WO2003026575A2 - Molecules specifiques des recepteurs npff et utilisations de ces dernieres - Google Patents

Molecules specifiques des recepteurs npff et utilisations de ces dernieres Download PDF

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WO2003026575A2
WO2003026575A2 PCT/US2002/030258 US0230258W WO03026575A2 WO 2003026575 A2 WO2003026575 A2 WO 2003026575A2 US 0230258 W US0230258 W US 0230258W WO 03026575 A2 WO03026575 A2 WO 03026575A2
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compound
branched
straight chained
heteroaryl
heteroarylalkyl
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PCT/US2002/030258
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WO2003026575A3 (fr
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Lakmal W. Boteju
Michael J. Konkel
Joel K. Kawakami
John Wetzel
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Synaptic Pharmaceutical Corporation
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Publication of WO2003026575A3 publication Critical patent/WO2003026575A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06191—Dipeptides containing heteroatoms different from O, S, or N
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06086—Dipeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Neuropeptide FF is an octapeptide isolated from bovine brain in 1985 by Yang (1) . F RFamide-like immmunoreactivity was observed in rat brain, spinal cord, and pituitary, suggesting the existence of mammalian homologs of the Phe-Met- Ag-Phe-amide (FMRFamide) family of invertebrate peptides.
  • FMRFamide Phe-Met- Ag-Phe-amide
  • the isolation of NPFF named for its N- and C-terminal phenylalanines and another mammalian peptide, NPAF, confirmed the existence of a mammalian family of peptides sharing the C- terminal homology with FMRFamide (1) .
  • NPFF is also called F ⁇ Famide and morphine modulating peptide
  • NPAF is also called Al ⁇ Famide in the literature.
  • NPFF and NPAF are encoded from the same gene, and cleaved from a common precursor protein (2) .
  • Studies of the localization, radioligand binding, and function of NPFF- like peptides indicate they are neuromodulatory peptides whose effects are likely to be mediated by G protein-coupled receptors (See PCT International Publication No. WO 00/18438) .
  • G protein-coupled receptors See PCT International Publication No. WO 00/18438, .
  • NPFF-1 and NPFF-2 NPFF receptor subtypes
  • NPFF is an endogenous modulator of opioid systems with effects on morphine analgesia, tolerance, and withdrawal (5, 6) .
  • NPFF appears to represent an endogenous "anti-opioid" system in the CNS, acting at specific high-affinity receptors that are distinct from opioid receptors (7, 8).
  • Endogenous NPFF has been suggested to play a role in morphine tolerance: agonists of NPFF precipitate "morphine abstinence syndrome" (symptoms of morphine withdrawal) in morphine-dependent animals (9, 10), while antagonists and anti-NPFF IgG restore morphine sensitivity and ameliorate symptoms of withdrawal.
  • NPFF has also been shown to participate in the regulation of pain threshold, showing both "anti-opiate” effects and analgesic effects, depending on the test system (5) .
  • NPFF peptides to modulate the opioid system raised the possibility that NPFF interacts directly with opiate receptors.
  • radioligand binding assays using a tyrosine-substituted NPFF analog [ 125 I]Y8Fa demonstrate that NPFF acts through specific high affinity binding sites distinct from opiate receptors (11-14) that are sensitive to - inhibition by guanine nucleotides (15).
  • NPFF and related peptidic agonists exhibit direct analgesic activity in some animal models.
  • NPFF has been shown to produce analgesia in the rat tail-flick and paw pressure models, upon intrathecal administration (16).
  • a NPFF-like peptide, SLAAPQRF-amide isolated from rat brain and spinal cord (17), produces antinociceptive action in the tail-flick and paw pressure models (18).
  • NPFF has also been observed to play a role in animal models of chronic pain. For example, NPFF has recently been shown to be involved in inflammatory pain (19) and neuropathic pain (20).
  • NPFF neuropeptide FF
  • lDMe In carrageenan inflammation, 5-10nmol of lDMe was effective against both thermal hyperalgesia and mechanical allodynia, and in a neuropathic pain model, lDMe showed antiallodynic effects against cold allodynia (24). lDMe also shows analgesic activity in the rat vocalization threshold upon intrathecal administration (25) .
  • NPFF neuropeptide FF
  • NPFF and related agonists show decrease in the contraction frequency of the rat bladder upon i.v. and i.t. administration (See PCT International Publication No. WO 00/18438) .
  • a potent NPFF agonist, PFRF- amide has been shown to increase blood pressure and heart rate in rats (26) .
  • NPFF and related peptides have a number of other biological activities that may be therapeutically relevant including effects on feeding (27-29) , psychotic behavior (30), nicotine addiction (31), and other cardiovascular functions (32, 33).
  • NPFF-like immunoreactive neurons as well as NPFF1 receptor mRNA
  • BIBP 3226 which is also a neuropeptide Y YI antagonist, blocks feeding through a nonspecific mechanism, not secondary to inhibition of YI (38) .
  • NPFF agonists and/or antagonists have great potential as being therapeutically useful agents for the treatment of a diverse array of clinically relevant human disorders.
  • NPFF agonists may have therapeutic potential, among others, for the treatment of pain, memory loss, circadian rhythm disorders, and micturition disorders.
  • Cloned receptor subtypes of NPFF and the development of high- efficiency in vitro assays, both for binding and receptor activation, have aided the discovery and development of novel NPFF ligands in our hands.
  • it is practically possible to design a molecule that is an agonist at one NPFF subtype, and an antagonist at the other (s). This concept of a dual-acting molecule provides an attractive means of designing drugs that can treat multiple disorders.
  • These molecules may be used by themselves as drugs or as valuable tools for the design of drugs for the treatment of various clinical abnormalities in a subject wherein the abnormality is alleviated by increasing or decreasing the activity of a mammalian NPFF receptor by administering to the subject an amount of a compound which is an antagonist or agonist of mammalian NPFF receptors to effect a treatment of the abnormality.
  • sulfonylamide-containing molecules which act as agonists and/or antagonists at one or more NPFF receptor subtypes.
  • Dansyl RFamide has been used by Brussaard
  • Bourguignon et . al. (35). Described herein are unique sulfonamido-peptidomimetic ligands which are either antagonists and/or agonists that show selectivity towards NPFF receptor subtype (s). Also, described herein are unique compounds that have improved pharmacological properties at the
  • NPFF receptor subtype NPFF receptor subtype
  • This invention provides a compound having the structure:
  • RI is straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; naphthyl; arylalkyl, heteroarylalkyl, phenyl or heteroaryl, wherein the arylalkyl, heteroarylalkyl, phenyl or heteroaryl is unsubstituted or substituted with one or more of the following substituents: halogen, hydroxy,
  • R7 is independently H, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl;
  • R3 and R4 are independently H, straight chained
  • R5 is -OR8 or -N(R8) 2 ; wherein each R8 is independently H, straight chained or branched C1-C7 alkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl;
  • This invention also provides a method of treating pain is a subject in need of such treatment comprising administering to the subject an effective amount of the aforementioned compound.
  • This invention further provides a method of treating a lower urinary tract disorder in a subject in need of such treatment comprising administering to the subject an effective amount of the aforementioned compound.
  • Figure 1 Shows the effect of compound (N- (4 , 7-dimethyl-2- quinolinyl) guanidine) on bladder activity in the anesthetized rat. Rhythmic elevations in bladder pressure, resulting from distension induced contractions, were unaffected by the i.v. administration of physiological saline. In contrast, the ⁇ PFF receptor ligand compound ( N- ( 4 , 7-dimethyl-2- quinolinyl) guanidine) produced an immediate inhibition of bladder activity, which persisted for 12 min.
  • Figure 2 Shows the effect of compound ( N- (6-chloro-4-methyl- 2-quinolinyl) guanidine) on bladder activity in the anesthetized rat. Rhythmic elevations in bladder pressure, resulting from distension induced contractions, were unaffected by the i.v. administration of physiological saline. In contrast, the ⁇ PFF receptor ligand compound (N- (6-chloro-4- methyl-2-quinolinyl) guanidine) produced an immediate inhibition of bladder activity, which persisted for 35 min.
  • compound N- (6-chloro-4-methyl- 2-quinolinyl) guanidine
  • This invention provides a compound having the structure:
  • RI is straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; naphthyl; arylalkyl, heteroarylalkyl, phenyl or heteroaryl, wherein the arylalkyl, heteroarylalkyl, phenyl or heteroaryl is unsubstituted or substituted with one or more of the following substituents: halogen, hydroxy,
  • R7 is independently H, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl;
  • R3 and R4 are independently H, straight chained
  • R5 is -OR8 or -N(R8) 2 ; wherein each R8 is independently H, straight chained or branched C1-C7 alkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl;
  • halogen hydroxy, C1-C6 alkoxy, aryloxy, straight chained or branched C2-C6 alkyl, aryl, heteroaryl, nitro, cyano, C1-C6 alkylthio, substituted or unsubstituted arylalkyl or
  • This invention also provides a compound having the structure:
  • RI is straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; naphthyl; arylalkyl, heteroarylalkyl, phenyl or heteroaryl, wherein the arylalkyl, heteroarylalkyl, phenyl or heteroaryl is unsubstituted or substituted with one or more of the following substituents: halogen, hydroxy,
  • R7 is independently H, straight chained or branched C1-C7 alkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; and
  • This invention also provides a compound having the structure:
  • RI is straight chained or branched C1-C7 alkyl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, monofluoroalkyl or polyfluoroalkyl; straight chained or branched C2-C7 alkenyl or alkynyl; C3-C7 cycloalkyl, monofluorocycloalkyl, or polyfluorocycloalkyl; C5-C7 cycloalkenyl; naphthyl; or arylalkyl, heteroarylalkyl, phanyl or heteroaryl, wherein the arylalkyl, heteroarylalkyl, phenyl or heteroaryl is unsubstituted or substituted with one or more of the following substituents: halogen, hydroxy, C1-C6 alkoxy, aryloxy, straight chained or branched C1-C6 alkyl, aryl, heteroaryl, nitro, hal
  • the compound has the structure:
  • the compound has the structure:
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  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
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  • the compound has the structure
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure:
  • the compound has the structure
  • the compound has the structure:
  • the compound has the structure:
  • This invention also provides a pharmaceutical composition comprising any of the aforementioned compounds together with a pharmaceutically acceptable carrier.
  • This invention further provides a method of preparing a pharmaceutical composition comprising mixing any of the aforementioned compounds with a pharmaceutical acceptable carrier.
  • the carrier may be phosphate buffered saline, physiological saline or water, for example.
  • This invention further provides a compound which is converted in vivo to any of the aforementioned compounds.
  • This invention yet further provides a compound which is a metabolite of any of the aforementioned compounds.
  • This invention also provides a salt of any of the aforementioned compounds.
  • This invention further provides a method of treating pain in a subject in need of such treatment comprising administering to the subject an effective amount of any of the aforementioned compounds.
  • This invention yet further provides a method of treating a lower urinary tract disorder in a subject in need of such treatment comprising administering to the subject an effective amount of any of the aforementioned compounds.
  • the lower urinary tract disorder may be interstitial cystitis, stress incontinence or urge incontinence.
  • enantiomers, diastereomers, double bond stereoisomers and double bond regioisomers exist. Some compounds have multiple chiral centers, each of which can independently be either the R or the S configuration.
  • This invention contemplates racemic mixtures of as well as isolated enantiomers, diastereomers, double bond stereoisomers and double bond regioisomers.
  • the invention also provides for each pure stereoisomer of any of the compounds described herein.
  • stereoisomers may include enantiomers, disastereomers, or E or Z alkene isomers.
  • the invention also provides for stereoisomeric mixtures, including racemic mixtures, diastereomeric mixtures, or E/Z isomeric mixtures.
  • Stereoisomers can be synthesized in pure form (N ⁇ gradi, M.; Stereoselective Synthesis, (1987) VCH Editor Ebel, H. and Asymmetric Synthesis, Volumes 3 - 5, (1983) Academic Press, Editor Morrison, J. ) Or they can be resolved by a variety of methods such as crystallization and chromatographic techniques (Jaques, J. ; Collet, A.; ilen, S.; Enantiomer, Racemates, and Resolutions, 1981, John Wiley and Sons and Asymmetric Synthesis, Vol. 2, 1983, Academic Press, Editor Morrison, J) .
  • the compounds of the present invention may be present as enatiomers, diasteriomers, isomers or two or more of the compounds may be present to form a racemic or diastereomeric mixture.
  • the compounds of the present invention are preferably 80% pure, more preferably 90% pure, and most preferably 95% pure.
  • aryl is used to include phenyl, benzyl, or naphthyl
  • roaryl is used to include pyrazinyl, imidazolyl, imidazolinyl , indolyl , benzimidazolyl, benzfuranyl, pyrimidinyl, benzothiophenyl , isoquinolyl, or quinolyl
  • arylalkyl is used to designate an C1-C6 alkyl chain substituted with an aryl group and the term heteroarylalkyl is used to designate a C1-C6 alkyl chain substituted with a heteroaryl group.
  • heteroaryl is used to include five and six membered unsaturated rings that may contain one or more oxygen, sulfur, or nitrogen atoms.
  • heteroaryl groups include, but are not limited to, furanyl, thienyl, pyrroyl, oxazolyl, thiasolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, and triazinyl.
  • heteroaryl is used to include fused bicyclic ring systems that may contain one or more heteroataoms such as oxygen, sulfur and nitrogen.
  • heteroaryl groups include, but are not limited to, indolizinyl, indolyl, isoindolyl, benzo [b] furanyl, benzo [b] thiophenyl, indazolyl, benzimidazolyl, purinyl, benaoxazolyl, benzisoxazolyl, benzo [b] thiazolyl, imidazo[2,l- b]thiazolyl, cinnolinyl, quinasolinyl, quinoxalinyl, 1,8- naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, phthalimidyl and 2, 1, 3-benzothiazolyl .
  • Heterocyclic is defined as a 3 to 10 atom-ring containing at least one saturated bond and containing in any position one or more of the following atoms: N,0,S.
  • heterocyclic rings include but are not limited to tetrahydrofuran, dihydrofuran, tetrahydropyran, kihydropyran piperidine, dihydropiperidine, pyrrolidine, dihydropyrrolidine dioxane, piperazin.
  • sulfonylamide compounds containing an arginine unit have agonist and/or antagonist activity at NPFF receptors. It is therefore reasonable to expect that replacement of arginine with lysine or known mimics of arginine will also provide agonists and/or antagonists of NPFF receptors.
  • mimetic structures described herein are derived from commercially-available known mimics of arginine. One source is, RSP Amino Acid Analogs Inc., 1999 Building Block Index, Worcester, MA 01605, USA.
  • the abnormality is a lower urinary tract disorder such as interstitial cystitis or urge incontinence such as urge incontinence or stress incontinence, particularly urge incontinence, a regulation of a steroid hormone disorder, an epinephrine release disorder, a gastrointestinal disorder, irritable bowel syndrome, a cardiovascular disorder, an electrolyte balance disorder, diuresis, hypertension, hypotension, diabetes, hypoglycemia, a respiratory disorder, asthma, a reproductive function disorder, an immune disorder, an endocrine disorder, a musculoskeletal disorder, a neuroendocrine disorder, a cognitive disorder, a memory disorder, a sensory modulation and transmission disorder, a motor coordination disorder, a sensory integration disorder, a motor integration disorder, a dopaminergic function disorder, an appetite disorder, obesity, a serotonergic function disorder, an olfaction disorder, nasal congestion, a sympathetic innervation disorder, an affective disorder, pain, migrane, psychotic behavior,
  • pharmaceutically acceptable carrier means any of the standard pharmaceutically acceptable carriers. Examples include, but are not limited to, phosphate buffered saline, physiological saline, water, and emulsions, such as oil/water emulsions.
  • the formulations of the present invention can be solutions, suspensions, emulsions, syrups, elixirs, capsules, tablets, and the like.
  • the compositions may contain a suitable carrier, diluent, or excipient, such as sterile water, physiological saline, glucose, or the like.
  • the formulations can also be lyophilized, and/or may contain auxiliary substances, such as wetting or emulsifying agents, pH buffering agents, adjuvants, gelling or viscosity enhancing additives, preservatives, flavoring agents, colors, and the like, depending upon the route of administration and the preparation desired. Standard texts, such as "Remington's Pharmaceutical Science", 17th Ed., 1985, incorporated herein by reference, may be consulted to prepare suitable preparations, without undue experimentation.
  • the formulations can include powdered carriers, such as lactose, sucrose, mannitol, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Further, tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of hours. Compressed tablets can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract. The formulations can also contain coloring and flavoring to enhance patient acceptance. The formulations can also include any of disintegrants, lubricants, plasticizers, colorants, and dosing vehicles .
  • water a suitable oil, saline, aqueous dextrose (glucose) , and related sugar solutions and glycols such as propylene glycol or polyethylene glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration contain preferably a water soluble salt of the active ingredient, suitable stabilizing agents, and, if necessary, buffer substances.
  • Antioxidants such as, for example, sodium bisulfate, sodium sulfite, citric acid and its salts, sodium EDTA, ascorbic acid, and the like can be used either alone or in combination with other suitable antioxidants or stabilizing agents typically employed in the pharmaceutical compositions.
  • parenteral solutions can contain preservatives, such as, for example, benzalkonium chloride, methyl- or propyl- paraben, chlorobutanol and the like.
  • the present invention includes within its scope prodrugs of the compounds of this inventions.
  • prodrugs will be functional derivatives of the compounds of the invention which are readily convertible in vivo into the required compound.
  • administering shall encompass the treatment of the various conditions described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound in vivo after administration to the patient.
  • Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985, the content of which is incorporated into the subject description by reference.
  • Prodrugs are considered to be any covalently bonded drug carriers that release the active parent drug upon in vivo administration.
  • Prodrugs of molecules containing guanidines or other basic functional groups are prepared by modifying these groups in such a way that the modifications are cleaved in vivo to the parent compounds.
  • Prodrugs also include compounds wherein hydroxyl, guanidino, amino, carboxy or sulfhydryl groups are ⁇ protected' with any group that, upon administration to a mammalian subject, these functional groups are re-generated.
  • prodrugs include, but are not limited to, acetate, formayl, benzoyl, polyethylene glycolyl derivatives of guanidinyl, amino, or alcohol compounds; phosphate esters, dimethylglycine esters, aminoalkylbenzyl esters, aminoalkyl esters and carbosyalkyl esters of alcholols and phenols, and various alkyl and aryl or polyethyleneglycol esters of carbosylic acids.
  • a prodrug of a guanidino or amino group may contain an acyl group (s) attached to the basic nitrogen(s), forming an N-acyl derivative (s) .
  • the salts include, but are not limited to, the following acids and bases: Inorganic acids which include hydrochloric acid, hydrofluoric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and boric acid; organic acids which include acetic acid, trifluoroacetic acid, formic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, maleic acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzoic acid, glycolic acid, lactic acid, and mandelic acid; inorganic bases include ammonia and hydrazine; and organic bases which include methylamine, ethylamine, hydroxyethylamine, propylamine, dimethylamine, diethylamine, t rimethylamine , triethylamine , ethylenediamine , hydroxye
  • This invention further provides for the hydrates and polymorphs of all of the compounds described herein.
  • the present invention further includes metabolites of the compounds of the present invention.
  • Metabolites include active species produced upon introduction of compounds of this invention into the biological milieu.
  • the compounds of the present invention may be synthesized by the routes shown in Schemes 1 and 2, or with appropriate modifications as described herein.
  • Method 1, and Method 2 the product is isolated at the end of the synthesis, and purified by a suitable procedure such as high performance liquid chromatography (HPLC) , crystallization, column chromatography, thin layer chromatography, etc. While preferred reactants have been identified herein, it is further contemplated that the present invention would include chemical equivalents to each reactant(s) specifically enumerated in this disclosure.
  • the resin was then treated with a pre-mixed solution of Fmoc-L-phenylalanine (1.54g, 4mmol) , HBTU (1.5g, 4mmol) and diisopropylethylamine (1.4mL, 8mmol) .
  • the resin slurry was shaken for 2h. After draining of the amino acid solution, the resin was washed three times with DMFrNMP (1:1, 25mL) .
  • the resin was treated with 30% piperidine in DMF (25mL) for 5 min. and the liquid was drained. The piperidine treatment was repeated for 25 min. The resin was then washed, for 5min.
  • the resin was treated with 30% piperidine in DMF (25mL) for 5 and 25 min, respectively, as described above. The resin was then washed, for 5min. each, with DMF:NMP (1:1, 25mL, three times), followed by methanol (25mL, two times) and DMF:NMP (1:1, 25mL, three times) . To the resin was then added 1- naphthalenesulfonyl chloride (0.53g, 2mmol) , and triethylamine (0.56mL, 4mmol) in DMF (lOmL). After shaking for 3h, the reagents were drained, and the resin was washed for 5min.
  • the product was purified by using reverse phase preparative HPLC (250 x 22.5mm, Primesphere C18-HC) with a gradient of 10% - 70% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min (25mL/min flow rate, detection at 215nm) .
  • the fractions containing the product were pooled and lyophilized to yield the product (107mg) .
  • the product was purified by using reverse phase preparative
  • N-amido-substituted products (where R3 and R4 in the generic structure is a substituent other than H)
  • R3 and R4 in the generic structure is a substituent other than H
  • modifying procedure 1 to accommodate the incorporation of R3 or R4 via alkylation or reductive coupling.
  • the resin is treated with the appropriate alkyl halide
  • the synthesis can be achieved by starting with the protected phenylalanine attached to Wang resin or 2-chlorotrityl chloride resin. Cleavage with the TFA cocktail after the synthesis is complete gives the product with the C-terminal acid.
  • the cleavage solution is neutralized with pyridine in methanol, and evaporated.
  • the crude compound containing a C-terminal acid is then coupled to an appropriate amine ((R8) 2 NH) by using a coupling procedure similar to that described in Method 2, to give the substituted amide .
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 18.9min;
  • This compound was synthesized as described in Method 1, except that 3-nitrophenylsulfonyl chloride (442 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 4-nitrophenylsulfonyl chloride (442 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2, 6-dichlorophenylsulfonyl chloride (425.2 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 4 -fluorophenylsulfonyl chloride (389.2 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 4 -chlorophenylsulfonyl chloride (422.14 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2-bromophenylsulfonyl chloride (511.04 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 4-methylphenylsulfonyl chloride (381.3 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that phenylsulfonyl chloride (353.24 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 4-methoxyphenylsulfonyl chloride (413.3 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2, 4-dichlorophenylsulfonyl chloride (491.02 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that a-toluenesulfonyl chloride (379.3 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 21.7 min;
  • This compound was synthesized as described in Method 1, except that 4-iodophenylsulfonyl chloride (605.04 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 19.7 min;
  • This compound was synthesized as described in Method 1, except that 2-thiophenesulfonyl chloride (365.3 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2-naphthalenesulfonyl chloride (453.36 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 19.0 min;
  • This compound was synthesized as described in Method 1, except that 3, 4-dimethoxyphenylsulfonyl chloride (473.36 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 14.9 min;
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 19.9 min;
  • HPLC Primesphere C-18 reverse phase column 4.6 x 250mm, 10 - 56% acetonitrile (0.1% TFA) in water (0.1% TFA) over 24 min, flow rate 1 mL / min, detection at 220nm, retention time 19.9 min;
  • This compound was synthesized as described in Method 1, except that 2-Nitro-4-trifluoromethylphenylsulfonyl chloride (579.24 mg, 2 mmol) was used in place of 1-naphthalenesulf onyl chloride .
  • This compound was synthesized as described in Method 1, except that 2, 6-dichlorophenylsulfonyl chloride (491.02 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 3- (2, 5-dichlorothiophene) sulfonyl chloride (503.08 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 3 -methyl -6 -methoxyphenylsulfonyl chloride (441.36 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2, 5-dichlorophenylsulfonyl chloride (491.02 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 3 , 4-dichlorophenylsulfonyl chloride (491.02 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 3 -cyanophenylsulfonyl chloride (403.26 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that pentafluorophenylsulfonyl chloride (533.14 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that 2-nitrophenylsulfonyl chloride (443.24 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that (D) Arginine (Pbf) was used in place of (L) Arginine (Pbf) , and 4 -fluorophenylsulfonyl chloride (389.22 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that (D) Phenylalanine was used in place of (L) Phenylalanine, and 2-naphthalenesulfonyl chloride (453.36 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that (D) Arginine (Pbf) was used to substitute (L) Arginine (Pbf) , and 2-bromophenylsulfonyl chloride (511.04 mg, 2 mmol) was used in ' place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that (D) Arginine (Pbf) was used in place of (L)Arginine (Pbf) .
  • This compound was synthesized as described in Method 1, except that (D) Phenylalanine was used to substitute (L) Phenylalanine, and 2, 6-difluorophenylsulfonyl chloride (425.20 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • This compound was synthesized as described in Method 1, except that (D) Phenylalanine was used to substitute (L) Phenylalanine, and 4 -fluorophenylsulfonyl chloride (389.22 mg, 2 mmol) was used in place of 1-naphthalenesulfonyl chloride.
  • Test 1 Radioligand Binding Assays
  • the binding data reflect competitive displacement of ( [ 125 I] lDMeNPFF) .
  • DIRC volume-induced rhythmic contraction
  • mice Female Sprague Dawley rats weighing approximately 300g were anesthetized with subcutaneous urethane (1.2g/kg) .
  • the trachea was cannulated with PE240 tubing to provide a clear airway throughout the experiment.
  • a midline abdominal incision was made and the left and right ureters were isolated.
  • the ureters were ligated distally (to prevent escape of fluids from the bladder) and cannulated proximally with PE10 tubing.
  • the incision was closed using 4-0 silk sutures, leaving the PE10 lines routed to the exterior for the elimination of urine.
  • the bladder was canulated via the transurethral route using PE50 tubing inserted 2.5cm beyond the urethral opening. This cannula was secured to the tail using tape and connected to a pressure transducer. To prevent leakage from the bladder, the cannula was tied tightly to the exterior urethral opening using 4-0 silk.
  • vehicle (saline) or test compounds were administered i.v. to examine their effects on bladder activity.
  • the effect of a compound which inhibited the micturition reflex was expressed as its "disappearance time", defined as the time between successive bladder contractions in the presence of the test compound minus the time between contractions before compound administration.
  • an agonist has an intrinsic activity (IA) >15%, while an antagonist has a Ki ⁇ 1.2 ⁇ M and an intrinsic activity (IA) ⁇ 15% at the rat cloned neuropeptide FF (NPFF) receptors.
  • IA intrinsic activity
  • NPFF rat cloned neuropeptide FF
  • Compounds 1001 to 1033 are concurrently agonists at NPFF1 and NPFF2 receptors;
  • Compounds 2001 to 2003 are agonists at NPFFl receptors, with weak or no affinity to NPFF2 receptors;
  • Compound 3001 is concurrently an antagonist at NPFFl receptors and an agonist at NPFF2 receptors.
  • Ki at rNPFF-l 88nM
  • Ki at rNPFF-2 2310 nM
  • EC50 at rNPFF-l 524 nM (I.A. 106%)
  • NPFF Mammalian Neuropeptide FF
  • FMRFamide-related peptides including the mammalian-derived FaRPs F-8-Famide (NPFF) and A-18- Famide, for opioid mu, delta, kappa 1, kappa 2a, or kappa 2b receptors.
  • NPFF mammalian-derived FaRPs F-8-Famide
  • A-18- Famide for opioid mu, delta, kappa 1, kappa 2a, or kappa 2b receptors.

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Abstract

La présente invention concerne un composé possédant la structure suivante :, dans laquelle R1 est un alkyle, hydroxyalkyle, alcoxyalkyle, alkylthioalkyle, monofluoroalkyle ou polyfluoroalkyle C1-C7 à chaîne droite ou ramifiée ; un alcényle ou alkynyle C2-C7 à chaîne droite ou ramifiée; un cycloalkyle, monofluorocycloalkyle ou polyfluorocycloalkyle C3-C7; un cycloalcényle C5-C7 ; un naphthyle; un arylalkyle, hétéroarylalkyle, phényle ou hétéroaryle, l'arylalkyle, l'hétéroarylalkyle, le phényle ou l'hétéroaryle étant non substitué ou substitué par un ou plusieurs des substituants suivants : halogène, hydroxy, alcoxy C1-C6, aryloxy, alkyle C2-C6 à chaîne droite ou ramifiée, aryle, hétéroaryle, nitro, cyano, alkylthio C1-C6, arylalkyle ou hétéroarylalkyle substitué ou non substitué,-C(=Y)R7, -C(=Y)OR7, -N(R7)2, -C(=Y)NR7, -NR7C(=Y)R7 ou -N(R7)C(=Y)N(R7)2, où Y est O ou S; où R7 est indépendamment H, alkyle C1-C7 à chaîne droite ou ramifiée, monofluoroalkyle ou polyfluoroalkyle; alcényle ou alkynyle C2-C7à chaîne droite ou ramifiée; cycloalkyle, monofluorocycloalkyle ou polyfluorocycloalkyle C3-C7; cycloalcényle C5-C7; où R2 est -(CH2)n-NH-C(=NH)-NH2; -(CH2)n-C(=NH)-NH2; -(CH2)n-N(R7)2; ou -J; où n est un entier entre 1 et 6, et où J est une quelconque des structures suivantes: dans lesquelles chacun de R3 et R4 est indépendamment H, alkyle, monofluoroalkyle ou polyfluoroalkyle C1-C7 à chaîne droite ou ramifiée; alcényle ou alkynyle C2-C7 à chaîne droite ou ramifiée; cycloalkyle, monofluorocycloalkyle ou polyfluorocycloalkyle C3-C7; ou cycloalcényle C5-C7; où R5 est -OR8 ou -N(R8)2; où chaque R8 est indépendamment H, alkyle C1-C7 à chaîne droite ou ramifiée, alcoxyalkyle, alkylthioalkyle, monofluoroalkyle ou polyfluoroalkyle; alcényle ou alkynyle C2-C7 à chaîne droite ou ramifiée; cycloalkyle C3-C7, monofluorocycloalkyle ou polyfluorocycloalkyle; cycloalcényle C5-C7; où R6 est arylalkyle, hétéroarylalkyle, aryle ou hétéroaryle, chacun étant facultativement substitué par un ou plusieurs des substituants suivants: halogène, hydroxy, alcoxy C1-C6, aryloxy, alkyle C1-C6 à chaîne droite ou ramifiée, aryle, hétéroaryle, nitro, cyano, alkylthio C1-C6, arylalkyle ou hétéroarylalkyle substitué ou non substitué, -C(=Y)R7, -C(=Y)OR7, -N(R7)2, -C(=Y)NR7, -NR/C(=Y)R7 ou -N(R7)C(=Y)N(R7)2, ou un sel pharmaceutiquement acceptable de ces derniers. L'invention se rapporte également à un procédé qui permet de traiter une affection des voies urinaires inférieures chez un sujet qui en a besoin, le traitement consistant à administrer au sujet une quantité efficace d'un quelconque des composés précités.
PCT/US2002/030258 2001-09-24 2002-09-24 Molecules specifiques des recepteurs npff et utilisations de ces dernieres WO2003026575A2 (fr)

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JP2007507473A (ja) * 2003-10-06 2007-03-29 オサケユイチア ユバンティア ファーマ リミティド ソマトスタチン受容体１及び／又は４選択的アゴニスト及びアンタゴニスト

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WO2005033124A1 (fr) * 2003-10-06 2005-04-14 Oy Juvantia Pharma Ltd Sulfonylamino-peptidomimetiques actifs sur les sous-types 4 (sstr4) et 1 (sstr1) du recepteur de somatostatine
JP2007507473A (ja) * 2003-10-06 2007-03-29 オサケユイチア ユバンティア ファーマ リミティド ソマトスタチン受容体１及び／又は４選択的アゴニスト及びアンタゴニスト
JP2007507472A (ja) * 2003-10-06 2007-03-29 ブルスター，ジークフリート ソマトスタチン受容体サブタイプ４（ｓｓｔｒ４）及び１（ｓｓｔｒ１）に作用するスルホニルアミノ−ペプチド模倣薬
US7741362B2 (en) 2003-10-06 2010-06-22 Siegfried Wurster Somatostatin receptor 1 and/or 4 selective agonists and antagonists

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