N(R13)-, -
S(O)N(R13)-, -N(R13)-, -C(=0)0-, -C(=0)0-W-, -C(=O)W-,
Figure imgf000095_0002
- CC=O)N(R1,)-, -C(=O)N(Rla)W-, -S(O)2W-, -S(O)W-, -S(O)2N(R13)W-, - S(O)N(Ri3)W- and -N(R12)W-;
W is selected from the group consisting of: C|-C4alkylene, d-C4alkenylene, and Ci-C4alkynylene;
R1 and Ru are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl;
Cyi is
Figure imgf000096_0001
or optionally substituted naphthyl;
Cy2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-C 10 heteroalicyclyl; and
R3, R3a,, R3b, R3c, and R3tl, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -CC=O)R1, -CC=O)OR1, -CC=O)NR1Ru, -C(R,)=NRla, -NR1R13, -N=CR1R13, -N(R,)-C(=O)Ru, -N(R,)-C(=O)NR,8R,b, -S(O)NR1R13, -S(O)2NR1R13, -N(R,)-S(=O)Rla, -N(Ri)-S(=O)2Ria, -OR1, -SR1, and -OC(O)R1; provided that at least one of R3, R3a>, R3b, R3c, and R3d, is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(=0)Ri, -C(=O)ORi, -C(O)NR1R1,, -C(R,)=NRla, -NR1R13, -N=CR1R13, -N(RO-C(O)R1., -N(R,)-C(O)NRlaRib, -S(O)NR1R13, -S(O)2NR1R13, -N(R,)-S(=O)Rla, -N(RO-S(O)2Ru, -OR1, -SRi, or -OC(O)R1.
24. The compound of according to Claim 23, wherein:
X is -N(Ri)-; and
Figure imgf000097_0001
25. The compound according to Claims 23 to 24, wherein Cy2 is optionally substituted phenyl.
26. The compound according to Claims 23 to 25, wherein Cy1 is an alkyl- substituted phenyl or naphtyl.
27. The compound according to Claims 23 to 26, wherein Cy1 is 4-methylphenyl or 2-naphthyl.
28. The compound of according to Claim 23, selected from the group consisting of:
N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino- 1 -(2-naphthyl)propyl]-4-phenylbenzamide; N-[3-Dimethylamino-l-(4-methylphenyl)propyl]-(S)-4-phenylbenzamide; and N-[3-Dimethylamino-l-(2-naphthyl)propyl]-(S)-4-phenylbenzamide.
29. A compound of Formula (Ib):
Figure imgf000098_0001
(Ib) as a single isomer, a mixture of isomers, or a as a racemic mixture of isomers; as a solvate or a pharmaceutically acceptable salt thereof, wherein:
X is selected from the group consisting of: Ci-G^alkylene, Ci-C4alkenylene, Ci-C4alkynylene, -N(Ri)-, and -O-;
Y is
Figure imgf000098_0002
W is selected from the group consisting of: Ci-C4alkylene, Ci^alkenylene, and Ci-C4alkynylene;
Ri and Rj2 are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heteroalicyclyl;
Cyi is
Figure imgf000098_0003
or optionally substituted naphthyl;
Cy2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
R2 and R2a are each independently selected from the group consisting of optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heteroalicyclyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, and optionally substituted aralkyl; or R2 and R2a can be taken together to form an optionally substituted C2-Ci0 heteroalicyclyl; and
R3, R3a,, R3b, R30 and R3(j, are each independently selected from the group consisting of hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heteroalicyclyl, optionally substituted hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, optionally substituted haloalkyl, optionally substituted haloalkoxy, -CN, -C(O)R1, -C(=0)0R,, -C(=O)NR,Rla, -C(RO=NR13, -NR1R13, -N=CR1Ru, -N(R0-C(=O)Rla, -N(R,)-C(=0)NRlaRlb, -S(O)NR1R13, . -S(O)2NR1R13, -N(R0-S(=O)Rl3, -N(RO-S(O)2R13, -OR1, -SR1, and -OC(O)R1; provided that at least one of R3> R33j, R3b, R3c, and R3J, is alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heteroalicyclyl, hydroxyl, nitro, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, -CN, -C(O)Ri, -C(O)OR1, -C(O)NRiR13, -C(RO=NR13, -NR1R13, -N=CR1R13, -N(RO-C(O)R13, -N(R0-C(O)NRuRib, -S(O)NR1R13, -S(O)2NR1R13, -N(RO-S(O)R13, -N(RO-S(O)2R13, -OR1, -SR1, or -OC(O)R1.
30. The compound according to Claim 29, wherein X is -N(R1)-.
31. The compound according to Claims 29 to 30, wherein Cy2 is optionally substituted phenyl.
32. The compound according to Claims 29 to 31, wherein R13 in Y is alkyl.
33. The compound according to Claim 29, selected from the group consisting of: N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(Λ)-2-methoxy-2- phenylacetamide;
(+)-N-[3-Dimethylaminopropyl-l-(4-methylphenyl)]-(/?)-2-methoxy-2- phenylacetamide ;
(-)-N-[3-Dimethylamiriopropyl-l-(4-methylphenyl)]-(/?)-2-methoxy-2- phenylacetamide; N-[3-Dimethylaminopropyl- 1 -(2-naphthyl)]-(i?)-2-methoxy-2- phenylacetamide;
(+)-N-[3-Dimethylaminopropyl- 1 -(2-naphthyl)]-(Λ)-2-methoxy-2- phenylacetamide; and
(-)-N-[3-Dimethylaminopropyl- 1 -(2-naphthyl)]-(/?)-2-methoxy-2- phenylacetamide .
34. The compound according to any one of Claims 1 to 33, wherein the carbon adjacent to both X and Cyi is in the S-configuration.
35. A salt, polymorph, ester, metabolite or prodrug of the compound of any one of Claims 1 to 34.
36. A pharmaceutical composition, comprising a therapeutically acceptable amount of one or more compounds of any one of Claims 1 to 35.
37. A method of treating or ameliorating a disorder selected from the group consisting of a CΝS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis, and diabetes comprising: identifying a subject in need of said treatment or amelioration; and administering to the subject a therapeutically effective amount of one or more compounds of any one of Claims 1 to 35.
38. The method of Claim 37, wherein the CΝS disorder is selected from group consisting of Parkinson's Disease, Alzheimer's Disease, amylotrophic lateral sclerosis, muscular dystrophy, childhood spinal muscular atrophy, progressive spinal muscular atrophy and progressive bulbar palsy, OPCA, ADHD, and schizophrenia.
39. The method of Claim 37, wherein the cardiovascular disorder is selected from the group consisting of heart failure, atherosclerosis, hypertension and hypotensive states related to shock, sepsis, major surgery, congestive heart failure, and pulmonary disorders.
40. The method of Claim 37, wherein the sleep disorder is selected from the group consisting of insomnia and narcolepsy.
41. The method of Claim 37, wherein the autonomic dysfunction is Shy Drager syndrome.
42. A method of identifying a compound which is an agonist, inverse agonist, or antagonist of a Urotensin II receptor, the method comprising: contacting the UII receptor with one or more test compounds of any one of Claims 1 to 35; and determining any increase or decrease in activity level of said UII receptor.
43. Use of one or more compounds according to any one of Claims 1 to 35 to treat or ameliorate a disorder selected from the group consisting of a CNS disorder, depression, a sleep disorder, an autonomic dysfunction a cardiovascular disorder, a renal disorder, incontinence, cancer, tumor growth, ischemia, stroke, asthma, restenosis, and diabetes.
PCT/US2007/023383 2006-11-06 2007-11-06 Uii-modulating compounds and their use WO2008057543A2 (en)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2793212A (en) * 1953-12-09 1957-05-21 Lilly Co Eli Substituted benzamidopiperidinopropanes
US4804662A (en) * 1987-05-05 1989-02-14 Schering A.G. Substituted 4-(1H-imidazol-1-yl)benzamides as antiarrhythmic agents
US6982348B2 (en) * 2001-01-26 2006-01-03 Takeda Pharmaceutical Company Limited Aminoethanol derivatives
US20060058374A1 (en) * 2002-06-10 2006-03-16 Lehmann Per F Urotensin II receptor agents

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2793212A (en) * 1953-12-09 1957-05-21 Lilly Co Eli Substituted benzamidopiperidinopropanes
US4804662A (en) * 1987-05-05 1989-02-14 Schering A.G. Substituted 4-(1H-imidazol-1-yl)benzamides as antiarrhythmic agents
US6982348B2 (en) * 2001-01-26 2006-01-03 Takeda Pharmaceutical Company Limited Aminoethanol derivatives
US20060058374A1 (en) * 2002-06-10 2006-03-16 Lehmann Per F Urotensin II receptor agents

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