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WO1999031062A1 - Nouveaux composes de pyridine - Google Patents

Nouveaux composes de pyridine Download PDF

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Publication number
WO1999031062A1
WO1999031062A1 PCT/JP1998/005561 JP9805561W WO9931062A1 WO 1999031062 A1 WO1999031062 A1 WO 1999031062A1 JP 9805561 W JP9805561 W JP 9805561W WO 9931062 A1 WO9931062 A1 WO 9931062A1
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WIPO (PCT)
Prior art keywords
substituted
unsubstituted
methoxyphenyl
alkyl
piperazine
Prior art date
Application number
PCT/JP1998/005561
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English (en)
Japanese (ja)
Inventor
Makoto Adachi
Takashi Sasatani
Nobuo Chomei
Yoshikazu Fukui
Mitsuru Yasui
Original Assignee
Shionogi & Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Shionogi & Co., Ltd. filed Critical Shionogi & Co., Ltd.
Priority to AU15045/99A priority Critical patent/AU1504599A/en
Priority to JP2000538989A priority patent/JP4321737B2/ja
Publication of WO1999031062A1 publication Critical patent/WO1999031062A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/70—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/62—Oxygen or sulfur atoms
    • C07D213/63—One oxygen atom
    • C07D213/68—One oxygen atom attached in position 4

Definitions

  • the present invention relates to a novel pyridine compound, a pharmacologically acceptable salt thereof, or a hydrate thereof.
  • the compounds of the invention from acting on 5- HT 7 (5-Hydroxy t ryp t ami ne 7) receptor, circadian rhythm disorders therapeutics, senile sleep disorder agent, anti Utsuyaku, antianxiety It is useful as a drug, a therapeutic agent for cardiovascular disorders, a therapeutic agent for migraine, and an analgesic.
  • Serotonin (5-hydroxytryptamine) is one of the physiologically active amines and functions as a kind of hormone. For example, it is present in the basal granule cells of the intestine and promotes intestinal motility. In addition, it is released into the blood from platelets during bleeding, and is involved in hemostasis by contracting capillaries.
  • serotonin also acts as a neurotransmitter in the brain and is involved in functions such as regulating the hypnotic-wake cycle, regulating pain thresholds, and regulating body temperature. Serotonin also plays a major role in mental activity, and these functions are expressed through serotonin receptors.
  • 5-HT 7 receptor mRNA in the central nervous system is highly distributed in hippocampus [/. Neurochem. 63 (1994) 456-464] and hypothalamus [. J. Pharmacol. ⁇ 7 (1995) 567-666] It is known.
  • the suprachiasmatic nucleus in the hypothalamus is said to be the source of circadian rhythm in mammals [J. Neurochem. 63— (1994) 456-464].
  • circadian rhythm disorders are associated not only with sleep disorders but also with depression [Psychiatry and Neuropharmacology, 11 (1996) 679-686]. Severe symptoms may lead to employment or inability to attend school. Many treatments have been tried for circadian rhythm abnormalities, but the effect is Not enough. In experimental systems in W ifo 5 recently - HT 7 receptor agonists have been reported to cause a change in the circadian rhythm [Neuron,] 1 (1 993 ) 449-458]. Accordance connection, 5 - HT 7 receptor agonists there is a possibility that can be a circadian rhythm disorder treatment drugs and senile sleep disorder treatment. It can also be an antidepressant because of the relationship between circadian rhythm disorders and depression. Furthermore, it is known that drugs with anxiolytic effects change the circadian rhythm [Psychiatry and Neuropharmacology, ⁇ (1996) 697-702], so they may be anxiolytics.
  • 5 - HT 7 receptor also has been shown to be distributed to the vascular system [. I ⁇ BS Le t t 370 (1 995) 21 5-221], 5- HT 7 receptor agonists vessel LS possible to expand is known I. Pharmacol. ⁇ (1 995) 383] 0 cerebral vasodilation from being said to cause migraine, 5-HT 7 receptor binding agent circulatory disorder treatment In addition to being a drug, the angelic gonist could be a migraine remedy. 5 - HT 7 receptors associated with pain has been suggested, 5-HT 7 receptor binding agents are also likely to be analgesic different type than the conventional.
  • An object of the present invention is to provide a novel 5-HT 7 receptor binding agent.
  • the present inventors have conducted intensive studies and found that the general formula (I)
  • Ar is substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl: is halogen, alkyl, alkenyl, alkyloxy, alkenyloxy, alkylthio, alkenylthio, substituted or unsubstituted alkylsulfonyloxy, alkenylsulfonyl Oxy, alkylsulfonyl, alkenylsulfonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio , substituted or unsubstituted Ariruchio, substituted or unsubstituted to the heteroaryl Arukiruokishi, substituted or unsubstituted ⁇ Li one Le sulfonyl O carboxymethyl, Heteroarir
  • a heterocyclic group may be formed:
  • R 8 is a hydrogen atom or alkyl: p is an integer of 2 to 4:
  • R 9 and R 1 () are each independently a hydrogen atom or alkyl):
  • R 2 And R 3 are each independently a hydrogen atom, substituted or unsubstituted alkyl, or R 2 and R 3 together form an substituted or unsubstituted heterocyclic group together with an adjacent nitrogen atom. May be:
  • Ar is a substituted or unsubstituted heteroaryl, is not alkyl, alkenyl or halogen. ), Or a pharmacologically acceptable salt, or a hydrate thereof.
  • the present invention provides, as an embodiment, a compound represented by the following general formula (II):
  • Ar is a substituted or unsubstituted aryl: R is an alkylsulfonyloxy, a substituted or unsubstituted arylalkyloxy, -OS0 2 NR 4 R 5 , or-0C0NR 4 R 5 (R 4 and R 5 is each independently hydrogen or an unsubstituted alkyl group): R 2 and R 3 To form a substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom: Compound (VI) wherein n is 1.
  • Ar is 3-hydroxyphenyl, 3-alkoxyphenyl or 3-halogenophenyl: Ri is methylsulfonyloxy: R 2 and R 3 are taken together with the adjacent nitrogen atom. -The compound (VI) of the above (1), which forms (2-hydroxyphenyl) piperazino.
  • Ar is 3-hydroxyphenyl, 3-methoxyphenyl or 3-fluorophenyl: R is methylsulfonyloxy: R 2 and R 3 are linked together with the adjacent nitrogen atom to form 4- ( (Hydroxyphenyl) Compound (VI) which forms piperazino.
  • the present invention provides a compound of the general formula (III):
  • Ar is a substituted or unsubstituted aryl or substituted or unsubstituted heteroaryl:
  • R is hydrogen, halogen, alkyl, alkenyl, alkyloxy, alkenyloxy, alkylthio, alkenylthio, substituted or unsubstituted alkylsulfonyloxy, a Lucenylsulfonyloxy, alkylsulfonyl, alkenylsulfonyl, alkylcarbonyloxy, alkenylcarbonyloxy, alkenylsulfonyloxy, substituted or unsubstituted arylalkyloxy, substituted or unsubstituted arylalkylthio, substituted or unsubstituted ⁇ Li one thio, terrorist ⁇ reel alkyl O carboxymethyl to the substituted or unsubstituted, substituted or unsubstituted ⁇ Li one Le sulfonyl
  • R 4 and R 5 are each independently a hydrogen atom, alkyl, or R 4 And R 5 may together form an substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom:
  • R 6 and R 7 are each independently a hydrogen atom, a substituted or unsubstituted alkyl Or R 6 and R 7 may together form a substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom:
  • R 8 is a hydrogen atom or alkyl:
  • P is 2 Integer to 4:
  • R 9 and R 10 are each independently a hydrogen atom or an alkyl):
  • R 2 and R 3 are each independently a hydrogen atom, substituted or unsubstituted alkyl, or R 2 and R 3 together form an substituted or unsubstituted heterocyclic group with an adjacent nitrogen atom May be:
  • n is an integer of 1 to 6
  • a pharmacologically acceptable salt or a medicament containing a hydrate thereof, preferably a serotonin receptor binding agent.
  • the present invention provides a serotonin receptor binding agent, which comprises the compound according to any one of the compounds (II) to (X) as an active ingredient.
  • Good Mashiku as the binder are those having affinity for 5-HT 7 receptors, i.e., Agonisuto or antagonists of 5-HT 7 receptor, more preferably Agonisuto.
  • the binder, 5 - HT 7 useful as a therapeutic agent, such as circadian rhythm disorders and senile sleep disorders attributed to receptor, also antidepressants, anxiolytics, migraine therapeutic agents, It is also considered useful as an analgesic.
  • the present invention further provides a compound of the formula (XI):
  • Y is an oxygen atom or a sulfur atom:
  • R reflexis a halogen or —NR 2 R 3 : Ar, R 2 and R! Are as defined above, or a salt thereof, and a compound represented by the general formula (XI I):
  • R 12 is alkyloxy, alkenyloxy, alkylsulfonyloxy, alkenylsulfonyloxy, or substituted or unsubstituted arylalkyloxy:
  • R 13 is acetyloxy, hydroxy or halogen: Ar Is the same as defined above
  • XIII a compound represented by the general formula (XIII):
  • R l 4 is hydrogen, alkyl, alkenyl, ⁇ reel alkyl, Heteroari Ruarukiru, alkylsulfonyl, ⁇ Luque sulfonyl sulfonyl, Arirusuruhoni Le or to Teroari one Rusuruhoniru: one of Ar of R 15 and R l 6 shown, the other is - CH shows a 2 NR 2 R 3: a r , R 2 and R 3 provides a compound or a salt thereof as defined above).
  • aryl when used alone or in combination with other terms, includes phenyl, naphthyl and the like, and is preferably phenyl.
  • Heteroaryl when used alone or in combination with other terms, includes pyrrolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indolyl, quinolyl, furyl, benzofuryl, 2,3-dihydrobenzozofuryl, thienyl, or Benzosoxazolyl and the like are exemplified.
  • aryl or “heteroaryl” When these "aryl” or “heteroaryl” have a substituent, they may have the same or different one or more substituents, and the substituent may be a halogen group (F, C1, Br, etc.), hydroxyl, alkyl (methyl, Echiru etc.), tri methyl halide (CF 3), alkenyl (Eparu, propenyl, etc.), Arukiruoki Si (methoxy, ethoxy, etc.), alkoxyalkoxy (methoxy methoxy, etc.), cyano, nitro, amino, alkyl rubamoyloxy, alkyl rubamoyloxy (methyl rubamoyloxy, etc.), alkanol (acetyl, etc.), aralkyl (benzyl, etc.), alkano It may be substituted with yloxy (such as acetyloxy), aralcanoyloxy (such as benzylcarbonyl
  • R 17, R 18 and R 19 each independently represent a hydrogen atom or an alkyl (methyl, Echiru etc.), also substituted or unsubstituted with the adjacent nitrogen atom becomes R, 8 and R 1 9 Heights cane May form a heterocyclic group (piperidino, piperazino, morpholino, pyrrolidinyl, etc.).
  • Ar is preferably a substituted aryl, particularly a substituted phenyl (substituent: preferably methyl, methoxy, hydroxy, carbamoyl, methylcarbamoyl, dioxomethylene, halogen, cyano, methoxymethoxy, methyl trihalide, etc. .
  • Alkyl when used alone or in combination with other terms, refers to one or more of methyl, ethyl, propyl, isopropyl, tert-butyl, n-butyl, n-pentyl, n-hexyl and the like. Includes linear or branched saturated hydrocarbon chains containing 6 carbon atoms. Examples of the substituent of the substituted alkyl include hydroxy, halogen, alkyloxy, C 3 -C 6 cycloalkyl, the above aryl, and the above heteroaryl.
  • Alkenyl refers to a straight or branched chain unsaturated carbon containing 2 to 6 carbon atoms such as ethenyl, probenyl, 1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl and the like. Includes hydrogen chains.
  • Halogen refers to fluorine, chlorine, bromine, and iodine.
  • each alkyl means the aforementioned alkyl.
  • Each alkenyl in alkenyloxy, alkenylthio, alkenylsulfonyloxy, alkenylsulfonyl, and alkenylcarbonyloxy of R i means the alkenyl.
  • R i arylalkyloxy, arylsulfonyloxy, heteroaryl
  • aryl and heteroaryl in the alkyloxy and the heteroarylsulfonyloxy have the same meanings as described above, respectively.
  • substituted arylalkyloxy particularly substituted benzyloxy (substituents: methoxy, halogen, etc.), alkylsulfonyloxy (methylsulfonyloxy, edlsulfonyloxy, etc.), dimethylsulfamoyloxy, And dimethylcarbamoyloxy.
  • substituted arylalkyloxy particularly substituted benzyloxy (substituents: methoxy, halogen, etc.), alkylsulfonyloxy (methylsulfonyloxy, edlsulfonyloxy, etc.), dimethylsulfamoyloxy, And dimethylcarbamoyloxy.
  • Each “heterocyclic group” formed by “R 4 and R 5 ” and “R 6 and R 7 ” in R t is a group having one or more nitrogen atoms, and is 1-pyrrolidinyl, piperidino, piperazino And morpholino.
  • the heterocyclic group formed by ⁇ R 2 and R 3 '' is a 5- to 7-membered monocyclic ring or a condensed ring thereof containing at least one nitrogen atom, and includes 1 monopyrrolidinyl, piperidino, piperazino, morpholino, Examples thereof include quinolino and their benzene condensed rings.
  • heterocyclic groups include alkyl, hydroxy, hydroxyalkyl, alkoxycarbonyl, phenyl, benzyl, pyridyl, pyrimidinyl, benzofuryl, 2,3-dihydrobenzofuryl, 1,4-benzodioxanyl, It may be substituted by benzophenyl, indolyl, quinolino, benzoisothiazolyl, benzimidazolyl, etc., and each of these substituents may be substituted with one or more halogen (F, Cl, Br), alkyl (Methyl, ethyl, etc.), hydroxyl group, alkoxy (methoxy, ethoxy, propoxy, etc.), alkoxyalkoxy (methoxy methoxy, etc.), nitro, cyano, carbamoyl, carbamoyloxy, alkylcarbamoyloxy (methylcarbamoyloxy) ), Methylenedioxy,
  • R 4 and R 5 are as defined above.
  • Preferred examples of the heterocyclic group formed by “R 2 and R 3 ” include substituted phenylpiperidino (substituent: hydroxy, methoxy, i-propoxy, cyano, etc.), benzofuran-7-ylpiperazino and the like.
  • n is an integer of 1 to 6, preferably 1 to 4, and more preferably 1 to 2.
  • the "5-HT 7 receptor binding agent” refers to a quality ones having a function of binding to 5-HT 7 receptor, promotes or suppresses the function of the 5-HT 7 receptor. That is, it includes an agonist or an angist for the receptor.
  • the pharmaceutically acceptable salt of the compound of the present invention include salts formed with inorganic bases, ammonia, organic bases, inorganic acids, organic acids, basic amino acids, halogen ions and the like, or inner salts.
  • Examples of the inorganic base include alkali metals (Na, K, etc.), alkaline earth metals (Ca, Mg, etc.), and examples of organic bases include trimethylamine, triethylamine, choline, pro-in, ethanolamine, etc. Is exemplified.
  • Examples of the inorganic acid include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Examples of the organic acid include p-toluenesulfonic acid, methanesulfonic acid, formic acid, trifluoroacetic acid, and maleic acid.
  • Examples of the basic amino acid include lysine, algin, ordinine, histidine and the like.
  • the compound of the present invention can be orally or parenterally administered to animals including humans as a preventive or therapeutic drug for various diseases caused by serotonin receptors.
  • examples of the dosage form include granules, tablets, capsules, injections, suppositories and the like.
  • various additives such as excipients (lactose, mannitol, crystalline cellulose, starch, etc.), disintegrants (carmellose, hydroxypropylmethylcellulose, polyvinylpolypyrrolidone, etc.), binders as required (Methylcellulose, hydroxypropylcellulose, polyvinyl alcohol, etc.), lubricants (magnesium stearate, talc, etc.), stabilizers, coloring agents, and coating agents can be used.
  • the dose may vary depending on the subject's age, body weight, symptoms, administration method, etc., but it is usually about 0.05 mg to 50 mg per day for an adult per day for oral administration in terms of the compound of the present invention. For parenteral administration, the dose is about 0.1 mg to 10 mg.
  • One of the compounds of the present invention represented by the general formula (IV) can be produced from the following reaction formulas 2-1 to 2-8.
  • the compound (21) is reacted with ammonia to obtain a compound (22).
  • Ammonia is used in an amount of 1.23 mol based on the compound (21), but usually 1.5 mol.
  • Solvents include alcohols such as methanol, ethanol, and propanol; ethers such as tetrahydrofuran, dioxane, and dimethoxetane; aromatic hydrocarbons such as benzene, toluene, and xylene; and halogenated carbons such as dichloromethane, chloroform, and dichloroethane. Examples include hydrogens, acetonitrile, dimethylformamide and the like.
  • the reaction temperature is usually from room temperature to 100 ° C (:, preferably, 280 ° C, and the reaction time is 13 hours. If necessary, organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, and trifluoroacetic acid are used. Add the acid.
  • the compound (22) is reacted with a base and a reagent to obtain a compound (24).
  • the alkylating agent of the reagent is methyl iodide, Lower alkyl halides such as propyl iodide, propyl bromide, isopropyl bromide, butyl bromide, pentyl bromide, hexyl bromide, benzyl bromide, benzyl chloride, and P-methoxybenzyl chloride Alkyl halides such as p-methoxybenzyl bromide, etc .; lower alkyl sulfates such as dimethyl sulfate and getyl sulfate; lower alkyl such as methyl methanesulfonate and ethyl methanesulfonate; lower alkyl sulfonates And methyl p-lower alkylarylsulfonates of toluenesulfonate.
  • Such an alkylating agent is used in an amount of 1 to 1.3 mol based on the raw material
  • alkylsulfonyl chlorides such as methanesulfonyl chloride, ethanesulfonyl chloride, and isopropylsulfonyl chloride
  • dialkylaminosulfonyl chlorides such as dimethylaminosulfonyl chloride and getylaminosulfonyl chloride
  • dialkylaminocarbamoylc mouth rides such as dimethylaminocarbamoylc mouth ride, and methylaminocarbamoylc mouth ride
  • alkyl chlorocarbonates such as methyl chlorocarbonate and ethyl chlorocarbonate.
  • the reaction temperature is usually under ice cooling to 5 °, preferably under ice cooling to room temperature. Reaction time is 30 minutes to 3 hours.
  • the compound (24) is reacted with a reagent to obtain a compound (25).
  • peracetic acid or m-chloroperbenzoic acid is used in an equimolar amount to the raw material (24), or in a slight excess (1.1 to 1.5 times the molar amount).
  • Solvents include aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, and chloroform. And halogenated hydrocarbons such as dichloroethane.
  • the reaction temperature is usually not ice-cooled or room temperature, and the reaction time is 1 to 65 hours. (Reaction formula 1-5 ')
  • the compound (25) is reacted with a reagent to obtain a compound (28).
  • arylsulfonium halides such as benzenesulfonium chloride and toluenesulfonium chloride are used.
  • Aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as dichloromethane, chloroform and dichloromethane are used as solvents.
  • the reaction temperature is 50-150 ° C and the reaction time is 548 hours.
  • Compound (28) can also be obtained by the following reaction formula 1-5 '.
  • compound (25) is reacted with a reagent to obtain compound (26).
  • the acid anhydride used as the reagent includes acetic anhydride, propionic anhydride, butyric anhydride and the like, but acetic anhydride is preferably used.
  • the reaction temperature is usually 70 to 130 ° C, preferably 790 ° C, and the reaction time is 100 minutes to 3 hours.
  • compound (26) is reacted with a base to obtain compound (27).
  • the base used include caustic alkalis such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate.
  • Solvents such as alcohols such as methanol, ethanol and propanol, ethers such as ethyl ether, tetrahydrofuran and dioxane, aromatic hydrocarbons such as benzene, toluene, xylene, acetonitrile, dimethylmuamide and mixtures thereof But
  • the reaction temperature is usually under ice cooling to 100 ° C, preferably room temperature to 50 ° C, and the reaction time is 30 minutes to 2 hours.
  • the compound (27) is reacted with an octalogenating agent to obtain a compound (28).
  • the halogenating agent include thionyl chloride, thionyl bromide, phosphorus oxychloride, and phosphorus pentachloride.
  • aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with halogenating agents, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform, and dichloroethane are used. Is done.
  • the reaction temperature is usually from ice-cooled to 100 ° C, preferably from ice-cooled to 50, and the reaction time is from 30 minutes to 3 hours.
  • the compound (28) is reacted with a primary amine or a secondary amine to obtain a compound (1).
  • Primary amines include methylamine, ethylamine, propylamine, isopylpyramine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine, ethanolamine, dimethylaminoethylamine and ethylaminoethylamine. .
  • Secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpiperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl) pi Peridine, ethyl 4-piperidinecarboxylate, piperazine, 1-methylbiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine, 1-piperonylbiperazine, 1-phenylbiperazine, 1- (4 1-chlorophenyl) pirazine, 1- (4-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1- (3-methoxyphenyl) piperazine, 1- (4-me Toxifenil) Piperazine, 1- (2-Isopropyloxyphenyl) Piperazine, 1- (2-Hydroxoxyphenyl) Piperazine, 1- (2-cyanopheny
  • the reaction is usually performed in a solvent.
  • the solvent include ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, and the like.
  • ethers such as getyl ether, tetrahydrofuran, dioxane, and dimethoxetane
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • dichloromethane chloroform
  • octogenated hydrocarbons such as dichloroethane, dialkyl ketones such as acetone, methylethyl ketone, and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.
  • the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times in molar amount) with respect to the compound (28), but it can be used in a large excess.
  • This reaction is preferably performed in the presence of an acid acceptor.
  • the acid acceptor include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and potassium carbonate.
  • an excess of a primary amine or a secondary amine can also be used as the acid receptor itself.
  • the reaction temperature is usually from room temperature to 130, preferably from room temperature to 80 ° C, and the reaction time is from 10 minutes to 15 hours.
  • One of the compounds of the present invention represented by the general formula (VI I) can be produced by the following Reaction Formulas 2-1 to 2-8.
  • the compound (2-2) is reacted with phenylboric acid to obtain a compound (2-3).
  • the phenylboric acids are 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 3.4-methylenedioxyphenyl, 3.4-dimethoxyphenyl, 2-hydroxyphenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-cyanophenyl, 3-cyanophenyl, 4-cyanophenylphosphoric acid and the like.
  • Solvents include dimethoxetane, toluene and dimethylformamide.
  • tetrakistriphenylphosphine palladium is used as a catalyst, and an aqueous solution of sodium carbonate is used as a base.
  • the reaction temperature is usually 80 to 100 ° C, and the reaction time is 1 to 24 hours.
  • Arylalkyl halides include benzyl chloride, benzyl bromide, p-methoxybenzyl chloride, p-methoxybenzylbutamate, 2.4-dimethoxybenzyl chloride, 2.4-dimethoxy Benzyl bromide and the like.
  • Examples of the base include alkali bicarbonate, alkali carbonate, caustic alkali, sodium hydride and the like.
  • the compound (2-4) is reacted with a peracid to obtain a compound (2-5).
  • the peracid is used in a molar amount of 1.1 to 1.5 times the molar amount of peracetic acid or m-chloroperbenzoic acid relative to the raw material (2-4).
  • Solvents include aromatic hydrocarbons such as benzene, toluene and xylene, dichloromethane, and chloroform. And halogenated hydrocarbons such as dichloroethane.
  • the reaction temperature is usually from ice-cold to room temperature, and the reaction time is 1 to 65 hours.
  • the compound (2-5) is reacted with a reagent to obtain a compound (2-6).
  • the acid anhydride used as the reagent includes acetic anhydride, propionic anhydride, butyric anhydride and the like, and usually acetic anhydride is used.
  • the reaction temperature is usually from 70 to 130 ° (: preferably from 70 to 90 ° C, and the reaction time is usually from 10 minutes to 3 hours.
  • Examples of the base used include caustic alkalis such as sodium hydroxide and potassium hydroxide, and alkali carbonates such as sodium carbonate and potassium carbonate.
  • Solvents include alcohols such as methanol, ethanol, and propanol, ethers such as ethyl ether, tetrahydrofuran, and dioxane; aromatic hydrocarbons such as benzene, toluene, and xylene; acetonitrile, dimethylformamide, and the like. And mixtures thereof.
  • the reaction temperature is usually under ice cooling to 100 ° C, preferably room temperature to 50 ° C, and the reaction time is 30 minutes to 2 hours.
  • the compound (2-7) was reacted with a halogenating agent to obtain a compound (2-8).
  • Halogenating agents include thionyl chloride, thionyl bromide, phosphorus oxychloride and phosphorus pentachloride.
  • aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with the halogenating agent, ethers such as ethyl ether, tetrahydrofuran, and dioxane, and halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane are used.
  • the reaction temperature is usually under ice cooling or 100: preferably under ice cooling to 50 ° C, and the reaction time is 30 minutes to 3 hours.
  • the compound (2-8) is reacted with a primary amine or a secondary amine to obtain a compound (2-9).
  • Primary amines include methylamine, ethylamine, propylamine, isopyruvylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, dimethylaminoethylamine.
  • Secondary amines are dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpyridine, 4-phenylbiperidine, 4- (2-methoxyphenyl) piamine.
  • the reaction is usually performed in a solvent, and specific examples of the solvent include tetrahydrofuran and dioxane.
  • Ethers such as sun and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated hydrocarbons such as dichloromethane, chloroform, dichlorobenzene, acetone, methyl ethyl ketone, and methyl isobutyl
  • dialkyl ketones such as ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.
  • the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times in molar amount) with respect to the compound (2-8), but a large excess can be used.
  • This reaction is preferably performed in the presence of an acid acceptor.
  • the acid acceptor include alkali carbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate, and carbonated lime.
  • a primary amine or a secondary amine can be used in excess to double as an acid acceptor.
  • the reaction temperature is usually room temperature to 130 ° C, preferably room temperature to 80 ° C, and the reaction time is 10 minutes to 15 hours.
  • One of the compounds of the present invention represented by the general formula (IX) can be produced from the following reaction formulas 3-1 to 2-2.
  • 5-Bromo-1-chloromethylpyridine (J. Heterocyclic Chem., 29, 971 (1992)) is reacted with a primary amine or a secondary amine to obtain a compound (3-1).
  • Primary amines include methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, and dimethylaminoethylamine.
  • the secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, and 4-benzene.
  • the reaction is usually performed in a solvent.
  • the solvent include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, and halogens such as dichloromethane, chloroform and dichloroethane.
  • ethers such as tetrahydrofuran, dioxane, and dimethoxetane
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • halogens such as dichloromethane, chloroform and dichloroethane.
  • fluorinated hydrocarbons dialkyl ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethylformamide, and mixtures thereof.
  • the primary amine or secondary amine is used in a molar excess or a slight excess (1.1 to 3 times the molar amount) with respect to the raw materials, but a large excess can be used.
  • This reaction is preferably performed in the presence of an acid acceptor.
  • the acid acceptor include alkali bicarbonate such as sodium bicarbonate and potassium bicarbonate, and alkali carbonate such as sodium carbonate and potassium carbonate.
  • an excess of a primary amine or a secondary amine can also be used as the acid receptor itself.
  • the reaction temperature is usually from room temperature to 130 ° C, preferably from room temperature to 80 ° C. Is 10 minutes to 15 hours
  • the arylboric acids include phenylboric acid, 2-methoxyphenylboric acid, 3-methoxyphenylboric acid, 4-methoxyphenylboric acid, 3.4-methylenedioxyphenylboric acid, and 3.4-dimethoxyphenylboric acid.
  • Acid 2-hydroxy phenyl boric acid, 3-hydr oxy phenyl boric acid, 4-hydr oxy phenyl boric acid, 2- cyano phenyl boric acid, 3- cyano phenyl boric acid , 4-Cyanophenylboric acid, 2-Chenylboric acid, 3-Cenylboric acid, 2-furylboric acid, 3-furylboric acid and the like.
  • Solvents include dimethyloxetane, toluene, and dimethylformamide. Generally, tetrakistriphenylphosphine palladium is used as a catalyst, and aqueous sodium carbonate solution is used as a base. The reaction temperature is usually 80 to 100 ° C, and the reaction time is 124 hours.
  • one of the compounds of the present invention represented by the general formula (X) can also be produced by the following reaction formulas 4-1 to 4-2. The production method itself does not limit the invention in any way.
  • Primary amines are methylamine, ethylamine, propylamine, isopropylamine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, dimethylaminoethylamine. Is mentioned.
  • the secondary amines include dimethylamine, getylamine, dipropylamine, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzylpiperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl).
  • Piberidine, ethyl 4 piperidinecarboxylate, piperazine, 1-methylbiperazine, 2, 6—dimethylbiperazine, 1-benzylpiperazine, 1-piperonylpiperazine, 1-phenylbiperazine, 1 _ (4-chlorophenyl) piperazine, 1- (4-fluorophenyl) piperazine, 1- (2-methoxyphenyl) piperazine, 1— (3-methoxyphenyl) piperazine, 1 One (4-methoxyphenyl) piperazine, One (2-isopropyloxyphenyl) piperazine, One (21 Xyiphenyl) piperazine, 1- (2-cyanophenyl) piperazine, 1- (3-cyanophenyl) piperazine, 1- (4-cyanophenyl) pirazine, 1- (3—hydroxyphenyl) pidazine Lazine, 1- (4-hydroxyphenyl) piperazine, 1_ (3-methoxy
  • halogenated hydrocarbons such as dichloromethane, chloroform and dichloroethane, and ethers such as tetrahydrofuran, dioxane and dimethoxyethane are used.
  • Sodium triacetoxyborohydride is used as a reducing agent.
  • the reaction temperature is under ice cooling to 80, preferably at room temperature, and the reaction time is 1 to 24 hours.
  • the compound (4-1) is reacted with an alkoxide or a thiophenoxide to obtain a compound (4-3).
  • the alkoxides are selected by reacting alkyl alcohols such as methanol, ethanol and propyl alcohol, and arylalkyl alcohols such as benzyl alcohol and p-methoxybenzyl alcohol with sodium hydride.
  • Thiofenoxides can be obtained by reacting thiophenols such as thiophenol and p-methoxythiophenol with sodium hydride.
  • As a solvent for etherification and thioetherification tetrahydrofuran, dimethylformamide, dimethyl sulfoxide and the like are used.
  • the reaction temperature is under ice cooling to 80 ° C., preferably at room temperature, and the reaction time is 1 to 24 hours.
  • One of the compounds of the present invention represented by the general formula (IX) can be produced from the following Reaction Formulas 11 to 11 according to Reaction Formulas 5-3.
  • 5- (2-Methoxyphenyl) -16-methoxynicotinic acid methyl ester (J. Org. Chem., 49, 5237 (1984)) is reacted with a reducing agent to obtain a compound (5-1).
  • a reducing agent include aluminum hydrides such as lithium aluminum hydride and diisobutylaluminum hydride.
  • the solvent include ethers such as ether and tetrahydrofuran, and aromatic hydrocarbons such as benzene and toluene.
  • the reaction is carried out at a temperature of 70 ⁇ 8O :, and the reaction time is 10min ⁇ 3pm Between
  • the compound (5-1) is reacted with a halogenating agent to obtain a compound (5-2).
  • halogenating agent examples include thionyl chloride, thionyl bromide, phosphorus oxychloride, and phosphorus pentachloride.
  • solvent examples include aromatic hydrocarbons such as benzene, toluene, and xylene that do not react with the halogenating agent, ethers such as dimethyl ether, tetrahydrofuran and dioxane, dichloromethane, chloroform and dichloroethane. Halogenated hydrocarbons are used.
  • the reaction temperature is usually under ice cooling or 100 ° C., preferably under ice cooling to 50, and the reaction time is 30 minutes to 3 hours.
  • the compound (5-2) is reacted with a primary amine or a secondary amine to obtain a compound (5-2).
  • Primary amines include methylamine, ethylamine, propylamine, isopyramine, butylamine, pentylamine, hexylamine, cyclopropylamine, cyclopentylamine, cyclohexylamine and ethanolamine, dimethylaminoethylamine, ethylaminoethylamine, etc. Are mentioned.
  • the secondary amines include dimethylamine, getylamine and dipropylamine. Min, dipropylamine, pyrrolidine, piperidine, morpholine, 4-benzyl piperidine, 4-phenylbiperidine, 4- (2-methoxyphenyl) piperidine, ethyl 4-piperidine carboxylate, pi Perazine, 1-methylpiperazine, 2,6-dimethylbiperazine, 1-benzylpiperazine, 1-piperonilpiperazine, 1-phenylbiperazine, 1- (4-chlorophenyl) piperazine, 1- (4— Fluorophenyl) piperazine, 1-1 (2-methoxyphenyl) piperazine, 1-1 (3-methoxyphenyl) piperazine, 1— (4-methoxyphenyl) piperazine, 1— (2 —Isopropyloxyphenyl) piperazine, 1- (2-hydroxyphenyl) piperazine, 1— (2-cyanophenyl) pipe
  • the reaction is usually performed in a solvent.
  • the solvent include ethers such as tetrahydrofuran, dioxane, and dimethoxetane, aromatic hydrocarbons such as benzene, toluene, and xylene, dichloromethane, chloroform, dichloroethane, and the like.
  • Halogenated hydrocarbons dialkyl ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, ethyl acetate, acetonitrile, dimethyl formamide, and mixtures thereof.
  • the primary amine or the secondary amine is used in a molar amount or a slight excess (1.1 to 3 times by molar amount) with respect to the compound (5-2), but it can be used in a large excess.
  • This reaction is preferably performed in the presence of an acid acceptor.
  • the acid acceptor include alkali carbonates such as sodium bicarbonate and potassium bicarbonate, sodium carbonate, and carbonated lime.
  • a primary amine or a secondary amine can be used in excess to double as an acid acceptor.
  • the reaction temperature is usually room temperature to 130 ° C, preferably room temperature to 80 ° C, and the reaction time is 10 minutes to 15 hours. Examples will be described below. Abbreviations are as follows.
  • Crystals of [4- (2-methoxyphenyl) phenyl.lasin-1-ylnutyl] -6- (2-methoxyphenyl) -4-methylthiopyridinine were obtained 250 mg (95.8%) of this The crystals were recrystallized from a mixed solvent of I-yl acetate-hexane to show a melting point of 122-124 ° C.
  • Example 367-370 The reaction was carried out in the same manner as in Example 366 to obtain compounds of (1-185) to (1-188). Their melting points and NMR are shown in Table 35.
  • Example 144 Compound (1) obtained in Example 144 can also be obtained by carrying out the reaction in the same manner as in Examples 371 to 385, and further in Example 302 shown below.
  • Example 67 The compound (28) obtained from Example 67 can be obtained by the following Example 405, Example 406 or Example 410.
  • Appendix 1 1 Ethyl acetate ⁇ Hexane eluate was recrystallized from hexane to give 2-chloromethyl-4-methanesulfonyloxy-6- (2-methoxyphenyl) pyridine with a melting point of 95-96 ° C. (28-42) 3.08 g are obtained.
  • Example 306 The compound (1-190) obtained in Example 306 was converted to a compound (1-190) by using the method described in Example 41 1 or Example 4 12 below. (1-19-1) was obtained.
  • 6-acetoxymethyl-3- (4-methoxybenzyloxy) -1-2- (2-methoxyphenyl) pyridine (2-6) 3.5 g (0.00891 mole) in methanol After dissolving in 25 ml, 6.7 ml (0.0134 ml) of 2N sodium hydroxide solution was added under ice cooling, and the mixture was reacted at room temperature for 6 hours. Add 4 ml of saturated ammonium chloride water and concentrate the solvent to precipitate crystals. The crystals were separated by filtration to obtain 6-hydroxymethyl-2- (2-methoxyphenyl) -13- (4-methoxybenzyloxy) pyridine (2-7). Recrystallization from 2.75 g (87.9%) of ethyl acetate-ether gives crystals with a melting point of 125-127 ° C.
  • 6-Hydroxymethyl-2 (2-methoxyphenyl) — 3- (4-methoxybenzyloxy) pyridine (2-7) 2.8 g (0.00798 mol) is dissolved in 70 ml of tetrahydrofuran, cooled with ice and stirred. 1.90 g (0.016 mol) of thionyl chloride was added and reacted at room temperature for 2 hours. The tetrahydrofuran was removed under reduced pressure, and the ice water was made alkaline with sodium hydrogen carbonate solution and extracted with chloroform. After drying over magnesium sulfate, the column was chromatographed on 80 g of alumina.
  • Example 4 The reaction was carried out in the same manner as in Example 20, and the compounds (2-9-2) to (2-9-4) were obtained. Their melting points and NMR are shown in Table 41.
  • the mixture was stirred at 00 ° C for 19 hours.
  • the reaction solution is obtained by evaporating the solvent under reduced pressure, dissolving in chloroform, washing with saturated aqueous sodium hydrogen carbonate solution and brine, drying over magnesium sulfate, and evaporating the solvent under reduced pressure.
  • Example 4 The same operation as in 37 was performed, and 1— (2—clo mouth—5— (2-methoxyphenyl) pyridine-13-ylmethyl) 141- (2-methoxyphenyl) piperazine
  • Example 4 4 The same operation as in 4 was carried out, and 1 _ (4-methoxybenzyl) — 3— (4- (2-methoxyphenyl) piperazine-1-ylmethyl) — 5-phenyl-1-H One pyridine-1 2-one (4-4-2) was obtained.
  • Example 4 51 The same operation as in 1 was carried out, and 1- (4-methoxybenzyl)-3- (2-methoxyphenyl) 5- (4- (2-methoxyphenyl) piperazine-1 —Y
  • the concentration of the metal, Kd indicates the dissociation constant.
  • the present invention compounds are particularly 5 -HT 7 (5-Hydroxytrpta mine7 ) compounds acting on receptors in the serotonin receptors, circadian rhythm disorders therapeutics, senile sleep failure therapeutic agent, antidepressant, anti It is useful as an anxiety drug, a cardiovascular drug, a migraine drug, an analgesic drug, etc.

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

Abstract

L'invention porte sur des composés représentés par la formule générale (I) et sur des agents de liaison du récepteur 5-HT7 contenant ces composés comme ingrédients actifs. Dans cette formule, Ar représente aryle éventuellement substitué ou hétéroaryle éventuellement substitué; R1 représente hydrogène, halogéno, alkyle, alcényle, alkyloxy, etc.; R2 et R3 représentent chacun, indépendamment, hydrogène ou alkyle éventuellement substitué, ou peuvent former avec le noyau d'azote adjacent un hétérocycle éventuellement substitué; et n est un nombre entier compris entre 1 et 6.
PCT/JP1998/005561 1997-12-17 1998-12-09 Nouveaux composes de pyridine WO1999031062A1 (fr)

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KR100869271B1 (ko) * 2000-06-12 2008-11-18 에자이 알앤드디 매니지먼트 가부시키가이샤 1,2-디하이드로피리딘 화합물 및 그의 용도
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