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WO1997020820A1 - Composes heteroaryles - Google Patents

Composes heteroaryles Download PDF

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Publication number
WO1997020820A1
WO1997020820A1 PCT/EP1996/005055 EP9605055W WO9720820A1 WO 1997020820 A1 WO1997020820 A1 WO 1997020820A1 EP 9605055 W EP9605055 W EP 9605055W WO 9720820 A1 WO9720820 A1 WO 9720820A1
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WIPO (PCT)
Prior art keywords
iower
substituted
alkoxy
carbocyclic
heterocyclic
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PCT/EP1996/005055
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English (en)
Inventor
Heinrich RÜEGER
Tibur Schmidlin
Pascal Rigollier
Yasuchika Yamaguchi
Marina Tintelnot-Blomley
Walter Schilling
Leoluca Criscione
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Novartis Ag
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Priority to AU76264/96A priority Critical patent/AU7626496A/en
Publication of WO1997020820A1 publication Critical patent/WO1997020820A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/95—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in positions 2 and 4

Definitions

  • Neuropeptide Y is a member of the pancreatic polypeptide family of peptides and is one of the most abundant and widely distributed peptides at the central and peripheral nervous system. NPY acts as a neurotransmitter playing an important role in the regulation of various diseases. Intensive evaluations lead to the finding that multiple NPY receptors are existing being responsible for different physiological and pharmacological activities. Recently, a new NPY receptor subtype has been characterized and cloned, designated as Y5 receptor. It has been demonstrated that the pharmacological function associated with Y5 relates, for example, to obesity and eating disorders. Accordingly, the provision of compounds which act as antagonists of this receptor subtype represents a promisable approach in the regulation of diseases or disorders, such as obesity and eating/food intake disorders.
  • the invention relates to a method of treatment of disorders and diseases associated with NPY receptor subtype Y5, to pharmaceutical compositions and to new compounds having Y5 antagonistic properties.
  • the invention relates to a method of treatment and prophylaxis of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm-blooded animal, including man, in need of such treatment a therapeutically effective amount of a compound of formula (I)
  • alk represents a single bond or lower alkylene; the integer n is 0 or 1 ;
  • R T represents (i) hydrogen, halogen, nitro, cyano, lower alkyl, lower alkenyl, lower alkynyl, C 3 -C 8 - cycloalkyl, C 3 -C ⁇ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, or lower alkyl which is substituted by halogen, by hydroxy, by lower alkoxy, by amino, by substituted amino, by carboxy, by lower alkoxycarbonyl, by (carbocyclic or heterocyclic) aryl-lower alkoxycarbonyl, by carbamoyl, or by N-substituted carbamoyl;
  • R 2 and R 3 independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, lower alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (II) lower alkyl which is substituted by a substituent selected from the group consisting of' halogen, hydroxy, lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, ammo, substituted ammo, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, N-substituted carbamoyl, and -S(O) n -
  • R 2 and R 3 together represent lower alkylene [which may be interrupted by O, S(O) n , NRo or which may be condensed at two adjacent carbon atoms with a benzene ring];
  • X represents N or CH; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, lower alkenyl, lower alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, lower alkynyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoy
  • lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl- lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • the compounds (I) can be present as salts, in particular pharmaceutically acceptable salts. If the compounds (I) have, for example, at least one basic centre, they can form acid addition salts. These are formed, for example, with strong inorganic acids, such as mineral acids, for example sulfuric acid, a phosphoric acid or a hydrohalic acid, with strong organic carboxylic acids, such as CrC -alkanecarboxylic acids which are unsubstituted or substituted, for example, by halogen, for example acetic acid, such as saturated or unsaturated dicarboxylic acids, for example oxalic, malonic, succinic, maleic, fumaric, phthalic or terephthalic acid, such as hydroxycarboxylic acids, for example ascorbic, glycolic, lactic, malic, tartaric or citric acid, such as amino acids, for example aspartic or glutamic acid, or such as benzoic acid, or with organic sulfonic acids, such as C C -al
  • Corresponding acid addition salts can also be formed having, if desired, an additionally present basic centre.
  • the compounds (I) having at least one acid group can also form salts with bases.
  • Suitable salts with bases are, for example, metal salts, such as alkaii metal or alkaline earth metal salts, for example sodium, potassium or magnesium salts, or salts with ammonia or an organic amine, such as morphoiine, thiomorpholine, piperidine, pyrrolidine, a mono-, di- or t ⁇ -lower alkylamine, for example ethyl-, tert-butyl-, diethyl-, dnsopropyl-, tnethyl-, tnbutyl- or dimethylpropylamine, or a mono-, di- or tnhydroxy lower alkylamine, for example mono-, di- or t ⁇ ethanolamine
  • Corresponding internal salts may furthermore be formed, if a compound of formula comprises
  • Carbocyclic or heterocyclic aryl in (carbocyclic or heterocyclic) aryl or aryloxy, respectively, represents, for example, phenyl, biphenylyl, naphthyl or an appropriate 5- or 6-membered and monocyclic radical or an appropriate bicyclic heteroaryl radical which, in each case, have up to four identical or different hetero atoms, such as nitrogen, oxygen or sulfur atoms, preferably one, two, three or four nitrogen atoms, an oxygen atom or a sulfur atom.
  • Appropriate 5-membered heteroaryl radicals are, for example, monoaza-, diaza-, tnaza-, tetraaza-, monooxa- or monothia-cyclic aryl radicals, such as pyrrolyl, pyrazolyl, imidazolyl, tnazolyl, tetrazolyl, furyl and thienyi, while suitable appropriate 6-membered radicals are in particular pyridyl
  • Appropriate bicyclic heterocyclic aryls are, for example, mdolyl, indazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinol yl, isoqumolinyl, or qu azolinyl
  • aromatic radicals, including ring A are radicals which may be monosubstituted or polysubstituted, for example di- or t ⁇ substituted, for example by identical or different radicals, for example selected
  • Carbocyclic or heterocyclic aroyl is in particular benzoyl, naphthoyl, furoyl, thenoyl, or pyndoyl
  • (Carbocyclic or heterocyclic) aryl-lower alkanoyl in (carbocyclic or heterocyclic) aryl-lower alkanoyloxy or (carbocyclic or heterocyclic) aryl-lower alkanoyl is in particular phenyl-lower alkanoyl, naphthyl-lower alkanoyl, or py ⁇ dyl-lower alkanoyl
  • (Carbocyclic or heterocyclic) aryl-lower alkyl is in particular phenyl-, naphthyl- or pyridyl- lower alkyl.
  • aryl-lower alkoxycarbonyl is in particular phenyl-, naphthyl- or pyridyl-lower alkoxy.
  • Lower alkyl which substituted by halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, or amino is in particular halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenyloxy-, naphthyloxy- or pyridyloxy- lower alkyl, phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl, amino-lower alkyl, or N- or N,N- substituted amino-lower alkyl.
  • An amino group which is mono-substituted by lower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl is in particular lower alkylamino, C 3 -C 8 -cycloalkyl-amino, C 3 -C 8 -cycloalkyl-loweralkyl-amino, phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-amino, phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkylamino.
  • An amino group which is, independently of one another, di-substituted by lower alkyl, C 3 -C 8 - cycloalkyl, C 3 -C 3 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, or (carbocyclic or heterocyclic) aryl-lower alkyl is in particular di-lower alkylamino, di-C 3 -C 8 -cycloalkyl-amino, di-(C 3 -C 8 -cycloalkyl-lower alkyl)-amino, di-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)- amino, di-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl)-amino, lower alkyl-C 3 -C 8 - cyclo
  • Lower alkyl which is substituted by carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, carbamoyl in which the amino group is mono-substituted or, independently of one another, di-substituted by lower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, and carbamoyl in which the am o group is di-substituted by lower alkylene [which may be interrupted by O, S(O) n , NR 0 , the integer n being 0, 1 or 2 and R 0 being hydrogen, lower alkyl, (carbocyclic or heterocyclic
  • Lower alkoxy which substituted by halogen, hydroxy, lower alkoxy, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, or amino is in particular halo-lower alkoxy, hydroxy-lower alkoxy, lower alkoxy-lower alkoxy, phenyloxy-, naphthyioxy- or pyridyloxy-lower alkyl, phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkoxy, amino- lower alkoxy, or corresponding N- or N,N- substituted amino-lower alkoxy.
  • Lower alkoxy which is substituted by carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, carbamoyl in which the amino group is mono-substituted or, independently of one another, di-substituted by lower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl, and carbamoyl in which the amino group is di-substituted by lower alkylene [which may be interrupted by O, S(O) n , NR 0 , the integer n being 0, 1 or 2 and R 0 being hydrogen, lower alkyl, (carbocyclic or heterocyclic)
  • Substituted lower alkyl or lower alkoxy, respectively, is mono- or poly-substituted, e.g. di- or tri-substituted.
  • the group of formula -N(R 2 )(R 3 ) in which R 2 and R 3 together represent lower alkylene which is condensedat two adjacent carbon atoms with a benzene ring represents, for example, lower alkylene-phenylene-lower alkylene-amino, such as 3,4-dihydro-1 H-isoquinolin-2-yl.
  • lower means that corresponding groups and compounds, in each case, in particular comprise not more than 7, preferably not more than 4, carbon atoms.
  • Halogen is in particular halogen of atomic number not more than 35, such as fluorine, chlorine or bromine, and also includes iodine.
  • Lower alkyl is in particular C1-C7- alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, and also includes corresponding pentyl, hexyl and heptyl radicals.
  • CrC 4 -alkyl is preferred.
  • Lower alkenyl is in particular C 3 -C 7 -alkenyl and is, for example, 2-propenyl or 1-, 2- or 3-butenyl. C 3 -C 5 -alkenyl is preferred.
  • Lower alkynyl is in particular C 3 -C 7 -alkynyl and is preferably propargyl.
  • Lower alkoxy is in particular C ⁇ -C 7 -alkoxy and is, for example, methoxy, ethoxy, n- propyloxy, isopropyloxy, n-butyloxy, isobutyloxy, sec-butyloxy, tert-butyloxy and also includes corresponding pentyloxy, hexyloxy and heptyloxy radicals.
  • C C 4 - alkoxy is preferred.
  • Lower alkenyloxy is in particular C 3 -C ⁇ -alkenyloxy, preferably allyloxycarbonyl, while lower alkynyloxy is in particular C3-C 5 -alkynyloxy, such as propargyloxy.
  • Oxy-lower alkylene-oxy is in particular oxy-d- 4 -alkyiene-oxy, preferably oxy- methylene-oxy or oxy-ethylene-oxy.
  • Lower alkanoyloxy is in particular C 2 -C ⁇ -alkanoyloxy, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy or pivaioyloxy.
  • C 2 -C 5 -alkanoyloxy is preferred.
  • Lower alkanoyl is in particular C 2 -C 7 -alkanoyl, such as acetyl, propionyl, butyryl, isobutyryl or pivaloyl.
  • C 2 -C 5 -alkanoyl is preferred.
  • NaphthoyI is 1 - or 2-naphthoyl, furoyi 2- or 3-furoyl, thenoyi 2- or 3-thenyl, and pyridoyi 2-, 3-, or 4-pyridoyl.
  • C 3 -C 8 -Cycloalkyl is, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Cyclopentyl and cyclohexyl are preferred.
  • C 3 -C 8 -Cycloalkyl-lower alkyl is in particular C 3 -C 8 -cycloalkyl-C ⁇ -C 4 -alkyl, in particular C 3 -C 6 - cycloalkyl-C ⁇ -C 2 -alkyl.
  • Preferred is cyclopropylmethyl, cyclopentylmethyl or cyclohexylmethyl.
  • C 3 -C 8 -Cycloalkoxy is, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy. Cyclopentyloxy and cyclohexyloxy are preferred.
  • C 3 -C 8 -Cycloalkyl-lower alkoxy is in particular C 3 -C 8 -cycloalkyl-C ⁇ -C 4 -alkoxy, in particular C 3 - C 6 -cycloalkyl-C ⁇ -C 2 -alkoxy.
  • Preferred is cyclopropylmethoxy, cyclopentylmethoxy or cyclohexylmethoxy.
  • Lower alkylene is in particular C ⁇ -C -alkylene, in particular d-Cs-alkylene, and is straight-chain or branched and is in particular methylene, ethyiene, propylene and butylene and also 1 ,2-propylene, 2-methyl-1 ,3-propylene, 3-methyl-1 ,5-pentylene and 2,2-d ⁇ methyl-1 ,3-propylene.
  • C 3 -C 5 -alkylene is preferred.
  • lower alkylene preferably is -(CH 2 ) P - the integer p being 1-3.
  • Lower alkylene in an substituted ammo group preferably is 1 ,2-ethylene, 1 ,3- propylene, 1 ,4-butylene, 1 ,5-pentylene, 1 ,6-hexylene, 2-methyl-1 ,3-propylene, or 2-methyl-butylene, or 3-methyl-1 ,5-pentylene Amino which di-substituted by lower alkylene is in particular C 3 -C ⁇ -alkyleneamino, preferably 1-azidino, 1 -pyrrolidino or 1-piperidino.
  • Amino which di-substituted by lower alkylene which is interrupted by O, S(O) n or NR 0 is in particular morpholino, thiomorpholino or the mono- or di-oxide thereof, or 4-R 0 -piperazino.
  • Lower alkanesulfonyl is in particular C ⁇ -C 4 -alkoxy-CrC 5 -alkoxycarbonyl, preferably ethoxyethoxycarbonyl, methoxyethoxycarbonyl and isopropyloxyethoxycarbonyi.
  • Lower alkoxycarbonyl is in particular C 2 -C 8 -alkoxycarbonyl and is, for example, methoxy-, ethoxy-, propyloxy- or pivaloyloxy-carbonyl.
  • C 2 -C 5 -alkoxycarbonyl is preferred.
  • Lower alkoxy-lower alkoxy-carbonyl is in particular C 1 -C4-alkoxy-C 2 -Cs- alkoxycarbonyl and is, for example, methoxy- or ethoxy-ethoxy-alkoxycarbonyl.
  • Hydroxy-lower alkyl is in particular hydroxy-C ⁇ -C 4 -alkyl, such as hydroxymethyl, 2- hydroxyethyl or 3-hydroxypropyl.
  • Hydroxy-lower alkoxy is in particular hydroxy-C 1 -C 4 -alkoxy, such as hydroxymethyl, 2- hydroxyethyl or 3-hydroxy propyl. Furthermore, hydroxy-lower alkyl may exhibit two hydroxy groups, such as 3-hydroxy-1-hydroxymethyl-propyl.
  • Lower alkoxy-lower alkoxy is in particular C ⁇ -C 4 -alkoxy-C rC -alkoxy and is, for example, 2- methoxyethoxy, 2-ethoxyethoxy, 2-n-propyloxyethoxy or ethoxymethoxy.
  • Amino which di-substituted by lower alkylene and is condensed at two adjacent carbon atoms with a benzene ring is in particular C 2 -C 6 -cyc!oa!kylenemino which is is condensed at two adjacent carbon atoms with a benzene ring.
  • Preferred is indolin-1 -yl or 1 ,2,3,4- tetrahydro-quinolin-1 -yl.
  • Halo-lower alkyl is in particular halo-C ⁇ -C 4 -alkyl, such as trifluoromethyl, 1 ,1 ,2- tr ⁇ fluoro-2-chloroethyl or chloromethyl.
  • Halo-lower alkoxy is in particular halo-C--C 4 -alkoxy, such as trifluoromethoxy, 1 ,1 ,2-tr ⁇ fluoro- 2-chloroethoxy or chloromethoxy
  • Phenyloxy-, naphthyloxy- or pyridyloxy-lower alkyl is in particular phenyloxy-, naphthyloxy- or py ⁇ dyloxy-CrOralkyl, such as phenoxy-methyl, 2-phenoxy-ethyl, 1- or 2-naphthyloxy- methyl, or 2-, 3-, or 4-pyridyloxy-methyl.
  • Phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl is in particular phenyl-, naphthyl- or pyr ⁇ dyl-C ⁇ -C 4 -alkyl, such as phenyl-methyl, 2-phenyl-ethyl, 1- or 2-naphthyl-methyl, or 2-, 3-, or 4-pyr ⁇ dyl-methyl.
  • Phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkoxy is in particular phenyl-, naphthyl- or pyridyl-C ⁇ -C 4 -alkoxy, such as phenyl-methoxy, 2-phenyl-ethoxy, 1 - or 2-naphthyl- methoxy, or 2-, 3-, or 4-pyridyl-methoxy.
  • Naphthyl is in particular 1 - or 2-naphthyl; furyl 2- or 3-furyl; thienyi 2- or 3-thienyl; pyridyl 2-, 3- or 4-pyr ⁇ dyl, mdolyl, indazolyl e.g. 6-1 (H)- ⁇ ndazolyl, benzofuryl e.g. 2-, 3- or 5- benzofuranyl, benzothienyl e.g. 2-, 3-, or 5-benzoth ⁇ enyl, benzimidazolyl e.g. 1 -, 2- or 5- benzimidazolyl, quinolmyl e.g.
  • 2-, 4-, 5-, 6-,7-, or 8-qu ⁇ nol ⁇ nyl isoquinolinyl e.g. 1 -, 3-, 4-, or 6- ⁇ soqu ⁇ nolyl, or quinazolinyl e.g. 2-, 4-, 5-, 6-, 7-, or 8-qu ⁇ nazol ⁇ nyl.
  • Amino-lower alkyl is in particular amino-C-i-Cralkyl, preferably am ⁇ no-C 1 -C 4 -alkyl, such as aminomethyl, 2-am ⁇ noethyl or 3-aminopropyl
  • Lower alkylamino is in particular CrC 7 alkylam ⁇ no and is, for example, methyl-, ethyl-, n-propyl- and isopropyl-amino.
  • CrC 4 alkylam ⁇ no is preferred.
  • C 3 -C 8 -Cycloalkyl-am ⁇ no is in particular C 3 -C 6 -cycloalkyl-am ⁇ no and is, for example, cyclopropyl-, cyclopentyl and cyclohexyl-amino.
  • C 3 -C 8 -Cycloalkyl-lower alkylamino is in particular C 3 -C 8 -cycloalkyl-CrCr alkylamino and is, for example, cyclopropylmethyl-amino or cyclohexylmethyl- amino.
  • C 3 -C 8 -Cycloalkyl-C ⁇ -C 4 -alkylamino is preferred.
  • Phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl-amino is in particular phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-C ⁇ -C 4 -alkyl-amino, preferably benzyl-amino, 2-phenethyl- amino, 1- or 2-naphthylmethyl-amino, or 2-, 3-, or 4-pyridylmethyl-amino.
  • Di-lower alkylamino is in particular di-C C 4 -alkylamino, such as dimethyl-, diethyl-, di-n- propyl-, methylpropyl-, methylethyl-, methylbutyl-amino and dibutyla ino.
  • Di-C 3 -C 8 -cycloalkyl-amino is in particular di-C 3 -C 6 -cycloalkylamino, preferably cyclopropylamino, cyclopentyla ino or cyclohexylamino.
  • Di-(C 3 -C 8 -cycloalkyl-lower alkyl)-amino is in particular di-(C 3 -C 6 -cycloalkyl-CrC 4 -alkyl)-amino, preferably cyclopropylmethyl-amino, cyclopentylmethyl-amino or cyclohexylmethyl-amino.
  • Di-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl)-amino is in particular di-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-C ⁇ -C 4 - alkyl)-amino, preferably di-benzyl-amino, di-(2- phenethyl)-amino, di-(1 - or 2-naphthylmethyl)-amino, or di-(2-, 3-, or 4-pyridylmethyl)-amino.
  • Lower alkyl-C 3 -C 8 -cycloalkyl-amino is in particular C 1 -C 4 -alkyl-C 3 -C 6 -cycloalkyi-amino, preferably methyl-cyclopropyl-amino, methyl-cyclopentyl-amino or methyl-cyclohexyl-amino.
  • Lower alkyl-(C 3 -C 8 -cycloalkyl-lower alkyl)-amino is in particular C C 4 -alkyl-(C 3 -C 6 -cycloalkyl- C -C 4 -alkyl)amino, preferably methyl-cyclopropylmethyl-amino, methyl-cyclopentylmethyl- amino or methyl-cyclohexylmethyl-amino.
  • Lower alkyl-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)-amino is in particular C--C 4 -alkyl- (phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)- amino, such as (m)ethyl-phenyl-amino.
  • Lower alkyl-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-lower alkyl)-amino is in particular C 1 -C 4 -alkyl-(phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl-C ⁇ -C 4 -aikyl)-amino, such as (m)ethyl-benzyl-amino or (m)ethyl-(2-phenethyl)-amino.
  • Carboxy-lower alkyl is in particular such as carboxy-methyl, 2-carboxy- ethyl, or 3-carboxy-propyl.
  • Lower alkoxy-carbonyl-lower alkyl is in particular C 2 -C 5 -alkoxycarbonyl-C 1 -C 4 -alkyl, such as (m)ethoxycarbonyl-methyl, 2-(m)ethoxycarbonyl-ethyl or 2-pivaloyl-ethyl.
  • Lower alkoxy-lower alkoxy-carbonyl-lower alkyl is in particular alkoxycarbonyl-C ⁇ -C 4 -alkyl, such as 2-methoxy-ethoxycarbonyl-methyl or 2-(2-ethoxy- ethoxycarbonyl)-ethyl.
  • (Phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl) -lower alkoxycarbonyl-lower alkyl is in particular (phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)-C 2 -C 5 -alkoxycarbonyl-C C -alkyl, such as benzyloxycarbonyl-methyl or 2-(2-phenethyloxy-carbonyl)-ethyl.
  • Carbamoyl-lower alkyl is in particular carbamoyl-d-C ⁇ alkyl, such as carbamoyl-methyl, 2- carbamoyl-ethyl or 3-carbamoyl-propyl.
  • Amino-lower alkoxy is in particular amino-CrC ⁇ alkoxy, such as aminomethoxy, 2- aminoethoxy, or 3-amino-propoxy.
  • Carboxy-lower alkoxy is in particular carboxy-CrC 4 -alkoxy, such as carboxy-methoxy, 2- carboxy-ethoxy, or 3-carboxy-propyloxy.
  • Lower alkoxy-carbonyl-lower alkoxy is in particular C 2 -C 5 -alkoxycarbonyl-Ci-C 4 -alkoxy, such as (m)ethoxycarbonyl-methoxy, 2-methoxycarbonyl-ethyl, or 2-(2-ethoxycarbonyl)-ethyl.
  • Lower alkoxy-lower alkoxy-carbonyl-lower alkoxy is in particular C 1 -C -alkoxy-C 2 -C 5 - alkoxycarbonyl-CrC 4 -alkoxy, such as (m)ethoxymethoxycarbonyl-methoxy, 2-ethoxy- methoxycarbonyl-ethyl, or 2-[(2-ethoxy-ethoxycarbonyl)]-ethyi.
  • (Phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)-lower alkoxycarbonyl-lower alkoxy is in particular (phenyl-, naphthyl-, furyl-, thienyi-, or pyridyl)-C 2 -C 5 -alkoxycarbonyl-C 1 -C 4 -alkoxy, such as benzyloxycarbonyl-methoxy, phenethyloxycarbonyl-methoxy, 2- (benzyloxycarbo ⁇ yl)-ethoxy, or 2-(2-phenethyloxycarbonyl)-ethoxy.
  • Carbamoyl-lower alkoxy is in particular carbamoyl-C ⁇ -C 4 -alkoxy, such as carbamoyl- methoxy, 2-carbamoyl-ethoxy, or 3-carbamoyl-propyloxy.
  • Obesity for example, is a wide-spread phenomena which e.g. causes a variety of pathological symptoms or influences the overall state of health. Also associated therewith are considerable socio-economic investments and a heavy financial burden for managed health care organisations.
  • the problem to be solved is to present an approach to systemically treat obesity or related diseases or disorders. Surprisingly, it has been manifested that the modulation of the NPY receptor subtype Y5 leads to a control of the eating behavior.
  • Neuropeptide Y is a member of the pancreatic polypeptide family with wide-spread distribution throughout the mammalian nervous system. NPY and its relatives (peptide YY or PYY, and pancreatic polypeptide or PP) elicit a broad range of physiological effects through activation of at least five G protein-coupled receptor subtypes known as Y1 , Y2, Y3, Y4 (or PP), and the "atypical Y1 ". The role of NPY as the most powerful stimulant of feeding behavior yet described is thought to occur primarily through activation of the hypothalamic "atypical Y1 " receptor.
  • This receptor is unique in that its classification is based solely on feeding behavior data, rather than radio gand binding data, unlike the Y1 , Y2, Y3, and Y4 (or PP) receptors, each of which are described previously in both radioligand binding and functional assays.
  • 125 I-PYY- based expression cloning technique may be used to isolate a rat hypothalamic cDNA encoding an "atypical Y1 " receptor referred to herein as the Y5 subtype.
  • Y5 homolog may be isolated and characterized of from human hippocampus Protein sequence analysis reveals that the Y5 receptor belongs to the G protein-coupled receptor superfamily.
  • NPY The peptide neurotransmitter neuropeptide Y
  • NPY is a 36 amino acid member of the pancreatic polypeptide family with widespread distribution throughout the mammalian nervous system. NPY is considered to be the most powerful stimulant of feeding behavior yet described (Clark, J.T., Kalra, P.S., Crowley, W.R., and Kalra, S.P. (1984).
  • Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115: 427-429, 1984; Levine, A.S., and Morley, J.E. (1984).
  • Neuropeptide Y A potent inducer of consummately behavior in rats. Peptides 5: 1025-1029; Stanley, B.G.
  • NPY neuropeptide Y and energy balance: one way ahead for the treatment of obesity? Eur. J. Gin. Invest. 24: 293-308).
  • Any credible means of studying or controlling NPY-dependent feeding behavior must necessarily be highly specific as NPY can act through at least 5 pharmacologically defined receptor subtypes to elicit a wide variety of physiological functions (Dumont, Y., J.-C. artel, A.
  • Rank orders of affinity for key peptides are based on previously reported binding and functional data (Schwartz, T.W., J. Fuhlendorff, LLKjems, M.S. Kristensen, M. Vervelde, M. O'Hare, J.L Krstenansky, and B. Bjornholm. (1990). Signal epitopes in the three-dimensional structure of neuropeptide Y. Ann. N.Y. Acad. Scj.
  • NPY receptor pharmacology has historically been based on structure/activity relationships within the pancreatic polypeptide family.
  • the entire family includes the namesake pancreatic polypeptide (PP), synthesized primarily by endocrine cells in the pancreas; peptide YY (PYY), synthesized primarily by endocrine cells in the gut; and NPY, synthesized primarily in neurons (Michel, M.C. (1991).
  • Receptors for neuropeptide Y multiple subtypes and multiple second messengers.
  • Trends Pharmacol.: 12: 389-394 Dumont et al. , 1992; Wahlestedt and Reis, 1993).
  • pancreatic polypeptide family members share a compact structure involving a "PP-fold” and a conserved C-terminal hexapeptide ending in Tyr 36 (or Y 36 in the singie letter code).
  • the striking conservation of Y 36 has prompted the reference to the pancreatic polypeptides' receptors as "Y-type" receptors (Wahlestedt, C, L. Edvinsson, E. Ekblad, and R. Hakanson. Effects of neuropeptide Y at sympathetic neuroeffector junctions: Existence of Yi and Y 2 receptors. In: Neuronal messengers in vascular function, Fernstrom Symp. No 10., pp. 231-242. Eds A. Nobin and OH. Owman. Elsevier: Amsterdam (1987)), all of which are proposed to function as seven transmembrane-spanning G protein-coupled receptors (Dumont et al., 1992).
  • the receptor requires both the N- and the C-terminal regions of the peptides for optimal recognition.
  • the Y1 receptor has been cloned from a variety of species including human, rat and mouse (Larhammar, D., A.G. Blomqvist, F. Yee, E. Jazin, H. Yoo, and C. Wahlestedt. (1992). Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type. J. Biol.
  • the Y2 receptor recognizes PYY ⁇ NPY » PP and is relatively tolerant of N-terminal deletion (Gêtmar, L. and Rl Hakanson (1994). Neuropeptide Y effector systems: perspectives for drug development. Trends. Pharmacol. 15:153-159).
  • the receptor has a strict requirement for structure in the C-terminus (Arg 33 -Gln 3 -Arg 35 -Tyr 36 -NH 2 ); exchange of Gin 34 with Pro 34 , as in PP, is not well tolerated.
  • the Y2 receptor has recently been cloned.
  • the Y3 receptor is characterized by a strong preference for NPY over PYY and PP (Wahlestedt, C, Karoum, F., Jaskiw, G., Wyatt, R.J., Larhammar, D., Ekman, R., and Reis, D.J. (1991). Cocaine-induced reduction of brain neuropeptide Y synthesis dependent on medial prefronta! cortex. Proc. Natl. Acad. Sci. 88: 2978-2082). [Pro 34 ] NPY is reasonably well tolerated even though PP, which also contains Pro 34 , does not bind well to the Y3 receptor. This receptor (Y3) has not yet been cloned.
  • the Y4 receptor binds PP > PYY > NPY. Like the Y1 , the Y4 requires both the N- and the C-terminal regions of the peptides for optimal recognition.
  • the "atypical Y1 " or "feeding" receptor is defined exclusively by injection of several pancreatic polypeptide analogs into the parave ⁇ tricular nucleus of the rat hypothalamus which stimulates feeding behavior with the following rank order: NPY 2 .-3 6 > NPY ⁇ PYY - [Leu 31 ,Pro 3 ]NPY > NPY 13 . 36 (Kalra, S.P., Dube, M.G., Fournier, A., and Kalra, P.S. (1991).
  • [D-Trp ⁇ Neuropeptide Y A competitive antagonist of NPY in rat hypothalamus. J. Med. Chem. 37: 311 -815 showed that feeding can be regulated by [D-Trp 32 ]NPY. While this peptide is presented as an NPY antagonist, the published data at least in part support a stimulatory effect of [D-Trp 32 ]NPY on feeding. [D- Trp 32 ]NPY thereby represents another diagnostic tool for receptor identification.
  • This plasmid (pcEXV-hY5) was deposited on November 4, 1994 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorgansims for the Purposes of Patent Procedure and was accorded ATCC Accession No. 75943.
  • the plasmid which comprises the regulatory elements necessary for expression of DNA in a mammalian cell operatively linked to the DNA encoding the rat Y5 receptor as to permit expression thereof has been designated as pcEXV-rY5 (ATCC Accession No. 75944).
  • This plasmid (pcEXV-rY5) was deposited on November 4, 1994 with the American Type Culture Collection (ATCC), 12301 Parklawn Drive, Rockville, Maryland 20852, U.S.A. under the provisions of the Budapest Treaty for the International Recognition of the Deposit of Microorgansims for the Purposes of Patent Procedure and was accorded ATCC Accession No. CRL 75944.
  • a method for determining whether a ligand can specifically bind to a Y5 receptor comprises contacting a cell transfected with and expressing DNA encoding the Y5 receptor with the ligand under conditions permitting binding of iigands to such receptor, detecting the presence of any such ligand specifically bound to the Y5 receptor, and thereby determining whether the ligand specifically binds to the Y5 receptor.
  • a method for determining whether a ligand is a Y5 receptor antagonist comprises contacting a ceil transfected with and expressing DNA encoding a Y5 receptor with the ligand in the presence of a known Y5 receptor agonist, such as PYY or NPY, under conditions permitting the activation of a functional Y5 receptor response, detecting a decrease in Y5 receptor activity, and thereby determining whether the ligand is a Y5 receptor antagonist.
  • a known Y5 receptor agonist such as PYY or NPY
  • the cell is non-neuronal in origin.
  • the non-neuronal cell is a COS-7 cell, 293 human embryonic kidney cell, NIH-3T3 cell or L-M(TK-) cell.
  • the cell lines are transfected with a vector which is adapted for expression in a mammalian cell which comprises the regulatory elements necessary for expression of the DNA in the mammalian cell operatively linked to the DNA encoding the mammalian Y5 receptor as to permit expression thereof.
  • such plasmid which comprises the regulatory elements necessary for expression of DNA in a mammalian ceil operatively linked to the DNA encoding the human Y5 receptor as to permit expression thereof designated pcEXV-hY5 (ATCC Accession No. 75943).
  • RNA was prepared by a modification of the guanidine thiocyanate method (Kingston, 1987), from 5 grams of rat hypothalamus (Rockland, Gilbertsville, PA). Poly A + RNA was purified with a FastTrack kit (Invitrogen Corp., San Diego, CA). Double stranded (ds) cDNA was synthesized from 7 mg of poly A + RNA according to Gubler and Hoffman (Gubler, U abd B.J. Hoffman. (1983). A simple and very efficient method for generating cDNA libraries. Gene. 25, 263-269), except that ligase was omitted in the second strand cDNA synthesis.
  • the resulting DS cDNA was ligated to Bstxl/EcoRI adaptors (Invitrogen Corp.), the excess of adaptors was removed by chromatography on Sephacryl 500 HR (Pharmacia®-LKB) and the ds-cDNA size selected on a Gen-Pak Fax HPLC column (Millipore Corp., Milford, MA). High molecular weight fractions were ligated in pEXJ.BS (A cDNA cloning expression vector derived from pcEXV-3; Okayama, H. and P. Berg (1983). A cDNA cloning vector that permits expression of cDNA inserts in mammalian cells. Mol. Cell. Biol.
  • the library was plated on Petri dishes (Ampicillin selection) in pools of 6.9 to 8.2 x 10 3 independent clones. After 18 hours amplification, the bacteria from each pool were scraped, resuspended in 4 ml of LB media and 1.5 ml processed for plasmid purification with a QIAprep-8 plasmid kit (Qiagen Inc, Chatsworth, CA). 1 ml aliquots of each bacterial pool were stored at -85°C in 20% glycerol. Isolation of a cDNA clone encoding an atypical rat hypothalamic NPY5 receptor
  • COS-7 cells DNA from pools of » 7500 independent clones was transfected into COS-7 cells by a modification of the DEAE-dextran procedure (Warden, D. and H.V. Thorne. (1968). Infectivity of polyoma virus DNA for mouse embryo cells in presence of diethylaminoethyl-dextran. J. Gen. Virol. 3, 371 ).
  • COS-7 cells were grown in Dulbecco's modified Eagle medium (DMEM) supplemented with 10% fetal calf serum, 100 U/ml of penicillin, 100 mg/ml of streptomycin, 2 mM L-glutamine (DMEM-C) at 37°C in 5% CO 2 .
  • DMEM Dulbecco's modified Eagle medium
  • the cells were seeded one day before transfection at a density of 30,000 cells/cm 2 on Lab-Tek chamber slides (1 chamber, Permanox slide from Nunc Inc., Naperville, IL). On the next day, cells were washed twice with PBS, 735 ml of transfection cocktail was added containing 1/10 of the DNA from each pool and DEAE-dextran (500 mg/ml) in Opti-MEM I serum free media (G ⁇ bco®BRL LifeTechnologies Inc. Grand Island, NY). After a 30 mm. incubation at 37°C, 3 ml of chloroquine (80 mM in DMEM-C) was added and the cells incubated a further 2.5 hours at 37°C.
  • the monolayers were fixed in 2.5% glutaraldehyde in PBS for five minutes, washed twice for two minutes in PBS, dehydrated in ethanol baths for two minutes each (70, 80, 95, 100%) and air dried.
  • the slides were then dipped in 100% photoemulsion (Kodak® type NTB2) at 42°C and exposed in the dark for 48 hours at 4°c in light proof boxes containing drierite.
  • a human hippocampal cDNA library has been screened using the polymerase chain reaction 1 ⁇ l (4 x 10 6 bacteria) of each of 450 amplified pools containing each »5000 independent clones and representing a total of 2.2 x 10 6 was subjected directly to 40 cycles of PCR and the resulting products analyzed by agarose gel electrophoresis One of three positive pools was analyzed further and by sib selection a single cDNA clone was isolated and characterized. This cDNA turned out to be full length and in the correct orientation for expression DS- DNA was sequenced with a sequenase kit (US Biochemical, Cleveland, OH) according to the manufacturer
  • COS-7 cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicill ⁇ n/100 mg/ml streptomycin) at 37°C, 5% CO 2 Stock plates of COS-7 cells were trypsmized and split 1 :6 every 3-4 days.
  • D-MEM Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml penicill ⁇ n/100 mg/ml streptomycin
  • Human embryonic kidney 293 celis were grown on 150 mm plates in D-MEM with supplements (minimal essential medium) with Hanks' salts and supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml pen ⁇ c ⁇ ll ⁇ n/100 mg/ml streptomycin) at 37 °C, 5% CO 2 .
  • supplements minimal essential medium
  • Hanks' salts and supplements Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml pen ⁇ c ⁇ ll ⁇ n/100 mg/ml streptomycin
  • Mouse fibroblast LMT(k)- cells were grown on 150 mm plates in D-MEM with supplements (Dulbecco's Modified Eagle Medium with 10% bovine calf serum, 4 mM glutamine, 100 units/ml pen ⁇ c ⁇ ll ⁇ n/100 mg/ml streptomycin) at 37 °C, 5% CO 2 Stock plates of COS-7 cells were trypsmized and split 1 :10 every 3-4 days
  • Human Y5 and rat Y5 receptors were co-transfected with a G-418 resistant gene into mouse fibroblast LMT(k)- cells by a calcium phosphate transfection method (Cullen, B (1987) Use of eurkaryotic expression technology in the functional analysis of cloned genes Methods Enzymol. 152: 685-704). Stably transfected cells were selected with G-418.
  • NPY (a Y1 specific ligand) is able to displace with high affinity (IC 50 of 0.38) 27% of the bound 125 l- PYY 3 3 e ligand (a Y2 specific ligand) (Fig.
  • Binding data reflect competitive displacement of 1 5 I- PYY and 125 I-PYY 3 36 from rat hypothalamic membranes Peptides were tested at concentrations ranging from 0 001 nM to 100 nM unless noted The IC50 value corresponding to 50% displacement, and the percentage of displacement relative to that produced by 300 nM human NPY, were determined by nonlinear regression analysis. Data shown are representative of at least two independent experiments. TABLE 2
  • a rat hypothalamic cDNA library of 3 x 1 0 6 independent recombinants with a 2.7 kb average insert size was fractionated into 450 pools of »7500 independent clones. All pools were tested in a binding assay with 125 I-PYY as described (Y2 patent). Seven pools gave rise to positive cells in the screening assay (# 81 , 92, 147, 246, 254, 290, 312). Since Y1 , Y2, Y4 and Y5 receptor subtypes (by PCR or binding analysis) are expressed in rat hypothalamus, applicants analyzed the DNA of positive pools by PCR with rat Y1 , Y2 and Y4 specific primers.
  • Pools # 147, 246, 254 and 312 turned out to contain cDNAs encoding a Y1 receptor, pool # 290 turned out to encode a Y2 subtype, but pools # 81 and 92 were negative by PCR analysis for Y1 , Y2 and Y4 and therefore likely contained a cDNA encoding a new rat hypothalamic NPY receptor (Y5). Pools # 81 and 92 later turned out to contain an identical NPY receptor cDNA. Pool 92 was subjected to sib selection as described until a single clone was isolated (designated CG-18).
  • the isolated clone carries a 2.8 kb cDNA.
  • This cDNA contains an open reading frame between nucleotides 779 and 2146 that encodes a 456 amino acid protein.
  • the long 5' untranslated region could be involved in the regulation of translation efficiency or mRNA stability.
  • the flanking sequence around the putative initiation codon does not conform to the Kozak consensus sequence for optimal translation initiation (Kozak, M. (1989).
  • the hydrophobicity plot displayed seven hydrophobic, putative membrane spanning regions which makes the rat hypothalamic Y5 receptor a member of the G-protein coupled superfamily.
  • the nucleotide and deduced amino acid sequences are shown in SEQ ID NOS: 1 and 2, respectively.
  • the human Y5 nucleotide and deduced amino acid sequences are shown in SEQ ID NOS 3 and 4, respectively. When compared to the rat Y5 receptor the human sequence shows 84.1 % nucleotide identity and 87.2% amino acid identity.
  • the rat protein sequence is one amino acid longer at the very end of both amino and carboxy tails of the receptor when compared to the rat. Both pharmacological profiles and functional characteristics of the rat and human Y5 receptor subtype homologs may be expected to match closely.
  • the compounds according to the present invention and their pharmaceutically acceptable salts have proven to exhibit pronounced and selective affinity to the Y5 receptor subtype (shown in Y5 binding test) and in vitro and in vivo antagonistic properties. These properties are shown in vitro by their ability to inhibit NPY-induced calcium increase in stable transfected cells expressing the Y5 receptor and in vivo by their ability to inhibit food intake induced by mtracerebroventricular application of NPY or 24 h food deprivation in conscious rats.
  • the selective affinity of the compounds according to the present invention to the Y5 receptor is detected in a Y5 binding assay using LM(tk-)-h-NPY5-7 cells which stably express the human NPY Y5 receptor or HEK-293 cells stably expressing the rat NPY Y5 receptor.
  • buffer 1 homogenisation buffer, pH 7.7 at 4°C
  • buffer 2 saliva buffer, pH: 7.4 at room temperature
  • HEPES N-2-hydroxyethyip ⁇ peraz ⁇ ne-N'-2-ethanesulfon ⁇ c acid
  • 0.1 % (1 mg/ml) bovine serum albumin is added.
  • 'l 25 l-[Pro 34 ]hPYY (60 pM, Anawa, Wangen, Switzerland) dissolved in buffer 3 is used as radioligand.
  • All test compounds are dissolved in dimethyl sulfoxide (DMSO) at 10 "2 M and diluted to 10" 3 M in buffer 3 Subsequent dilutions are in buffer 3 plus 10% DMSO Incubations are performed in Millipore Multiscreen FC filter plates [Millipore, Bedford, USA] The filters in each well are pretreated with 2% polyethyleneimi ⁇ e for 30 mm and rinsed once with 300 microL buffer 3 before use.
  • DMSO dimethyl sulfoxide
  • IC50 values of the compounds according to this invention at the human Y5 receptor range especially between about 0.1 nM and about 10 microM.
  • stably transfected LM(tk-)-hY5-7 cells are used in which a NPY-induced calcium transient is measured as described below.
  • Cells are harvested in a medium containing EDTA (0.5 mM) and phosphate buffered saline (PBS).
  • EDTA 0.5 mM
  • PBS phosphate buffered saline
  • Cells are then washed in phosphate buffered saline solution and loaded for 90 min at room temperature and pH 7.4 with 10 microM FLUO-AM (fluoro-3-acetoxy methylester, supplemented with pluronic acid as suggested by the manufacturer, Molecular Probes Inc., Eugene, Oregon, USA) in a cell culture buffer of the following composition (NaCl 120 mM, MgCI 2 1 mM , KCl 5.4 mM, NaH 4 PO 4 0.33 mM, glucose 1 1 mM, taurine 5 mM, pyruvate 2 mM, glutamine 1.5 mM HEPES 10 mM, insulin 10 U/l, BSA 0.1% at for 90 min at room temperature. After centrifugation the cells are resuspended in the cell culture buffer at a concentration of 3-4 million ceils/ml and supplemented with 200 microM sulfinpyrazone.
  • FLUO-AM fluoro-3-acetoxy methyl
  • Calcium transients are measured at room temperature in a millititer plate using a Cytofluor 2350 (Millipore) with wavelength settings at 485 nm for excitation and 530 nm for emission. 180 microL of cells suspension are preincubated in the presence of various amounts of compounds dissolved in 2 microL DMSO in triplicates ( or 2 microL DMSO for the controls) for 5 min and then NPY is added at a final concentration of 100 nM. The compound concentrations giving 50% inhibition of the maximum of the Ca transients are then calculated.
  • NPY induces Ca transients with an EC50 of 50 nM.
  • the data are analyzed using a Microsoft Excel software.
  • the concentrations which cause a 50% inhibition of the initial control values are given as IC50 values.
  • the IC50 values are determined for the compounds according to the present invention and their pharmaceutically acceptable salts.
  • the property of the compounds according to the present invention and their pharmaceutically acceptable salts to inhibit NPY-induced increase intracellular calcium indicates their antagonistic properties with IC50 values ranging especially between about 0.1 nM and about 10 microM. Representatives are, for example, the final products of working examples 1 and 2, for which following IC50 values [ ⁇ M/L] were determined: 0.008 (Ex. 1 ); 0.01 (Ex. 2).
  • this antagonistic property of the Y5 receptor subtype is also observed in-vivo in conscious rats by their ability to inhibit NPY-induced food intake.
  • food intake is measured in normal satiated rats after intracerebroventricular application (i.c.v.) of neuropeptide Y [BACHEM, Feinchemikalien, Bube ⁇ dorf, Switzerland] in the presence or absence of the compounds according to the present invention.
  • Male Sprague- Dawiey rats weighing 180-220 g are used for all experiments. They are individually housed in stainless steel cages and maintained on a 1 1 :13 h light-dark schedule (lights off at 1800 h) under controlled temperature (21-23 °C) at all times.
  • Water and food (NAFAG lab chow pellets) [NAFAG, Gossau, Switzerland] are available ad libitum.
  • Cannula placement is checked postoperatively by testing all rats for their drinking response to a 50 ng intracerebroventricular (icv) injection of angiotensin II . Only rats which drink at least 2.5 ml of water within 30 min after angiotensin If injection are used in the feeding studies. Injections are made in the morning 2 hours after light onset. Peptides are injected in artificial cerebrospinal fluid (ACSF) [FLUKA, Buchs, Switzerland] in a volume of 5 ⁇ l. The ACSF contains NaCl 124 mM, KCl 3.75 mM, CaCI 2 2.5 mM, MgSO 4 2.0 mM, KH 4 PO 4 0.22 mM, NaHCO 3 26 mM and glucose 10 mM.
  • ACSF cerebrospinal fluid
  • NPY 300 pmole
  • NPY 300 pmole
  • Food intake is measured by placing preweighed pellets into the cages at the time of NPY injection. Pellets are removed from the cage subsequently at each time point indicated in the figures and replaced with a new set of preweighed pellets.
  • the compounds according to the present invention inhibit NPY-induced food intake in rats in a range especially of about 0.01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration
  • NPY mediates food intake induced by food deprivation.
  • the compounds according to the present invention are also tested in rats after 24 hours food deprivation. These experiments are conducted with male Sprague-Dawley (CIBA-GEIGY AG, Sisseln, Switzerland] rats weighing between 220 and 250 g The animals are housed in individual cages for the duration of the study and allowed free access to normal food together with tap water. The animals are maintained in room with a 12 h light/dark cycle (8 a m to 8.00 p.m.
  • the compounds according to the present invention inhibit food intake in this food deprived rat model in a range especially of about 0 01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration
  • Representatives are, for example, the final products of working examples 3 and 4, for which an inhibition o ⁇ food intake of 58% or 55%, respectively, versus the respective control vehicle-treated animals after i.p. application of 30 mg/kg was determined.
  • the antiobesity efficacy of the compounds according to the present invention can also be shown in Zucker obese rats, an art-known animal model of obesity, These studies are conducted with male Zucker fatty rats (fa/fa) [HARLAN CPB, Austerlitz, NL] weighing between 480 and 500 g. Animals are individually housed in metabolism cages for the duration of the study and allowed free access to powdered food together with tap water. The animals are maintained in a room with a 12 hour light/dark cycle (8 a.m. to 8.00 p.m. light) at 24°C and monitored humidity. After placement into the metabolism cages the rats undergo a 6 day equilibration period, during which they are habituated to their new environment and to eating a powdered diet.
  • the compounds according to the present invention inhibit food intake in Zucker obese rats in a range especially of about 0.01 to about 100 mg/kg after oral, intraperitoneal, subcutaneous or intravenous administration.
  • the compounds according to the present invention can inhibit food intake induced either by intracerebroventricular application of NPY or by food deprivation or as well as spontaneous eating in the Zucker obese rat.
  • the compounds according to the present invention can especially be used for the prophylaxis and treatment of disorders or diseases associated with the Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.
  • the compounds according to the present invention act as antagonists of neuropeptide Y (NPY) binding at the Y5 receptor subtype.
  • NPY neuropeptide Y
  • the compounds of the formula (I) and their pharmaceutically acceptable salts can therefore be used, for example, as pharmaceutical active ingredients in pharmaceutical compositions which are employed, for example, for the prophylaxis and treatment of diseases and disorders associated with NPY Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.
  • the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof as described hereinbefore and hereinafter for the manufacture of a pharmaceutical composition for the prophylaxis and treatment of diseases or disorders associated with NPY Y5 receptor subtype, especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.
  • diseases or disorders associated with NPY Y5 receptor subtype especially in the treatment of disorders or disease states in which the NPY-Y5 receptor subtype is involved, preferably, in the treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa
  • the invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as described hereinbefore and hereinafter for the treatment of diseases or disorders associated with NPY Y5 receptor subtype, preferably, in the prophylaxis and treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment of sexual/reproductive disorders, depression, anxiety, cerebral hemorrhage, shock, congestive heart failure, nasal congestion and diarrhea.
  • diseases or disorders associated with NPY Y5 receptor subtype preferably, in the prophylaxis and treatment of diseases caused by eating disorders, such as obesity, bulimia nervosa, diabetes, dyspilipidimia, and hypertension, furthermore in the treatment of memory loss, epileptic seizures, migraine, sleep disturbance, and pain, and additionally in the treatment
  • the invention relates especially to a method of treatment and prophylaxis of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents a single bond or lower alkylene;
  • R 2 and R 3 independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (ii) lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, amino, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, N- substituted carbamoyl, and -S(O) ⁇ -R;
  • R 2 and R 3 together represent lower alkylene [which may be interrupted by O, S(O) n , or NRo] or represent lower alkylene which is condensed at two adjacent carbon atoms with a benzene ring;
  • X represents N or CH; and the integer n is 0 or 1 ; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;
  • lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, amino, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower aikoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C 3 -C 8 -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, amino, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived and selected from the group consisting of phenyl, biphenylyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyi, pyridyl, indolyl, indazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, or quinazolinyl;
  • the invention relates especially to a method of treatment and prophylaxis of disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents a single bond or lower alkylene;
  • R- represents (i) hydrogen, halogen.nitro, cyano, lower alkyl, C 3 -C 8 -cycloalkyl, (carbocyclic or heterocyclic) aryl, or lower alkyl which is substituted by halogen, by lower alkoxy, by substituted amino, by lower alkoxycarbonyl, or by substituted carbamoyl; (ii) substituted amino;
  • lower alkyl which is substituted by a substituent selected from the group consisting of: lower alkoxy, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, and substituted carbamoyl;
  • R 2 and R 3 together represent lower alkylene [which may be interrupted by O, S(O) n , or NR 0 ];
  • X represents N or CH; and the integer n is 0 or 1 ; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, lower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, lower alkoxy, lower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, lower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, lower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkanoyl, nitro, cyano;
  • lower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • lower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, lower alkoxy, C 3 -C 8 -cycloalkyl, (carbocyclic or heterocyclic) aryloxy, amino, substituted amino, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl; (iv) substituted amino;
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, lower alkyl, lower alkoxy, and oxy-lower alkylene-oxy;
  • R 3 represents hydrogen
  • X represents N or CH; and the integer n is 0 or 1 ; wherein any aryl moiety, if not designated otherwise, and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, halo-alkyl, lower alkoxy, hydroxy, hydroxy-lower alkoxy, and lower alkoxy-lower alkoxy.
  • the invention relates especially to a method of treatment of and prophylaxis disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents a single bond or lower alkylene;
  • Ri represents (i) hydrogen, halogen, cyano, nitro, lower alkyl, C 3 -C 8 -cycloalkyl, or phenyl;
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of halogen, cyano, lower alkyl, lower alkoxy, and oxy-lower alkylene-oxy, R 3 represents hydrogen;
  • X represents N or CH; and the integer n is 0 or 1 ; wherein any aryl moiety, if not designated otherwise, and the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, lower alkyl, halo-lower alkyl, lower alkoxy, hydroxy, and hydroxy-lower alkoxy.
  • the invention relates especially to a method of treatment of and prophylaxis disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents a single bond or lower alkylene;
  • R represents hydrogen, amino which is disubstituted by by C 2 -C 6 -alkylene, especially pentylene, or C 1 -C 4 -alkoxy, especially methoxy; or a group selected from -NH-SO 2 -R , -SO 2 - R, or -SO 2 -NH-R, [R being C C 4 -alkyl, or naphthyl, or the group -NH(R) represents amino which is mono-substituted by CrC 4 -alkyl, by hydroxy-C ⁇ -C 4 -alkyl, or by naphthyl, or which is di-substituted by C--C 4 -alkyl or by C 2 -C e -alkylene ⁇ which may be interrupted by O or NR 0 , R 0 being hydrogen or d-C 4 -alkyl ⁇ ]; and, in each case,
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, C C -alkyl, CrC 4 -alkoxy, and oxy- C ⁇ -C 4 -alkylene-oxy; and
  • R 3 represents hydrogen
  • X represents N or CH; and the integer n is 0 or 1 ; wherein the benzo ring A is unsubstituted or substituted by C ⁇ -C 4 -alkoxy.
  • the invention relates especially to a method of treatment of and prophylaxis disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents -(CH 2 ) n - and the integer n is 1 -3; Ri represents the group of formula NH-SO 2 -R and R is naphthyl; R 2 and R 3 each are hydrogen; X is N or CH; and the ring A is unsubstituted or substituted by C ⁇ -C 4 -alkoxy, especially methoxy.
  • the invention relates especially to a method of treatment of and prophylaxis disorders and diseases associated with NPY receptor subtype Y5 comprising administering to a warm ⁇ blooded animal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents -(CH 2 ) 0 - and the integer o is 1 or 2; R T represents the group of formula NH- SO 2 -R and R is naphthyl; R 2 and R 3 each are hydrogen; X is CH; the integer n is 1 ;and the ring A is unsubstituted.
  • a compound of formula (I) or a pharmaceutically acceptable salt thereof in which alk represents -(CH 2 ) 0 - and the integer o is 1 or 2; R T represents the group of formula NH- SO 2 -R and R is naphthyl; R 2 and R 3 each are hydrogen; X is CH; the integer n is 1 ;and the ring A is
  • the invention likewise relates to a new compound of formula (I) or a salt thereof as described hereinbefore or hereinafter.
  • the invention relates especially to a new compound of formula (I) or a salt thereof, e.g. in which alk represents a single bond or lower alkylene; the integer n is 0 or 1 ,
  • R T represents (vi) a group selected from -CH(OH)-R, -CO-R, -NR0 1 -CO-O-R, -NR 01 -CO-R, -NR 0 ⁇ -CO-NR 0 r R, -NR D1 -SO 2 -R, -NR 0 ,-SO2-NRoi-R, -SO 2 -R, -SO 2 -NR 0 ⁇ -R, or -SO 2 -NR 01 -CO-R, [R and R, being as defined below, or the group -N(R)(R 0 ⁇ ) represents ammo which is di-substituted by lower alkylene ⁇ which may be interrupted by O, S(O) ⁇ or NR 0 or which may be condensed at two adjacent carbon atoms with a benzene ring ⁇ ]; or
  • R 2 and R 3 independently of one another, represent (i) hydrogen, lower alkyl, lower alkenyl, iower alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C ⁇ -cycloalkyl- lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (II) Iower alkyl which is substituted by a substituent selected from the group consisting of halogen, hydroxy, Iower alkoxy, hydroxy-lower alkoxy, Iower alkoxy-lower alkoxy, am o, substituted amino, carboxy, lower alkoxy-carbonyl, lower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, N-substituted carbamoyl, and -S
  • R and R 3 together represent Iower alkylene [which may be interrupted by O, S(O)neig, NRo or which may be condensed at two adjacent carbon atoms with a benzene ring];
  • X represents N or CH; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, Iower alkyl, lower alkenyl, Iower alkynyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, Iower alkoxy, Iower alkenyloxy, Iower alkynyloxy, oxy-lower alkylene-oxy, hydroxy, Iower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, Iower alkanoyl, (carbocyclic or
  • Iower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl- lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • Iower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, C 3 -C 8 -cycioalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryloxy, (carbocyclic or heterocyclic) aryl, amino, substituted amino, carboxy, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl- lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl; (iv) amino, substituted amino;
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents a single bond or Iower alkylene;
  • Ri represents (vi) a group selected from -CH(OH)-R, -CO-R, -NRorCO-O-R, -NR o CO-R, -NR,-CO-NR 01 - R, -NRorSO 2 -R, -NR 0 ⁇ -SO 2 -NRo ⁇ -R, -SO 2 -R, -SO 2 -NR 0 ⁇ -R, or -SO 2 -NR 0 ⁇ -CO-R, [R and R-, being as defined below, or the group -N(R)(R 0 ⁇ ) represents amino which is di-substituted by Iower alkylene ⁇ which may be interrupted by O, S(O) n or NR 0 ⁇ or which is di-substituted by Iower alkylene which is condensed at two adjacent carbon atoms with a benzene ring]; or (vii) an element of formula -X ⁇ (X 2 )(Xs) wherein
  • R 2 and R 3 independently of one another, represent (i) hydrogen, Iower alkyl, Iower alkenyl, C 3 -C 8 -cycloalkyl, C 3 -C 8 -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, (carbocyclic or heterocyclic) aryl-lower alkyl; or (ii) Iower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, amino, substituted amino, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, substituted carbamoyl, and -S(O) n -R; R 2 and R 3 together represent lower alkylene [which may be interrupted by O, S(O) n , or NR
  • X represents N or CH; and the integer n is 0 or 1 ; wherein, in each case, any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, as well as the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of (i) halogen, Iower alkyl, C 3 -C 8 -cycloalkyl, C 3 -C ⁇ -cycloalkyl-lower alkyl, (carbocyclic or heterocyclic) aryl, Iower alkoxy, Iower alkenyloxy, oxy-lower alkylene-oxy, hydroxy, Iower alkanoyloxy, (carbocyclic or heterocyclic) aryl-lower alkanoyloxy, Iower alkanoyl, (carbocyclic or heterocyclic) aryl-lower alkan
  • Iower alkyl which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, amino, substituted amino, carboxy, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • Iower alkoxy which is substituted by a substituent selected from the group consisting of: halogen, hydroxy, Iower alkoxy, C 3 -C 8 -cycloal yl, (carbocyclic or heterocyclic) aryloxy, amino, substituted amino, Iower alkoxy-carbonyl, Iower alkoxy-lower alkoxy-carbonyl, (carbocyclic or heterocyclic) aryl-lower alkoxy-carbonyl, carbamoyl, and N-substituted carbamoyl;
  • any aryl moiety, for example, of (carbocyclic or heterocyclic) aryl, aroyl, or aryloxy, respectively, is derived and selected from the group consisting of phenyl, biphenylyl, naphthyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, furyl, thienyi, pyridyl, indolyl, indazolyl, benzofuryl, benzothiophenyl, benzimidazolyl, quinolinyl, isoquinolinyl, or quinazol
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents a single bond or C ⁇ -C 3 -alkyiene;
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, Iower alkyl, Iower alkoxy, and oxy-lower alkylene-oxy;
  • R 3 represents hydrogen
  • X represents N or CH; wherein the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, Iower alkyl, halo-lower alkyl, iower alkoxy, hydroxy, hydroxy-lower alkoxy, and Iower alkoxy-lower alkoxy.
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents a single bond or C-,-C 3 -alkylene;
  • R T represents a group selected from -NR 0 r CO-R, -NR 0 ⁇ -SO 2 -R, -NRo -SO 2 -NR 0 ⁇ -R, -SO 2 -R, or -SO 2 -NR 01 -R, [R being Iower alkyl, halo- lower alkyl, phenyl, pyridyl, or naphthyl, R 0 , being hydrogen or Iower alkyl; or the group - N(R)(R 0 ⁇ ) represents amino which is mono-substituted by Iower alkyl, by hydroxy-lower alkyl, or by naphthyl, or which is di-substituted by Iower alkyl or by C 2 -C 6 -alkylene ⁇
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, Iower alkyl, Iower alkoxy, and oxy-lower alkylene-oxy;
  • R 3 represents hydrogen
  • X represents N or CH; wherein the benzo ring A is unsubstituted or substituted by one or more substituents selected from the group consisting of halogen, Iower alkyl, halo-lower alkyl, Iower alkoxy, hydroxy, hydroxy-lower alkoxy, and Iower alkoxy-lower alkoxy.
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents a single bond or C ⁇ -C 3 -alkylene;
  • R T represents (iv) a group selected from -NH-SO 2 -R , -SO 2 -R, or -SO 2 -NH-R, [R being C ⁇ -C 4 -alkyl, or naphthyl, or the group -NH(R) represents amino which is mono-substituted by C ⁇ -C 4 -alkyl, by hydroxy-C ⁇ -C 4 -alkyl, or by naphthyl, or which is di-substituted by C ⁇ -C 4 -alkyl or by C 2 -C 6 -alkyiene ⁇ which may be interrupted by O or NR 0 , R 0 being hydrogen or CrC 4 - alkyl ⁇ ]; and, in each case,
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by a substituent selected from the group consisting of: halogen, cyano, CrC 4 -alkyl, CrC 4 -alkoxy, and oxy- C--C 4 -alkylene-oxy; and
  • R 3 represents hydrogen
  • X represents N or CH; wherein the benzo ring A is unsubstituted or substituted by C,-C 4 -alkoxy.
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents a single bond or d- or C 2 -alkylene; and R-, represents -SO 2 -R or -SO 2 -
  • NH-R and R being naphthyl, especially 1 - or 2-naphthyl; and, in each case,
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by Iower alkoxy
  • R 3 represents hydrogen; and X represents CH; wherein the benzo ring A is unsubstituted or substituted by C,-C 4 -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.
  • the invention relates especially to a new compound of formula (I) or a salt thereof in which alk represents methylene; and Rt represents -SO 2 -NH-R and R being naphthyl, especially 1 - or 2-naphthyl; and, in each case,
  • R 2 represents hydrogen or phenyl which is unsubstituted or is substituted by Iower alkoxy
  • R 3 represents hydrogen
  • X represents CH; wherein the benzo ring A is unsubstituted or substituted by C ⁇ -C -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.
  • R 2 represents hydrogen
  • R 3 represents hydrogen
  • X represents CH; wherein the benzo ring A is unsubstituted or substituted by CrO t -alkoxy, especially, methoxy, preferably in position 8 of the quinazoline ring.
  • the invention relates in particular to the novel compounds shown in the examples and to the modes of preparation described therein.
  • the invention relates to processes for the preparation of the compounds according to the invention.
  • the preparation of new compounds of the formula (I) and their salts comprises, for example, (a) reacting a compound of formula (lla) or a salt thereof - 47
  • Z 2 is a leaving group, with a compound of formula HN(R 2 )(R 3 ) (1Mb) or a salt thereof, and, if desired, converting a compound (I) obtainable according to the process or in another manner, in free form or in salt form, into another compound (I), separating a mixture of isomers obtainable according to the process and isolating the desired isomer and/or converting a free compound (I) obtainable according to the process into a salt or converting a salt of a compound (I) obtainable according to the process into the free compound (I) or into another salt.
  • Salts of starting materials which have at least one basic centre, for example of the formula 11 lb, are appropriate acid addition salts, while salts of starting materials which have an acidic group, for example of the formula (lib), are present as salts with bases, in each case as mentioned above in connection with corresponding salts of the formula (I).
  • a leaving group Zi or Z 2 is, for example, reactive esterrfied hydroxy, or is R'-S(O) p - [the integer u being 0, 1 or 2 and R' being Iower alkyl, halo-lower alkyl or aryl, such as methyl, trifluoromethyl or p-toluyl], or is Iower alkoxy
  • Reactive esterrfied hydroxyl Z4 is in particular hydroxyl esterified with a strong inorganic acid or organic sulfonic acid, for example halogen, such as chlorine, bromine or iodine, sulfonyloxy, such as hydroxysulfonyloxy, halosulfonyloxy, for example fluorosulfonyloxy, C ⁇ C ⁇ alkane-sulfonyloxy which is unsubstituted or substituted, for example by halogen, for example methane- or t ⁇ fluoromethanesulfonyl
  • Preferred T or Z 2 is chloro, bromo or lodo, methanesulfonyloxy or t ⁇ fluoromethanesulfonyloxy, or p-toluenesulfonyloxy, or methylthio or methoxy
  • Suitable bases are, for example, alkaii metal hydroxides, hydrides, amides, alkanolates, carbonates, triphenylmethylides, di-lower alkylamides, aminoalkylamides or Iower alkylsilylamides, naphthaleneamines, Iower alkylamines, basic heterocycles, ammonium hydroxides, and carbocyclic amines.
  • Examples which may be mentioned are sodium hydroxide, sodium hydride, sodium amide, sodium methoxide, sodium ethoxide, potassium tert- butoxide, potassium carbonate, lithium triphenylmethylide, lithium diisopropylamide, potassium 3-(aminopropyl)amide, potassium bis(trimethylsilyl)amide, dimethylaminonaphthalene, di- or triethylamine, or ethyldiisopropylamine, N-methylpiperidine, pyridine, benzyltrimethylammonium hydroxide, 1 ,5-diazabicyclo[4.3.0]non-5-ene (DBN) and 1 ,8-diaza- bicyclo[5.4.0]undec-7-ene (DBU).
  • the starting material of fomulae (lla), (lib), (Ilia), and (lllb) is essentially known or is accessible analogously to preparation processes known per se.
  • R 2 represents N-acylated or N- alkylated amino, such as a group of formula -NRrCO-O-R, -NR ⁇ CO-R, -NR CO- NRrR, -NR 1 -SO 2 -R,-NR SO 2 -NR 1 -R, or N-substituted amino, is accessible, for example, by N-acylating or by N-alkylating, respectively, a, preferably N- protected, compound of the formula NH(R 1 )-alk 1 -X-alk 2 -Z 3 (lie) in which Z 3 represents a group which is convertable to R 2 , such as amino, carboxy, or hydroxy.
  • R 2 represents N-acylated or N- alkylated amino, such as a group of formula -NRrCO-O-R, -NR ⁇ CO-R, -NR CO- NRrR, -NR 1 -SO 2 -R,-NR SO 2 -NR 1 -R, or
  • protecting groups may be used, for example, t- butoxycarbonyl which will be splitt off after the N-acylation or the N-alkylation, respectively.
  • the starting material of formula (lib) in which R 2 represents carbamoyl or N-substituted carbamoyl, or esterified carboxy can be manufactured starting from a compound of formula (lie) in which Z 3 represents carboxy.
  • the esterification or amidation can be carried out in a manner known per se.
  • Starting fom a compound of formula (lie) in which Z 3 is hydroxy, corresponding etherified or esterified derivatices are accessible using etherification or esterifaction methods known in the art.
  • the starting material of formula (Ilia) is accessible, for example, by selectively converting the 4-Z 2 -group into a group which is desactivated, for example, by selectively hydrolyzing a compound of formula (Mic) or a salt thereof to form a corresponding 4-hydroxy-compound which is in the next step reacted with a compound of formula (lib) to introduce the corresponding side chain into position 2 of the quinazolin ring.
  • Reactivation of the 4-position for example, by reaction with a halogenating agent, such as POCI 3 , leads to corresponding compounds of formula (Ilia).
  • a compound according to the invention which is obtainable by the process can be converted into another compound according to the invention in a manner known per se
  • a compound according to the invention containing hydroxyl can be etherified by methods known per se.
  • the etherification can be carried out, for example, using an alcohol, such as a substituted or unsubstituted Iower alkanol, or a reactive ester thereof.
  • Suitable reactive esters of the desired alcohols are, for example, those with strong inorganic or organic acids, such as corresponding halides, sulfates, Iower alkanesulfonates or substituted or unsubstituted benzenesulfonates, for example chlorides, bromides, iodides, methane-, benzene- or p-toluenesulfonates.
  • the etherification can be carried out, for example, in the presence of a base, an alkali metal hydride, hydroxide or carbonate, or of an amine.
  • corresponding ethers such as Iower alkoxy compounds, can be cleaved, for example, by means of strong acids, such as mineral acids, for example the hydrohalic acids hydrobromic or hydriodic acid, which may advantageously be present in the form of pyridinium halides, or by means of Lewis acids, for example halides of elements of mam group III or the corresponding sub-groups.
  • reaction can be carried out, if necessary, with cooling or warming, for example in a temperature range from about -20° to about 100°C, in the presence or absence of a solvent or diluent, under inert gas and/or under pressure and, if appropriate, in a closed vessel.
  • Compounds according to the invention containing hydroxymethyl groups can be prepared, for example, starting from compounds containing corresponding carboxyl or esterified carboxyl, corresponding compounds being reduced in a manner known per se, for example by reduction with a hydride which, if desired, may be complex, such as a hydride formed from an element of the 1 st and 3rd main groups of the periodic table of the elements, for example borohydride or aiuminohydride, for example lithium borohydride, lithium aluminium hydride, diisobutylaluminium hydride (an additional reduction step using alkali metal cyanoborohydride, such as sodium cyanoborohydride, may be necessary), and also diborane.
  • a hydride which, if desired, may be complex, such as a hydride formed from an element of the 1 st and 3rd main groups of the periodic table of the elements, for example borohydride or aiuminohydride, for example lithium borohydride, lithium
  • Suitable oxidising agents for the oxidation to the suifoxide step are, for example, inorganic peracids, such as peracids of mineral acids, for example periodic acid or persulfuric acid, organic peracids, such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid, or mixtures of hydrogen peroxide and acids, for example a mixture of hydrogen peroxide with acetic acid.
  • inorganic peracids such as peracids of mineral acids, for example periodic acid or persulfuric acid
  • organic peracids such as appropriate percarboxylic or persulfonic acids, for example performic, peracetic, trifluoroperacetic or perbenzoic acid or p-toluenepersulfonic acid
  • mixtures of hydrogen peroxide and acids for example a mixture of hydrogen peroxide with acetic acid.
  • the oxidation is commonly carried out in the presence of suitable catalysts, catalysts which can be mentioned being suitable acids, such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid, or transition metal oxides, such as oxides of elements of sub-group VII, for example vanadium oxide, molybdenum oxide or tungsten oxide.
  • suitable acids such as substituted or unsubstituted carboxylic acids, for example acetic acid or trifluoroacetic acid
  • transition metal oxides such as oxides of elements of sub-group VII, for example vanadium oxide, molybdenum oxide or tungsten oxide.
  • the oxidation is carried out under mild conditions, for example at temperatures from about -50° to about +100°C.
  • the oxidation to the sulfone step may also be carried out appropriately at low temperatures using dinitrogen tetroxide as the catalyst in the presence of oxygen, just like the direct oxidation of (Iower) alkylthio to (Iower) alkanesulfonyl.
  • the oxidising agent is customarily employed in an excess. If one of the variables contains amino, corresponding compounds of the formula (I), their tautomers or salts can be N-alkylated in a manner known per se; likewise, carbamoyl or radicals containing carbamoyl can be N-alkylated.
  • the (aryl)alkylation is carried out, for example, using a reactive ester of an (aryl)C- j - C ⁇ alkyl halide, for example a bromide or iodide, (aryl)C-
  • Amino can also be
  • a group of this type can be converted into a free carboxyl group, for example by means of hydrolysis, for example in the presence of a basic agent, or of an acidic agent, such as a mineral acid.
  • Tert-butyloxycarbonyl for example, can furthermore be converted into carboxyl, for example in a manner known per se, such as treating with trihaloacetic acid, such as trifluoroacetic acid, and benzyloxycarbonyl can be converted into carboxyl, for example by catalytic hydrogenation in the presence of a hydrogenation catalyst, for example in the manner described below.
  • this can be converted into an esterified carboxyl group, for example, by treating with an alcohol, such as a Iower alkanol, in the presence of a suitable esterifying agent, such as an acid reagent, for exampie an inorganic or organic acid or a Lewis acid, for example zinc chloride, or a condensing agent which binds water, for example a carbodiimide, such as N,N'-dicyclohexylcarbodiimide, or by treating with a diazo reagent, such as with a diazo-lower alkane, for example diazomethane.
  • an alcohol such as a Iower alkanol
  • a suitable esterifying agent such as an acid reagent, for exampie an inorganic or organic acid or a Lewis acid, for example zinc chloride
  • a condensing agent which binds water
  • a carbodiimide such as N,N'-dicyclohexylcarbodiimide
  • Compounds of the formula (I) which contain an esterified carboxyl group as a substituent can be transesterified into other ester compounds of the formula (I) by transesterification, for example by treating with an alcohol, customarily a higher appropriate alcohol than that of the esterified carboxyl group in the starting material, in the presence of a suitable transesterifying agent, such as a basic agent, for example an alkali metal (C T C / Jalkanoate, (d-C 7 )alkanolate or alkali metal cyanide, such as sodium acetate, sodium methoxide, sodium ethoxide, sodium tert-butoxide or sodium cyanide, or a suitable acid agent, if appropriate with removal of the resulting alcohol, for example by distillation.
  • a suitable transesterifying agent such as a basic agent, for example an alkali metal (C T C / Jalkanoate, (d-C 7 )alkanolate or alkali metal cyanide, such as
  • activated esters of the formula (I) which contain an activated esterified carboxyl group as a substituent may also be used as starting materials (see below), and these may be converted into another ester by treating with a (C 1 -C7)- alkanol.
  • this can also first be converted into a reactive derivative, such as an anhydride, including a mixed anhydride, such as an acid halide, for example an acid chloride (for example by treating with a thionyl halide, for example thionyl chloride), or an anhydride using a formic acid ester, for example a (C ⁇ -C7)alkyl ester (for example by treating a salt, such as an ammonium or alkali metal salt, with a haloformic acid ester, such as a chloroformic acid ester, such as a (C-
  • an activated ester such as a 4-nitrophenyl ester
  • a compound of the formula (I) containing a carboxyl group can first be reacted with a 1 -unsubstituted imidazole and the 1-imidazolylcarbonyl compound obtained in this way brought to reaction with an amine.
  • other non-activated esters such as (C-
  • an aromatic ring in the compounds according to the invention contains an amino group
  • this can be diazotized in a customary manner, for example by treating with a nitrite, for example sodium nitrite, in the presence of a suitable protonic acid, for example a mineral acid, the reaction temperature advantageously being kept below about 5°C.
  • a nitrite for example sodium nitrite
  • a suitable protonic acid for example a mineral acid
  • the diazonium group present in the salt form and obtainable in this way can be substituted by analogous processes, for example as follows: by the hydroxyl group analogously to the boiling-out of phenol in the presence of water; by an alkoxy group by treating with an appropriate alcohol, energy having to be added; by the fluorine atom analogously to the Schiemann reaction in the thermolysis of corresponding diazonium tetrafluoro bo rates; by the halogen atoms chlorine, bromine or iodine and also the cyano group analogously to the Sandmeyer reaction in the reaction with corresponding Cu(l) salts, initially with cooling, for example to below about 5°C, and then heating, for example to about 60° to about 150°C.
  • the compounds of the formula (I) contain unsaturated radicals, such as (Iower) alkenyl or (Iower) alkynyl groups, these can be converted into saturated radicals in a manner known per se.
  • unsaturated radicals such as (Iower) alkenyl or (Iower) alkynyl groups
  • these can be converted into saturated radicals in a manner known per se.
  • multiple bonds are hydrogenated by catalytic hydrogenation in the presence of hydrogenation catalysts, suitable catalysts for this purpose being, for example, nickel, such as Raney nickel, and noble metals or their derivatives, for example oxides, such as palladium or platinum oxide, which may be applied, if desired, to support materials, for example to carbon or calcium carbonate.
  • the hydrogenation may preferably be carried out at pressures between 1 and about 100 at and at room temperature between about -80° to about 200°C, in particular between room temperature and about 100°C.
  • the reaction is advantageously carried out in a solvent, such as water, a Iower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a Iower alkanecarboxylic acid, for example acetic acid.
  • a solvent such as water, a Iower alkanol, for example ethanol, isopropanol or n-butanol, an ether, for example dioxane, or a Iower alkanecarboxylic acid, for example acetic acid.
  • halogen such as chlorine
  • halogen can be replaced by reaction with a substituted or unsubstituted amine, an alcohol or a mercaptan.
  • the invention relates in particular to the processes described in the examples.
  • Salts of compounds of the formula (I) can be prepared in a manner known per se.
  • acid addition salts of compounds of the formula (I) are obtained by treating with an acid or a suitable ion exchange reagent. Salts can be converted into the free compounds in a customary manner, and acid addition salts can be converted, for example, by treating with a suitable basic agent.
  • the compounds according to the invention having salt-forming, in particular basic properties can be obtained in free form or preferably in the form of salts.
  • novel compounds can be present in the form of one of the possible isomers or as mixtures thereof, for example as pure optical isomers, such as antipodes, or as isomer mixtures, such as racemates, diastereoisomer mixtures or racemate mixtures, depending on the number of asymmetric carbon atoms.
  • the invention also relates to those embodiments of the process, according to which a compound obtainable as an intermediate in any step of the process is used as a starting material and the missing steps are carried out or a starting material in the form of a derivative or salt and/or its racemates or antipodes is used or, in particular, formed under the reaction conditions ln the process of the present invention, those starting materials are preferably used which lead to the compounds described as particularly useful at the beginning.
  • the invention likewise relates to novel starting materials which have been specifically developed for the preparation of the compounds according to the invention, to their use and to processes for their preparation, the variables alk, Ri, R 2l R 3 . and X having the meanings indicated for the preferred compound groups of the formula (I) in each case.
  • the invention likewise relates to pharmaceutical preparations which contain the compounds according to the invention or pharmaceutically acceptable salts thereof as active ingredients, and to processes for their preparation.
  • compositions according to the invention which contain the compound according to the invention or pharmaceutically acceptable salts thereof are those for enteral, such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • enteral such as oral, furthermore rectal, and parenteral administration to (a) warm-blooded animal(s), the pharmacological active ingredient being present on its own or together with a pharmaceutically acceptable carrier.
  • the daily dose of the active ingredient depends on the age and the individual condition and also on the manner of administration.
  • compositions for oral use can be obtained by combining the active ingredient with solid carriers, if desired granulating a mixture obtained, and processing the mixture or granules, if desired or necessary, after addition of suitable excipients to give tablets or sugar-coated tablet cores.
  • Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol, cellulose preparations and/or calcium phosphates, for example tricalcium phosphate or calcium hydrogen phosphate, furthermore binders, such as starch paste, using, for example, corn, wheat, rice or potato starch, gelatin, tragacanth, methylcellulose and/or polyvinylpyrrolidone, if desired, disintegrants, such as the abovementioned starches, furthermore carboxymethyi starch, crosslinked polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate; auxiliaries are primarily glidants, flow-regulators and lubricants, for example silicic acid, talc, stearic acid or salts thereof, such as magnesium or calcium stearate, and/or polyethylene glycol.
  • fillers such as sugars, for example
  • Sugar-coated tablet cores are provided with suitable coatings which, if desired, are resistant to gastric juice, using, inter alia, concentrated sugar solutions which, if desired, contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of gastric juice-resistant coatings, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. Colorants or pigments, for example to identify or to indicate different doses of active ingredient, may be added to the tablets or sugar-coated tablet coatings.
  • hard gelatin capsules and also soft closed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the hard gelatin capsules may contain the active ingredient in the form of granules, for example in a mixture with fillers, such as lactose, binders, such as starches, and/or lubricants, such as talc or magnesium stearate, and, if desired, stabilizers.
  • the active ingredient is preferably dissolved or suspended in suitable liquids, such as fatty oils, paraffin oil or liquid polyethylene glycols, it also being possible to add stabilizers.
  • Suitable rectally utilizable pharmaceutical preparations are, for example, suppositories, which consist of a combination of the active ingredient with a suppository base.
  • Suitable suppository bases are, for example, natural or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols.
  • gelatin rectal capsules which contain a combination of the active ingredient with a base substance may also be used.
  • Suitable base substances are, for example, liquid triglycerides, polyethylene glycols or paraffin hydrocarbons.
  • Suitable preparations for parenteral administration are primarily aqueous solutions of an active ingredient in water-soluble form, for example a water- soluble salt, and furthermore suspensions of the active ingredient, such as appropriate oily injection suspensions, using suitable lipophilic solvents or vehicles, such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides, or aqueous injection suspensions which contain viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers
  • suitable lipophilic solvents or vehicles such as fatty oils, for example sesame oil, or synthetic fatty acid esters, for example ethyl oleate or triglycerides
  • viscosity-increasing substances for example sodium carboxymethylcellulose, sorbitol and/or dextran, and, if necessary, also stabilizers
  • the dose of the active ingredient depends on the warm-blooded animal species, the age and the individual condition and on the manner of administration In the normal case, an approximate daily dose of about 10 mg to about 250 mg is to be estimated in the case of oral administration for a patient weighing approximately 75 kg
  • Example 1 Naphthalene-1 -sulfonic acid ⁇ 2-H-(4-amino-gu ⁇ nazolin-2-yl)-p ⁇ peridin-4-yll- ethyll-amide hydrochloride
  • the starting material can be prepared, for example, as follows:
  • Example 2 Naphthalene-1 -sulfonic acid f 1 -(4-amino-quinazolin-2-yl)-piperidin-4-ylmethyll- amide hydrochloride
  • the starting material can be prepared, for example, as follows: a) 4-[(Naphthalene-1 -sulfonylam ⁇ no)-methyll-p ⁇ per ⁇ d ⁇ ne-1 -carboxylic acid tert-butyl ester
  • Example 3 Naphthalene-1 -sulfonic acid 2-[4-(4-am ⁇ no-qu ⁇ nazol ⁇ n-2-yl)-p ⁇ peraz ⁇ n-1 -yll- ethyl ⁇ -am ⁇ de hydrochloride
  • the starting material can be prepared, for example, as follows:
  • the starting material can be prepared, for example, as follows
  • Example 5- Tablets each containing 50 mg of active ingredient, for example, naphthalene-1 -sulfonic acid ⁇ 2-[1 -(4-am ⁇ no-qu ⁇ nazol ⁇ n-2-yl)-p ⁇ per ⁇ d ⁇ n-4-yl]-ethyl ⁇ - amide hydrochloride, can be prepared as follows
  • composition for 10,000 tablets
  • the active ingredient is mixed with the lactose and 292 g of potato starch, and the mixture is moistened using an alcoholic solution of the gelatin and granulated by means of a sieve. After drying, the remainder of the potato starch, the talc, the magnesium stearate and the highly disperse silica are admixed and the mixture is compressed to give tablets of weight 145 0 mg each and active ingredient content 50.0 mg which, if desired, can be provided with breaking notches for finer adjustment of the dose
  • Coated tablets each containing 100 mg of active ingredient, for example, naphthalene-1 -sulfonic acid ⁇ 2-[1 -(4-am ⁇ no-qu ⁇ nazol ⁇ n-2-yl)-p ⁇ per ⁇ d ⁇ n-4- yl]-ethyl ⁇ -amide hydrochloride, can be prepared as follows:
  • Composition for 1000 tablets:
  • the active ingredient, the lactose and 40 g of the corn starch are mixed and moistened and granulated with a paste prepared from 15 g of corn starch and water (with warming).
  • the granules are dried, and the remainder of the corn starch, the talc and the calcium stearate are added and mixed with the granules.
  • the mixture is compressed to give tablets (weight: 280 mg) and these are coated with a solution of the hydroxypropylmethylcellulose and the shellac in dichloromethane (final weight of the coated tablet: 283 mg).
  • Example 7 Tablets and coated tablets containing another compound of the formula (I) or a pharmaceutically acceptable salt of a compound of the formula (I), for example as in one of Examples 1 to 4, can also be prepared in an analogous manner to that described in Examples 5 and 6.
  • GGT TTT GCC ATC TGT TCT CCC CTT CCA GTG TTT CAC
  • GGT CTT GTG GAA 636 Gly Phe Ala He Cys Ser Pro Leu Pro Val Phe His Ser Leu Val Glu 180 185 190

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

Abstract

L'invention concerne une méthode de traitement de troubles et maladies associés au sous-type Y5 du récepteur du neuropeptide Y, laquelle consiste à administrer à un animal à sang chaud nécessitant un tel traitement, notamment à l'homme, une dose efficace sur le plan thérapeutique d'un composé de la formule (I) dans laquelle les variables sont telles que définies. L'invention se rapporte également à des nouveaux composés de la formule (I) ou à un sel de ceux-ci, à des compositions pharmaceutiques ainsi qu'à la production de ces nouveaux composés et des sels de ceux-ci.
PCT/EP1996/005055 1995-12-01 1996-11-18 Composes heteroaryles WO1997020820A1 (fr)

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AU76264/96A AU7626496A (en) 1995-12-01 1996-11-18 Heteroaryl compounds

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US56634995A 1995-12-01 1995-12-01
US08/566,349 1995-12-01

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Cited By (124)

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US6645774B1 (en) 1994-12-02 2003-11-11 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior using compounds with afinity for the human hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5)
US6818445B2 (en) 1994-12-02 2004-11-16 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5)
EP1007073A1 (fr) * 1996-06-04 2000-06-14 Synaptic Pharmaceutical Corporation Procedes de modification du comportement alimentaire, composes utiles dans lesdits procedes, et adn codant un recepteur y5 atypique hypothalamique de neuropeptide y/peptide yy
EP1007073A4 (fr) * 1996-06-04 2002-03-27 Synaptic Pharma Corp Procedes de modification du comportement alimentaire, composes utiles dans lesdits procedes, et adn codant un recepteur y5 atypique hypothalamique de neuropeptide y/peptide yy
US6713265B1 (en) 1997-06-04 2004-03-30 Synaptic Pharmaceutical Corporation Methods of modifying feeding behavior, compounds useful in such methods, and DNA encoding a hypothalamic atypical neuropeptide Y/peptide YY receptor (Y5)
WO1999027965A1 (fr) * 1997-11-28 1999-06-10 Banyu Pharmaceutical Co., Ltd. Agents anti-hyperlipemiques
US6187777B1 (en) 1998-02-06 2001-02-13 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
US6583154B1 (en) 1998-02-06 2003-06-24 Amgen Inc. Compounds and methods which modulate feeding behavior and related diseases
US6518265B1 (en) 1998-08-12 2003-02-11 Hokuriku Seiyaku Co., Ltd. 1H-imidazopyridine derivatives
US6191160B1 (en) 1998-11-10 2001-02-20 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6495559B2 (en) 1998-11-10 2002-12-17 Merck & Co., Inc. NPY Y5 receptor antagonists
US6313298B1 (en) 1998-11-10 2001-11-06 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6638942B1 (en) 1998-11-10 2003-10-28 Merck & Co., Inc. Spiro-indolines as Y5 receptor antagonists
US6407120B1 (en) 1999-02-18 2002-06-18 Pfizer Inc. Neuropeptide Y antagonists
US6713473B1 (en) 1999-04-20 2004-03-30 Meiji Seika Kaisha, Ltd. Tricyclic compounds
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