[go: up one dir, main page]

WO1999064002A1 - Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine - Google Patents

Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine Download PDF

Info

Publication number
WO1999064002A1
WO1999064002A1 PCT/US1999/013252 US9913252W WO9964002A1 WO 1999064002 A1 WO1999064002 A1 WO 1999064002A1 US 9913252 W US9913252 W US 9913252W WO 9964002 A1 WO9964002 A1 WO 9964002A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
treatment
prevention
formula
heteroaryl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1999/013252
Other languages
English (en)
Inventor
Ravi P. Nargund
Zhixiong Ye
Brenda L. Palucki
Raman K. Bakshi
Arthur A. Patchett
Leonardus H. T. Van Der Ploeg
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Merck and Co Inc
Original Assignee
Merck and Co Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from GBGB9817179.6A external-priority patent/GB9817179D0/en
Application filed by Merck and Co Inc filed Critical Merck and Co Inc
Priority to AU46801/99A priority Critical patent/AU742425B2/en
Priority to JP2000553071A priority patent/JP2002517444A/ja
Priority to CA002334551A priority patent/CA2334551A1/fr
Priority to EP99930220A priority patent/EP1085869A4/fr
Publication of WO1999064002A1 publication Critical patent/WO1999064002A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Spiropiperidine derivatives are melanocortin receptor agonists, and as such are useful in the treatment of disorders responsive to the activation of melanocortin receptors, such as obesity, diabetes as well as male and/or female sexual dysfunction.
  • Pro-opiomelanocortin (POMC) derived peptides are known to affect food intake.
  • GPCRs G-protein coupled receptors
  • M-R melanocortin receptor
  • MC-Rs evidence for the involvement of MC-Rs in obesity includes: i) the agouti (A ) mouse which ectopically expresses an antagonist of the MC-1R, MC-3R and -4R is obese, indicating that blocking the action of these three MC-Rs can lead to hyperphagia and metabolic disorders; ii) MC-4R knockout mice (Huszar et al., Cell, 88, 131-141, 1997) recapitulate the phenotype of the agouti mouse and these mice are obese; iii) the cyclic heptapeptide MT-II (MC-1R, -3R, -4R, -5R, agonist) injected intracerebroventricularly (ICV) in rodents, reduces food intake in several animal feeding models (NPY, oh/oh, agouti, fasted) while ICV injected SHU-9119 (MC-3R, -4R antagonist; MC-1R and -5R
  • MC-1R Five MC-Rs have thus far been identified, and these are expressed in different tissues.
  • MC-1R was initially characterized by dominant gain of function mutations at the Extension locus, affecting coat color by controlling phaeomelanin to eumelanin conversion through control of tyrosinase.
  • MC-1R is mainly expressed in melanocytes.
  • MC-2R is expressed in the adrenal gland and represents the ACTH receptor.
  • MC-3R is expressed in the brain, gut and placenta and may be involved in the control of food intake and thermogenesis.
  • MC-4R is uniquely expressed in the brain and its inactivation was shown to cause obesity.
  • MC-5R is expressed in many tissues including white fat, placenta and exocrine glands. A low level of expression is also observed in the brain.
  • MC-5R knock out mice reveal reduced sebaceous gland lipid production (Chen et al., Cell, 1997, 91, 789-798).
  • MT-II melanotan -II
  • Intramuscular administration of MT-II (0.025 mg/kg and 0.1 mg/kg) to 10 non-organic impotent patients caused transient erections (8 responders) with onset from 50-180 minutes; penile erections subsided after ejaculation (15th American Peptide Symposium 6/14-19, 1997, Nashville, TN, study now published in J. Urology, 160, 389-393, 1998).
  • the present invention provides compounds having the formula I:
  • Cy2 is . a six-membered aromatic ring containing 0 or 1 N atom or cyclohexane
  • X is O, CH2, SO2, CHCO2RD, CHSO2R , CHC(O)N(Rb) , NRb,
  • NSO2R a NSO2N(Rb)2, NCORa, NCON(Rb) 2 , CHN(Rb)COR a , CHN(Rb)SO2R a , CHCH2ORb, or CH(CH2)-heteroaryl
  • Rl is H, Ci- ⁇ alkyl, CH(Rb)-aryl, CH(Rb)-heteroaryl, (CH2) n -
  • R2 is H or halo
  • Ra is Rb, (CH2) n N(Rb)2, (CH2) n NH-2- pyridyl, (CH2) n NH-2-imidazolyl, (CH2) n NH-2-thiazolyl, (CH2) n NH-2-pyrimidinyl,
  • Rb is H, Ci-8alkyl, (CH2) n aryl, (CH2) n heteroaryl, C3-6cycloalkyl; or 2 Rb together with the nitrogen atom to which they are attached form a 5- or 6-membered ring optionally containing an additional heteroatom selected from 0, S, and NRl ;
  • Rc is Rb, halo, ORb, NHSO2R , N(Rb) 2 , CN, NO2, SO2N(Rb)2, SO2R ,
  • Rd is H, NO2, or CN
  • Cy is aryl, 5- or 6-membered heteroaryl, 5- or 6-membered heterocyclyl, or
  • n is 0 to 3 ; m, p and q are independently 0, 1 or 2; r is 1 , 2 or 3 ; or a pharmaceutically acceptable salt thereof.
  • compounds of formula I are compounds wherein Cy2 is benzene or cyclohexane.
  • compounds of formula I are compounds wherein X is CHCO2R b , CHC(O)N(Rb)2, NSO2R a CHN(Rb)COR a , CHN(Rb)SO2R a CHCH2ORb or CHCH2-heteroaryl.
  • Rb and R c are as defined under formula I, and Cy is aryl, 5- or 6-membered heteroaryl, or 5-or 6-membered carbocyclyl.
  • Cy is benzene or cyclohexane.
  • X is CHCO2Rb, CHC(O)N(Rb)2, NSO2R a CHN(Rb)CORa, or
  • R2 is H or halo
  • Ra is Rb, (CH2) n N(R )2, (CH2) n NH-2-pyridyl, (CH2) n H-2-imidazolyl,
  • Rb is H, C i - ⁇ alkyl, (CH2)naryl, (CH2)nheteroaryl, or C3-6cycloalkyl;
  • Cy is benzene, pyridine, imidazole or cyclohexane; nis 0to3; or a pharmaceutically acceptable salt thereof.
  • R is H, Ci-8alkyl, (CH2)naryl, (CH2)nheteroaryl, or C3-6cycloalkyl;
  • Rc is H, halo, Rb, ORb, CF3, OCF3;
  • Cyis benzene pyridine, imidazole or cyclohexane; nis 0to3; or a pharmaceutically acceptable salt thereof.
  • the carbon atom marked with * has the R configuration.
  • Cy is benzene or cyclohexane.
  • Another aspect of the present invention provides a method for the treatment or prevention of obesity or diabetes in a mammal which comprises administering to said mammal an effective amount of a compound of formula I.
  • Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a patient in need of such treatment or prevention an effective amount of a compound of formula I.
  • Another aspect of the present invention provides a method for the treatment or prevention of male or female sexual dysfunction including erectile dysfunction which comprises administering to a patient in need of such treatment or prevention an effective amount of an agonist of melanocortin-4 receptor.
  • Yet another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula I and a pharmaceutically acceptable carrier.
  • alkyl groups specified above are intended to include those alkyl groups of the designated length in either a straight or branched configuration. Exemplary of such alkyl groups are methyl, ethyl, propyl, isopropyl. butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl, isohexyl, and the like.
  • halogen is intended to include the halogen atoms fluorine, chlorine, bromine and iodine.
  • aryl includes phenyl and naphthyl.
  • heteroaryl includes mono- and bicyclic aromatic rings containing from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur.
  • "5- or 6-membered heteroaryl” are monocyclic heteroaromatic rings, examples thereof include thiazole. oxazole, thiophene, furan, pyrrole, imidazole, isoxazole, pyrazole, triazole, thiadiazole, tetrazole, oxadiazole, pyridine, pyridazine, pyrazine, and the like.
  • Bicyclic heteroaromatic rings include, but are not limited to, benzothiadiazole.
  • indole benzothiophene, benzofuran, benzimidazole, benzisoxazole, benzothiazole, quinoline, benzotriazole, benzoxazole, isoquinoline.
  • purine furopyridine and thienopyridine.
  • 5- or 6-membered carbocyclyl is intended to include non- aromatic rings containing only carbon atoms such as cyclopentyl and cyclohexyl.
  • 5 and 6-membered heterocyclyl is intended to include non- aromatic heterocvcles containing one to four heteroatoms selected from nitrogen, oxygen and sulfur.
  • Examples of a 5 or 6-membered heterocyclyl include piperidine, morpholine, thiamorpholine, pyrrolidine, imidazolidine, tetrahydrofuran, piperazine, and the like.
  • NR b Rb may represent NH2, NHCH3, N(CH3)CH2CH3, and the like.
  • composition as in pharmaceutical composition, is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
  • pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of the present invention and a pharmaceutically acceptable carrier.
  • Erectile dysfunction is a disorder involving the failure of a male mammal to achieve erection, ejaculation, or both. Symptoms of erectile dysfunction include an inability to achieve or maintain an erection, ejaculatory failure, premature ejaculation, inability to achieve an orgasm. An increase in erectile dysfunction is often associated with age and is generally caused by a physical disease or as a side-effect of drug treatment.
  • Female sexual dysfunction encompasses, without limitatin. conditions usch as a lack of sexual desire and related arousal disorders, inhibited orgasm, lubrication difficulties, and vaginismus.
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers.
  • the present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • Some of the compounds described herein contain olefmic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
  • Some of the compounds described herein may exist as tautomers such as keto-enol tautomers.
  • the individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example methanol or ethyl acetate or a mixture thereof.
  • a suitable solvent for example methanol or ethyl acetate or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active acid as a resolving agent.
  • any enantiomer of a compound of the general Formula I or la may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, lithium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins such as
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, formic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric, pamoic, pantothenic, phosphoric, propionic, succinic, sulfuric, tartaric, p-toluenesulfonic acid, trifluoroacetic acid, and the like.
  • Particularly preferred are citric, fumaric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • Compounds of formula I are melanocortin receptor agonists and as such are useful in the treatment, control or prevention of diseases, disorders or conditions responsive to the activation of one or more of the melanocortin receptors including, but are not limited to, MC-1, MC-2, MC-3, MC-4, or MC-5.
  • Such diseases, disorders or conditions include, but are not limited to, obesity (by reducing appetite, increasing metabolic rate, reducing fat intake or reducing carbohydrate craving), diabetes mellitus (by enhancing glucose tolerance, decreasing insulin resistance), hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladder disease, sleep apnea, depression, anxiety, compulsion, neuroses, insomnia/sleep disorder, substance abuse, pain, male and female sexual dysfunction (including impotence, loss of libido and erectile dysfunction), fever, inflammation, immune modulation, rheumatoid arthritis, skin tanning, acne and other skin disorders, neuroprotective and cognitive and memory enhancement including the treatment of Alzheimer's disease.
  • Some compounds of formula I show highly specific activity toward the melanocortin- 4 receptor which makes them especially useful in the prevention and treatment of obesity, as well as male and female sexual dysfunction.
  • Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention.
  • oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
  • Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
  • compounds of Formula I are administered orally.
  • the effective dosage of active ingredient employed may vary depending on the particular compound employed, the mode of administration, the condition being treated and the severity of the condition being treated. Such dosage may be ascertained readily by a person skilled in the art.
  • the compounds of the present invention are administered at a daily dosage of from 0.01 milligram to about 100 milligrams per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.7 milligrams to about 3500 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • the compounds of the present invention are administered at a daily dosage of from about 0.001 milligram to about 100 milligram per kilogram of animal body weight, preferably given in a single dose or in divided doses two to six times a day, or in sustained release form.
  • the total daily dose will generally be from about 0.07 milligrams to about 350 milligrams. This dosage regimen may be adjusted to provide the optimal therapeutic response.
  • sexual dysfunction compounds of the present invention are given in a dose range of 0.001 milligram to about 100 milligram per kilogram of body weight, preferably as a single dose orally or as a nasal spray.
  • compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
  • pharmaceutically acceptable salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
  • the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous).
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as.
  • oral solid preparations such as, for example, powders, hard and soft capsules and tablets, with the solid oral preparations being preferred over the liquid preparations.
  • tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques. Such compositions and preparations should contain at least 0.1 percent of active compound. The percentage of active compound in these compositions may, of course, be varied and may conveniently be between about 2 percent to about 60 percent of the weight of the unit. The amount of active compound in such therapeutically useful compositions is such that an effective dosage will be obtained.
  • the active compounds can also be administered intranasally as, for example, liquid drops or spray.
  • the tablets, pills, capsules, and the like may also contain a binder such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, lactose or saccharin.
  • a dosage unit form is a capsule, it may contain, in addition to materials of the above type, a liquid carrier such as a fatty oil.
  • tablets may be coated with shellac, sugar or both.
  • a syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and a flavoring such as cherry or orange flavor.
  • Compounds of formula I may also be administered parenterally.
  • Solutions or suspensions of these active compounds can be prepared in water suitably mixed with a surfactant such as hydroxy-propylcellulose.
  • Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol
  • Combination Therapy Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
  • a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
  • the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I. Examples of other active ingredients that may be combined with a compound of Formula I, either administered separately or in the same pharmaceutical compositions, include, but are not limited to:
  • insulin sensitizers including (i) PPAR ⁇ agonists such as the glitazones (e.g. troglitazone, pioglitazone, englitazone, MCC-555. BRL49653 and the like), and compounds disclosed in WO97/27857, 97/28115, 97/28137 and 97/27847; (ii) biguanides such as metformin and phenformin;
  • ⁇ -glucosidase inhibitors such as acarbose
  • e cholesterol lowering agents
  • HMG-CoA reductase inhibitors lovastatin, simvastatin and pravastatin, fluvastatin.
  • atorvastatin and other statins
  • sequestrants cholesterolestyramine, colestipol and a dialkylaminoalkyl derivatives of a cross-linked dextran
  • nicotinyl alcohol nicotinic acid or a salt thereof e.g., proliferator-activater receptor ⁇ agonists such as fenofibric acid derivatives (gemfibrozil, clofibrat, fenofibrate and benzafibrate).
  • inhibitors of cholesterol absorption for example beta-sitosterol and (acyl CoA holesterol acyltransferase) inhibitors for example melinamide,
  • probucol. vitamin E, and (vii) thyromimetics
  • PPAR ⁇ agonists such as those disclosed in W097/28149;
  • antiobesity compounds such as fenfluramine, dexfenfluramine, phentermine, sibutramine, orlistat, or ⁇ 3 adrenergic receptor agonists;
  • feeding behavior modifying agents such as neuropeptide Y antagonists (e.g. neuropeptide Y5) such as those disclosed in WO 97/19682, WO 97/20820, WO 97 ⁇ '20821, WO 97/20822 and WO 97/20823;
  • PPAR ⁇ agonists such as described in WO 97'36579 by Glaxo;
  • growth hormone secretagogues such as MK-0677.
  • agents useful in the treatment of male and/or female sexual dysfunction such as phosphodiester V inhibitors such as sildenafil, and ⁇ -2 adrenergic receptor antagonists.
  • A. Binding Assay The membrane binding assay is used to identify competitive inhibitors of 125 I- ⁇ -NDP-MSH binding to cloned human MCRs expressed in L- or CHO- cells.
  • Cell lines expressing melanocortin receptors are grown in T-l 80 flasks containing selective medium of the composiiton: 1 L Dulbecco's modified Eagles Medium (DMEM) with 4.5 g L-glucose, 25 mM Hepes, without sodium pyruvate, (Gibco/BRl); 100 ml 10% heat-inactivated fetal bovine serum (Sigma); 10 ml 10,000 unit/ml penicillin & 10,000 ug/ml streptomycin (Gibco/BRl); 10 ml 200 mM L-glutamine (Gibco BRl); 1 mg/ml Geneticin (G418) (Gibco/BRl). The cells are grown at 37°C with CO2 and humidity control until the
  • the medium is poured off and 10 mls/monolayer of enzyme-free dissociation media (Specialty Media Inc.) is added.
  • the cells are incubated at 37°C for 10 minutes or until cells slough off when flask is banged against hand.
  • the cells are harvested into 200 ml centrifuge tubes and spun at 1000 rpm, 4° C, for 10 min. The supernatant is discarded and the cells are resuspended in 5 mls/monolayer membrane preparation buffer having the composition: 10 mM Tris pH 7.2-7.4; 4 ug/ml Leupeptin (Sigma); 10 uM Phosphoramidon (Boehringer Mannheim); 40 ug/ml Bacitracin (Sigma); 5 ug/ml Aprotinin (Sigma); 10 mM Pefabloc (Boehringer Mannheim). The cells are homogenized with motor-driven dounce (Talboy setting 40), using 10 strokes and the homogenate centrifuged at 6,000 rpm, 4 C, for 15 minutes.
  • pellets are resuspended in 0.2 mls/monolayer membrane prep buffer and aliquots are placed in tubes (500-1000 ul tube) and quick frozen in liquid nitrogen and then store at -80 ° C.
  • Test compounds or unlabelled NDP- ⁇ -MSH is added to 100 ⁇ L of membrane binding buffer to a final concentration of 1 ⁇ M.
  • the membrane binding buffer has the composition: 50 mM Tris pH 7.2; 2 mM CaC12; 1 mM MgC12; 5 mM KCl; 0.2% BSA; 4 ug/ml Leupeptin (SIGMA); 10 uM Phosphoramidon (Boehringer Mannheim); 40 ug ml Bacitracin (SIGMA); 5 ug ml Aprotinin (SIGMA); and 10 mM Pefabloc (Boehringer Mannheim).
  • membrane binding buffer containing 10-40 ug membrane protein is added, followed by 100 ⁇ M 125I-NDP- ⁇ - MSH to final concentration of 100 pM.
  • the resulting mixture is vortexed briefly and incubated for 90-120 min at room temp while shaking.
  • the mixture is filtered with Packard Microplate 196 filter apparatus using Packard Unifilter 96-well GF/C filter with 0.1% polyethyleneimine (Sigma).
  • the filter is washed (5 times with a total of 10 ml per well) with room temperature of filter wash having the composition: 50mM Tris-HCl pH 7.2 and 20 mM NaCl.
  • the filter is dried, and the bottom sealed and 50 ul of Packard Microscint-20 is added to each well. The top is sealed and the radioactivity quantitated in a Packard Topcount Microplate Scintillation counter.
  • Functional assay Functional cell based assays are developed to discriminate agonists and antagonists.
  • Cells for example, CHO- or L-cells or other eukaryotic cells
  • a human melanocortin receptor see e.g. Yang-YK; Ollmann-MM; Wilson-BD; Dickinson-C; Yamada-T; Barsh-GS; Gantz-I; Mol-Endocrinol. 1997 Mar; 11(3): 274-80
  • Ca and Mg free phosphate buffered saline 14190-136, Life Technologies, Gaithersburg, MD
  • enzyme free dissociation buffer S-014-B, Specialty Media, Lavellette, NJ
  • cAMP detection assay RPA556
  • the amount of cAMP production which results from an unknown compound is compared to that amount of cAMP produced in response to alpha-MSH which is defined as a 100 % agonist.
  • the EC50 is defined as the compound concentration which results in half maximal stimulation, when compared to its own maxim level of stimulation.
  • Antagonist activity is defined as the ability of a compound to block cAMP production in response to alpha-MSH.
  • Solution of test compounds and suspension of receptor containing cells are prepared and mixed as described above; the mixture is incubated for 15 min., and an EC50 dose (approximately 10 nM alpha-MSH) is added to the cells.
  • the assay is terminated at 45 min. and cAMP quantitated as above. Percent inhibition is determined by comparing the amount of cAMP produced in the presence to that produced in the absence of test compound.
  • the lower torso and hind limbs are restrained with a non- adhesive material (vetrap).
  • Penile responses will be observed, typically termed ex copula genital reflex tests. Typically, a series of penile erections will occur spontaneously within a few minutes after sheath retraction.
  • the types of normal reflexogenic erectile responses include elongation, engorgement, cup and flip. An elongation is classified as an extension of the penile body. Engorgement is a dilation of the glans penis.
  • a cup is defined as an intense erection where the distal margin of the glans penis momentarily flares open to form a cup.
  • a flip is a dorsiflexion of the penile body.
  • Baseline and or vehicle evaluations are conducted to determine how and if an animal will respond. Some animals have a long duration until the first response while others are non-responders altogether. During this baseline evaluation latency to first response, number and type of responses are recorded. The testing time frame is 15 minutes after the first response. After a minimum of 1 day between evaluations, these same animals are administered the test compound at 20 mg/kg and evaluated for penile reflexes. All evaluations are videotaped and scored later. Data are collected and analyzed using paired 2 tailed t-tests to compared baseline and/ or vehicle evaluations to drug treated evaluations for individual animals. Groups of a minimum of 4 animals are utilized to reduce variability.
  • mice can be dosed by a number of routes of administration depending on the nature of the study to be performed.
  • the routes of administration includes intravenous (IV), intraperitoneal (IP), subcutaneous (SC) and intracerebral ventricular (ICV).
  • E. Models of Female sexual Dysfunctioin Rodent assays relevant to female sexual receptivity include the behavioral model of lordosis and direct observations of copulatory activity. There is also a urethrogenital reflex model in anesthetized spinally transected rats for measuring orgasm in both male and female rats. These and other established animal models of female sexual dysfunction are described in McKenna KE et al, A Model For The Study Of Sexual Function In Anesthetized Male And Female Rats, Am. J. Physiol. (Regulatory Integrative Comp.
  • the preparation of compounds of Formula I of the present invention may be carried out in sequential or convergent synthetic routes. Syntheses detailing the preparation of the compounds of Formula I in a sequential manner are presented in the following reaction schemes.
  • the instant compounds are generally isolated in the form of their pharmaceutically acceptable salts, such as those described previously hereinabove.
  • standard peptide coupling reaction conditions is used repeatedly here, and it means coupling a carboxylic acid with an amine using an acid activating agent such as EDC, DCC, and BOP in a inert solvent such as dichloromethane in the presence of a catalyst such as HOBT.
  • an acid activating agent such as EDC, DCC, and BOP
  • a inert solvent such as dichloromethane
  • HOBT a catalyst
  • protective groups for amine and carboxylic acid to facilitate the desired reaction and minimize undesired reactions are well documented. Conditions required to remove protecting groups which may be present and can be found in Greene, T, and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, Inc.. New York, NY 1991. CBZ and BOC are used extensively in the synthesis, and their removal conditions are known to those skilled in the art.
  • removal of CBZ groups can be achieved by a number of methods known in the art; for example, catalytic hydrogenation with hydrogen in the presence of a noble metal or its oxide such as palladium on activated carbon in a pro tic solvent such as ethanol.
  • removal of CBZ groups can also be achieved by treatment with a solution of hydrogen bromide in acetic acid, or by treatment with a mixture of TFA and dimethylsulfide.
  • Removal of BOC protecting groups is carried out in a solvent such as methylene chloride or methanol or ethyl acetate, with a strong acid, such as trifluoroacetic acid or hydrochloric acid or hydrogen chloride gas.
  • the protected amino acid derivatives 1 are, in many cases, commercially available, where the protecting group L is, for example, BOC or CBZ groups.
  • Other protected amino acid derivatives 1 can be prepared by literature methods (Williams, R. M. Synthesis of Optically Active a-Amino Acids, Pergamon Press: Oxford, 1989).
  • Many of the piperidines of Formula 2 are either commercially available or known in the literature and others can be prepared following literature methods described for analogous compounds. Some of these methods are illustrated in the subsequent schemes. The skills required in carrying out the reaction and purification of the resulting reaction products are known to those in the art. Purification procedures include crystallization, normal phase or reverse phase chromatography.
  • amino acid ester intermediates of Formula 5 wherein L' is a small alkyl such as methyl or ethyl or a benzyl or allyl unit, can be synthesized by well documented methods in the literature. Coupling of intermediates 4 and 5 under standard peptide coupling conditions followed by removal of the ester group L' yields the intermediate 6. Compounds of formula I are obtained by coupling intermediates of Formula 6 to spiropiperidines of formula 2 under standard peptide coupling reaction conditions, followed by the removal of the amino protecting group, L.
  • the compounds of the present invention may also be prepared from a variety of substituted natural and unnatural amino acids of formulas 8.
  • the spiropiperidines of formula 12 may be prepared by a number of methods, including the syntheses described below. In cases where a sulfide is present in the molecule, it may be oxidized to a sulfoxide or to a sulfone with oxidizing agents such as sodium periodate, m-chloroperbenzoic acid or Oxone " in an solvent such as dichloromethane, alcohol or water or their mixtures.
  • oxidizing agents such as sodium periodate, m-chloroperbenzoic acid or Oxone
  • the indoline nitrogen of 13 can be reacted by with a variety of electrophiles to yield spiro piperidines of formula 14, wherein the substitutent can be a variety of functionalities, including Rb, SO2R a , SO2N(Rb)2, CORa, CON(Rb) 2 .
  • Compound 13 can be reacted with, for example, isocyanates in an inert solvent like dichloromethane to yield urea derivatives, chloroformates in an inert solvent such as dichloromethane to yield carbamates, acid chlorides, anhydrides, or acyl imidazoles to generate amides, sulfonyl chlorides to generate sulfonamides. sulfamyl chlorides to yield sulfamides.
  • the indoline nitrogen of 13 can be reductively alkylated with aldehydes with conditions known in the art.
  • Aromatic units, including substituted heteroaryl groups, can be introduced by reacting 13 with a fluoro phenyl or fluoro heteroaryl reagent. This chemistry is detailed by H. Ong et al J. Med. Chem. 1983, 23, 981-986.
  • Demethylation of 14 be accomplished by reacting it with cyanogen bromide and potassium carbonate in an inert solvent solvent such as dichloromethane to yield a cyanamide which can reduced to give 15 by treatment with lithium aluminum hydride in refluxing tetrahydrofuran, refluxing strong acid like aqueous hydrochloric acid, or with Grignard reagents like methyl magnesium bromide.
  • demethylation of 14 can be effected with the ACE-C1 method as described in R. Olofson et al. J Org.
  • Debenzylation can be accomplished by reductive methods including hydrogenation in the presence of platinum or palladium catalyst in a protic solvent like methanol.
  • debenzylation of 14 can be effected with the ACE-C1 method as described in R. Olofson et al. J. Org. Chem. 1984, 49, 2795 and references therein.
  • the spiro heterocyclic compounds of formula 15 can be prepared by a number of methods, including the syntheses as described in Scheme 7. Allylic oxidation of the protected piperidine 17 is accomplished by classical methods familiar to those skilled in the art (Rabjohn, N. Org. React. 1976, 24, 261). The resulting allylic alcohol is treated with thionyl chloride in an inert solvent such as benzene to provide the corresponding chloride 18.
  • X S(O)
  • SO2 sulfone
  • sodium periodate is often used for the synthesis of sulfoxides
  • Oxone is used for the synthesis of sulfones. Removal of the protecting group provides the amine 16 which then can be elaborated to melanocortin agonists.
  • spiro indanone 21 provides easy access to spiroindanyl intermediates containing acid and ester groups.
  • This chemistry is described in Scheme 10.
  • Treatment of 21 with a base in an inert solvent such as THF followed by the addition of a triflating agent provides the enol triflate.
  • Carboxylation of the enol triflate according to the procedure of Cacchi, S. Tetrahedron Letters, 1985, 1109-1112 provides the ester 23.
  • Hydrogenation of 23 using a palladium catalyst in an inert solvent provides the saturated ester 24.
  • the protecting group can then be removed as described above and the resulting amine can be incorporated into the subject compound via the chemistry depicted in earlier schemes.
  • estonification of the ester of 24 provides an acid which can be conveniently derivatized as for example reaction with an amine in the presence of a coupling agent such as EDC gives amides, which can then be incorporated into final compounds.
  • the ester 24 may also be reduced to a primary alcohol with LAH and to a aldehyde with DIBALH. Reductive alkylation of the aldehyde with ammonium acetate and sodium cyanoborohydride affords an amino methyl analog. These aminomethyl analogs may then be further reacted with acylating and sulfonylating agents to afford additional melanocortin compounds of the general formula I.
  • spiroindanes can be hydrogenated with Pt/C or Rh alumina as catalysts in solvents such as methanol. ethanol or acetic acid to afford corresponding perhydroindanes. High pressures are often required to carry out this saturation reaction.
  • the L protecting group can be removed by standard methods as discussed above.
  • Chiral acids are available by a variety of methods known to those skilled in the art including asymmetric catalytic hydrogenation and resolution of a pair of diastereomeric salts formed by reaction with a chiral amine such as D or L ⁇ - methylbenzylamine.
  • the absolute stereochemistry can be determined in a number of ways including X-ray crystallography of a suitable crystalline derivative.
  • a substituted phenyl alanine derivative 25 can be treated with aqueous formaldehyde in concentrated hydrochloric acid to afford, after protection of the amino functionality in a second step by well documented methods, the tetrahydroisoquinoline compound 26.
  • This reaction can also be effected with heterocyclic amino acids such as 2- and 3-thienyl Ala. Since the above chemistry works generally with retention of stereochemistry, D- and L-amino acids of general formula 5 can be prepared from D- and L- amino acids.
  • a strong base such as NaH in DMF
  • esters of formula 28 with alkali leads to formation of the corresponding mono carboxylic acid which can be treated with refluxing hydrochloric to affect hydrolysis of the acetamide derivative to provide amino acid of formula 29.
  • standard protection of the amino functionality provides intermediates of formula 30.
  • Saturated amino side chains of formula 31 can be prepared by hydrogenating compounds of formula 30 in the presence of rhodium or platinum catalysts.
  • compound 30 can be hydrogenated in the presence of 5% Rh on alumina to give compound 31.
  • Individual diastereomers of 31 can be resolved via classical resolution methods.
  • Schemes 14 illustrates one method for the preparation of tetrahydroisoquinolineacetic acid of formula 33. This is carried out conveniently by the Arndt-Eistert reaction which proceeds with retention of stereochemistry. Other methods involve require reduction of the acid or its ester derivative to an alcohol, conversion of the alcohol to a leaving group such as a mesylate or halide, displacement of it with cyanide anion and hydrolysis of the nitrile to the carboxylic acid by well documented literature methods.
  • the starting material, l,2-dihydro-5-fluoro-l-methanesulfonylspiro[3H-indole-3,4'- piperidine] hydrochloride may be prepared according to general method disclosed in US Patent 5536716.
  • Step A Preparation of 3 -oxo- 1 '-(t-butyloxycarbony l)spiro [ 1 H-indan- 1.4'-piperidine]
  • Step B Preparation of 3-[(trifluoromethanesulfonyl)oxy]-l'-(t- butyloxycarbonyl)spiro[lH-indene-l ,4'-piperidine]
  • Step C Preparation of 3-(ethoxycarbonyl)-l'-(t-butyloxycarbonyl
  • Step D Preparation of 3-(carboxy)-l'-(t-butyloxycarbonyl)spiro[lH-indan-l, 4'- piperidine]
  • Step E Preparation of 3 S-3-(carboxy)- 1 '-(t-butyloxycarbonyl)spiro [ 1 H-indan- 1 ,4'- piperidine]
  • Step F Preparation of 3R-3-(carboxy)-r-(t-butyloxycarbonyl)spiro[lH-indan-l,4'- piperidine]
  • Step G Preparation of 3R-3-[[(benzyloxy)carbonyl]amino]- -(t- buty loxy carbony l)spiro [ 1 H-indan- 1 ,4'-piperidine]
  • Step H Preparation of 3R-3-amino-l'-(t-butyloxycarbonyl)spiro[lH-indan-l,4'- piperidine] hydrochloride salt
  • Step G of Intermediate 10 The general procedure described in Step G of Intermediate 10 was followed using cvclopropylamine instead of benzyl alchol to react with the isocyanato compound to provide the N-Boc protected title compound.
  • the N-Boc protecting group was removed according to the general procedure described in Intermediate 11 to provide the title compound.
  • Step A Preparation of 3S-N-Boc-3-decahydroisoquinolinecarboxylic acid
  • N-Boc-(I)-Tic methyl ester (1.17 g) as a yellow oil.
  • a solution of N-Boc-(I)-Tic methyl ester (1.05 g, 3.60 mmol) and 12 mL of methanol was charged with 5% rhodium on alumina (0.53 g) and then heated at 55-60 °C under 40 psi of hydrogen for 36 h.
  • Step A Preparation of [3S(3 ⁇ ,4a ⁇ ,8a ⁇ )]-N-Boc-decahydro-3-isoquinolinecarboxylic acid

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Obesity (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Reproductive Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Hematology (AREA)
  • Emergency Medicine (AREA)
  • Child & Adolescent Psychology (AREA)
  • Gynecology & Obstetrics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Peptides Or Proteins (AREA)

Abstract

De nouveaux composés de spiropipéridine sont des agonistes des récepteurs de la mélanocortine et sont utiles pour le traitement, la suppression ou la prévention des maladies et des troubles sensibles à l'activation des récepteurs de la mélanocortine. Les composés selon l'invention sont par conséquent utiles pour le traitement des maladies et des troubles tels que l'obésité, le diabète et les dysfonctions sexuelles, y compris la dysérection et les dysfonctions sexuelles féminines.
PCT/US1999/013252 1998-06-11 1999-06-10 Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine Ceased WO1999064002A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
AU46801/99A AU742425B2 (en) 1998-06-11 1999-06-10 Spiropiperidine derivatives as melanocortin receptor agonists
JP2000553071A JP2002517444A (ja) 1998-06-11 1999-06-10 メラノコルチン受容体作動薬としてのスピロピペリジン誘導体
CA002334551A CA2334551A1 (fr) 1998-06-11 1999-06-10 Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine
EP99930220A EP1085869A4 (fr) 1998-06-11 1999-06-10 Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
US8890898P 1998-06-11 1998-06-11
US60/088,908 1998-06-11
GBGB9817179.6A GB9817179D0 (en) 1998-08-06 1998-08-06 Spiropiperidine derivatives as melanocortin receptor agonists
GB9817179.6 1998-08-06
US12326099P 1999-03-08 1999-03-08
US60/123,260 1999-03-08

Publications (1)

Publication Number Publication Date
WO1999064002A1 true WO1999064002A1 (fr) 1999-12-16

Family

ID=27269429

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/013252 Ceased WO1999064002A1 (fr) 1998-06-11 1999-06-10 Derives de spiropiperidine en tant qu'agonistes des recepteurs de la melanocortine

Country Status (5)

Country Link
EP (1) EP1085869A4 (fr)
JP (1) JP2002517444A (fr)
AU (1) AU742425B2 (fr)
CA (1) CA2334551A1 (fr)
WO (1) WO1999064002A1 (fr)

Cited By (152)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001000224A1 (fr) * 1999-06-29 2001-01-04 Palatin Technologies Inc. Compositions et methodes de traitement de dysfonctionnements sexuels
WO2001055109A1 (fr) * 2000-01-28 2001-08-02 Melacure Therapeutics Ab Amides aromatiques agissant sur les recepteurs de la melanocortine
WO2001010842A3 (fr) * 1999-08-04 2001-08-16 Millennium Pharm Inc Composes fixant les recepteurs de melanocortine-4 et procedes d'utilisation de ces composes
WO2002000654A1 (fr) * 2000-06-28 2002-01-03 Pfizer Products Inc. Ligands du recepteur de melanocortine
WO2001055107A3 (fr) * 2000-01-28 2002-01-17 Melacure Therapeutics Ab Nouveaux amines et amides aromatiques agissant sur les recepteurs de la melanocortine
WO2002012178A1 (fr) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab Composants agissant comme ligands de recepteur de la melanocortine
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
WO2001074844A3 (fr) * 2000-04-04 2002-06-13 Hoffmann La Roche Peptides lineaires selectifs possedant une activite d'agoniste du recepteur 4 de la melanocortine (mc4-r)
WO2002059095A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Agonistes de recepteurs de melanocortine
WO2002059107A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Piperidines/piperazines substituees utilisees comme agonistes du recepteur de melanocortine
WO2002059108A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Derives de piperazine agonistes du recepteur de la melanocortine
WO2002018327A3 (fr) * 2000-08-31 2002-08-08 Chiron Corp Nouveau guadininobenzamides
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
WO2002062766A3 (fr) * 2001-02-07 2002-10-03 Millennium Pharm Inc Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
WO2002094825A1 (fr) * 2001-05-22 2002-11-28 Banyu Pharmaceutical Co., Ltd. Nouveau derive de spiropiperidine
WO2003009850A1 (fr) * 2001-07-25 2003-02-06 Amgen Inc. Piperazines substituees comme modulateurs du recepteur de melanocortine
KR20030027439A (ko) * 2001-09-28 2003-04-07 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
KR20030035592A (ko) * 2001-10-31 2003-05-09 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
KR20030035589A (ko) * 2001-10-31 2003-05-09 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
WO2003061660A1 (fr) * 2002-01-23 2003-07-31 Eli Lilly And Company Agonistes du recepteur de la melanocortine
WO2003094918A1 (fr) * 2002-05-10 2003-11-20 Neurocrine Biosciences, Inc. Utilisation de piperazines substituees comme ligands du recepteur de la melanocortine
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
EP1285658A3 (fr) * 2001-08-21 2004-01-28 Pfizer Productors Inc. Traitement de la dysfonction sexuelle chez la femme
US6699873B1 (en) 1999-08-04 2004-03-02 Millennium Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
WO2003066587A3 (fr) * 2002-02-04 2004-03-11 Chiron Corp Nouveaux derives de guanidinyl
US6713487B2 (en) 2001-03-02 2004-03-30 Bristol-Myers Squibb Co. Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same
EP1295608A4 (fr) * 2000-06-27 2004-03-31 Taisho Pharmaceutical Co Ltd Agent therapeutique contre l'anxiete nevrotique ou la depression et derive de piperazine
US6716840B2 (en) 2001-04-09 2004-04-06 Chiron Corporation Guanidino compounds
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
WO2004083209A1 (fr) * 2003-03-20 2004-09-30 Santhera Pharmaceuticals (Schweiz) Gmbh Derives a substitution piperidine et piperazine agissant comme modulateurs du recepteur de la melanocortine 4
US6818658B2 (en) 2001-02-28 2004-11-16 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists
EP1289526A4 (fr) * 2000-05-30 2005-03-16 Merck & Co Inc Agonistes du recepteur de la melanocortine
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
US6911447B2 (en) 2001-04-25 2005-06-28 The Procter & Gamble Company Melanocortin receptor ligands
WO2005058836A1 (fr) * 2003-12-12 2005-06-30 Syngenta Participations Ag Derives de spiroindane insecticides
US6916812B2 (en) 2001-10-09 2005-07-12 Bristol-Myers Squibb Company Alpha-aminoamide derivatives as melanocortin agonists
WO2005097759A1 (fr) 2004-03-29 2005-10-20 Merck & Co., Inc. Utilisation de diaryltriazoles comme inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase-1
WO2006017542A1 (fr) 2004-08-06 2006-02-16 Merck & Co., Inc. Composés de sulfonyle comme inhibiteurs de la 11-béta-hydroxystéroide déshydrogénase-1
US7012084B2 (en) 2001-02-28 2006-03-14 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists
US7026335B2 (en) 2002-04-30 2006-04-11 The Procter & Gamble Co. Melanocortin receptor ligands
US7034033B2 (en) 2002-05-23 2006-04-25 Chiron Corporation Substituted quinazolinone compounds
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
US7049323B2 (en) 2003-04-25 2006-05-23 Bristol-Myers Squibb Company Amidoheterocycles as modulators of the melanocortin-4 receptor
US7049331B2 (en) 2001-11-08 2006-05-23 Ortho-Mcneil Pharmaceutical, Inc. 1,2,4-thiadiazole derivatives as melanocortin receptor modulators
EP1425029A4 (fr) * 2001-08-10 2006-06-07 Palatin Technologies Inc Peptidomimetiques de metallopeptides biologiquement actifs
US7115628B2 (en) 2001-07-18 2006-10-03 Merck & Co., Inc. Bridged piperidine derivatives as melanocortin receptor agonists
US7125885B2 (en) 2001-05-04 2006-10-24 Amgen Inc. Fused heterocyclic compounds
US7132539B2 (en) 2002-10-23 2006-11-07 The Procter & Gamble Company Melanocortin receptor ligands
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
US7160886B2 (en) 2003-03-03 2007-01-09 Merck & Co., Inc. Acylated piperazine derivatives as melanocortin-4 receptor agonists
US7176279B2 (en) 2000-06-28 2007-02-13 Palatin Technologies, Inc. Cyclic peptide compositions and methods for treatment of sexual dysfunction
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
WO2007029847A1 (fr) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Dérivé de pyridone substitué aromatique bicylique
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
WO2007049798A1 (fr) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Nouveau derive de benzoxathiine
WO2007055418A1 (fr) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Derive spiro aza-substitue
EP1801098A1 (fr) 2005-12-16 2007-06-27 Merck Sante Dérivés de 2-Adamantylurea comme inhibiteurs de 11B-HSD1
US7253179B2 (en) 2002-11-06 2007-08-07 Amgen Inc. Fused heterocyclic compounds
US7276520B2 (en) 2003-03-26 2007-10-02 Merck & Co., Inc. Bicyclic piperidine derivatives as melanocortin-4 receptor agonists
US7307063B2 (en) 2001-02-13 2007-12-11 Palatin Technologies, Inc. Melanocortin metallopeptides for treatment of sexual dysfunction
US7319107B2 (en) 2001-11-08 2008-01-15 Johnson & Johnson Consumer Companies, Inc. 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators
EP1880996A1 (fr) 2002-06-14 2008-01-23 Syngenta Limited Dérivé de spiroindolinpiperdin
US7323462B2 (en) 2002-12-10 2008-01-29 Pfizer Inc. Morpholine dopamine agonists
US7329673B2 (en) 2003-04-04 2008-02-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists
WO2007100664A3 (fr) * 2006-02-22 2008-03-06 Vertex Pharma Modulateurs des récepteurs muscariniques
WO2008038692A1 (fr) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. dÉrivÉ de diarylcÉtimine
US7368453B2 (en) 2003-11-19 2008-05-06 Chiron Corporation Quinazolinone compounds with reduced bioaccumulation
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7375125B2 (en) 1999-08-04 2008-05-20 Ore Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
WO2008071980A1 (fr) 2006-12-14 2008-06-19 Acure Pharma Ab Utilisation de nouvelles aminoguanidines comme ligands des récepteurs de la mélanocortine
WO2008074384A1 (fr) 2006-12-21 2008-06-26 Merck Patent Gmbh Dérivés de 2-adamantyle-butyramide en tant qu'inhibiteurs sélectifs de 11βêta-hsd1
US7414057B2 (en) 2002-09-11 2008-08-19 Merck & Co., Inc. Piperazine urea derivatives as melanocortin-4 receptor agonists
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2008039418A3 (fr) * 2006-09-27 2008-10-02 Merck & Co Inc Dérivés de pipéridine acylés utilisés en tant que modulateurs du récepteur de la mélanocortine-4
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
WO2008039863A3 (fr) * 2006-09-27 2009-01-08 Braincells Inc Modulation de la neurogenèse médiée par le récepteur de la mélanocortine
AU2004202804B2 (en) * 1999-08-04 2009-01-29 Ore Pharmaceuticals Inc. Melanocortin-4 Receptor Binding Compounds and Methods of use thereof
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2009110510A1 (fr) 2008-03-06 2009-09-11 萬有製薬株式会社 Dérivé d'alkylaminopyridine
WO2009119726A1 (fr) 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine
EP2110374A1 (fr) 2008-04-18 2009-10-21 Merck Sante Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs FXR
US7618987B2 (en) 2004-07-19 2009-11-17 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin 4-receptor agonists
US7625909B2 (en) 2003-05-23 2009-12-01 Novartis Vaccines And Diagnostics, Inc. Substituted quinazolinone compounds
WO2009154132A1 (fr) 2008-06-19 2009-12-23 萬有製薬株式会社 Dérivé de spirodiamine-diarylcétoxime
US7652024B2 (en) 2005-10-18 2010-01-26 Merck Sharp & Dohme Corp. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2010013595A1 (fr) 2008-07-30 2010-02-04 萬有製薬株式会社 Dérivé de cycloalkylamine à noyaux fusionnés à (5 chaînons)-(5 chaînons) ou (5 chaînons)–(6 chaînons)
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010056717A1 (fr) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Amines bicycliques substituées pour le traitement du diabète
US7795378B2 (en) 2002-07-09 2010-09-14 Palatin Technologies, Inc. Peptide compositions for treatment of sexual dysfunction
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
WO2011011506A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011011508A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composés d’oxazépine benzofusionnés en tant qu’inhibiteurs de la coenzyme-stéaroyle a delta-9 désaturase
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
WO2011058193A1 (fr) 2009-11-16 2011-05-19 Mellitech Dérivés de [1,5]-diazocine
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
EP2332526A2 (fr) 2005-10-21 2011-06-15 Novartis AG combinaison d'un inhibiteur de rénine avec un agent anti-dyslipidémique ou un agent anti-obèse
EP2348016A1 (fr) 2006-06-09 2011-07-27 Action Pharma A/S Dérivés de phényl pyrrole aminoguanidin
WO2011095581A1 (fr) 2010-02-05 2011-08-11 Intervet International B.V. Composés spiroindolines destinés à être utilisés comme agents anthelminthiques
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2011137024A1 (fr) 2010-04-26 2011-11-03 Merck Sharp & Dohme Corp. Nouveaux inhibiteurs de spiropipéridine prolylcarboxypeptidase
WO2011143057A1 (fr) 2010-05-11 2011-11-17 Merck Sharp & Dohme Corp. Inhibiteurs inédits de la prolylcarboxypeptidase
WO2011156246A1 (fr) 2010-06-11 2011-12-15 Merck Sharp & Dohme Corp. Nouveaux inhibiteurs de prolylcarboxypeptidase
US8148429B2 (en) 2000-08-07 2012-04-03 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US8247453B2 (en) 2008-02-21 2012-08-21 Janssen Pharmaceutica, Nv Methods for the treatment of dermatological disorders
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
US8299058B2 (en) 2003-12-12 2012-10-30 Syngenta Crop Protection Llc Spiro-condensed indoline derivatives as pesticides
US8309567B2 (en) 2003-12-12 2012-11-13 Syngenta Crop Protection Llc Spiroindoline derivatives having insecticidal properties
WO2013017678A1 (fr) 2011-08-04 2013-02-07 Intervet International B.V. Nouveaux composés de spiroindoline
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
WO2015054500A2 (fr) 2013-10-09 2015-04-16 Synergy Pharmaceuticals, Inc. Agonistes de guanylate cyclase utiles pour la régulation négative de cytokines pro-inflammatoires
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
US9018395B2 (en) 2011-01-27 2015-04-28 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
EP2881391A1 (fr) 2013-12-05 2015-06-10 Bayer Pharma Aktiengesellschaft Dérivés de carbocycle spiroindoline et leurs compositions pharmaceutiques
EP2933265A2 (fr) 2005-06-03 2015-10-21 Amicus Therapeutics, Inc. Chaperons pharmacologiques pour le traitement de l'obésité
WO2016030534A1 (fr) 2014-08-29 2016-03-03 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US9468639B2 (en) 2001-10-20 2016-10-18 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US9546141B2 (en) 2008-12-15 2017-01-17 Sprout Pharmaceuticals, Inc. Salts
US9688660B2 (en) 2015-10-30 2017-06-27 Heptares Therapeutics Limited CGRP receptor antagonists
US9730927B2 (en) 2005-08-03 2017-08-15 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US9802935B2 (en) 2015-10-30 2017-10-31 Heptares Therapeutics Limited CGRP receptor antagonists
US9808457B2 (en) 2015-10-30 2017-11-07 Heptares Therapeutics Limited CGRP receptor antagonists
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2018069532A1 (fr) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms
US10294214B2 (en) 2016-06-07 2019-05-21 Vanderbilt University Positive allosteric modulators of human melanocortin-4 receptor
WO2020104456A1 (fr) 2018-11-20 2020-05-28 Tes Pharma S.R.L Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
WO2021133563A1 (fr) 2019-12-23 2021-07-01 Crinetics Pharmaceuticals, Inc. Antagonistes du récepteur du sous-type 2 de la mélanocortine à base de pipéridine spirocyclique (mc2r) et leurs utilisations
US12171807B2 (en) 2020-01-21 2024-12-24 Cosette Pharmaceuticals, Inc. Use of bremelanotide in patients with controlled hypertension
US12239631B2 (en) 2021-06-21 2025-03-04 Synact Pharma Aps Polymorphs of phenyl pyrrole aminoguandium salts
US12280046B2 (en) 2021-03-19 2025-04-22 Crinetics Pharmaceuticals, Inc. Melanocortin subtype-2 receptor (MC2R) antagonist for the treatment of disease
US12303489B2 (en) 2019-05-10 2025-05-20 Synact Pharma Aps Combination treatment of arthritic disease
US12479825B2 (en) 2020-10-30 2025-11-25 Crinetics Pharmaceuticals, Inc. Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008056687A1 (fr) * 2006-11-09 2008-05-15 Daiichi Sankyo Company, Limited Nouveau dérivé de spiropipéridine

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996005203A1 (fr) * 1994-08-08 1996-02-22 Merck Sharp & Dohme Limited Derives azacycliques spiro-substitues et leur utilisation comme agents therapeutiques
US5578593A (en) * 1992-12-11 1996-11-26 Merck & Co., Inc. Spiro piperidines and homologs promote release of growth hormone
US5731408A (en) * 1995-04-10 1998-03-24 Arizona Board Of Regents On Behalf Of The University Of Arizona Peptides having potent antagonist and agonist bioactivities at melanocortin receptors

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5578593A (en) * 1992-12-11 1996-11-26 Merck & Co., Inc. Spiro piperidines and homologs promote release of growth hormone
WO1996005203A1 (fr) * 1994-08-08 1996-02-22 Merck Sharp & Dohme Limited Derives azacycliques spiro-substitues et leur utilisation comme agents therapeutiques
US5731408A (en) * 1995-04-10 1998-03-24 Arizona Board Of Regents On Behalf Of The University Of Arizona Peptides having potent antagonist and agonist bioactivities at melanocortin receptors

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP1085869A4 *

Cited By (228)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6350760B1 (en) 1999-06-04 2002-02-26 Merck & Co., Inc. Substituted piperidines as melanocortin-4 receptor agonists
US7473760B2 (en) 1999-06-29 2009-01-06 Palatin Technologies, Inc. Cyclic peptide compositions for treatment of sexual dysfunction
US7897721B2 (en) 1999-06-29 2011-03-01 Palatin Technologies, Inc. Cyclic peptide compositions for treatment of sexual dysfunction
US6579968B1 (en) 1999-06-29 2003-06-17 Palatin Technologies, Inc. Compositions and methods for treatment of sexual dysfunction
WO2001000224A1 (fr) * 1999-06-29 2001-01-04 Palatin Technologies Inc. Compositions et methodes de traitement de dysfonctionnements sexuels
WO2001010842A3 (fr) * 1999-08-04 2001-08-16 Millennium Pharm Inc Composes fixant les recepteurs de melanocortine-4 et procedes d'utilisation de ces composes
AU2004202804B2 (en) * 1999-08-04 2009-01-29 Ore Pharmaceuticals Inc. Melanocortin-4 Receptor Binding Compounds and Methods of use thereof
US7375125B2 (en) 1999-08-04 2008-05-20 Ore Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
US6699873B1 (en) 1999-08-04 2004-03-02 Millennium Pharmaceuticals, Inc. Melanocortin-4 receptor binding compounds and methods of use thereof
WO2001055109A1 (fr) * 2000-01-28 2001-08-02 Melacure Therapeutics Ab Amides aromatiques agissant sur les recepteurs de la melanocortine
WO2001055107A3 (fr) * 2000-01-28 2002-01-17 Melacure Therapeutics Ab Nouveaux amines et amides aromatiques agissant sur les recepteurs de la melanocortine
EP1268449A4 (fr) * 2000-03-23 2004-09-15 Merck & Co Inc Piperidines substituees en tant qu'agonistes du recepteur de la melanocortine
US6458790B2 (en) 2000-03-23 2002-10-01 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) 2000-03-23 2002-10-29 Merck & Co., Inc. Spiropiperidine derivatives as melanocortin receptor agonists
EP1268000A4 (fr) * 2000-03-23 2004-12-29 Merck & Co Inc Derives de spiropiperidine utilises comme agonistes du recepteur de la melanocortine
US6600015B2 (en) 2000-04-04 2003-07-29 Hoffmann-La Roche Inc. Selective linear peptides with melanocortin-4 receptor (MC4-R) agonist activity
WO2001074844A3 (fr) * 2000-04-04 2002-06-13 Hoffmann La Roche Peptides lineaires selectifs possedant une activite d'agoniste du recepteur 4 de la melanocortine (mc4-r)
EP1289526A4 (fr) * 2000-05-30 2005-03-16 Merck & Co Inc Agonistes du recepteur de la melanocortine
JP5002881B2 (ja) * 2000-06-27 2012-08-15 大正製薬株式会社 不安神経症又はうつ症治療薬、及びピペラジン誘導体
US6949552B2 (en) 2000-06-27 2005-09-27 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
EP1295608A4 (fr) * 2000-06-27 2004-03-31 Taisho Pharmaceutical Co Ltd Agent therapeutique contre l'anxiete nevrotique ou la depression et derive de piperazine
WO2002000654A1 (fr) * 2000-06-28 2002-01-03 Pfizer Products Inc. Ligands du recepteur de melanocortine
US7176279B2 (en) 2000-06-28 2007-02-13 Palatin Technologies, Inc. Cyclic peptide compositions and methods for treatment of sexual dysfunction
US8410174B2 (en) 2000-08-07 2013-04-02 Anamar Ab Method for treating arthritis
US8148429B2 (en) 2000-08-07 2012-04-03 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
KR100911888B1 (ko) 2000-08-07 2009-08-11 아큐어 파르마 아베 멜라노코르틴 수용체 리간드로서 작용하는 화합물
US9227927B2 (en) 2000-08-07 2016-01-05 Anamar Ab Method of treating inflammation
WO2002012178A1 (fr) * 2000-08-07 2002-02-14 Melacure Therapeutics Ab Composants agissant comme ligands de recepteur de la melanocortine
US8309609B2 (en) 2000-08-07 2012-11-13 Anamar Ab Use of benzylideneaminoguanidines and hydroxyguanidines as melanocortin receptor ligands
US7153881B2 (en) 2000-08-07 2006-12-26 Acure Pharma Ab Compounds acting as melanocortin receptor ligands
US6767915B2 (en) 2000-08-23 2004-07-27 Merck & Co., Inc. Substituted piperidines as melanocortin receptor agonists
US6995269B2 (en) 2000-08-31 2006-02-07 Chiron Corporation Guanidinobenzamides
US6638927B2 (en) 2000-08-31 2003-10-28 Chiron Corporation Guanidinobenzamides
WO2002018327A3 (fr) * 2000-08-31 2002-08-08 Chiron Corp Nouveau guadininobenzamides
US7186715B2 (en) 2001-01-08 2007-03-06 Eli Lilly And Company Piperazine- and piperidine-derivatives as melanocortin receptor agonists
WO2002059108A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Derives de piperazine agonistes du recepteur de la melanocortine
US7157463B2 (en) 2001-01-23 2007-01-02 Eli Lilly And Company Substituted piperidines/piperazines as melanocortin receptor agonists
US7169777B2 (en) 2001-01-23 2007-01-30 Eli Lilly And Company Melanocortin receptor agonists
WO2002059107A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Piperidines/piperazines substituees utilisees comme agonistes du recepteur de melanocortine
US7291619B2 (en) 2001-01-23 2007-11-06 Eli Lilly And Company Melanocortin receptor agonists
WO2002059095A1 (fr) * 2001-01-23 2002-08-01 Eli Lilly And Company Agonistes de recepteurs de melanocortine
WO2002062766A3 (fr) * 2001-02-07 2002-10-03 Millennium Pharm Inc Composes de liaison au recepteur de la melanocortine-4 et procedes d'utilisation de tels composes
US7307063B2 (en) 2001-02-13 2007-12-11 Palatin Technologies, Inc. Melanocortin metallopeptides for treatment of sexual dysfunction
US7700778B2 (en) 2001-02-28 2010-04-20 Merck Sharp & Dohme Corp. Acylated piperidine derivatives as melanocortin-4 receptor agonists
US6818658B2 (en) 2001-02-28 2004-11-16 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists
US7012084B2 (en) 2001-02-28 2006-03-14 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin-4 receptor agonists
US6713487B2 (en) 2001-03-02 2004-03-30 Bristol-Myers Squibb Co. Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same
EP1363898A4 (fr) * 2001-03-02 2004-12-08 Bristol Myers Squibb Co Composes utiles comme modulateurs de recepteurs de la melanocortine et compositions pharmaceutiques les comprenant
US6979691B2 (en) 2001-03-02 2005-12-27 Bristol-Myers Squibb Company Compounds useful as modulators of melanocortin receptors and pharmaceutical compositions comprising same
US7067525B2 (en) 2001-03-02 2006-06-27 Bristol-Myers Squibb Co. Compounds useful as modulators of Melanocortin Receptors and pharmaceutical compositions comprising same
US7189727B2 (en) 2001-04-09 2007-03-13 Chiron Corporation Guanidino compounds
US7456183B2 (en) 2001-04-09 2008-11-25 Novartis Vaccines And Diagnostics, Inc. Guanidino compounds
US6960582B2 (en) 2001-04-09 2005-11-01 Chiron Corporation Guanidino compounds
US6716840B2 (en) 2001-04-09 2004-04-06 Chiron Corporation Guanidino compounds
US7087759B2 (en) 2001-04-25 2006-08-08 The Procter & Gamble Company Melanocortin receptor ligands
US6911447B2 (en) 2001-04-25 2005-06-28 The Procter & Gamble Company Melanocortin receptor ligands
US7125885B2 (en) 2001-05-04 2006-10-24 Amgen Inc. Fused heterocyclic compounds
WO2002094825A1 (fr) * 2001-05-22 2002-11-28 Banyu Pharmaceutical Co., Ltd. Nouveau derive de spiropiperidine
US7115628B2 (en) 2001-07-18 2006-10-03 Merck & Co., Inc. Bridged piperidine derivatives as melanocortin receptor agonists
US7560460B2 (en) 2001-07-25 2009-07-14 Amgen Inc. Substituted piperazines and methods of use
WO2003009850A1 (fr) * 2001-07-25 2003-02-06 Amgen Inc. Piperazines substituees comme modulateurs du recepteur de melanocortine
US7115607B2 (en) 2001-07-25 2006-10-03 Amgen Inc. Substituted piperazinyl amides and methods of use
US7326707B2 (en) 2001-08-10 2008-02-05 Palatin Technologies Incorporated Bicyclic melanocortin-specific compounds
EP1425029A4 (fr) * 2001-08-10 2006-06-07 Palatin Technologies Inc Peptidomimetiques de metallopeptides biologiquement actifs
EP1285658A3 (fr) * 2001-08-21 2004-01-28 Pfizer Productors Inc. Traitement de la dysfonction sexuelle chez la femme
KR20030027439A (ko) * 2001-09-28 2003-04-07 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
US6916812B2 (en) 2001-10-09 2005-07-12 Bristol-Myers Squibb Company Alpha-aminoamide derivatives as melanocortin agonists
US9782403B2 (en) 2001-10-20 2017-10-10 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US9468639B2 (en) 2001-10-20 2016-10-18 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US11058683B2 (en) 2001-10-20 2021-07-13 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
US10675280B2 (en) 2001-10-20 2020-06-09 Sprout Pharmaceuticals, Inc. Treating sexual desire disorders with flibanserin
KR20030035589A (ko) * 2001-10-31 2003-05-09 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
KR20030035592A (ko) * 2001-10-31 2003-05-09 주식회사 엘지생명과학 멜라노코틴 수용체의 항진제
US7786311B2 (en) 2001-11-08 2010-08-31 Ortho-Mcneil Pharmaceutical, Inc. 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators
US7375123B2 (en) 2001-11-08 2008-05-20 Ortho-Mcneil Pharmaceutical, Inc. 1,2,4-thiadiazole derivatives as melanocortin receptor modulators
US8501791B2 (en) 2001-11-08 2013-08-06 Ortho-Mcneil Pharamaceutical, Inc. 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators
US7319107B2 (en) 2001-11-08 2008-01-15 Johnson & Johnson Consumer Companies, Inc. 1,2,4-thiadiazolium derivatives as melanocortin receptor modulators
US7049331B2 (en) 2001-11-08 2006-05-23 Ortho-Mcneil Pharmaceutical, Inc. 1,2,4-thiadiazole derivatives as melanocortin receptor modulators
US7314879B2 (en) 2002-01-23 2008-01-01 Eli Lilly And Company Melanocortin receptor agonists
WO2003061660A1 (fr) * 2002-01-23 2003-07-31 Eli Lilly And Company Agonistes du recepteur de la melanocortine
WO2003066587A3 (fr) * 2002-02-04 2004-03-11 Chiron Corp Nouveaux derives de guanidinyl
US7026335B2 (en) 2002-04-30 2006-04-11 The Procter & Gamble Co. Melanocortin receptor ligands
WO2003094918A1 (fr) * 2002-05-10 2003-11-20 Neurocrine Biosciences, Inc. Utilisation de piperazines substituees comme ligands du recepteur de la melanocortine
US7858641B2 (en) 2002-05-23 2010-12-28 Novartis Vaccines And Diagnostics, Inc. Substituted dihydroisoquinolinone compounds
US7858631B2 (en) 2002-05-23 2010-12-28 Novartis Vaccines And Diagnostics, Inc. Substituted pyrido [2,3-d] pyrimidinone compounds
US7034033B2 (en) 2002-05-23 2006-04-25 Chiron Corporation Substituted quinazolinone compounds
EP1880996A1 (fr) 2002-06-14 2008-01-23 Syngenta Limited Dérivé de spiroindolinpiperdin
WO2004002986A2 (fr) 2002-06-28 2004-01-08 Banyu Pharmaceutical Co., Ltd. Nouveaux dérivés de benzimidazole
US7795378B2 (en) 2002-07-09 2010-09-14 Palatin Technologies, Inc. Peptide compositions for treatment of sexual dysfunction
US7414057B2 (en) 2002-09-11 2008-08-19 Merck & Co., Inc. Piperazine urea derivatives as melanocortin-4 receptor agonists
US7045527B2 (en) 2002-09-24 2006-05-16 Amgen Inc. Piperidine derivatives
US7132539B2 (en) 2002-10-23 2006-11-07 The Procter & Gamble Company Melanocortin receptor ligands
US7253179B2 (en) 2002-11-06 2007-08-07 Amgen Inc. Fused heterocyclic compounds
US7902188B2 (en) 2002-12-10 2011-03-08 Pfizer Inc. Morpholine dopamine agonists
US7576081B2 (en) 2002-12-10 2009-08-18 Pfizer Inc. Morpholine dopamine agonists
US7323462B2 (en) 2002-12-10 2008-01-29 Pfizer Inc. Morpholine dopamine agonists
US7160886B2 (en) 2003-03-03 2007-01-09 Merck & Co., Inc. Acylated piperazine derivatives as melanocortin-4 receptor agonists
WO2004083209A1 (fr) * 2003-03-20 2004-09-30 Santhera Pharmaceuticals (Schweiz) Gmbh Derives a substitution piperidine et piperazine agissant comme modulateurs du recepteur de la melanocortine 4
US7276520B2 (en) 2003-03-26 2007-10-02 Merck & Co., Inc. Bicyclic piperidine derivatives as melanocortin-4 receptor agonists
US7329673B2 (en) 2003-04-04 2008-02-12 Merck & Co., Inc. Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists
US7049323B2 (en) 2003-04-25 2006-05-23 Bristol-Myers Squibb Company Amidoheterocycles as modulators of the melanocortin-4 receptor
US7625909B2 (en) 2003-05-23 2009-12-01 Novartis Vaccines And Diagnostics, Inc. Substituted quinazolinone compounds
WO2005028438A1 (fr) 2003-09-22 2005-03-31 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
US7371759B2 (en) 2003-09-25 2008-05-13 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
US7368453B2 (en) 2003-11-19 2008-05-06 Chiron Corporation Quinazolinone compounds with reduced bioaccumulation
US7420059B2 (en) 2003-11-20 2008-09-02 Bristol-Myers Squibb Company HMG-CoA reductase inhibitors and method
WO2005058836A1 (fr) * 2003-12-12 2005-06-30 Syngenta Participations Ag Derives de spiroindane insecticides
US8354423B2 (en) 2003-12-12 2013-01-15 Syngenta Crop Protection Llc Insecticidal spironindane derivatives
US8309567B2 (en) 2003-12-12 2012-11-13 Syngenta Crop Protection Llc Spiroindoline derivatives having insecticidal properties
US8846907B2 (en) 2003-12-12 2014-09-30 Syngenta Crop Protection Llc Spiro-condensed indoline derivatives as pesticides
US8299058B2 (en) 2003-12-12 2012-10-30 Syngenta Crop Protection Llc Spiro-condensed indoline derivatives as pesticides
EP2088154A1 (fr) 2004-03-09 2009-08-12 Ironwood Pharmaceuticals, Inc. Procédés et compositions pour le traitement de troubles gastro-intestinaux
WO2005097759A1 (fr) 2004-03-29 2005-10-20 Merck & Co., Inc. Utilisation de diaryltriazoles comme inhibiteurs de la 11-beta-hydroxysteroide deshydrogenase-1
EP2305352A1 (fr) 2004-04-02 2011-04-06 Merck Sharp & Dohme Corp. Inhibiteurs de la 5-alpha-reductase pour le traitement d'hommes aux troubles métaboliques et anthropométriques
US7618987B2 (en) 2004-07-19 2009-11-17 Merck & Co., Inc. Acylated piperidine derivatives as melanocortin 4-receptor agonists
WO2006017542A1 (fr) 2004-08-06 2006-02-16 Merck & Co., Inc. Composés de sulfonyle comme inhibiteurs de la 11-béta-hydroxystéroide déshydrogénase-1
WO2006129826A1 (fr) 2005-05-30 2006-12-07 Banyu Pharmaceutical Co., Ltd. Nouveau derive de piperidine
EP2933265A2 (fr) 2005-06-03 2015-10-21 Amicus Therapeutics, Inc. Chaperons pharmacologiques pour le traitement de l'obésité
US9730927B2 (en) 2005-08-03 2017-08-15 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
US10874668B2 (en) 2005-08-03 2020-12-29 Sprout Pharmaceuticals, Inc. Use of Flibanserin in the treatment of obesity
US10335407B2 (en) 2005-08-03 2019-07-02 Sprout Pharmaceuticals, Inc. Use of flibanserin in the treatment of obesity
WO2007018248A1 (fr) 2005-08-10 2007-02-15 Banyu Pharmaceutical Co., Ltd. Composé de pyridone
WO2007024004A1 (fr) 2005-08-24 2007-03-01 Banyu Pharmaceutical Co., Ltd. Dérivé phénylpyridone
WO2007029847A1 (fr) 2005-09-07 2007-03-15 Banyu Pharmaceutical Co., Ltd. Dérivé de pyridone substitué aromatique bicylique
AU2006297443B2 (en) * 2005-09-29 2010-08-12 Merck Sharp & Dohme Corp. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
WO2007041052A3 (fr) * 2005-09-29 2007-05-31 Merck & Co Inc Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
US8293900B2 (en) 2005-09-29 2012-10-23 Merck Sharp & Dohme Corp Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
JP2009510067A (ja) * 2005-09-29 2009-03-12 メルク エンド カムパニー インコーポレーテッド メラノコルチン−４受容体モジュレーターとしてのアシル化スピロピペリジン誘導体
WO2007041052A2 (fr) 2005-09-29 2007-04-12 Merck & Co., Inc. Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4
US7652024B2 (en) 2005-10-18 2010-01-26 Merck Sharp & Dohme Corp. Acylated spiropiperidine derivatives as melanocortin-4 receptor modulators
EP2332526A2 (fr) 2005-10-21 2011-06-15 Novartis AG combinaison d'un inhibiteur de rénine avec un agent anti-dyslipidémique ou un agent anti-obèse
WO2007049798A1 (fr) 2005-10-27 2007-05-03 Banyu Pharmaceutical Co., Ltd. Nouveau derive de benzoxathiine
WO2007055418A1 (fr) 2005-11-10 2007-05-18 Banyu Pharmaceutical Co., Ltd. Derive spiro aza-substitue
EP1801098A1 (fr) 2005-12-16 2007-06-27 Merck Sante Dérivés de 2-Adamantylurea comme inhibiteurs de 11B-HSD1
US7858635B2 (en) 2005-12-22 2010-12-28 Vertex Pharmaceuticals Incorporated Spiro compounds as modulators of muscarinic receptors
US8263605B2 (en) 2006-02-22 2012-09-11 Vertex Pharmaceutical Incorporated Modulators of muscarinic receptors
WO2007100664A3 (fr) * 2006-02-22 2008-03-06 Vertex Pharma Modulateurs des récepteurs muscariniques
EP2348016A1 (fr) 2006-06-09 2011-07-27 Action Pharma A/S Dérivés de phényl pyrrole aminoguanidin
US8058306B2 (en) 2006-06-09 2011-11-15 Action Pharma A/S Phenyl pyrrole aminoguanidine derivatives
US7858790B2 (en) 2006-06-29 2010-12-28 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
US10004731B2 (en) 2006-06-30 2018-06-26 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US9763936B2 (en) 2006-06-30 2017-09-19 Sprout Pharmaceuticals, Inc. Flibanserin for the treatment of urinary incontinence and related diseases
US7696201B2 (en) 2006-08-15 2010-04-13 Vertex Pharmaceuticals Incorporated Modulators of muscarinic receptors
EP2946778A1 (fr) 2006-09-22 2015-11-25 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras
EP2698157A1 (fr) 2006-09-22 2014-02-19 Merck Sharp & Dohme Corp. Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras
WO2008039418A3 (fr) * 2006-09-27 2008-10-02 Merck & Co Inc Dérivés de pipéridine acylés utilisés en tant que modulateurs du récepteur de la mélanocortine-4
WO2008039863A3 (fr) * 2006-09-27 2009-01-08 Braincells Inc Modulation de la neurogenèse médiée par le récepteur de la mélanocortine
WO2008038692A1 (fr) 2006-09-28 2008-04-03 Banyu Pharmaceutical Co., Ltd. dÉrivÉ de diarylcÉtimine
WO2008071980A1 (fr) 2006-12-14 2008-06-19 Acure Pharma Ab Utilisation de nouvelles aminoguanidines comme ligands des récepteurs de la mélanocortine
US8372878B2 (en) 2006-12-14 2013-02-12 Anamar Ab Aminoguanidines as melanocortin receptor ligands
WO2008074384A1 (fr) 2006-12-21 2008-06-26 Merck Patent Gmbh Dérivés de 2-adamantyle-butyramide en tant qu'inhibiteurs sélectifs de 11βêta-hsd1
WO2008120653A1 (fr) 2007-04-02 2008-10-09 Banyu Pharmaceutical Co., Ltd. Dérivé d'indoledione
EP2998314A1 (fr) 2007-06-04 2016-03-23 Synergy Pharmaceuticals Inc. Agonistes de guanylase cyclase utiles pour le traitement de troubles gastro-intestinaux, d'inflammation, de cancer et d'autres troubles
US10166230B2 (en) 2007-09-12 2019-01-01 Sprout Pharmaceuticals Inc. Treatment of vasomotor symptoms
US8536226B2 (en) 2008-02-21 2013-09-17 Janssen Pharmaceutica, Nv Methods for the treatment of dermatological disorders
US8247453B2 (en) 2008-02-21 2012-08-21 Janssen Pharmaceutica, Nv Methods for the treatment of dermatological disorders
WO2009110510A1 (fr) 2008-03-06 2009-09-11 萬有製薬株式会社 Dérivé d'alkylaminopyridine
WO2009119726A1 (fr) 2008-03-28 2009-10-01 萬有製薬株式会社 Dérivé de diarylméthylamide à activité antagoniste sur un récepteur d'hormone concentrant la mélanine
EP2110374A1 (fr) 2008-04-18 2009-10-21 Merck Sante Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs FXR
WO2009127321A1 (fr) 2008-04-18 2009-10-22 Merck Patent Gmbh, Dérivés de benzofurane, benzothiophène, benzothiazol en tant que modulateurs de fxr
EP2810951A2 (fr) 2008-06-04 2014-12-10 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utile dans le traitement de troubles gastro-intestinaux, d'une inflammation, d'un cancer et d'autres troubles
WO2009154132A1 (fr) 2008-06-19 2009-12-23 萬有製薬株式会社 Dérivé de spirodiamine-diarylcétoxime
EP3241839A1 (fr) 2008-07-16 2017-11-08 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de troubles gastro-intestinaux, inflammatoires, cancéreux et autres
WO2010013595A1 (fr) 2008-07-30 2010-02-04 萬有製薬株式会社 Dérivé de cycloalkylamine à noyaux fusionnés à (5 chaînons)-(5 chaînons) ou (5 chaînons)–(6 chaînons)
WO2010047982A1 (fr) 2008-10-22 2010-04-29 Merck Sharp & Dohme Corp. Nouveaux dérivés de benzimidazole cycliques utiles comme agents anti-diabétiques
WO2010051206A1 (fr) 2008-10-31 2010-05-06 Merck Sharp & Dohme Corp. Nouveaux agents antidiabétiques utiles avec des dérivés de benzimidazole cycliques
WO2010056717A1 (fr) 2008-11-17 2010-05-20 Merck Sharp & Dohme Corp. Amines bicycliques substituées pour le traitement du diabète
US9546141B2 (en) 2008-12-15 2017-01-17 Sprout Pharmaceuticals, Inc. Salts
WO2011011506A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composés oxazépine spirocyclique en tant qu'inhibiteurs de la stéaroyl-coenzyme a delta-9 désaturase
WO2011011508A1 (fr) 2009-07-23 2011-01-27 Schering Corporation Composés d’oxazépine benzofusionnés en tant qu’inhibiteurs de la coenzyme-stéaroyle a delta-9 désaturase
WO2011058193A1 (fr) 2009-11-16 2011-05-19 Mellitech Dérivés de [1,5]-diazocine
US8765728B2 (en) 2009-11-16 2014-07-01 Mellitech [1,5]-diazocin derivatives
EP2923706A1 (fr) 2009-12-03 2015-09-30 Synergy Pharmaceuticals Inc. Agonistes de guanylate cyclase utiles pour le traitement de l'hypercholestérolémie
WO2011069038A2 (fr) 2009-12-03 2011-06-09 Synergy Pharmaceuticals, Inc. Agonistes de la guanylate cyclase utiles dans le traitement de l'hypercholestérolémie, de l'athérosclérose, d'une coronaropathie, des calculs biliaires, de l'obésité et d'autres maladies cardiovasculaires
US9340523B2 (en) 2009-12-30 2016-05-17 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
US8648073B2 (en) 2009-12-30 2014-02-11 Fochon Pharma, Inc. Certain dipeptidyl peptidase inhibitors
WO2011095581A1 (fr) 2010-02-05 2011-08-11 Intervet International B.V. Composés spiroindolines destinés à être utilisés comme agents anthelminthiques
US9598412B2 (en) 2010-02-05 2017-03-21 Intervet Inc. Spiroindoline compounds for use as anthelminthics
WO2011106273A1 (fr) 2010-02-25 2011-09-01 Merck Sharp & Dohme Corp. Nouveaux dérivés benzimidazole cycliques utiles comme agents antidiabétiques
WO2011137024A1 (fr) 2010-04-26 2011-11-03 Merck Sharp & Dohme Corp. Nouveaux inhibiteurs de spiropipéridine prolylcarboxypeptidase
WO2011143057A1 (fr) 2010-05-11 2011-11-17 Merck Sharp & Dohme Corp. Inhibiteurs inédits de la prolylcarboxypeptidase
WO2011156246A1 (fr) 2010-06-11 2011-12-15 Merck Sharp & Dohme Corp. Nouveaux inhibiteurs de prolylcarboxypeptidase
US9018395B2 (en) 2011-01-27 2015-04-28 Université de Montréal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
US9493456B2 (en) 2011-01-27 2016-11-15 Universite De Montreal Pyrazolopyridine and pyrazolopyrimidine derivatives as melanocortin-4 receptor modulators
WO2012116145A1 (fr) 2011-02-25 2012-08-30 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
EP3243385A1 (fr) 2011-02-25 2017-11-15 Merck Sharp & Dohme Corp. Nouveaux dérivés d'azabenzimidazole cyclique utiles en tant qu'agents antidiabétiques
WO2013017678A1 (fr) 2011-08-04 2013-02-07 Intervet International B.V. Nouveaux composés de spiroindoline
WO2013138352A1 (fr) 2012-03-15 2013-09-19 Synergy Pharmaceuticals Inc. Formulations d'agonistes de la guanylate cyclase c et procédés d'utilisation
EP3708179A1 (fr) 2012-03-15 2020-09-16 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
EP4309673A2 (fr) 2012-03-15 2024-01-24 Bausch Health Ireland Limited Formulations d'agonistes de guanylate cyclase c et leurs procédés d'utilisation
WO2014022528A1 (fr) 2012-08-02 2014-02-06 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2014130608A1 (fr) 2013-02-22 2014-08-28 Merck Sharp & Dohme Corp. Composés bicycliques antidiabétiques
WO2014139388A1 (fr) 2013-03-14 2014-09-18 Merck Sharp & Dohme Corp. Nouveaux dérivés d'indole utiles en tant qu'agents antidiabétiques
WO2014151200A2 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Compositions utiles pour le traitement de troubles gastro-intestinaux
WO2014151206A1 (fr) 2013-03-15 2014-09-25 Synergy Pharmaceuticals Inc. Agonistes de la guanylate cyclase et leurs utilisations
WO2014197720A2 (fr) 2013-06-05 2014-12-11 Synergy Pharmaceuticals, Inc. Agonistes ultra-purs de guanylate cyclase c, leur procédé de production et d'utilisation
EP4424697A2 (fr) 2013-06-05 2024-09-04 Bausch Health Ireland Limited Agonistes ultra-purs de guanylate cyclase c, leur procédé de fabrication et d'utilisation
WO2015051725A1 (fr) 2013-10-08 2015-04-16 Merck Sharp & Dohme Corp. Composés tricycliques antidiabétiques
WO2015054500A2 (fr) 2013-10-09 2015-04-16 Synergy Pharmaceuticals, Inc. Agonistes de guanylate cyclase utiles pour la régulation négative de cytokines pro-inflammatoires
EP2881391A1 (fr) 2013-12-05 2015-06-10 Bayer Pharma Aktiengesellschaft Dérivés de carbocycle spiroindoline et leurs compositions pharmaceutiques
US11254644B2 (en) 2014-08-29 2022-02-22 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
US9708272B2 (en) 2014-08-29 2017-07-18 Tes Pharma S.R.L. Inhibitors of α-amino-β-carboxymuconic acid semialdehyde decarboxylase
US10513499B2 (en) 2014-08-29 2019-12-24 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2016030534A1 (fr) 2014-08-29 2016-03-03 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
US9802935B2 (en) 2015-10-30 2017-10-31 Heptares Therapeutics Limited CGRP receptor antagonists
US10166226B2 (en) 2015-10-30 2019-01-01 Heptares Therapeutics Limited CGRP receptor antagonists
US10259812B2 (en) 2015-10-30 2019-04-16 Heptares Therapeutics Limited CGRP receptor antagonists
US9925178B2 (en) 2015-10-30 2018-03-27 Heptares Therapeutics Limited CGRP receptor antagonists
US10300056B2 (en) 2015-10-30 2019-05-28 Heptares Therapeutics Limited CGRP receptor antagonists
US9808457B2 (en) 2015-10-30 2017-11-07 Heptares Therapeutics Limited CGRP receptor antagonists
US9688660B2 (en) 2015-10-30 2017-06-27 Heptares Therapeutics Limited CGRP receptor antagonists
US12178813B2 (en) 2015-10-30 2024-12-31 Nxera Pharma Uk Limited CGRP receptor antagonists
US10888561B2 (en) 2015-10-30 2021-01-12 Heptares Therapeutics Limited CGRP receptor antagonists
US10294214B2 (en) 2016-06-07 2019-05-21 Vanderbilt University Positive allosteric modulators of human melanocortin-4 receptor
WO2018069532A1 (fr) 2016-10-14 2018-04-19 Tes Pharma S.R.L. Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
WO2018106518A1 (fr) 2016-12-06 2018-06-14 Merck Sharp & Dohme Corp. Composés hétérocycliques antidiabétiques
WO2018118670A1 (fr) 2016-12-20 2018-06-28 Merck Sharp & Dohme Corp. Composés de spirochromane antidiabétiques
US12186317B2 (en) 2018-11-20 2025-01-07 Tes Pharma S.R.L. Inhibitors of alpha-amino-beta-carboxymuconic acid semialdehyde decarboxylase
WO2020104456A1 (fr) 2018-11-20 2020-05-28 Tes Pharma S.R.L Inhibiteurs de la semialdéhyde décarboxylase de l'acide alpha-amino-bêta-carboxymuconique
US12303489B2 (en) 2019-05-10 2025-05-20 Synact Pharma Aps Combination treatment of arthritic disease
WO2021133563A1 (fr) 2019-12-23 2021-07-01 Crinetics Pharmaceuticals, Inc. Antagonistes du récepteur du sous-type 2 de la mélanocortine à base de pipéridine spirocyclique (mc2r) et leurs utilisations
EP4603142A3 (fr) * 2019-12-23 2025-08-27 Crinetics Pharmaceuticals, Inc. Antagonistes du récepteur du sous-type 2 de la mélanocortine à base de pipéridine spirocyclique (mc2r) et leurs utilisations
US12466829B2 (en) 2019-12-23 2025-11-11 Crinetics Pharmaceuticals, Inc. Spirocyclic piperidine melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof
US12171807B2 (en) 2020-01-21 2024-12-24 Cosette Pharmaceuticals, Inc. Use of bremelanotide in patients with controlled hypertension
US12479825B2 (en) 2020-10-30 2025-11-25 Crinetics Pharmaceuticals, Inc. Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof
US12280046B2 (en) 2021-03-19 2025-04-22 Crinetics Pharmaceuticals, Inc. Melanocortin subtype-2 receptor (MC2R) antagonist for the treatment of disease
US12239631B2 (en) 2021-06-21 2025-03-04 Synact Pharma Aps Polymorphs of phenyl pyrrole aminoguandium salts
US12479828B2 (en) 2023-11-17 2025-11-25 Crinetics Pharmaceuticals, Inc. Melanocortin subtype-2 receptor (MC2R) antagonists and uses thereof

Also Published As

Publication number Publication date
AU742425B2 (en) 2002-01-03
AU4680199A (en) 1999-12-30
JP2002517444A (ja) 2002-06-18
EP1085869A4 (fr) 2001-10-04
EP1085869A1 (fr) 2001-03-28
CA2334551A1 (fr) 1999-12-16

Similar Documents

Publication Publication Date Title
US6294534B1 (en) Spiropiperidine derivatives as melanocortin receptor agonists
AU742425B2 (en) Spiropiperidine derivatives as melanocortin receptor agonists
JP4336196B2 (ja) メラノコルチン受容体作動薬としての架橋ピペリジン誘導体
US6350760B1 (en) Substituted piperidines as melanocortin-4 receptor agonists
US6376509B2 (en) Melanocortin receptor agonists
US6458790B2 (en) Substituted piperidines as melanocortin receptor agonists
US6472398B1 (en) Spiropiperidine derivatives as melanocortin receptor agonists
US6767915B2 (en) Substituted piperidines as melanocortin receptor agonists
AU2001264977A1 (en) Melanocortin receptor agonists
AU2001288285A1 (en) Substituted piperidines as melanocortin receptor agonists
AU2002320494A1 (en) Bridged piperidine derivatives as melanocortin receptor agonists
AU2001249296A1 (en) Substituted piperidines as melanocortin receptor agonists
AU2001249281A1 (en) Spiropiperidine derivatives as melanocortin receptor agonists

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AE AL AM AU AZ BA BB BG BR BY CA CN CU CZ EE GD GE HR HU ID IL IN IS JP KG KR KZ LC LK LR LT LV MD MG MK MN MX NO NZ PL RO RU SG SI SK TJ TM TR TT UA US UZ VN YU ZA

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SL SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
WWE Wipo information: entry into national phase

Ref document number: 46801/99

Country of ref document: AU

ENP Entry into the national phase

Ref document number: 2334551

Country of ref document: CA

ENP Entry into the national phase

Ref country code: JP

Ref document number: 2000 553071

Kind code of ref document: A

Format of ref document f/p: F

WWE Wipo information: entry into national phase

Ref document number: 1999930220

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1999930220

Country of ref document: EP

WWG Wipo information: grant in national office

Ref document number: 46801/99

Country of ref document: AU

WWW Wipo information: withdrawn in national office

Ref document number: 1999930220

Country of ref document: EP