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WO1998035944A1 - Amides utilises comme antagonistes du recepteur de npy5 - Google Patents

Amides utilises comme antagonistes du recepteur de npy5 Download PDF

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Publication number
WO1998035944A1
WO1998035944A1 PCT/US1998/002122 US9802122W WO9835944A1 WO 1998035944 A1 WO1998035944 A1 WO 1998035944A1 US 9802122 W US9802122 W US 9802122W WO 9835944 A1 WO9835944 A1 WO 9835944A1
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WO
WIPO (PCT)
Prior art keywords
substituted
lower alkyl
phenyl
unsubstituted
group
Prior art date
Application number
PCT/US1998/002122
Other languages
English (en)
Inventor
Richard D. Connell
Timothy G. Lease
Gaetan H. Ladouceur
Martin H. Osterhout
Original Assignee
Bayer Corporation
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
Application filed by Bayer Corporation filed Critical Bayer Corporation
Priority to AU62671/98A priority Critical patent/AU6267198A/en
Priority to EP98904909A priority patent/EP0927166A1/fr
Priority to JP10535803A priority patent/JP2000510870A/ja
Publication of WO1998035944A1 publication Critical patent/WO1998035944A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • A61K31/422—Oxazoles not condensed and containing further heterocyclic rings
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    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic rings
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245—Oxadiazoles
    • A—HUMAN NECESSITIES
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    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • A—HUMAN NECESSITIES
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/433—Thidiazoles
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/33—Heterocyclic compounds
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
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    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
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    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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Definitions

  • This invention is a method for inhibiting the neuropeptide Y ("NPY”) Y5 receptor
  • compositions are useful in treating obese mammals, mammals with
  • bulimia for treating mammals with obesity related disorders including, but not limited to type II diabetes, insulin resistance, hyperlipidemia, hypertension, polycystic ovarian disease,
  • pulmonary disease pulmonary disease, sleep apnea, and for treating mammals suffering from NPY Y5 receptor
  • inhibition related disorders such as memory disorders, epilepsy, dyslipidemia, and
  • NPY is a 36 amino acid peptide that is a member of a larger peptide family which
  • NPY peptide YY
  • PP pancreatic peptide
  • NPY is the most prevalent peptide in the mammalian
  • NPY neuropeptide
  • NPY is believed to stimulate food intake by activating a hypothalamic eating
  • hypothalamus which the authors designated Y5.
  • Hu et al. the localization of Y5 mRNA in critical areas of the brain hypothalamus and other brain regions known to regulate food intake together with an in vitro pharmacological profile consistent with the in
  • a human homologue of the Y5 receptor has also been
  • Antagonists of NPY receptors other than the Y5 receptors have been identified.
  • U.S. Patent No. 5,554,621 discloses NPY antagonists that act on the Yl, Y2, Y3 and other Yl-like or Y4-type receptors.
  • the reported antagonists are dihydropyridine based
  • U.S. Patent No. 5,506,248 also discloses NPY receptor antagonists. The
  • compositions disclosed each include sulphamadyl and amidino radicals.
  • compositions do not include sulfur or oxygen in the backbone structure.
  • WO 96/16542 discloses genetically modified NPY receptors.
  • NPY receptors namely, Yl, Y2, Y3 and Y4/PP1
  • Another object of this invention are novel ⁇ -alkoxy and ⁇ -thioalkoxyamide
  • compositions that are useful as NPY Y5 receptor antagonists and therapeutic compositions that are useful as NPY Y5 receptor antagonists and therapeutic compositions
  • this invention is a method for treating mammalian disorders
  • NPY Y5 receptor mediated by the NPY Y5 receptor comprising the administration to a mammal of a therapeutically effective amount of at least one compound having the formula:
  • RrR 5 are each individually selected
  • acyl aryloxy, amino, amido, carboxyl, aryl, substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl, cycloalkyl, substituted cycloalkyl, alkylcycloalkyl,
  • alkylcycloheteroalkyl nitro, phenyl, substituted phenyl, benzothiophene, furan, fluoride, cyano, naphthyl, substituted naphthyl, fluorene, substituted fluorene and dibenzofuran and
  • X is oxygen or sulfur.
  • this invention is a class of novel ⁇ -alkoxy and ⁇ -
  • compositions having the same general formula disclosed above except for compounds 137-188 identified in Table 4 as prior art
  • this invention is a pharmaceutical dosage form
  • the present invention relates to methods for using ⁇ -alkoxy and ⁇ -thioalkoxyamide
  • the present invention also includes
  • compositions that fall within the scope of this invention have the general formula:
  • R'-R 5 are each individually selected from the group of substituents including
  • aryl substituted aryl, heterocycle, heteroaryl, substituted heterocycle, heteroalkyl
  • cycloalkyl substituted cycloalkyl, alkylcycloalkyl, alkylcycloheteroalkyl, phenyl,
  • R' may be any substituent other than
  • R 1 is a substituted phenyl, then the substituted phenyl may be substituted
  • substituents including phenyl, cyanophenyl, halogens including fluoride,
  • chloride iodide and bromide, a branched or straight chain alkyl group having from 1 to 6
  • R 2 is hydrogen, or an unsubstitued or substituted alkyl group
  • R 1 and R 2 can together with an adjacent nitrogen atom form a 3 atom to 7 atom
  • R 3 and R 4 are individually selected from the group hydrogen
  • R 1 and R 4 are
  • R 3 and R 4 are most preferably
  • R 5 is a lower alkyl; a substituted lower alkyl wherein the
  • substituted lower alkyl may be substituted with one or more substituents selected from the
  • alkyl group alkoxy, thioalkoxy, amino, aminoacyl, hydroxyl or fluoro group; pyridine;
  • pyridine N-oxide unsubstituted pyrimidine; pyrimidine substituted with from one to three substituents selected from the group including lower alkyl, hydroxyl, nitroso, amino, trifluoromethyl, and thiol; 1,3,5-triazine substituted up to two times with amino, thiol, or a
  • amino an aminoalkyl group having from 1 to 6 carbon atoms, and with lower alkyl;
  • imidazole that is substituted with one or more substituents
  • thiazole unsubstituted thiazole, thiazole that is mono-substituted or bi-substituted with lower alkyl or
  • substituents including alkoxy, chloride, trifluoromethyl or mixtures thereof, amino,
  • substituents including lower alkyl, alkoxy, nitro, trifluoromethyl, and mixtures
  • substituted is mono- or bi-substituted with amine, hydroxy, 3, 4-dihydroxy-5-
  • halogen refers to fluorine, bromine, chlorine, and iodine atoms.
  • hydroxyl refers to the group -OH.
  • furan refers to a five membered oxygen containing saturated or
  • thiol and mercapto refers to the groups -SH, and -S(O) 0 . 2 ,
  • lower alkyl refers to a cyclic, branched, or straight chain alkyl group of one to ten carbon atoms. This term is further exemplified by such groups as methyl, ethyl,
  • n-propyl i-propyl, n-butyl, t-butyl, i-butyl (or 2-methylpropyl), cyclopropylmethyl, i-amyl, n-amyl, hexyl and the like.
  • substituted lower alkyl refers to lower alkyl as just described including
  • substituents such as hydroxyl, thiol, alkylthiol, halogen, alkoxy, amino, amido,
  • cycloheteroalkyl acyl, carboxyl, aryl, substituted aryl, aryloxy, heteroaryl, substituted
  • aryl substituted aryl, heteroaryl, substituted heteroaryl or the like.
  • alkynyl refers to a group -C ⁇ C-R'; where R' is selected from hydrogen, halogen, lower alkyl, substituted lower alkyl, acyl, aryl, substituted aryl,
  • heteroaryl substituted heteroaryl or the like.
  • heteroaryl or substituted heteroaryl.
  • alkyl alkynyl refers to a group -RC ⁇ CR' where R is lower alkyl or
  • R' is hydrogen, lower alkyl, substituted lower alkyl, acyl, aryl,
  • alkoxy refers to the group -OR, where R is lower alkyl, substituted lower
  • alkyl acyl, aryl, substituted aryl, arylalkyl. substituted arylalkyl, heteroarylalkyl, cycloalkyl. substituted cycloalkyl, cycloheteroalkyl, or substituted cycloheteroalkyl.
  • substituted lower alkyl aryl, substituted aryl, arylalkyl or substituted arylalkyl.
  • acyl refers to groups -C(O)R, where R is hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl and the like.
  • aryloxy refers to groups -OAr, where Ar is an aryl, substituted aryl, heteroaryl, or substituted heteroaryl group.
  • amino refers to the group NRR', where R and R' may independently be hydrogen, lower alkyl, substituted lower alkyl, aryl, substituted aryl, heteroaryl, cycloalkyl, substituted heteroaryl, or acyl.
  • heteroaryl substituted heteroaryl.
  • carboxyl refers to the group -C(O)OR, where R may independently
  • aryl and “Ar” refer to an aromatic carbocyclic group having at least one
  • aromatic ring e.g., phenyl or biphenyl
  • multiple condensed rings in which at least one
  • ring is aromatic, (e.g., 1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl).
  • substituted aryl refers to aryl optionally substituted with one or more
  • heterocycle refers to a saturated, unsaturated, or aromatic carbocyclic
  • hetero atom such as N, O, or S
  • ring at least one hetero atom, such as N, O, or S, within the ring, which can optionally be
  • heteroaryl refers to a heterocycle in which at least one heterocyclic ring is aromatic.
  • substituted heteroaryl refers to a heterocycle optionally substituted with one or more substituents including halogen, lower alkyl, lower alkoxy, lower alkylthio,
  • arylalkyl refers to the group -R-Ar where Ar is an aryl group and R is lower alkyl or substituted lower alkyl group.
  • Aryl groups can optionally be unsubstituted or
  • heteroalkyl refers to the group -R-Het where Het is a heterocycle group and R is a lower alkyl group. Heteroalkyl groups can optionally be unsubstituted or
  • heteroaryl refers to the group -R-HetAr where HetAr is a heteroaryl
  • R is a lower alkyl or substituted lower alkyl.
  • Heteroarylalkyl groups can be
  • cycloalkyl refers to a divalent cyclic or polycyclic alkyl group containing
  • one of the distal rings may be aromatic (e.g., indanyl, tetrahydronaphthalene, etc. . . .).
  • substituted cycloalkyl refers to a cycloalkyl group comprising one or
  • substituents with, e.g., halogen, lower alkyl, substituted lower alkyl, alkoxy, alkylthio, aryl, aryloxy, heterocycle, heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol,
  • cycloheteroalkyl refers to a cycloalkyl group wherein one or more of the
  • ring carbon atoms is replaced with a heteroatom (e.g., N, O, S or P).
  • a heteroatom e.g., N, O, S or P.
  • substituted cycloheteroalkyl refers to a cycloheteroalkyl group as herein
  • heterocycle heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and
  • alkyl cycloalkyl refers to the group -R-cycloalkyl where cycloalkyl is a
  • cycloalkyl group and R is a lower alkyl or substituted lower alkyl.
  • Cycloalkyl groups can be
  • heterocycle heteroaryl, substituted heteroaryl, nitro, cyano, alkylthio, thiol, sulfamido and
  • Acid addition salts of the compounds are prepared in a
  • hydrochloric hydrobromic, sulfuric, phosphoric, acetic, maleic, succinic, or
  • the parent compound is treated with an excess of an alkaline reagent,
  • Na + , K ⁇ Ca 2+ and NH 4+ are examples of cations present in pharmaceutically acceptable salts.
  • compositions identified herein all fall within the scope of compositions that
  • the process for manufacturing compounds according to the invention can be any process for manufacturing compounds according to the invention.
  • Solvents useful in the processes are customary organic solvents that do not change
  • ethers such as diethyl ether, dioxane,
  • tetrahydrofuran glycol dimethyl ether
  • alcohols for example methanol, ethanol,
  • propanol isopropanol, butanol, iso butanol or tert butanol, or hydrocarbons such as
  • hydrocarbons such as dichloromethane, trichloromethane, tetrachloromethane,
  • Bases which can be employed for the process are in general inorganic or organic
  • bases preferably include alkali metal hydroxides, for example sodium hydroxide or
  • potassium hydroxide alkaline earth metal hydroxides, for example barium hydroxide, alkali
  • metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as calcium carbonate, or alkali metal or alkaline earth metal alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide or potassium tert-
  • DABCO l ,4-diazabicyclo[2.2.2]octane
  • DABCO l,8-diazabicyclo[5.4.0]undec-7-ene
  • alkali metals such as sodium or their hydrides such as sodium
  • auxiliaries are also dehydrating reagents. These include, for example,
  • carbodiimides such as diisopropylcarbodiimide. dicyclohexylcarbodiimide or N-(3-
  • dehydrating reagents are in general employed in an amount from 0.5 to 3 mol, preferably
  • the base is employed in an amount from 0.05 to 10 mol, preferably from 1 to 2 mol, relative to 1 mol of the compound (2).
  • Suitable solvents for the reaction with thiols or alcohols in this case are inert organic solvents which do not change under the reaction conditions.
  • These preferably include ethers, such as diethyl ether or tetrahydrofuran, halogenated hydrocarbons such as
  • Bases useful in the synthesis process are, in general, inorganic or organic bases
  • alkali metal hydroxides for example sodium hydroxide or potassium hydroxide
  • alkaline earth metal hydroxides for example barium hydroxide, alkali metal carbonates such
  • alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate, alkaline earth metal carbonates such as sodium carbonate or potassium carbonate
  • amines such as triethylamine, or heterocycles such as 1,4-
  • DABCO diazabicyclo[2.2.2]octane
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • pyridine diazabicyclo[2.2.2]octane
  • DBU diazabicyclo[2.2.2]octane
  • DBU l,8-diazabicyclo[5.4.0]undec-7-ene
  • potassium carbonate and triethylamine are preferred bases.
  • the base is employed in an amount from 1 mol to 5 mol, preferably from 1 mol to 3
  • the compounds of the present invention are useful for treating mammalian disorders
  • eating disorders such as eating disorders, obesity, hypertension, depression, brain or bodily disorders, and
  • method of this invention is used to treat obesity and eating disorders such as and bulimia.
  • the method of this invention can be used to inhibit the onset of obesity and to
  • the method of this invention is used to treat obesity in humans.
  • the compounds of the present invention are useful for treating disorders mediated
  • mammals are characterized by NPY via the Y5 receptor in mammals.
  • mammals are characterized by NPY via the Y5 receptor in mammals.
  • mammals are characterized by NPY via the Y5 receptor in mammals.
  • Livestock and related animals include, mammals such as cattle, horses, sheep, pigs, goats,
  • mink mink
  • chinchilla raccoon
  • birds such as chickens, geese, turkeys and ducks.
  • mice mice, rats, guinea pigs, golden hamsters, and pets
  • the compounds of this invention may be administered to mammals both
  • Non-limiting examples of useful administration protocols include orally, parenterally, dermally, transdermally,
  • the pharmaceutical dosage form may be administered in suitable pharmaceutical dosage forms.
  • the pharmaceutical dosage form may be administered in suitable pharmaceutical dosage forms.
  • pharmaceutical dosage form refers to items such as tablets, capsules, liquids and powders, comprising Y5 receptor
  • inhibitors of this invention alone or in the presence of one or more pharmaceutical additives.
  • compositions of this invention may also be controlled by combining the useful compositions of this invention with suitable
  • compounds of this invention may be combined with additives to give an immediate or fast
  • compositions can be used as a dietary supplement to reduce or inhibit appetite.
  • Those skilled in the pharmaceutical arts will recognize a wide variety of formulations and vehicles for administering compositions of this invention.
  • emulsions which can be administered orally, or boli, in medicated food, or in drinking
  • Internal administration may also be accomplished using a timed release formulation including additives such as surfactant or starch coated capsules, or using a quick release formulation such as a freeze-dried fast dissolving tablet. Dermal administration is effected,
  • transdermal patches for example, in the form of transdermal patches, spraying or pouring-on and spotting-on.
  • Parenteral administration is effected, for example, in the form of injection (intramuscularly,
  • this invention include but are not limited to solutions such as solutions for injection, oral solutions, concentrates for oral administration after dilution, solutions for use on the skin or
  • the active compound is incorporated in cream base or in an oil-in- water or water-in-oil
  • emulsion base emulsion base
  • solid preparations such as powders, premixes or concentrates, granules,
  • pellets, tablets, boli, capsules; aerosols and inhalants, and shaped articles containing active compound are included in the production of pharmaceuticals.
  • compositions may be administered by injection
  • solubilizers such as solubilizers, acids, bases, buffer salts, antioxidants and preservatives.
  • the solutions are sterile-filtered and drawn off.
  • solutions including compositions of this invention may be
  • compositions of this invention are preferably
  • Solutions for use on the skin are applied dropwise, brushed on, rubbed in, splashed on or sprayed on. These solutions are prepared as described above in the case of solutions for injection.
  • Gels are applied to the skin, or introduced into body cavities. Gels are prepared by
  • spot-on formulations are prepared by dissolving, suspending or emulsifying the active
  • Emulsions can be administered orally, dermally or in the form of injections.
  • Emulsions are either of the water-in-oil type or of the oil-in- water type. They are prepared by dissolving Y5 receptor antagonists either in the hydrophobic or in the hydrophilic phase
  • adjuvants such as emulsifiers, colorants, reso ⁇ tion accelerators, preservatives, antioxidants,
  • Suspensions can be administered orally, dermally or in the form of injection. They
  • adjuvants such as wetting agents, colorants, reso ⁇ tion accelerators, preservatives, antioxidants and light stabilizers.
  • compositions of this invention may include one or more
  • additives in the form of pharmaceutically acceptable additives.
  • useful additives include solvents, solubilizers, preservatives, thickeners, wetting agents, colorants, reso ⁇ tion accelerators, antioxidants, light stabilizers, tackifiers, viscosity increasing substances, fillers,
  • the additive may be a solvent such as water, alcohols such as ethanol, butanol,
  • benzyl alcohol glycerol, propylene glycol, polyethylene glycols, N-methyl-pyrrolidone,
  • alkanols glycerol
  • aromatic alcohols such as benzyl alcohol, phenylethanol,
  • esters such as ethyl acetate, butyl acetate, benzyl benzoate, ethers such as
  • alkylene glycol alkyl ethers such as dipropylene glycol mono-methyl ether, diethylene
  • glycol mono-butyl ether ketones such as acetone, methyl ethyl ketone, aromatic and/or
  • additives may be useful as solubilizers of the compositions of this
  • polyvinylpyrrolidone polyoxyethylated castor oil
  • polyoxyethylated sorbitan esters examples are polyvinylpyrrolidone, polyoxyethylated castor oil, polyoxyethylated sorbitan esters.
  • Useful preservatives are, for example, benzyl alcohol, trichlorobutanol, p- hydroxybenzoic esters, and n-butanol.
  • Useful thickeners include inorganic thickeners such as bentonite, colloidal silica,
  • organic thickeners such as cellulose derivatives, polyvinyl alcohols and their copolymers, acrylates and methacrylates.
  • colorants are, for example, homogeneous solvents, solvent mixtures, and wetting agents (dispersants) which are typically surfactants.
  • Useful colorants are all colorants which are non-toxic and which can be dissolved or
  • Useful reso ⁇ tion accelerators are DMSO, spreading oils such as isopropyl
  • dipropylene glycol pelargonate silicone oils, fatty acid esters, triglycerides, fatty
  • antioxidants are sulphites or metabisulphites such as potassium
  • metabisulphite ascorbic acid, butylhydroxytoluene, butylhydroxyanisole, tocopherol.
  • a useful light stabilizer is novantisolic acid.
  • Useful tackifiers include cellulose derivatives, starch derivatives, polyacrylates,
  • Useful emulsifiers include non-ionic surfactants such as polyoxyethylated castor oil,
  • ampholytic surfactants such as Di-Na
  • anionic surfactants such as Na-lauryl- beta -iminodipropionate or lecithin
  • emulsion examples include carboxymethylcellulose, methylcellulose and other cellulose and starch
  • the active compound is mixed with suitable additives, if appropriate with the addition of adjuvants, and the mixture is formulated as desired.
  • suitable additives include sodium chloride, carbonates such as calcium carbonate, hydrogen carbonates, aluminum
  • solid organic additives include sugars, cellulose, foods such as dried milk, animal meals,
  • lubricants and gliding agents such as magnesium stearate, stearic acid, talc, bentonites;
  • disintegrants such as starch or crosslinked polyvinylpyrrolidone
  • binders such as, starch
  • gelatin or linear polyvinylpyrrolidone; and dry binders such as microcrystalline cellulose.
  • the active compounds can be any active compounds.
  • the active compounds can be any active compounds.
  • Y5 receptor antagonist compound present in the form of a mixture with at least one other Y5 receptor antagonist compound.
  • the pharmaceutical dosage forms of the invention can, in
  • Y5 receptor antagonist examples include any pharmaceutical compound that is
  • Methods for treating NPY mediated diseases and disorders comprises the administration of an effective quantity of the chosen compound or combinations thereof,
  • forms of this invention contain the active compound in concentrations of from 10 ppm to 20
  • dosage forms of this invention that are diluted prior to administration, preferably contain
  • the active compound in concentrations of from 0.5 to 90 per cent by weight, and preferably
  • dosage units may be administered one to ten times daily for
  • preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous
  • Such a liquid formulation may be administered directly p.o. or filled into a
  • compositions described herein may be administered as described above, (i.e., intramuscular, intravenous and subcutaneous etc .), it is preferred that the method of
  • this invention is achieved by administering the compound described herein orally.
  • compositions of this invention have non-therapeutic utility as well.
  • compositions of this invention are useful as analytical standards for Y5 receptor agonist or antagonist assays.
  • Compounds 1-136 identified in the Examples and in Tables 1 and 2 below are identified in the Examples and in Tables 1 and 2 below.
  • the compounds useful in the therapeutic method of this invention are prepared by:
  • FAB Fast atom bombardment
  • Compound 1 was prepared according to the following general method:
  • Compound 8 was prepared according to both of the following methods:
  • MC cells (ATCC, Rockville, MD) were plated in 24-well plates. Once confluent, cells are rinsed with Dulbecco's phosphate buffered saline (DPBS). Cells were then preincubated in DPBS.
  • DPBS Dulbecco's phosphate buffered saline
  • binding buffer containing serum-free DMEM, 25 mM HEPES (pH 7.3), 0.5%> bovine serum
  • BSA albumin
  • bacitracin 0.15% bacitracin and 0.1 mM phenylmethylsulfonylfluoride for 30 minutes
  • Nonspecific binding is defined with 1 ⁇ M NPY.
  • Binding assays were performed on GF/C Millipore 96-well plates pretreated with
  • the binding buffer for rat Y2 binding is Krebs-Ringer bicarbonate (pH 7.4) containing 0.01% BSA and 0.005%> bacitracin.
  • Samples consist of membrane protein, 25 pM [125IJPYY and drug dilution. Nonspecific binding is defined by
  • the binding buffer for human Y4/PP1 binding consists of 137 mM NaCl, 5.4 mM KC1, 0.44 mM KH 2 PO 4 , 1.26 mM CaCl 2 , 0.81 mM MgSO 4 , 20 mM HEPES, 1 mM
  • bacitracin 100 mg/1 streptomycin sulfate, 1 mg/1 aprotinin, 10 mg/ml
  • hPP is used to define nonspecific binding.
  • radioactivity in each well is quantitated with either gamma counting or liquid scintillation.
  • Binding assays are performed on GF/C Millipore 96-well plates pretreated with
  • the binding buffer is 25 mM Tris, 120 mM NaCl, 5 mM KC1, 1.2
  • Samples consist of membrane protein, 75-100 pM [125I]PYY (porcine, NEN-DuPont) and
  • Nonspecific binding is defined by 1 ⁇ M PYY. After a 2 hour incubation at
  • IC50 values which correspond to 50%> inhibition of specific binding, are determined with non-linear regression
  • the assay is stopped by placing the samples in boiling water for 3 minutes.
  • the cAMP produced in each sample is quantitated with a radioimmunoassay kit (NEN).
  • Example are known compounds. The name of each known compound and its source is set forth in Table 4 immediately below. TABLE 4
  • This example describes the preparation of a tablet that includes composition 1 as prepared in Example 2.
  • Each tablet contains:
  • the tablet coating contains:
  • Macrogol 4000 rec. INN 2.0 mg (polyethylene glycol DAB) 2.0 mg
  • Titanium(IV) oxide 10.0 mg

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Abstract

L'invention concerne des compositions à base d'α-alcoxy et de α-thioalcoxyamide de formule (I) ou des sels pharmaceutiquement acceptables de celles-ci, ainsi que des procédés d'administration desdites compositions à des mammifères pour le traitement de troubles tels que l'obésité, troubles liés au neuropeptide NPY par le truchement du récepteur de Y5. Dans la formule (I), R1-R5 sont choisis séparément dans le groupe de substituants comprenant hydrogène, halogène, hydroxyle, thiol, alkyle inférieur, alkyle inférieur substitué, alcényle, alcynyle, alkylalcényle, alkylalcynyle, alcoxy, alkylthio, acyle, aryloxy, amino, amido, carboxyle, aryle, aryle substitué, hétérocycle, hétéroaryle, hétérocycle substitué, hétéroalkyle, cycloalkyle, cycloalkyle substitué, alkylcycloalkyle, alkylcyclohétéroalkyle, phényle, phényle substitué, benzothiophène, furan, fluorure, nitro, cyano, naphtyle, naphtyle substitué, fluorène, fluorène substitué et dibenzofuran, X représentant oxygène ou soufre.
PCT/US1998/002122 1997-02-14 1998-02-05 Amides utilises comme antagonistes du recepteur de npy5 WO1998035944A1 (fr)

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US6222040B1 (en) 1999-06-30 2001-04-24 Synaptic Pharmaceutical Corporation Selective NPY (Y5) antagonists (tricyclics)
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JP2003503486A (ja) * 1999-06-30 2003-01-28 シナプティック・ファーマスーティカル・コーポレーション 選択的ｎｐｙ（ｙ５）アンタゴニスト
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
US6967216B2 (en) 2000-05-05 2005-11-22 Astrazeneca Ab Amino substituted dibenzothiophene derivatives for the treatment of disorders mediated by NP Y5 receptor
US6989379B1 (en) 1999-04-22 2006-01-24 H. Lundbick A/S Selective NPY (Y5) antagonists
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US7273880B2 (en) 1999-06-30 2007-09-25 H. Lunbeck A/S Selective NPY (Y5) antagonists
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US9332757B2 (en) 2010-10-25 2016-05-10 Vanderbilt University Composition for inhibition of insect host sensing
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