WO1998052890A1 - Antagonistes du recepteur des 3-arylpropylamino neuropeptides y - Google Patents

Antagonistes du recepteur des 3-arylpropylamino neuropeptides y Download PDF

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WO1998052890A1
WO1998052890A1 PCT/US1998/010264 US9810264W WO9852890A1 WO 1998052890 A1 WO1998052890 A1 WO 1998052890A1 US 9810264 W US9810264 W US 9810264W WO 9852890 A1 WO9852890 A1 WO 9852890A1
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preparation
propylamine
neuropeptide
phenyl
receptor
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PCT/US1998/010264
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James Erwin Fritz
Philip Arthur Hipskind
Stephen Warren Kaldor
Karen Lynn Lobb
James Arthur Nixon
William Leonard Scott
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Eli Lilly And Company
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Priority to AU75809/98A priority Critical patent/AU7580998A/en
Publication of WO1998052890A1 publication Critical patent/WO1998052890A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/50—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D333/52—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes
    • C07D333/54—Benzo[b]thiophenes; Hydrogenated benzo[b]thiophenes with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C07D333/58—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/29—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by halogen atoms or by nitro or nitroso groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/26—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring
    • C07C211/30—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing at least one six-membered aromatic ring the six-membered aromatic ring being part of a condensed ring system formed by two rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2602/00—Systems containing two condensed rings
    • C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane

Definitions

  • Neuropeptide Y is a peptide present in the central and peripheral nervous systems.
  • the peptide co-exists with noradrenaline in many neurons and acts as a neurotransmitter per se or synergisticalry together with noradrenaline.
  • Neuropeptide Y-containing fibers are numerous around arteries in the heart, but are also found around the arteries in the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Neuropeptide Y is also present in the cerebrum with effects on blood pressure, feeding, and the release of different hormones. Alterations in central concentrations of neuropeptide Y have been implicated in the etiology of psychiatric disorders.
  • Neuropeptide Y was discovered, isolated and sequenced in 1982 from porcine brain as part of a general screening protocol to discover carboxy- terminal amidated peptides and was named neuropeptide Y due to its isolation form neural tissue and the presence of tyrosine as both the amino and carboxy terminal amino acid.
  • Neuropeptide Y is a member of the pancreatic family of peptides and shares significant sequence homology with pancreatic polypeptide, and peptide YY.
  • Neuropeptide Y and the other members of its family of peptides all feature a tertiary structure consisting of an N-terminal polyproline helix and an amphiphilic ⁇ -helix, connected with a ⁇ -turn, creating a hairpin-like loop, which is sometimes referred to as the pancreatic polypeptide (PP) fold.
  • the helices are kept together by hydrophobic interactions.
  • the amidated C- terminal end projects away from the hairpin loop.
  • neuropeptide Y was identified as being the most abundant peptide in the central nervous system with widespread distribution including the cortex, brainstem, hippocampus, hypotahlamus, amygdala, and thalamus as well as being present in the peripheral nervous system in sympathetic neurons and adrenal chromaffin cells.
  • Neuropeptide Y seems to fulfill the main neurotransmitter criteria, as it is stored in synaptic granules, is released upon electrical nerve stimulation, and acts at specific receptors. It is clear that neuropeptide Y is an important messenger in its own right, probably in the brain, where neuropeptide Y potently inhibits the activity of adenylate cyclase and induces an increase in the intracellular levels of calcium.
  • Central injection of neuropeptide Y results in blood pressure changes, increased feeding, increased fat storage, elevated blood sugar and insulin, decreased locomotor activity, reduced body temperature, and catalepsy.
  • Neuropeptide Y acts upon membrane receptors that are dependent on guanyl-nucleotide binding proteins, known as G protein-coupled receptors.
  • G proteins are a family of membrane proteins that become activated only after binding guanosine triphosphate. Activated G proteins in turn activate an amplifier enzyme on the inner face of a membrane; the enzyme then converts precursor molecules into second messengers.
  • Neuropeptide Y appears to interact with a family of closely related receptors. These receptors are generally classified into several subtypes based upon the ability of different tissues and receptors to bind different fragments of neuropeptide Y and other members of the PP family of peptides.
  • the Yl receptor subtype appears to be the major vascular neuropeptide Y receptor.
  • the Y2 receptor subtypes can also occur postjunctionally on vascular smooth muscle.
  • the as-yet-unisolated Y3 receptor subtype appears to be neuropeptide Y-specific, not binding peptide YY. This receptor is likely to be present in the adrenal tissues, medulla, heart, and brain stem , among other areas.
  • neuropeptide Y receptor antagonists In view of the wide number of clinical maladies associated with an excess of neuropeptide Y, the development of neuropeptide Y receptor antagonists will serve to control these clinical conditions.
  • the earliest such receptor antagonists such as Patent Cooperation Treaty Patent Publication WO 91/08223, published June 13, 1991, and Patent Cooperation Treaty Patent Publication WO 94/00486, published January 6, 1994, were peptide derivatives. These antagonists are of limited pharmaceutical utility because of their metabolic instability.
  • Patent Cooperation Treaty Patent Publication WO 97/09308, published March 13, 1997 describes a series of potent indolyl neuropeptide Y receptor antagonists.
  • United States patent application 08/775,538, filed January 9, 1997 describe a series of potent benzimidazolyl neuropeptide Y receptor antagonists.
  • this invention provides a class of potent nonpeptidyl neuropeptide Y receptor antagonists.
  • the compounds of the present invention do not suffer from the shortcomings, in terms of metabolic instability, of most known peptide-derived neuropeptide Y receptor antagonists.
  • This invention encompasses methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I
  • R 1 , R la , R lb , and R lc are independently hydrogen, halo, C C 6 alkoxy, C.-C 6 alkyl, trifluoromethyl, trifluoromethoxy, or phenyl;
  • R 1 , R la , R lb , and R lc is phenyl
  • R 2 is naphthyl, pyridyl, phenyl, benzothienyl, indanyl, indenyl, indolyl, benzofuryl, or pyrrolyl,
  • phenyl being optionally substituted with one or more moieties selected from the group consisting of halo, C.-C 6 alkyl, C.-C 6 alkoxy, phenyl, and trifluoromethyl;
  • This invention also encompasses the novel compounds of Formula I as well as pharmaceutical formulations comprising a compound of Formula I in combination with one or more pharmaceutically acceptable carriers, diluents, or excipients therefor.
  • the current invention concerns the discovery that a select group of substituted 3-arylpropylamines, those of Formula I, are useful as neuropeptide Y receptor antagonists. More specifically, these compounds are useful as antagonists of the neuropeptide Y5 receptor.
  • Ci-C ⁇ alkoxy represents a straight or branched alkyl chain having from one to six carbon atoms attached to an oxygen atom.
  • Typical Ci- CQ alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, t- butoxy, pentoxy and the like.
  • C ⁇ -CG alkoxy includes within its definition the terms “C 1 -C4 alkoxy” and "C 1 -C3 alkoxy”.
  • C 1 -C 1 2 alkyl refers to straight or branched, monovalent, saturated aliphatic chains of 1 to 12 carbon atoms and includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, and hexyl.
  • C 1 -C 1 2 alkyl includes within its definition the terms "Ci-C ⁇ alkyl” and "C 1 -C4 alkyl”.
  • Halo represents chloro, fluoro, bromo or iodo.
  • amino-protecting group refers to substituents of the amino group commonly employed to block or protect the amino functionality while reacting other functional groups on the compound.
  • amino-protecting groups include formyl, trityl (herein abbreviated as "Tr"), phthalimido, trichloroacetyl, chloroacetyl, bromoacetyl, iodoacetyl, and urethane-type blocking groups such as benzyloxycarbonyl, 4-phenylbenzyloxycarbonyl, 2-methylbenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-fluorobenzyloxycarbonyl, 4-chlorobenzyloxycarbonyl, 3-chlorobenzyloxycarbonyl, 2 -chlorobenzyloxycarbonyl, 2 , 4- dichlorobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl, 3-bromobenzyl
  • amino-protecting group employed is usually not critical so long as the derivatized amino group is stable to the condition of subsequent reactions on other positions of the intermediate molecule and can be selectively removed at the appropriate point without disrupting the remainder of the molecule including any other amino-protecting groups.
  • Preferred amino-protecting groups are trityl, £-butoxycarbonyl (t,-BOC), allyloxycarbonyl and benzyloxycarbonyl. Further examples of groups referred to by the above terms are described by E. Haslam, "Protective Groups in Organic Chemistry", (J.G.W. McOmie, ed., 1973), at Chapter 2; and T.W. Greene and P.G.M.
  • the compounds of the present invention may have one or more asymmetric centers. As a consequence of these chiral centers, those compounds of the present invention occur as racemates, mixtures of enantiomers and as individual enantiomers, as well as diastereomers and mixtures of diastereomers. All asymmetric forms, individual isomers and combinations thereof, are within the scope of the present invention.
  • R and S are used herein as commonly used in organic chemistry to denote specific configuration of a chiral center.
  • the term “R” (rectus) refers to that configuration of a chiral center with a clockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the term “S” (sinister) refers to that configuration of a chiral center with a counterclockwise relationship of group priorities (highest to second lowest) when viewed along the bond toward the lowest priority group.
  • the priority of groups is based upon their atomic number (in order of decreasing atomic number).
  • the older D-L system may also be used in this document to denote absolute configuration, especially with reference to amino acids.
  • a Fischer projection formula is oriented so that the number 1 carbon of the main chain is at the top.
  • the prefix "D” is used to represent the absolute configuration of the isomer in which the functional (determining) group is on the right side of the carbon atom at the chiral center and "L", that of the isomer in which it is on the left.
  • the skilled practitioner can proceed by one of two routes.
  • the practitioner may first prepare the mixture of enantiomers and then separate the two enantiomers.
  • a commonly employed method for the resolution of the racemic mixture (or mixture of enantiomers) into the individual enantiomers is to first convert the enantiomers to diastereomers by way of forming a salt with an optically active salt or base. These diastereomers can then be separated using differential solubility, fractional crystallization, chromatography, or like methods. Further details regarding resolution of enantiomeric mixtures can be found in J. Jacques, et al.. ENANTIOMERS, RACEMATES, AND RESOLUTIONS, (1991).
  • the practitioner of this invention may also choose an enantiospecific protocol for the preparation of the compounds of Formula I.
  • a protocol employs a synthetic reaction design which maintains the chiral center present in the starting material in a desired orientation.
  • These reaction schemes usually produce compounds in which greater than 95 percent of the title product is the desired enantiomer.
  • this invention includes the pharmaceutically acceptable salts of the compounds defined by Formula I.
  • a compound of this invention can possess a sufficiently acidic, a sufficiently basic, or both functional groups, and accordingly react with any of a number of organic and inorganic bases, and inorganic and organic acids, to form a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salt refers to salts of the compounds of the above formula which are substantially non-toxic to living organisms.
  • Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds of the present invention with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts.
  • Acids commonly employed to form acid addition salts are inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as j-toluenesulfonic acid, methanesulfonic acid, oxalic acid, jD-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like
  • organic acids such as j-toluenesulfonic acid, methanesulfonic acid, oxalic acid, jD-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like.
  • salts examples include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate
  • Salts of amine groups may also comprise quaternary ammonium salts in which the amino nitrogen carries a suitable organic group such as an alkyl, alkenyl, alkynyl, or aralkyl moiety.
  • Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like.
  • bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like.
  • the potassium and sodium salt forms are particularly preferred.
  • any salt of this invention is usually not of a critical nature, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole.
  • This invention further encompasses the pharmaceutically acceptable solvates of the compounds of Formulas I. Many of the Formula I compounds can combine with solvents such as water, methanol, ethanol and acetonitrile to form pharmaceutically acceptable solvates such as the corresponding hydrate, methanolate, ethanolate and acetonitrilate.
  • This invention also encompasses the pharmaceutically acceptable prodrugs of the compounds of Formula I.
  • a prodrug is a drug which has been chemically modified and may be biologically inactive at its site of action, but which may be degraded or modified by one or more enzymatic or other in vivo processes to the parent bioactive form.
  • This prodrug should have a different pharmacokinetic profile than the parent, enabling easier absorption across the mucosal epithelium, better salt formation or solubility, or improved systemic stability (an increase in plasma half-life, for example).
  • chemical modifications include:
  • ester or amide derivatives which may be cleaved by esterases or lipases;
  • the compounds of the present invention are generally prepared using several methods known to those of ordinary skill in the art.
  • a most preferred means of synthesizing the compounds of Formula I employs combinatorial chemistry efforts utilizing commercially available reagents.
  • One such effort is depicted in Scheme I, infra.
  • a portion of the molecule is covalently linked to a support.
  • a support may be a resin bead, the wall of a container, some type of removable fiber or post, or any similar support.
  • Such a bound molecule may then serve as a lattice or scaffold upon which the remainder of the molecule is formed.
  • the covalent linkage to the support provides for rapid, quantitative purification of the molecule of interest.
  • the molecule is cleaved from the support using standard chemistry means.
  • One such way of removing the molecule of interest from the support is depicted below.
  • Rink amide resin (3.0 g, 1.41 mmol) (Novabiochem, loading capacity 0.47 mmol/g) was slurried in 30% piperidine in N-methylpyrrolidone (40 ml total). After thirty minutes the resin was filtered and the reaction repeated, after which the resin was washed with N-methylpyrrohdone (4 x 80 ml).
  • the amino-protected 3-(naphth-l-yl)alanine coupled to the rink resin was deprotected by slurrying in 45 ml of 30% piperidine in N- methylpyrrohdone for thirty minutes and was then filtered. The reaction mixture was repeated and the resin was washed in N-methylpyrrohdone (3 x 40 ml) and methylene chloride (3 x 40 ml). The resin was dried under vacuum and split into 20 separate 150 mg portions and loaded into glass reaction vials.
  • reaction mixtures were then filtered and washed with methylene chloride (3 x 2 ml), methanol (2 x 2 ml), methylene chloride (2 x 2 ml), methanol (1 x 2 ml) and methylene chloride (3 x 2 ml) to afford a reduced amino acid linked to the resin.
  • the amino acid was cleaved from the resin by treating wtih 10% trifluoroacetic acid in methylene chloride for 45 minutes and the resin filtered and washed with 3 ml methylene chloride. The filtrate was collected and concentrated. The resulting residues were loaded onto SCX columns (VARIAN® SCX column 3 x 500 mg) and washed with methanol (3 3 ml).
  • the compounds of the present invention bind to receptors specific for neuropeptide Y as well as the closely related neuropeptides.
  • Receptors for neuropeptide Y and peptide YY have considerable overlap while pancreatic polypeptide appears to have its own distinct set of receptors. Many, but not all, of the effects of neuropeptide Y can be replicated using peptide YY.
  • Two subtypes of receptors for neuropeptide Y were initially proposed on the basis of the affinity of the 13-36 fragment of neuropeptide Y using a preparation of the sympathetic nervous system. While these are the best established receptors for neuropeptide Y, a substantial body of evidence exists that there are additional receptor subtypes. The best established is a Y-3 receptor that is responsive to neuropeptide Y, but not to peptide YY. Another recently delineated receptor has been described that binds peptide YY with high affinity and neuropeptide Y with lower affinity. While the pharmacology of the feeding response to neuropeptide Y appears to be Y-l in nature, a separate "feeding receptor" has been proposed. The Y-l receptor is the only one that has been successfully cloned to date. The following paragraphs summarize the available information on the known neuropeptide Y receptor subtypes and their potential role in physiological function.
  • the Y-l receptor is the best characterized receptor for neuropeptide Y.
  • This receptor is generally considered to be postsynaptic and mediates many of the known actions of neuropeptide Y in the periphery.
  • this receptor was described as having poor affinity for C-terminal fragments of neuropeptide Y, such as the 13-36 fragment, but interacts with the full length neuropeptide Y and peptide YY with equal affinity.
  • the cloned human Y- 1 receptor can couple to either phosphotidylinositol hydrolysis or the inhibition of adenylate cyclase, depending on the type of cell in which the receptor is expressed. H. Herzog, et al.. Proceedings of the National Academy of Sciences (USA'). 89:5794-5798 (1992).
  • the Y-l receptor has been reported to couple to either second messenger system when studied using tissue preparations or cell hnes naturally expressing the receptor. D. Gehlert, supra, at 553.
  • the Y-l receptor cannot, therefore, be distinguished solely on the basis of coupling to a single second messenger.
  • Modulation of a Y-l receptor is believed to influence multiple physiological conditions, including, but not hmited to , obesity or appetite disorder, adult onset diabetes, buhmia nervosa, pheochromocytoma-induced hypertension, subarachnoid hemorrhage, neurogenic vascular hypertrophy, hypertension, anxiety, and anorexia nervosa.
  • PCT Patent Pubhcation WO 96/16542 published June 6, 1996, at page 135, and the references cited therein.
  • this receptor subtype was first delineated using vascular preparations.
  • the Y-2 receptor is distinguished from Y-l by exhibiting affinity for C-terminal fragments of neuropeptide Y.
  • the receptor is most often differentiated by the use of neuropeptide Y(13-36), though the 3-36 fragment of neuropeptide Y and peptide YY provides improved affinity and selectivity.
  • this receptor is coupled to the inhibition of adenylate cyclase, though in some preparations it may not be sensitive to pertussis toxin.
  • the Y-2 receptor was found to reduce the intracellular levels of calcium in the synapses by selective inhibition of N-type calcium channels. Like the Y-l receptor, the Y-2 receptor may exhibit differential coupling to second messengers. The Y2 receptor is believed to be involved in modulating hypertension, epileptic seizure, and neurogenic vascular hypertrophy.
  • the Y-2 receptors are found in a variety of brain regions, including the hippocampus, substantia nigra-lateralis, thalamus, hypothalamus, and brainstem. In the periphery, Y-2 is found in the peripheral nervous system, such as sympathetic, parasympathetic, and sensory neurons. In all these tissues, Y-2 receptors mediate a decrease in the release of neurotransmitters.
  • This receptor is the newest and least studied of the estabhshed neuropeptide Y receptor subtypes. While neuropeptide Y is a fully efficacious agonist at this receptor population, peptide YY is weakly efficacious. This pharmacological property is used to define this receptor.
  • a receptor that has similar pharmacology to the Y-3 receptor has been identified in the CA3 region of the hippocampus using electrophysiological techniques. This receptor may potentiate the excitatory response of these neurons to N-methyl- D-aspartate (NMDA).
  • NMDA N-methyl- D-aspartate
  • Peptide YY Preferring Receptor A fourth receptor has been described that exhibits a modest preference for peptide YY over neuropeptide Y. This receptor was first described in the rat small intestine as having a 5-10 fold higher affinity for peptide YY over neuropeptide Y. M. Laburthe, et al.. Endocrinology. 118:1910-1917 (1986). Subsequently, this receptor was found in the adipocyte and a kidney proximal tubule cell hne. This receptor is coupled in an inhibitory manner to adenylate cyclase and is sensitive to pertussis toxin. In the intestine, this receptor produces a potent inhibition of fluid and electrolyte secretion.
  • the receptor is localized to the crypt cells where intestinal chloride secretion is believed to take place.
  • the peptide YY preferring receptor in adipocytes mediates a reduction in lipolysis by way of a cychc adenosine monophosphate (cAMP)-dependent mechanism.
  • cAMP cychc adenosine monophosphate
  • the ability of the compounds of the instant invention were assessed as to their ability to bind to neuropeptide Y using a protocol essentially as described in M.W. Walker, et al.. supra.
  • the cell hne SK-N-MC was employed. This cell hne was received from Sloane- Kettering Memorial Hospital, New York. These cells were cultured in T-150 flasks using Dulbecco's Minimal Essential Media (DMEM) supplemented with 5% fetal calf serum. The cells were manually removed from the flasks by scraping, pelleted, and stored at -70°C.
  • DMEM Dulbecco's Minimal Essential Media
  • pellets were resuspended using a glass homogenizer in 25 mM HEPES (pH 7.4) buffer containing 2.5 mM calcium chloride, 1 M magnesium chloride, and 2 g/L bacitracin. Incubations were performed in a final volume of 200 ⁇ l containing 0.1 nM 125 I- ⁇ eptide YY (2200 Ci/mmol) and 0.2-0.4 mg protein for about two hours at room temperature.
  • Nonspecific binding was defined as the amount of radioactivity remaining bound to the tissue after incubating in the presence of 1 ⁇ M neuropeptide Y. In some experiments various concentrations of compounds were included in the incubation mixture.
  • Incubations were terminated by rapid filtration through glass fiber filters which had been presoaked in 0.3% polyethyleneimine using a 96- well harvester.
  • the filters were washed with 5 ml of 50 mM Tris (pH 7.4) at 4°C and rapidly dried at 60°C.
  • the filters were then treated with melt-on scintillation sheets and the radioactivity retained on the filters were counted.
  • the ability of the compounds of Formula I to bind to the Y5 receptor was demonstrated employing assays essentially similar to those in United States Patent 5,602,024, issued February 11, 1997.
  • the major distinction between the assays described therein and those employed in the present invention is the specific sequence of the Y5 receptor employed.
  • the present invention employs a truncated form of the receptor described in the above-identified patent, said receptor initiating at an internal initiation codon. Such a receptor exhibits pharmacological characteristics more consistent with those observed in vivo.
  • the compounds prepared supra showed significant activity as neuropeptide Y receptor antagonists.
  • the compounds of Formula I are effective neuropeptide Y receptor antagonists, these compounds are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y.
  • the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of Formula I or a pharmaceutically acceptable salt, solvate or prodrug thereof.
  • physiological disorder associated with an excess of neuropeptide Y encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present in the locale.
  • disorders or diseases pertaining to the heart, blood vessels or the renal system such as vasospasm, heart failure, shock, cardiac hypertrophy, increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract; cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, cocaine addiction, and dementia; conditions related to pain or nociception; diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, diarrhea, gastric ulcer, neurogenic voiding dysfunction, urinary incontinence, and Crohn's disease; abnormal drink and food intake disorders, such as obesity, anorexia, bu
  • the compounds of Formula I are usually administered in the form of pharmaceutical compositions. These compounds can be administered by a variety of routes including oral, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. These compounds are effective as both injectable and oral compositions. Such compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound.
  • the present invention also includes methods employing pharmaceutical compositions which contain, as the active ingredient, the compounds of Formula I associated with pharmaceutically acceptable carriers.
  • the active ingredient is usually mixed with an excipient, diluted by an excipient or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container.
  • the excipient serves as a diluent, it can be a solid, semi-solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient.
  • compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing for example up to 10% by weight of the active compound, soft and hard gelatin capsules, suppositories, sterile injectable solutions, and sterile packaged powders.
  • the active compound In preparing a formulation, it may be necessary to mill the active compound to provide the appropriate particle size prior to combming with the other ingredients. If the active compound is substantially insoluble, it ordinarily is milled to a particle size of less than 200 mesh. If the active compound is substantially water soluble, the particle size is normally adjusted by milling to provide a substantially uniform distribution in the formulation, e.g. about 40 mesh.
  • excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystal ⁇ ne cellulose, polyvinylpyrrolidone, cellulose, water, syrup, and methyl cellulose.
  • the formulations can additionally include: lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl- and propylhydroxybenzoates; sweetening agents; and flavoring agents.
  • the compositions of the invention can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the patient by employing procedures known in the art.
  • compositions are preferably formulated in a unit dosage form, each dosage containing from about 5 to about 100 mg, more usually about 10 to about 30 mg, of the active ingredient.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human subjects and other mammals, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical excipient.
  • the active compound is effective over a wide dosage range.
  • dosages per day normally fall within the range of about 0.5 to about 30 mg/kg of body weight. In the treatment of adult humans, the range of about 1 to about 15 mg/kg/day, in single or divided dose, is especially preferred.
  • the amount of the compound actually administered will be determined by a physician, in the light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound administered, the age, weight, and response of the individual patient, and the severity of the patient's symptoms, and therefore the above dosage ranges are not intended to limit the scope of the invention in any way.
  • sohd compositions such as tablets the principal active ingredient is mixed with a pharmaceutical excipient to form a sohd preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • a sohd preformulation composition containing a homogeneous mixture of a compound of the present invention.
  • the active ingredient is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.
  • This sohd preformulation is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 500 mg of the active ingredient of the present invention.
  • the tablets or pills of the present invention may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by enteric layer which serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.
  • liquid forms in which the novel compositions of the present invention may be incorporated for administration orally or by injection include aqueous solutions, suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders.
  • the liquid or sohd compositions may contain suitable pharmaceutically acceptable excipients as described supra.
  • compositions are administered by the oral or nasal respiratory route for local or systemic effect.
  • Compositions in preferably pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be breathed directly from the nebuhzing device or the nebuhzing device may be attached to a face mask, tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices which dehver the formulation in an appropriate manner.
  • Hard gelatin capsules containing the following ingredients are prepared:
  • the above ingredients are mixed and filled into hard gelatin capsules in 340 mg quantities.
  • a tablet formula is prepared using the ingredients below:
  • Quantity Ingredient (mg/tablet)
  • a dry powder inhaler formulation is prepared containing the following components:
  • the active mixture is mixed with the lactose and the mixture is added to a dry powder inhaling apphance.
  • Tablets each containing 30 mg of active ingredient, are prepared as follows:
  • the active ingredient, starch and cellulose are passed through a No. 20 mesh U.S. sieve and mixed thoroughly.
  • the solution of polyvinylpyrrohdone is mixed with the resultant powders, which are then passed through a 16 mesh U.S. sieve.
  • the granules so produced are dried at 50-60°C and passed through a 16 mesh U.S. sieve.
  • the sodium carboxymethyl starch, magnesium stearate, and talc previously passed through a No. 30 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 120 mg.
  • Capsules each containing 40 mg of medicament are made as follows:
  • Suppositories each containing 25 mg of active ingredient are made as follows:
  • the active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2.0 g capacity and allowed to cool.
  • Suspensions each containing 50 mg of medicament per 5.0 ml dose are made as follows:
  • Purified water to 5.0 ml The medicament, sucrose and xanthan gum are blended, passed through a No. 10 mesh U.S. sieve, and then mixed with a previously made solution of the microcrystalhne cellulose and sodium carboxymethyl ceUulose in water.
  • the sodium benzoate, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume.
  • Capsules each containing 15 mg of medicament, are made as follows:
  • the active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 20 mesh U.S. sieve, and filled into hard gelatin capsules in 425 mg quantities.
  • An intravenous formulation may be prepared as follows:
  • a topical formulation may be prepared as follows:
  • the white soft paraffin is heated until molten.
  • the hquid paraffin and emulsifying wax are incorporated and stirred until dissolved.
  • the active ingredient is added and stirring is continued until dispersed.
  • the mixture is then cooled until sohd.
  • Sublingual or buccal tablets each containing 10 mg of active ingredient, may be prepared as follows:
  • the glycerol, water, sodium citrate, polyvinyl alcohol, and polyvinylpyrrohdone are admixed together by continuous stirring and maintaining the temperature at about 90°C.
  • the solution is cooled to about 50-55°C and the medicament is slowly admixed.
  • the homogenous mixture is poured into forms made of an inert material to produce a drug-containing diffusion matrix having a thickness of about 2-4 mm. This diffusion matrix is then cut to form individual tablets having the appropriate size.
  • transdermal delivery devices Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds of the present invention in controlled amounts.
  • transdermal patches for the dehvery of pharmaceutical agents is well known in the art. See, e.g.. U.S. Patent 5,023,252, issued June 11, 1991, herein incorporated by reference.
  • patches may be constructed for continuous, pulsatile, or on demand dehvery of pharmaceutical agents.
  • Direct techniques usually involve placement of a drug dehvery catheter into the host's ventricular system to bypass the blood-brain barrier.
  • a drug dehvery catheter used for the transport of biological factors to specific anatomical regions of the body, is described in U.S. Patent 5,011,472, issued April 30, 1991, which is herein incorporated by reference.
  • Indirect techniques which are generally preferred, usually involve formulating the compositions to provide for drug latentiation by the conversion of hy drophilic drugs into lipid-soluble drugs or prodrugs.
  • Latentiation is generally achieved through blocking of the hydroxy, carbonyl, sulfate, and primary amine groups present on the drug to render the drug more hpid soluble and amenable to transportation across the blood-brain barrier.
  • the dehvery of hydrophihc drugs may be enhanced by intra-arterial infusion of hypertonic solutions which can transiently open the blood-brain barrier.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention porte sur une série de 3-arylpropylamines substituées servant à traiter ou prévenir des états liés à un excès de neuropeptide Y. L'invention porte également sur les 3-arylpropylamines substituées et sur des préparations pharmaceutiques comprenant comme principe actif un ou plusieurs de ces thiophènes substitués.
PCT/US1998/010264 1997-05-21 1998-05-20 Antagonistes du recepteur des 3-arylpropylamino neuropeptides y WO1998052890A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75809/98A AU7580998A (en) 1997-05-21 1998-05-20 3-arylpropylamino neuropeptide y receptor antagonists

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4733897P 1997-05-21 1997-05-21
US60/047,338 1997-05-21

Publications (1)

Publication Number Publication Date
WO1998052890A1 true WO1998052890A1 (fr) 1998-11-26

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PCT/US1998/010264 WO1998052890A1 (fr) 1997-05-21 1998-05-20 Antagonistes du recepteur des 3-arylpropylamino neuropeptides y

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Country Link
AU (1) AU7580998A (fr)
WO (1) WO1998052890A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
WO2002047670A1 (fr) * 2000-12-15 2002-06-20 Pfizer Limited Traitement du dysfonctionnement sexuel male
CN104725249A (zh) * 2013-12-20 2015-06-24 广东东阳光药业有限公司 苄胺类衍生物及其在药物上的应用

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5530009A (en) * 1994-07-12 1996-06-25 Eli Lilly And Company Bis-piperidinyl non-peptidyl neurokinin receptor antagonists

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6313298B1 (en) 1998-11-10 2001-11-06 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6495559B2 (en) 1998-11-10 2002-12-17 Merck & Co., Inc. NPY Y5 receptor antagonists
US6638942B1 (en) 1998-11-10 2003-10-28 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
WO2002047670A1 (fr) * 2000-12-15 2002-06-20 Pfizer Limited Traitement du dysfonctionnement sexuel male
CN104725249A (zh) * 2013-12-20 2015-06-24 广东东阳光药业有限公司 苄胺类衍生物及其在药物上的应用

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