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  • 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
  • C07D295/08—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 bound oxygen or sulfur atoms
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Definitions

• FIELD OFTHEINVENTION This invention relates to the treatment of diseases in which serotonin, Substance P or Neurokinin A are implicated, for example, in the treatment of disorders or conditions such as hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, eating disorders, obesity, chemical dependencies, cluster headache, migraine, pain, Alzheimer's disease, obsessive- compulsive disorder, panic disorder, memory disorders, Parkinson's disease, endocrine disorders vasospasm, cerebellar ataxia, gastrointestinal tract disorders, negative symptoms of schizophrenia, premenstrual syndrome, fibromyalgia syndrome, stress incontinence, Tourette's syndrome, trichotillomania, kleptomania, male impotence, attention deficit hyperactivity disorder, chronic paroxysmal hemicrania and headache.
• disorders or conditions such as hypertension, depression, generalized anxiety disorder, phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation
• the mammalian neurokinins are peptide neurotransmitters found in the peripheral and central nervous systems.
• the three principal neurokinins are Substance P (SP), Neurokinin A (NKA) and Neurokinin B (NKB).
• SP Substance P
• NKA Neurokinin A
• NKB Neurokinin B
• NKA Neurokinin A
• NKB Neurokinin B
• NKA Neurokinin 1
• NK 2 neurokinin 2
• NK 3 neurokinin 3
• C-afferent sensory neurons which neurons are characterized by non-myelinated nerve endings known as C-fibers, and are released by selective depolarization of these neurons, or selective stimulation of the C-fibers.
• C-Fibers are located in the airway epithelium, and the tachykinins are known to cause profound effects which clearly parallel many of the symptoms observed in asthmatics.
• the effects of release or introduction of tachykinins in mammalian airways include bronchoconstriction, increased microvascular permeability, vasodilation, increased mucus secretion and activation of mast cells.
• NKi Neurokinin antagonists that interact with NKi, NK 2 and NK 3 receptors, having different chemical structures have been described.
• NKi activity is also implicated in depression and anxiety, mice with genetically altered
• NKi receptors have decreased anxiety related behavior (Santarelli, L., et. al, Proc. Nat. Acad.
• SSRIs Selective Serotonin Reuptake Inhibitors
• NKi antagonists and serotonin reuptake inhibitors may also provide a new class of antidepressants. Indeed, compounds combining NKi antagonism and serotonin reuptake inhibition have been described (Ryckmans, T., et. al,
• the present invention encompasses compounds having neurokinin 1 ("NKi”) antagonist activity and/or serotonin reuptake inhibitory (“SRI”) activity.
• NKi neurokinin 1
• SRI serotonin reuptake inhibitory
• Aryl glycine compounds of the invention are those on accord with formula I
• R and R are independently selected from C ⁇ - 6 alkyl or C ⁇ - 6 alkenyl, or together with the N to which they are bound, form a heterocycle containing 6, 7 or 8 atoms or such a heterocycle substituted with moieties independently selected from hydrogen, halogen, C ⁇ - 4 alkyl, ⁇ alkoxy or C ⁇ .
• the invention also encompasses in vivo-hydrolysable precursors and pharmaceutically-acceptable salts of compounds of Formula I, pharmaceutical compositions and formulations containing them, methods of using them to treat diseases and conditions either alone or in combination with other therapeutically-active compounds or substances, processes and intermediates used to prepare them, uses of them as medicaments, uses of them in the manufacture of medicaments and uses of them for diagnostic and analytic purposes.
• Compounds of this invention have NKi antagonist activity and/or SRI activity.
• this invention comprises such compounds, pharmaceutical compositions containing such compounds and methods of using such compounds to treat central nervous system (CNS) and other disorders.
• CNS central nervous system
• Compounds of the invention are those in accord with formula I:
• R 1 and R 2 are independently selected from C ⁇ - 6 alkyl or C ⁇ - 6 alkenyl, or together with the N to which they are bound, form a heterocycle containing 6, 7 or 8 atoms or such a heterocycle substituted with moieties independently selected from hydrogen, halogen,
• R 4 is hydrogen; n is 0, 1 or 2;
• Ar 1 is phenyl or phenyl substituted with moieties independently selected from hydrogen, halogen, -S-C ⁇ - alkyl, C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy or C ⁇ - 4 alkyl substituted with 1, 2 or 3 halo moieties; and
• Ar 2 phenyl, naphthyl, tetralin, or phenyl, naphthyl or tetralin substituted with moieties independently selected from hydrogen, halogen, cyano, nitro, C ⁇ - 4 alkyl, C ⁇ - 4 alkoxy or C ⁇ - 4 alky
• Particular compounds of the invention are those of the examples herein.
• Another aspect of the invention is pharmaceutically-acceptable salts of a compounds as described herein made with an inorganic or organic acid which affords a physiologically- acceptable anion.
• Particular pharmaceutically-acceptable salts of compounds of the invention are those wherein the inorganic or organic acid is selected from hydrochloric, hydrobromic, sulfuric, phosphoric, methanesulfonic, sulfamic, para-toluenesulfonic, acetic, citric, lactic, tartaric, malonic, fumaric, ethanesulfonic, benzenesulfonic, cyclohexylsulfamic, salicyclic and quinic acids.
• Another aspect of the invention is a pharmaceutical composition
• a pharmaceutical composition comprising a compound of the invention or an in vivo-hydrolysable precursor or a pharmaceutically- acceptable salt thereof and a pharmaceutically-acceptable carrier.
• a method of treating a disease condition wherein antagonism of NKi receptors and/or SRI activity is beneficial which method comprises administering to a warm-blooded animal an effective amount of a compound of the invention or an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof.
• Still another aspect of the invention is the use of a compound of the invention or an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof in the preparation of a medicament for use in a disease condition wherein antagonism of the NKi receptors and/or SRI activity is beneficial.
• a further aspect of the invention is a method for treating a disorder or condition selected from hypertension, depression in cancer patients, depression in Parkinson's patients, postmyocardial infarction depression, subsyndromal symptomatic depression, depression in infertile women, pediatric depression, major depression, single episode depression, recurrent depression, child abuse induced depression, post partum depression, generalized anxiety disorder, agoraphobia, social phobia, simple phobias, posttraumatic stress syndrome, avoidant personality disorder, premature ejaculation, anorexia nervosa, bulimia nervosa, obesity, addictions to alcohol, cocaine, heroin, phenobarbital, nicotine or benzodiazepines; cluster headache, migraine, pain, Alzheimer's disease, obsessive-compulsive disorder, panic disorder, dementia, amnestic disorders, age-related cognitive decline, dementia in Parkinson's disease, neuroleptic-induced parkinsonism, tardive dyskinesias, hyperprolactinaemia, vasospasm, cerebral vas
• the method for treating a disorder or condition mentioned herein comprises administering a compound of the invention in combination with a pharmaceutically-acceptable carrier.
• a pharmaceutically-acceptable carrier for treating a disorder or condition mentioned herein.
• Compounds in accord with formula I and their in vivo-hydrolysable precursors or a pharmaceutically-acceptable salts may be made by processes as described and exemplified herein and by processes similar thereto and by processes known in the chemical art. If not commercially available, starting materials for these processes may be made by procedures which are selected from the chemical art using techniques which are similar or analogous to the synthesis of known compounds.
• Pharmaceutically-acceptable salts may be prepared from the corresponding acid in a conventional manner. Non-pharmaceutically-acceptable salts may be useful as intermediates and as such are another aspect of the present invention.
• enantiomers are compounds of this invention. Further, the mixture of enantiomers can have either or both serotonin and neurokinin activity and/or either of the pure enantiomers can have serotonin and or neurokinin activity.
• the following biological test methods, data and Examples serve to illustrate and further describe the invention.
• the utility of a compound of the invention or an in vivo-hydrolysable precursor or a pharmaceutically-acceptable salt thereof hereinafter, collectively referred to as a
• Test A SERT Binding Assay: Frozen membrane preparations of a stably transfected HEK293 cell line expressing human 5-HTT receptors were purchased from Receptor Biology (PerkinElmer). Frozen alliquots were rapidly thawed, homogenized, and diluted in assay buffer (AB) containing 50 mM TRIS-HCL, 120 mM NaCl, 5 mM KC1 and adjusted to pH 7.4 with NaOH. Final protein concentration was 40 ⁇ g/ l. Test compounds were evaluated in competition assays utilizing [ 3 H]-Imipramine Hydrochloride purchased from NEN (PerkinElmer) as the radioligand.
• the stock radioligand was diluted with AB for a final concentration of approximately 2 nM.
• Kd for [ 3 H]-Imipramine Hydrochloride was determined to be 2.7 nM.
• the competition assays were performed on 96-well assay plates - two drugs per plate. Ten serial dilutions (normally 1 ⁇ M to 38 pM final concentration) from stock 10 mM solutions of compounds prepared in DMSO. All serial dilutions were made using 20% DMSO. DMSO content in assay is less than 1%. Incubation mixtures were prepared in quadruplicate in 96-well plates (Costar).
• Final assay volumes per well were 10 ⁇ l compound/nonspecific/control (1% DMSO), 20 ⁇ l membranes, 20 ⁇ l [ 3 H]-Imipramine Hydrochloride, and 150 ⁇ l AB. Specific binding was defined by using 10 ⁇ M Imipramine. The binding reaction was initiated by adding membranes immediately after adding the radioligand to wells containing buffer plus either test compound, nonspecific, or control. The assay plates were placed on a plate shaker and shaken for thirty min while the reactions reached equilibrium. The plates were then filtered through Beckman GF B filters, presoaked in 6% PEI, using a Packard Filtermate 196.
• Test B NKt FLIPR Assay using Fluo-4 Dye: FLIPR assays are performed with a device marketed by Molecular Devices, Inc., designed to precisely measure cellular fluorescence in a high throughput whole-cell assay. (Schroeder et. al., J. Biomolecular Screening, 1(2), p 75-80, 1996). Compounds were evaluated for potency in blocking the response of U373 cells to the
• NKi receptor agonist Acetyl-[Arg 6 , Sar 9 , Met(O 2 ) n ]-Substance P (ASMSP) using a FLIPR instrument.
• U373 cells were loaded with Fluo-4 dye (Molecular Probes) for 45 min at 37 °C and exposed to graded concentrations of compounds for 15 min at room temperature before being challenged with 10 nM - 12 nM ASMSP (an approximately EC 80 concentration). Responses were measured as the peak relative fluorescence after agonist addition.
• pIC 50 s were calculated from eleven-point concentration-response curves for each compound.
• Cell culture medium Eagle's MEM with Earle's salts and 1-glutamine (500 mL) Cellgro 10-010-CV
• Non-essential amino acids 100 x (5 mL) Cellgro 25-025-CI Sodium pyruvate, 100 mM (5 mL) Cellgro 25-000-CI L-Glutamine, 200 mM (5 mL) Cellgro 25-005-CI FBS (50 mL) Cellgro 35-010-CN
• Cell harvesting reagents DPBS, lx without Ca ⁇ & Mg 1-1" Cellgro 21-031-CN lx Trypsin -EDTA (0.5% Trypsin, 0.53% EDTA-4Na) Cellgro 25-052-CI
• Cell plating medium 100 x (5 mL) Cellgro 25-025-CI Sodium pyruvate, 100 mM (5 mL) Cellgro 25-000-CI L-Glutamine, 200 mM (5 mL) Cellgro 25-005-CI FBS (
• Cells were passaged at a transfer density of 1 :4 every four days. For experiments, cells were counted, pelleted by centrifugation at 400 x g for 5 min and resuspended in cell plating medium at a density of 480,000 cells/mL. 25 ⁇ L of this cell suspension was added to each well of a black-walled 384-well plate (Falcon Microtest, 35 3962) using a Labsystems Multidrop 384 to give 12,000 cells per well. Plates were incubated at 37 °C overnight (minimum 15 h, maximum 23 h) before use.
• Compound and agonist preparation Compounds were dissolved in DMSO at a concentration of 10 mM and 120 ⁇ L of these solutions were transferred to the first well (column 1) of each row of a 96-well, round- bottomed, polypropylene storage plate (Costar 3365). Compounds on two such plates were then serially diluted simultaneously in DMSO using a Biomek 2000. 4 ⁇ L of each dilution was transferred to a deep well plate (Beckman Coulter 267006) which had been prepared previously to contain 400 ⁇ L of freshly made working buffer in each well. Concentrations resulting from this procedure are shown in Table 1. The final compound concentrations in the assay span 11 points, between 10 ⁇ M and 0.1 nM, in half-log increments.
• the contents of the wells were mixed, and 45 ⁇ L of each dilution were transferred - in duplicate - to a 384-well polypropylene compound loading plate (Fisher 12-565-507) so that the 384-well plate contained duplicates of each of the compounds from both 96-well plates over the concentration ranges.
• Columns 23 and 24 of the plate contain no compound and serve as controls.
• Wells A -N in columns 23 and 24 were loaded with agonist only and therefore represent the maximal response.
• Wells O - P in columns 23 and 24 were loaded with only buffer, no agonist, and therefore represent the minimum response.
• An ASMSP agonist loading plate was made by taking stock concentration of ASMSP and diluting in working buffer to give a concentration of 3.3 x 10 "8 M.
• the cell plate was returned to a 37 °C incubator for 45 min to allow the dye to permeate the cells. After 45 min of dye loading, the cell plates were washed twice with working buffer, leaving a 30 ⁇ L volume of buffer in each well. 5 ⁇ L of compound dilutions were transferred from the compound plate to the cell plate using a PlateMate. Assay plates were incubated in the presence of compound for 15 min at room temperature in the dark, and then loaded onto FLIPR.
• Ki values obtained in the SERT assay for compounds of the invention ranged from less than 2 nM to about 180 nM.
• IC 50 values obtained in the FLIPR assay for compounds of the invention ranged from about 70 nM to about 2 ⁇ M.
• heterocycle used alone or as a suffix or prefix, refers to a ring structure or molecule of at least three and up to 20 atoms having one or more multivalent heteroatoms, such atoms independently selected from O, N, P or S as part of the ring structure.
• Heterocycles may be saturated, partially-saturated or unsaturated, may have atoms linked by on or more double bonds and may form one or more rings that may be linked or fused where fused rings share at least two atoms therebetween.
• Heterocycles may or may not have aromatic character. Temperatures are given in degrees Celsius (°C); unless otherwise stated, operations were carried out at room or ambient temperature (18-25 °C).
• Example 1 4- ⁇ r2-(3-Chloro-4-fluorophenylV2-piperazin- 1 -ylethoxylmethyl) -3 -methoxy-2- naphthonitrile.

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