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WO1999067235A1 - Composes cycliques a cinq elements - Google Patents

Composes cycliques a cinq elements Download PDF

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Publication number
WO1999067235A1
WO1999067235A1 PCT/JP1999/003288 JP9903288W WO9967235A1 WO 1999067235 A1 WO1999067235 A1 WO 1999067235A1 JP 9903288 W JP9903288 W JP 9903288W WO 9967235 A1 WO9967235 A1 WO 9967235A1
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Prior art keywords
group
optionally substituted
substituted
pharmaceutically acceptable
ring
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PCT/JP1999/003288
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English (en)
Japanese (ja)
Inventor
Kazuhiko Okazaki
Yasuyuki Ueki
Kazuo Kumagai
Jun Nagamine
Hitoshi Seki
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Sumitomo Pharmaceuticals Co., Ltd.
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Publication of WO1999067235A1 publication Critical patent/WO1999067235A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems

Definitions

  • the present invention relates to a five-membered ring compound useful as a growth hormone release enhancer or the like.
  • growth hormone is the most important factor in growth, since excessive secretion of growth hormone causes giantosis and acromegaly and growth hormone deficiency causes dwarfism. It is clear that this is a factor.
  • growth hormone is known to have basic effects on the body's metabolic processes, such as increasing the rate of protein synthesis, decreasing the rate of carbohydrate utilization, increasing the distribution of free fatty acids, and increasing fatty acid utilization.
  • Various substances that have the effect of releasing growth hormone are known, such as arginine, L-3,4-dihydroxyphenylalanine (L-DOPA), glucagon, vasoprescine, and insulin that induces hypoglycemia.
  • L-DOPA L-3,4-dihydroxyphenylalanine
  • glucagon glucagon
  • vasoprescine vasoprescine
  • insulin that induces hypoglycemia.
  • activities such as sleep and exercise also have the effect of releasing growth hormone.
  • GRF growth hormone-releasing factor
  • GRF growth hormone-releasing factor
  • growth hormone is derived from pituitary pituitary gland or is a recombinant product, but these are very expensive and pituitary gland extract is a source of disease-related growth hormone associated with the source of the material. With the danger of transmission to the elderly. Growth hormone is difficult to administer orally, so it was necessary to administer it by injection or nasal spray.
  • a second way to increase growth hormone levels in the body is to use endogenous GRF or its derivatives (Schoen WR et al., "Growth hormone secretagogues" in Annual Reports in Medicinal Chemistry, Academic Press, Vol.
  • UK Patent 2,297,972 describes non-peptidic compounds useful as growth hormone release enhancers.
  • the compound is stable in a variety of physiological environments and has not yet reached potential clinical applications where it can be administered by the parenteral, nasal, or oral route. Disclosure of the invention
  • the present inventors have studied various non-peptidic compounds, and have found that a five-membered ring compound or a pharmaceutically acceptable salt thereof is useful as a growth hormone release-enhancing agent that is pharmaceutically applicable. Thus, the present invention has been completed.
  • the present invention relates to the following [1] to [10].
  • ring A represents a substituted or unsubstituted 5-membered hydrocarbon ring or a substituted or unsubstituted 5-membered heterocyclic ring.
  • X represents a single bond or a chain divalent group having 1 to 5 chain atoms.
  • R 1 represents a hydrogen atom, an optionally substituted aryl group or an optionally substituted unsaturated heterocyclic group.
  • R 2 represents a hydrogen atom, an optionally substituted alkyl group, an optionally substituted alkenyl group or an optionally substituted alkynyl group.
  • R 3 is an amino group which may be substituted, an aminoalkyl group which may be substituted, an optionally substituted nitrogen-containing heterocyclic group, or an alkyl group which may be substituted or substituted with a nitrogen-containing heterocyclic group. Represents a group.
  • R 4 and R 5 are as described in (1) or (2) below.
  • R 4 represents a group represented by the formula: Ar 1
  • R 5 represents a hydrogen atom or a lower alkyl group.
  • Ar is an optionally substituted phenyl group, an optionally substituted naphthyl group, an optionally substituted tetrahydronaphthyl group, an optionally substituted indenyl group, an optionally substituted indenyl group or an optionally substituted
  • R 6 is alkylene having 1 to 4 carbon atoms which may be substituted, alkenylene having 2 to 4 carbon atoms which may be substituted, alkynylene having 2 to 4 carbon atoms which may be substituted or substituted.
  • Ring Q represents a saturated nitrogen-containing heterocyclic ring.
  • E represents a hydrogen atom bonded to a benzene ring, or optionally substituted ethylene, optionally substituted vinylene, one CH 2 N (R 8 ) — and single N (R 8) CH 2 - .
  • R 7 is a hydrogen atom or a substituent
  • R 8 represents a hydrogen atom, a lower alkyl group, a lower alkanoyl group or a lower alkylsulfonyl group.
  • Ring A is cyclopentene, cyclopentadiene, pyrazol, thiophene, furan, pyrrol, imidazole, isothiazol, isoxazol, pyrroline, triazol or virazoline, or substituted
  • X is a single bond, optionally substituted alkylene having 2 to 4 carbon atoms, optionally substituted, alkenylene having 2 to 4 carbon atoms, optionally substituted, carbon atom 2 to 4 alkynylenes, one NH—CO—, one CO—NH—, one CH 2 — 0—, one CO—NH—CH 2 —, one NH—CO—CH 2 —, one CH 2 — CO—
  • the five-membered ring compound according to any one of [1] to [3], which is NH— or one CH 2 —NH—CO—, or a pharmaceutically acceptable salt thereof.
  • E and R 7 have the same meanings as in [1], wherein E is a divalent group.
  • the group represented by R 4 and R 5 together with a nitrogen atom may be a substituted spiro (indane-1,4′-piperidine) monopropyl group, an optionally substituted 1, 2 Dihydrospiro (3H-indole-1, 4'-piperidine) — di-yl group, optionally substituted 4-1-phenylbiperazine-11-yl group, optionally substituted 4-phenylpyridin Lysine 1-yl group, optionally substituted 3-phenylpropyl group, optionally substituted 1-naphthylmethyl group, optionally substituted 2-naphthylmethyl group, optionally substituted 2- ( A five-membered ring compound according to [6] or a 2,3-dihydro-2-indolyl) ethyl group or an optionally substituted 2- (1,2,3,4-tetrahydro-2-quinolyl) ethyl group; Pharmaceutically acceptable salts.
  • a medicament comprising the five-membered ring compound of any one of [1] to [9] or a pharmaceutically acceptable salt thereof.
  • [12] A method for treating a disease caused by growth hormone deficiency by administering the five-membered ring compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [9].
  • the “five-membered hydrocarbon ring” and the “five-membered heterocyclic ring” in ring A have two or more consecutive sp 2 carbon atoms or two nitrogen atoms as described above. Specific examples of such rings include unsaturated 5-membered hydrocarbon rings such as cyclopentene and cyclopentadiene, pyrazole, thiophene, furan, pyrrole, imidazole, isothiazole, isoxazole, and pyrroline. And unsaturated 5-membered heterocycles containing 13 heteroatoms selected from nitrogen, oxygen and sulfur such as triazole and virazoline. Preferred and five-membered heterocycles include, for example, virazole.
  • the “chain divalent group having 15 chain atoms” is, for example, a chain composed of 15 atoms selected from the group consisting of carbon, nitrogen, oxygen and sulfur atoms. Divalent groups. Specifically, alkylene having 14 carbon atoms which may be substituted, alkylene which may be substituted, alkenylene having 24 carbon atoms, and alkylene having 24 carbon atoms, An amide bond, a thioamide bond, a sulfonamide bond, an ester bond, an ether bond, a thioether bond, a sulfinyl, a sulfonyl, a urea bond, a urethane bond, an imide bond, etc.
  • One CO— CH 2 —, One CO— CH 2 — CH 2 — CO—, One CO— CH CH— CO—, One CH 2 — CH 2 — NH—CO—, One CH 2 — CH 2 — C 0 — NH—, one CH 2 — NH— CO— CH 2 —, — CH 2 — CO—NH CH 2 —, one NH—CO—CH 2 one CH 2 —, one CO—NH—CH 2 — CH 2- , One CH 2 — CH 2 — NH— CS—, -CH 2 one CH 2 — CS— NH—, one CH 2 — NH— CS— CH 2 —, one CH 2 — CS— NHCH 2 one, one NH— CS— CH 2 —, one CH 2 — CS— NHCH 2 one, one NH—
  • Examples of preferred chain divalent groups include, for example, optionally substituted alkylene having 2 to 4 carbon atoms, optionally substituted alkylene having 2 to 4 carbon atoms, and optionally substituted carbon.
  • ethylene which may be substituted and trimethylene which may be substituted.
  • alkylene having 1 to 4 carbon atoms examples of the alkylene having 1 to 4 carbon atoms, alkenylene having 2 to 4 carbon atoms and alkynylene having 2 to 4 carbon atoms are CH 2 — and —CH 2 —CH 2 — —CH 2 —CH 2 —CH, respectively.
  • saturated heterocyclic group examples include monocyclic rings containing one to three nitrogen atoms, oxygen atoms, and Z or sulfur atoms such as piperidyl, piperazinyl, morpholyl, piperidyl, virazolidyl, and tetrahydrofuryl. Or a bicyclic 5- to 7-membered saturated heterocyclic group.
  • the “unsaturated heterocyclic group” include pyridyl, virazyl, indolyl, isoindolyl, isothiazolyl, isobenzofuranyl, chromenyl, pyrrolyl, furyl, phenyl, quinolyl, isoquinolyl, thiazolyl, imidazolyl, pyrimidinyl, and thiazilyl.
  • the “nitrogen-containing heterocyclic group” may be, for example, a monocyclic or bicyclic monocyclic or bicyclic group containing one nitrogen atom, and may further contain one or two nitrogen atoms, oxygen atoms and Z or sulfur atoms.
  • a 5- to 7-membered heterocyclic group is preferred, and a saturated nitrogen-containing heterocyclic group is preferred.
  • the “saturated nitrogen-containing heterocyclic group” includes, for example, a monocyclic or bicyclic saturated ring containing one nitrogen atom, and may further contain up to two nitrogen atoms, oxygen atoms and Z or sulfur atoms. 5- to 7-membered heterocyclic groups. Preferably, a monocyclic or bicyclic saturated heterocyclic group containing 1 to 3 nitrogen atoms is mentioned, and more preferably, a 5- to 7-membered monocyclic saturated heterocyclic group containing 1 nitrogen atom.
  • Heterocyclic group power specifically, Piberidylka S, and particularly preferably, 3-piridyl.
  • the “saturated nitrogen-containing heterocycle” represented by ring Q includes, for example, one nitrogen atom, and further contains one or two nitrogen atoms, oxygen atoms, and nitrogen or sulfur atoms.
  • the monocyclic or bicyclic saturated 5- to 7-membered heterocyclic force can be mentioned.
  • Preferable is a monocyclic or bicyclic saturated heterocyclic force containing 1 to 3 nitrogen atoms ⁇ More preferably, a 6-membered monocyclic saturated heterocyclic ring containing 1 to 2 nitrogen atoms
  • Specific examples thereof include a piperidine ring and a piperidine ring. Examples include a azine ring and the like, and particularly preferred is a piperidine ring.
  • benzoheterocyclic group refers to a group formed by removing a hydrogen atom from a condensed ring that is bonded to a benzene ring and a heterocyclic ring, and examples of the heterocyclic ring constituting such a condensed ring include a monocyclic ring. Heterocyclic force.
  • Monocyclic heterocycles include monocyclic 5- to 7-membered saturated or unsaturated heterocycles containing from 1 to 3 nitrogen, oxygen and or sulfur atoms.
  • Preferred benzoheterocyclic groups include a benzene ring such as 2,3-dihydroindolyl, tetrahydrinoquinolyl, tetrahydroisoquinolyl, tetrahydroquinoxanyl, and tetrahydrophthalazyl, and a monocyclic ring containing one or two nitrogen atoms.
  • 5- to 7-membered condensed heterocyclic group consisting of a heterocyclic ring and a benzene ring such as indolyl, isoindolyl, quinolyl, isoquinolyl, and a monocyclic 5- to 7-membered ring containing one or two nitrogen atoms And a condensed heterocyclic group comprising an unsaturated heterocyclic ring.
  • the substitution position of the naphthyl group in Ar may be any of the 1-position and the 2-position, but preferably the 1-position.
  • the substitution position of the tetrahydronaphthyl group in Ar may be any, but preferably includes the 1- and 2-positions in 1,2,3,4-tetrahydronaphthalene, and particularly preferably the 1-position force.
  • the substitution position of the indenyl group in Ar may be any position, preferably 1 position, 2 position, or 3 position, particularly preferably 1 position.
  • the substitution position of the indanyl group in Ar may be any position, but is preferably a 1-position or 2-position force.
  • the substitution position of the benzoheterocyclic group in Ar may be any position, but is preferably a position force on the heterocyclic ring.
  • the substituent in the hydronaphthyl group, the substituted indenyl group, the substituted indanyl group and the substituted benzoheterocyclic group, and the substituent represented by R 7 may be one or more, and for example, any of the substituents exemplified below You can choose.
  • Examples of preferred substituents include a hydroxyl group, an amino group, an alksole group, a heterocyclic group, a carbamoyl group, a carboxyl group, an alkylsulfonyl group, a hydroxyalkyl group, a dihydroxyalkyl group, a trihydroxyalkynole group, and a valvamoyl group.
  • Examples thereof include an alkyl group, a carboxyalkyl group, and an alkylsulfonylamino group.
  • substituents examples include hydroxyl, 1 H-tetrazol-5-yl, carboxyl, hydroxyethyl, hydroxypropyl, dihydroxypropyl, and methylsulfonylamino groups.
  • Preferred examples of the substituent in the substituted aryl group, the substituted phenyl group and the substituted unsaturated heterocycle include a fluorine atom, a chlorine atom, a bromine atom, methylenedioxy, methoxy, ethoxy, benzyloxy, phenyl and the like.
  • alkyl group examples include a linear or branched alkyl group having 1 to 6 carbon atoms, and specifically, methyl, ethyl, propyl, 1-methylethyl, butyl, 2-methylpropyl, 1, 1 —Dimethylethyl, pentyl, 3-methylbutyl, hexyl, 4-methylpentyl and the like.
  • the lower alkyl group includes, for example, a linear or branched alkyl group having 1 to 3 carbon atoms.
  • alkyl and “lower alkyl” are described as part of another group in the present specification (for example, aminoalkyl, alkylsulfonyl, alkylsulfinyl, and alkylthio), the same examples as described above can be mentioned. Can be The same applies to the case where the group described below is a part of another group.
  • alkenyl group for example, a linear or branched alkenyl group having 2 to 6 carbon atoms can be mentioned, and specific examples thereof include vinyl, aryl, crotyl, methacryl, butadienyl, 2-pentenyl, 3-hexenyl and the like; ⁇ .
  • alkynyl group includes, for example, a linear or branched alkynyl group having 2 to 6 carbon atoms, and specific examples include ethynyl and 2-propynyl.
  • R 2 is an alkenyl group or alkynyl
  • examples when R 2 is an alkenyl group or alkynyl include, for example, vinyl, aryl, 2-propynyl and the like.
  • aryl group examples include aryl groups having 6 to 10 carbon atoms, and specific examples include phenyl, 1.1-naphthyl, 2-naphthyl and the like.
  • alkoxy group includes, for example, a linear or branched alkoxy group having 1 to 6 carbon atoms s ′, and specific examples thereof include methoxy, ethoxy, propoxy, 1-methylethoxy, butoxy, and 2-methyl. Examples include propoxy, 1,1-dimethylethoxy, pentoxy, 3-methylbutoxy, hexoxy, and 4-methylpentoxy.
  • Examples of the ⁇ alkanoinole group '' include straight-chain or branched alkanoisole groups having 1 to 6 carbon atoms, such as formyl, acetyl, propanoyl, butanol, pentanoyl, and hexanoyl.
  • Examples of the lower alkanoyl group include a linear or branched alkanoyl group having 1 to 3 carbon atoms.
  • cycloalkyl group examples include a cycloalkyl group having 3 to 8 carbon atoms, and specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and the like.
  • Alkylene includes straight-chain or branched-chain alkylene forces. Specific examples of alkylene having 1 to 4 carbon atoms include methylene, ethylene, ethylidene, propylene, trimethylene, tetramethylene, and 2-methyltrialkylene. Examples include methylene and the like.
  • Alkenylene includes straight-chain or branched-chain alkenylene, and specific examples of alkenylene having 2 to 4 carbon atoms include vinylene, vinylidene, propenylene, and butenylene. .
  • Alkynylene includes straight-chain or branched-chain alkynylene forces S.
  • alkynylene having 2 to 4 carbon atoms include ethynylene, propynylene, and petynylene.
  • the "cycloalkanediyl” includes, for example, cycloalkanediyl having 3 to 7 carbon atoms, and specifically, 1,2-cyclopropanediyl, 1,3-cyclobutanediyl, 1,3-cyclopentanediyl , 1,3-cyclohexandiyl, 1,4-cyclohexandiyl, 1,4-cycloheptandiyl and the like.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • Examples of the substituent in the substituted alkylene, substituted alkenylene, and substituted alkynylene also include an oxo group and a thioxo group.
  • the substituted aminoalkyl group includes, for example, a residue obtained by removing a carboxyl group from an amino acid.
  • the present invention relates to a method for separating a pure optical isomer, a partially purified optical isomer, a racemic mixture, or a diastereomer. It may be any of those mixtures as one and includes all such optical isomers.
  • the pharmaceutically acceptable salt of the five-membered ring compound for example, a salt with an inorganic acid or an organic acid can be mentioned.
  • the inorganic acid include hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, and the like.
  • examples include formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, citric acid, malonic acid, methanesulfonic acid and the like.
  • the five-membered ring compound of the present invention has an acidic functional group such as a carboxyl group, it may be converted into a salt with a base.
  • Examples of the salt with a base include salts with basic amino acids such as arginine and lysine, alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.
  • the present invention also includes solvates such as hydrates of the five-membered ring compound or a pharmaceutically acceptable salt thereof.
  • the five-membered ring compound of the present invention can be produced, for example, as follows.
  • the compound of formula 1 can be produced by reacting the compound of formula 2 with the compound of formula 3 by a peptide bond formation method, and subsequently reacting the compound of formula 4 by a peptide bond formation method.
  • the peptide bond generation method include a general peptide bond generation method described in “Peptide Synthesis” Maruzen Co., Ltd. 1975, “Peptide Synthesis Basics and Experiments” Maruzen Co., Ltd. 1985 and the like.
  • a preferred method for forming a peptide bond is an acid chloride method in which a carboxylic acid component is derived into a carboxylic acid chloride.
  • the reaction can be carried out by reacting a carboxylic acid chloride with an amine in an aprotic solvent such as pyridine in the presence of a non-protonic organic base such as 4-dimethylaminopyridine.
  • a compound that is R 2 hydrogen atom in Formula 1 a corresponding group R 2 (for example, an alkyl group which may be substituted) is introduced into the compound according to a general method.
  • Compounds of formula 1 can also be produced.
  • the compound of formula 3 is commercially available or can be obtained by a known method (Williams RM "Synthes is of Opt i cally Active ⁇ -amino Acids Pergamon Press, Vol. 7, 1989).
  • the amines of formula 4 are commercially available or Alternatively, it can be produced according to the method described in, for example, British Patent 2,297,972, Patchett AA et al., Proc. Natl. Acad. ScI., 92, 7001 (1995).
  • the compound of the formula 2 can be easily produced by combining known methods. Examples of known methods include the methods described in Oomprehensive Heterocyclic Chemistry “Pergamon Press, Vol. 4-6, 1984," The Chemistry of Heterocycl IC and ompounds "John Wiley & Sons Inc. 'No.
  • a compound of the formula 2 having a pyrazole ring can be produced according to the following production methods 1 and 2.
  • the compound of formula 7 can be obtained by reacting the compound of formula 5 with a commercially available compound of formula 6 to hydrolyze the ester and, if necessary, introducing a group represented by R 2. it can.
  • the reaction between the compound of the formula 5 and the compound of the formula 6 can be carried out, for example, by the method described in Schmidt P. et al., Helv. Chim. Acta., 36, 986 (1956). Ester hydrolysis is described, for example, in “New Experimental Chemistry Course 14 Syntheses and Reactions of Organic Compounds II” Maruzen Co., Ltd., 1978. It can be carried out by the method described in Maruzen 1992 or the like.
  • the compound of formula 6 is converted into an ester that can be deprotected by a reaction other than hydrolysis, such as t-butyl ester.
  • a reaction other than hydrolysis such as t-butyl ester.
  • Examples of the method for introducing the group represented by R 2 include a reductive amination reaction and the like.
  • the compound of formula 5 is commercially available or can be produced according to a known method (eg, Hoffman RV et al., Tetrahedron Lett., 31, 2953 (1990), etc.).
  • the compound of the formula 5 having —S 0 2 —NH— in the chain divalent group of X can be produced, for example, by using a usual sulfonamide bond forming method.
  • a sulfonyl chloride or the like can be reacted with an amine in an inert solvent such as acetonitrile in the presence of an aprotic organic base such as triethylamine.
  • the chain divalent group moiety of X can be prepared according to a general method generally used.
  • Amino acids having a pyrazonore ring of the formula 10 are, for example, a compound of the formula 8 and a commercially available compound of the formula 9 in the same manner as described in Tarzia G. et al. Farmaco.Ed.Sci., 39, 618 (1984). Can be produced by reacting The compound of formula 8 can be obtained as a commercial product, or can be obtained by a known method (for example, “New Experimental Chemistry Course 14 Synthesis and Reaction of Organic Compounds III” Maruzen Co., Ltd. 1978; Lecture 2 0 Organic Synthesis II —Alcohol '' Amine— ”Maruzen. 1992).
  • the functional group can be protected as required.
  • Protecting groups include known ones, which can be protected and deprotected by commonly used general methods (for example, Greene T., Wuts PGM “Protective Groups in Organic Synthesis” John Wiley & Sons Inc. ., 1991) c
  • the five-membered ring compound of the present invention can enhance the release of growth hormone endogenously, it has the same effects and uses as growth hormone.
  • Examples of uses of growth hormone include the following.
  • the five-membered ring compound and the like of the present invention can be applied not only to humans but also to various mammals such as mice, rats, dogs, horses, horses, goats, sheep, horses, and pigs.
  • the five-membered ring compound of the present invention can be administered by a usual administration route, for example, oral, intramuscular, intravenous, subcutaneous, intraperitoneal, intranasal or intracerebral administration.
  • the dose and frequency of administration vary depending on the animal species, administration route, degree of symptoms, body weight, etc., and are not particularly limited.In humans, however, usually about 1 ⁇ g to lg, preferably about l to 5 per adult per day. 0 mg is given once or more times.
  • Dosage forms include, for example, powders, fine granules, granules, tablets, capsules, suppositories, and injections! ], Nasal drugs and the like.
  • it can be produced by an ordinary method using a usual pharmaceutical carrier.
  • excipients and, if necessary, binders, disintegrants, lubricants, coloring agents, etc. are added to the active ingredient, and tablets, granules, powders, turnips, etc. Cell agents and the like can be used.
  • adjust pH Additives, stabilizers, solubilizers, etc. can be added to make injections in the usual manner.
  • amino acids protecting groups, active groups, solvents, and the like may be represented by abbreviations based on IUPAC-IUB and commonly used abbreviations in the art.
  • B oc means t-butyloxycarbonyl.
  • HPLC conditions used in the following examples are as follows.
  • Solution A water / 0.1% trifluoroacetic acid
  • Solution B acetonitrile / 0.1% trifluoroacetic acid
  • the intermediate (1-7) (54.5 mg) was dissolved in thionyl chloride (3.0 ml), 1 drop of dimethylformamide was added, the mixture was stirred at room temperature for 1.5 hours, and the reaction solution was concentrated under reduced pressure. To this, 40.7 mg of the intermediate (1-2), 52.6 mg of 4-dimethylaminopyridine, and 5 ml of pyridine were added, and the mixture was heated under reflux for 4 hours. After the reaction solution was concentrated under reduced pressure, ethyl acetate was added, and the mixture was washed sequentially with saturated aqueous sodium hydrogen carbonate, 1N aqueous hydrochloric acid, and saturated saline. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the obtained residue was purified by a silica gel column to obtain 63.6 mg (85%) of an intermediate (1-8).
  • the obtained demethylated product was dissolved in 30 ml of dioxane / aqueous solution (2: 1), 5.6 ml of a 1N aqueous solution of sodium hydroxide and 1.036 g of d-butyldicarbonate were added under ice cooling, and the mixture was stirred overnight.
  • Example 4 In the same manner as in the method described in Example 1, the intermediate (4-1-2) described in Example 4 was used in place of the intermediate (114), and the Example was used instead of the intermediate (1-2).
  • the reaction was carried out using the intermediate (3-8) described in 3 and purified by HPLC (using a 3 cm0 column, water-CH 3 CN-TFA system) to obtain 22.3 mg of the above compound.
  • Example 7 In the same manner as in the method described in Example 7, the intermediate (1-4) described in Example 1 was used in place of the intermediate (42), and Example 3 was used instead of the intermediate (1-2). Using the intermediate (3-8) described in (3), the above compound 33. Img was obtained.
  • the intermediate (18-2) (59.lmg) was dissolved in 1HBr / acetic acid (5ml), and the mixture was stirred under ice-cooling for 1 hour, and the reaction solution was concentrated under reduced pressure. The residue was dissolved in aqueous solution of acetonitrile Z and purified by HPLC (using a 3 cm 0 column, water-CH 3 CN-TFA system) to obtain 33.5 mg (59%) of compound (18-3).
  • FAB-MS 506 (M + H)
  • Other preferred five-membered ring compounds include, for example, the following compound or a pharmaceutically acceptable salt thereof.
  • the action of the five-membered ring compound of the present invention to enhance the release of growth hormone (GH) was measured with reference to the method described by Smith R. G. et al., Science, 260, 1640 (1993).
  • the pituitary gland excised from a 7-week-old male Wi star / ST rat was washed three times with HBSS (-), and then the tissue was minced with scissors so as to have an angle of about 1 awake.
  • the tissue was transferred to a 15 ml round-bottom centrifuge tube and washed three times with 10 ml HBSS (-).
  • 0.1 lml of enzyme solution per pituitary gland was calorie, and enzyme digestion was started in a 37 ° C water bath. Pipetting was performed every 5 minutes on the way, and the cells were treated for about 20 to 30 minutes until dispersed cells were obtained.
  • the mixture was centrifuged at 1,200 rpm for 2 to 3 minutes at room temperature, the supernatant was removed, and 8 ml of the culture solution was added.
  • Cells were seeded in a 96-well plate at 0.1 ⁇ 10 4 cells / 100 ⁇ 1 / well, and culture was started at 37 ° C. and 5% CO 2 .
  • Atsusi solution After culturing started 3 days, added Atsusi solution discarded supernatant, washed once with Atsusi was incubated for 1.5 hours, the test I ⁇ product solution in was 37 ° C, 5% C0 2 incubator one added 15 Allowed to react for minutes. After collecting the supernatant, the GH concentration in the supernatant was measured by the RIA method.
  • the EC5 () value (B) was obtained by regression calculation by substituting the compound concentration XnM used in the test and the measured GH concentration Yng / ml in the test supernatant into the following formula.
  • a and C both show the values obtained from the regression calculation, C shows the GH concentration in the supernatant without adding the Eich compound, and A shows the infinite X concentration of the X compound. The difference between the GH concentration and C in the culture supernatant in each case is shown.
  • the composition of the culture solution was 10% serum serum, 2.5% fetal serum, 1% non-essential amino acids, 1 antibiotic / DMEM, and the composition of Atsushi solution was 25 mM HEPES / culture solution (pH 7.3).
  • the test conjugate solution was prepared by adding 1 ml of the compound solution 1a1 adjusted to a 1000-fold concentration with DMS0 to 1 ml of Atsushi solution.
  • enzyme solution use Collagenase 400 mg, DNase type I lmg, BSA lg.
  • HEPES-Buffer (0.8% NaCU 0.037 % KC1, 0.% Glucose, 1% streptomycin 'Penicillium phosphorus, 0.7mM Na 2 HP0 4, 25mM HEPES (pH7.4)) was dissolved in 40ml, lmg / mlCaCl ⁇ ZS 1 was added, and HEPES-Buffer was added to a final volume of 50 ml. The mixture was sterilized by filtration through a 0.222111 filter and used.
  • a novel five-membered ring compound useful as a growth hormone release enhancer can be provided.

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Abstract

L'invention concerne des composés cycliques à cinq éléments représentés par la formule générale (1), qui sont utiles comme médicaments (par exemple, accélérateurs de la sécrétion d'hormone de croissance). Dans ladite formule, A est une chaîne hydrocarbure éventuellement substituée à cinq éléments ou un hétérocycle éventuellement substitué à cinq éléments; les atomes marqués '*' sont chacun indépendamment un atome de carbone sp2 ou un atome d'azote; X est une liaison unique ou un groupe à chaîne divalente dans lequel la chaîne comprend entre 1 et 5 atomes; R1 est hydrogène, aryle éventuellement substitué ou un groupe hétérocyclique insaturé éventuellement substitué; R2 est hydrogène, alkyle éventuellement substitué, alcényle éventuellement substitué ou alkynyle éventuellement substitué; R3 est amino éventuellement substitué, aminoalkyle éventuellement substitué, un groupe hétérocyclique azoté éventuellement substitué ou alkyle substitué par un groupe hétérocyclique azoté éventuellement substitué; R4 est un groupe représenté par la formule générale Ar-R6- ou autre; R5 est hydrogène, alkyle inférieur ou autre; Ar est phényle éventuellement substitué ou autre; et R6 est alkylène C¿1-4? éventuellement substitué ou autre.
PCT/JP1999/003288 1998-06-25 1999-06-18 Composes cycliques a cinq elements WO1999067235A1 (fr)

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase
US8293767B2 (en) 2005-01-21 2012-10-23 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09502961A (ja) * 1993-07-26 1997-03-25 メルク エンド カンパニー インコーポレーテッド 成長ホルモンの放出を促進するベンゾ−縮合ラクタム
WO1997023508A1 (fr) * 1995-12-22 1997-07-03 Novo Nordisk A/S Composes avec des proprietes de liberation de l'hormone de croissance

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH09502961A (ja) * 1993-07-26 1997-03-25 メルク エンド カンパニー インコーポレーテッド 成長ホルモンの放出を促進するベンゾ−縮合ラクタム
WO1997023508A1 (fr) * 1995-12-22 1997-07-03 Novo Nordisk A/S Composes avec des proprietes de liberation de l'hormone de croissance

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
VEINBERGS G, ET AL.: "A NEW METHOD FOR THE PREDICTION OF ANTIBACTERIAL PROPERTIES OF SEMISYNTHETIC PENICILINES. 2. ASSESMENT OF ACTIVITY LEVEL", CHEMISTRY OF HETEROCYCLIC COMPOUNDS, SPRINGER NEW YORK LLC, US, no. 05, 1 January 1989 (1989-01-01), US, pages 683 - 687, XP002926344, ISSN: 0009-3122 *
WAMHOFF H, WEHLING B: "PYRROLO¬2,3-D¾- UND PYRROLO¬1,2-ALPHA¾PYRIMIDINE AUS HETEROCYCLISCHEN BETA-ENAMINOESTERN BZW. -NITRILEN UND ISOCYANATEN UND ACETYLACETON", CHEMISCHE BERICHTE, VCH, DE, vol. 109, 1 January 1976 (1976-01-01), DE, pages 2983 - 2995, XP002926345, ISSN: 0009-2940 *
Y FULMER SHEALY, CLAYTON J D: "4-UREIDO- AND 4-AMINO-1,2,5-THIADIAZOLE-3-CARBOXYLIC ACID DERIVATIVES FROM Ä1,2,5ÜTHIADIAZOLOÄ3,4-DÜPYRIMIDINE-5,7(4H,6H)-DIONES", HETEROCYCLIC COMPOUNDS, XX, XX, vol. 38, 1 January 1964 (1964-01-01), XX, pages 8306, XP002926346 *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141585B2 (en) 2000-07-07 2006-11-28 Agouron Pharmaceuticals, Inc. Pyrazole derivatives
US8779147B2 (en) 2003-07-22 2014-07-15 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US9051278B2 (en) 2003-07-22 2015-06-09 Astex Therapeutics, Ltd. 3,4-disubstituted 1H-pyrazole compounds and their use as cyclin dependent kinase and glycogen synthase kinase-3 modulators
US8293767B2 (en) 2005-01-21 2012-10-23 Astex Therapeutics Limited 4-(2,6-dichloro-benzoylamino)-1H-pyrazole-3-carboxylic acid piperidin-4-ylamide acid addition salts as kinase inhibitors
US8404718B2 (en) 2005-01-21 2013-03-26 Astex Therapeutics Limited Combinations of pyrazole kinase inhibitors
US7728029B2 (en) 2006-03-22 2010-06-01 Hoffmann-La Roche Inc. Adamantyl-pyrazole carboxamides as inhibitors of 11β-hdroxysteroid dehydrogenase

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