WO1994006801A1 - Compose de thienodiazepine et son utilisation comme medicament - Google Patents

Compose de thienodiazepine et son utilisation comme medicament Download PDF

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Publication number
WO1994006801A1
WO1994006801A1 PCT/JP1992/001198 JP9201198W WO9406801A1 WO 1994006801 A1 WO1994006801 A1 WO 1994006801A1 JP 9201198 W JP9201198 W JP 9201198W WO 9406801 A1 WO9406801 A1 WO 9406801A1
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Prior art keywords
substituent
ethyl
thieno
chlorophenyl
triazolo
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PCT/JP1992/001198
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English (en)
Japanese (ja)
Inventor
Minoru Moriwaki
Hiroyuki Kitani
Syuji Ehara
Hiroshi Yasumatsu
Hirotsugu Komatsu
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Tanabe Pharma Corp
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Yoshitomi Pharmaceutical Industries Ltd
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Priority to PCT/JP1992/001198 priority Critical patent/WO1994006801A1/fr
Priority to CA002144985A priority patent/CA2144985A1/fr
Publication of WO1994006801A1 publication Critical patent/WO1994006801A1/fr
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a novel chenodiazepine compound or a salt thereof, which has an excellent antagonism against cholecystokinin and gastrin, and also has an excellent cell adhesion inhibitory action, and a pharmaceutical use thereof.
  • CCK Cholecystokinin
  • Gastrin is composed of 34 amino acids and pentagastrin, which consists of 5 amino acids on the C-terminal side, is also active.
  • the amino acid sequence of penguin gastrin is identical to the N-terminal of CCK. Both and their receptors are present in the gastrointestinal tissues and central nervous system, and are thought to be involved in the control of enzymatic secretion of knee and knee, gastric acid secretion, and emotions such as anxiety.
  • CCK antagonists include benzotribute (Proc. Natl. Acad. Sci. USA), Proc. Of National . Academia, Ob . Science of Ob . , P. 634, pp. 198], but as a gastrin antagonist, burogurmid [Journal of Medicinal Chemistry (J. Med. Chem.) Vol. Pp. 1597 (1994)] is known. However, these compounds are relatively weak, have higher activity, and are desired to be compounds with excellent safety.
  • peptide antagonists are not always satisfactory because of their short duration of action, instability, and poor absorption.
  • CCK antagonists and gastrin antagonists that have been reported to date have never been satisfactory in their effects, and there is a demand for the development of compounds that have more convenient actions. There is also a need for the development of excellent anti-inflammatory and anti-allergic drugs that have an inhibitory effect on leukocyte adhesion to vascular endothelial cells.
  • the present inventors have conducted a search for the purpose of developing better CCK antagonists, gastrin antagonists and Z or cell adhesion inhibitors, and have found that certain chenodiazepine compounds have superior CCK antagonism, They have found that they have a gastrin antagonism or an action of inhibiting leukocyte adhesion to vascular endothelial cells, and have completed the present invention.
  • the present invention provides a compound represented by the general formula: Ar
  • Ar represents an aryl which may have a substituent or a heteroaryl which may have a substituent.
  • R 1 represents hydrogen, halogen, alkyl having 1 to 20 carbons, or aralkyl which may have a substituent.
  • R 2 represents hydrogen, halogen, C 1-20 alkyl carbons, it may also have a substituent group I Ararukiru, a 2-20 alkenyl or several 2-20 alkynyl carbon atoms.
  • R 1 and R 1 may be bonded to each other to form a 5- to 7-membered ring, or may form a 5- to 7-membered heterocyclic ring together with a heteroatom, and further have a substituent. It may be.
  • R 3 has the formula:
  • R 4 represents hydrogen, alkyl having 1 to 20 carbons, or an optionally substituted substituent.
  • R s and R 8 are the same or different and each represents hydrogen, alkyl having 1 to 20 carbons, cycloalkyl which may have a substituent, cycloalkyl which may have a substituent, Alkylalkyl, aryl which may have a substituent, aralkyl which may have a substituent, heteroaryl which may have a substituent or may have a substituent Represents teroarylalkyl.
  • a 0 or an integer of 1 to 6.
  • R represents hydrogen, alkyl having 1 to 20 carbons or aralkyl which may have a substituent.
  • R 7 represents 1 to 6 carbons.
  • R is hydrogen, alkyl having 1 to 20 carbons or has a substituent.
  • R e and R 1 are alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, and a substituent.
  • Cycloalkyl, cycloalkylalkyl which may have a substituent, aryl which may have a substituent, heteroaryl which may have a substituent, and substituent R 1 R 12 or Ris and R 14 are the same or different and each represents hydrogen, alkyl having 1 to 20 carbons, or 2 to 20 carbons.
  • R "and R 1 R 1 are alkyl having 1 to 20 carbon atoms, aryl which may have a substituent, heteroaryl which may have a substituent, and a substituent which may have a substituent.
  • X represents an oxygen atom or a sulfur atom.
  • Y is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, aralkyl which may have a substituent, or even having a substituent A good heteroarylalkyl, or a compound of the formula: (CH 2 ) bCOOR 18 (where R le is hydrogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons or a substituent And b represents an integer of 1 to 6. 2) represents a group represented by.
  • N-CH C (R t0 ) one (where R * is hydrogen, halogen, alkyl having 1 to 20 carbons, alkenyl having 2 to 20 carbons, alkynyl having 2 to 20 carbons, Cycloalkyl which may have a substituent, cycloalkylalkyl which may have a substituent, aryl which may have a substituent, heteroaryl which may have a substituent, and substitution Aralkyl which may have a group, heteroarylalkyl which may have a substituent, or a group represented by the formula: (CH 2 ) bCOOR 20 ′ (where R 20 is hydrogen, and has 1 to 1 carbon atoms) 20 alkyl, alkenyl having 2 to 20 carbon atoms or aralkyl which may have a substituent, b represents an integer of 1 to 6. b) represents a group represented by). Shows the group represented.
  • R 3 is a group represented by the above (1) or (2)
  • the thienodiazepine compound represented by or a salt thereof represented by or a salt thereof
  • R 1 R 2 and R 21 are as described above.
  • A represents a nitrogen atom or CH.
  • R 22 has the formula:
  • R 23 is a group represented by the formula (CHj) aN (R,) S0, R, (3) ⁇ (CH,) aN (R ') C00R l (4) One (CH 2 ) aOCON (RH) (R ") (5) One (CH 2 ) aCON (R) S ) (R") (6) One (CH «) aOCOR li (7)-(CH aOSOiR 1 , (8)-(CH,) aC0R 17 (9), and one (CH aSCO) ⁇ 11 (10) (wherein each symbol is as described above. )
  • Preferred compounds of the general formula (la) include:
  • Preferred compounds of the general formula (Ib) include:
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of general formula (I), (Ia) or (lb) and a pharmaceutically acceptable excipient;
  • A represents a nitrogen atom or CH. Other symbols are as described above.
  • aryl refers to halogen, alkyl having 1 to 6 carbons, alkokidi having 1 to 6 carbons, trifluoromethyl, nitro, amino, cyano and hydroxyl on the aromatic ring.
  • Phenyl, 1-naphthyl, 2-naphthyl, etc. which may have 1 to 3 substituents selected from
  • Heteroaryl means that the heteroatoms that make up the ring are nitrogen, oxygen, sulfur, etc., and the ring contains halogens and carbon atoms! May have 1 to 3 substituents selected from up to 6 alkyl, alkoxy having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl groups.
  • pyridyl (2 —Pyridyl, 3-pyridyl, 4-pyridyl), quinolyl (2-quinolyl, 3-quinolyl, etc.), indolyl (2-indolyl, 3-indolyl, etc.), chenyl (2-phenyl, 3-phenyl, frill) (2-furyl, 3-furyl), benzofuranyl (2-benzofuranyl, 3-benzofuranyl, etc.), 1H-benzimidazole-2-yl, 2-benzothiazolyl and the like.
  • Halogen refers to chlorine, fluorine, bromine and iodine.
  • Alkyl having 1 to 20 carbon atoms may be straight-chain or branched, for example, methyl, ethyl, propyl, isopropyl, butyl, isoptyl, tert-butyl, pentyl, isopentyl, tertiary pentyl Hexyl, octyl, 2-ethylhexyl, 2,2-ethylethyloctyl, 1,3,3-tetramethylbutyl, nonyl, decyl, dodecyl, tetradecyl, octadecyl, eicosyl and the like. It is.
  • the alkyl preferably has 1 to 6 carbon atoms.
  • Aralkyl which may have a substituent means that the alkyl moiety has 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, and an alkyl having 1 to 6 carbon atoms on its aromatic ring. Which may have 1 to 3 substituents selected from alkoxides having 1 to 6 carbon atoms, trifluoromethyl, nitro, amino, cyano and hydroxyl groups, benzyl,
  • Alkenyl having 2 to 20 carbon atoms means bier, bronil, 2-methyl-l-bronyl, 3-methyl-l-butenyl, 2,3-dimethyl-l-butenyl, 3,4,5-trimethyl-l-butenyl And 3-butenyl, 3-hexenyl, 5-dodecenyl, 6-ethyl-3-decenyl, 11,11-dimethyl-7-tetradecenyl, 14-octadecenyl, 8-eicosenyl and the like.
  • the alkenyl preferably has 2 to 8 carbon atoms.
  • Alkynyl having 2 to 20 carbon atoms refers to 1-butyl ⁇ -butyl, 3-methyl-11-butynyl, 1,4-dimethyl-11-hexyl, ethynyl, propagyl, 3-hexynyl, 3,4- Jethyl-1 11-year-old cutinyl, 5-dodecinyl, 6-ethyl-3-decinyl, 11-, 11-dimethyl-7-tetradecinyl, 14-year-old kutadecinyl, 8-eicosinyl and the like.
  • the alkynyl preferably has 2 to 8 carbon atoms.
  • Cycloalkyl optionally having substituent (s) has 3 to 10 carbon atoms, and includes, for example, cyclobutyl mouth building, 2,3-dimethylcyclobutyl mouth building, cyclo ⁇ butyl 3-methylcycloalkyl Butyl, cyclobentyl, 3,4-dimethylcyclopentyl cyclohexyl, 4-methylcyclohexyl, cyclohexyl, cyclooctyl norbornyl, adamantyl, bicyclo (3.3.0) octane-11-yl, bicyclo [3.3 . 1] Nonan 9-yl.
  • the cycloalkylalkyl which may have a substituent means that the cycloalkyl moiety is It has 3 to 10 carbon atoms, and the alkyl portion has 1 to 6 carbon atoms, preferably 1 to 3 carbon atoms. Examples thereof include propyl methyl cyclobutyl, 2,3-dimethylcyclobutyryl, cyclobutylmethyl, and 3-methylcyclo.
  • Heteroarylalkyl optionally having substituent (s) means halogen, alkyl having 1 to 6 carbons, alkoxy having 1 to 6 carbons, trifluoromethyl, nitro, amino, cyano on the ring. And may have 1 to 3 substituents selected from hydroxyl groups, and the alkyl portion has 1 to 4 carbon atoms, preferably 1 to 2 carbon atoms, and the hetero atom constituting the ring is nitrogen. , Oxygen or sulfur.
  • R 1 and R 2 may combine with each other to form a 5- to 7-membered ring, or may form a 5- to 7-membered heterocyclic ring together with a heteroatom.
  • Rings that may be used include cyclopentene, cyclobenzene, cyclohexene, cyclohexadiene, cycloheptene, cycloheptadiene, cyclohexatriene benzene, dihydropyran, dihydrothiapyran, tetrahydropyridine, etc.
  • the substituent include alkyl such as methyl and ethyl, and aralkyl such as benzyl and 2-phenylethyl.
  • Halogen in the exchange group means chlorine, fluorine, bromine, and iodine, and has 1 carbon atom.
  • Up to 6 alkyls include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, isopentyl, tertiary pentyl, hexyl, etc., and alkoxy having 1 to 6 carbon atoms. Examples of methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, 3-butoxy, pentyloxy, isopentyloxy, 3-pentyloxy, hexyloxy, and the like.
  • Salts of the compounds of the general formula (I) include acid addition salts with inorganic or organic acids and salts with inorganic bases, organic bases or amino acids; for the purposes of the present invention, these salts are non-toxic. Are preferred.
  • any racemic, optically active or diastereomeric compounds based on the compound have all chiral carbon atoms. It is included in the present invention.
  • the compound of (la) is, for example, a single-arm type
  • R 7 has the same meaning as described above, and W is a deprotecting group (hydroxyl group, halogen, ester group (such as phenoxy, p-ditrophenoxy) or a thioester group (phenylthio, 2, 6- Dimethylviridine-14-thio, etc.))].].
  • the addition reaction between the compound of the general formula (II) and the compound of the general formula (III) is performed in a suitable solvent that does not inhibit the reaction.
  • a suitable solvent for example, an organic solvent such as tetrahydrofuran, methyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, quinylene, dimethylformamide, and dimethylacetamide is used.
  • the temperature of this reaction varies depending on the reagents and solvent used, but the boiling point of the solvent is preferably from 20 to one.
  • the compounding reaction between the compound of the general formula (II) and the one-armed compound ([V]) is carried out in a suitable solvent.
  • the solvent include organic solvents such as tetrahydrofuran, dimethyl ether, diisobutyryl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, dimethylformamide, and dimethylacetamide.
  • the reaction is carried out using a solvent, if necessary, in the presence of a base or a dehydrating condensing agent at a temperature from 120 "C to the boiling point of the solvent.
  • Bases used as necessary include alkali metal hydroxides (sodium hydroxide, lithium hydroxide, etc.), alkali metal carbonates (sodium carbonate, carbonated lithium, etc.), alkali metal hydrogen carbonate (Such as sodium hydrogen carbonate and potassium hydrogen carbonate), metal hydrides such as sodium hydride, and organic bases (such as triethylamine, pyridine, picoline, and N-methylmorpholine).
  • a phase transfer catalyst such as tetrabutylammonium bromide or benzyltriethyl ammonium iodide in the two-phase system of the above organic solvent and water to form an alkali metal hydroxide. Can also be used.
  • dehydrating condensing agent those used for amide synthesis are preferred, such as dicyclohexylcarpoimide, N-ethyl-N '— (3-dimethylaminomethyl) carbodiimidide chloride at the mouth, diphenylphosphoryl azide, N-methyl-2-cyclopyridinamide vide, and the like.
  • R represents alkyl such as ethyl, and the other symbols have the same meanings as described above.
  • the compound represented by the general formula (VI) is converted to a base (sodium hydroxide). , Potassium hydroxide, barium hydroxide, lithium hydroxide, etc.) in a mixture of water or water and an organic solvent (preferably methanol, ethanol, getyl ether, tetrahydrofuran, dioxane, etc.).
  • the hydrolysis reaction is carried out at a temperature from about O'C to the boiling point of the solvent used, and the resulting reaction solution is treated with an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • Is converted to an appropriate solvent eg, acetyl ether, diisobutyryl ether, tetrahydrofuran, dioxane, benzene, toluene
  • Bases sodium hydride, potassium tertiary butoxide, lithium diisopropylamide, butyllithium, pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.
  • benzene, dimethylformamide, etc. It can be obtained by reacting at a temperature below 120 ° C to the boiling point of the solvent used, or by reacting with an aldehyde in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride. .
  • a ′ represents an integer of 1 to 6, and Q represents halogen.
  • a compound represented by the general formula (X) is obtained by using a base (sodium hydroxide, potassium hydroxide). , Barium hydroxide, lithium hydroxide, etc.) in a solvent mixture of water or water and an organic solvent (preferably methanol, ethanol, getyl ether, tetrahydrofuran, dioxane, etc.).
  • the hydrolysis reaction is performed at a temperature up to the boiling point of the solvent used, and the resulting reaction solution is acidified using an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • a single-branched ( ⁇ ) alkyl halide in a suitable solvent eg, getyl ether, diisopropyl ether, tetrahydrofuran, siloxane, benzene, toluene, xylene, dimethylformamide, etc.
  • a base such as sodium hydride, potassium tert-butoxide, lithium diisopropylamide, butyllithium pyridine, triethylamine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate, etc.
  • a reducing agent such as sodium borohydride, sodium cyanoborohydride or the like.
  • R ′′ represents alkyl such as methyl and ethyl, and R 21 has the same meaning as described above.
  • reaction of the compound of the general formula (XII) with the compound of the general formula (XIII) is usually carried out in an inert solvent (benzene, toluene, xylene, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof) in an organic acid ( Acetic acid, propionic acid, etc.)-inorganic acid (Hydrochloric acid, sulfuric acid, etc.) or in the presence of silica gel at room temperature to the reflux temperature of the solvent used in 30 minutes to 5 hours.
  • an inert solvent benzene, toluene, xylene, tetrahydrofuran, dioxane, etc., or a mixed solvent thereof
  • organic acid Acetic acid, propionic acid, etc.
  • organic acid Hydrochloric acid, sulfuric acid, etc.
  • silica gel at room temperature to the reflux temperature of the solvent used in 30 minutes to 5 hours.
  • reaction of the compound of the general formula (X [I) with hydrazine hydrate is usually carried out in a solvent inert to the reaction (methanol, ethanol, propanol, isopropyl alcohol, butanol, etc.). (It will take about 5 minutes to 3 hours.
  • the reaction of the compound of the general formula (XIV) with the compound of the general formula (XV) or a reactive derivative thereof or the compound of the general formula (XVI) is carried out by using a solvent inert to the reaction (benzene, toluene, xylene, In the presence of an organic acid (acetic acid, propionic acid, etc.), an inorganic acid (hydrochloric acid, sulfuric acid, etc.) or silica gel in tetrahydrofuran, dioxane, or a mixed solvent thereof, the solvent used at room temperature should be refluxed for 30 minutes to 6 minutes. Progress in time.
  • a solvent inert benzene, toluene, xylene
  • an organic acid acetic acid, propionic acid, etc.
  • an inorganic acid hydrochloric acid, sulfuric acid, etc.
  • silica gel silica gel in tetrahydrofuran, dioxane, or a mixed solvent thereof
  • R 7 represents alkyl such as methyl or ethyl, or aralkyl such as benzyl, and has the same meaning as described above.
  • the reaction is usually performed in a solvent inert to the reaction (methanol, ethanol, dioxane, dimethylformamide, tetrahydrofuran, benzene, toluene, xylene, or a mixed solvent thereof), and an acid catalyst (hydrochloric acid, sulfuric acid, polyphosphoric acid).
  • a solvent inert to the reaction
  • an acid catalyst hydroochloric acid, sulfuric acid, polyphosphoric acid
  • mineral acids such as, for example, formic acid, acetic acid, low-handled fatty acids such as propionic acid, and organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid
  • mineral acids such as, for example, formic acid, acetic acid, low-handled fatty acids such as propionic acid, and organic sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid
  • the acid catalyst itself when it is in a liquid state, it can be used also as a solvent.
  • the reaction is carried out without a solvent, the reaction is carried out at a temperature slightly higher than the melting point of the compound of the general formula (V), usually at 150 to 220.
  • Method 2 A compound of the general formula (lib) is converted into an inactive solvent such as chloroform, dichloromethane, benzene toluene, dimethylformamide, tetrahydrofuran, dioxane, etc.
  • an inactive solvent such as chloroform, dichloromethane, benzene toluene, dimethylformamide, tetrahydrofuran, dioxane, etc.
  • R 28 represents one of R u and R 12.
  • the reaction is carried out in an appropriate solvent (organic solvent such as tetrahydrofuran, dimethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc.).
  • organic solvent such as tetrahydrofuran, dimethyl ether, diisopropyl ether, dioxane, dichloromethane, chloroform, carbon tetrachloride, ethyl acetate, benzene, toluene, xylene, dimethylformamide, dimethylacetamide, etc.
  • a base or a dehydrating condensing agent examples include triethylamine, pyridine, N-methylmorpholine and the like.
  • dehydration condensing agent those usually used for peptide synthesis are good, for example, dicyclohexylcarpoimide, N-ethyl-N '-(3-dimethylaminomethyl) carbodiimide hydrochloride, diphenylphosphoryl azide, N-Methyl-2-chloropyridinium iodide, molecular sieve and the like.
  • Method 5 The compound of the general formula (Vb) is converted into an inert solvent such as dichloromethane, chloroform, benzene, toluene, dimethylformamide, carbon tetrachloride, and the like.
  • an inert solvent such as dichloromethane, chloroform, benzene, toluene, dimethylformamide, carbon tetrachloride, and the like.
  • R 29 represents alkyl such as methyl and ethyl, and other symbols are as defined above.
  • a suitable solvent methanol, ethanol, tetrahydrofuran, etc.
  • a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, barium hydroxide.
  • Hydrolysis is carried out at a temperature from 0 to the boiling point of the solvent used in a mixed solvent with dioxane, etc., and then acid (hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, trifluoroacetic acid). Tansulphonic acid, etc.) to obtain the general formula
  • Method 8 Phosphorus oxychloride, phosphorus tribromide, chlorine in an inert solvent such as dichloromethane, chloroform, carbon tetrachloride, benzene, toluene, dioxane, dimethylformamide, etc. , Bromine, N-bromosuccinic acid imido, etc., and react with a halogenating agent, and then react with a suitable solvent (methanol, ethanol, dimethylacetamide, dimethylformamide, etc.) in a general formula:
  • n ′ represents 1 or 2, and the other symbols have the same meanings as described above.
  • the compound in which a is 0 is a compound represented by the general formula obtained by a method described in JP-A-2-28181, for example:
  • R 8 ′ represents R E other than hydrogen, and Q has the same meaning as described above.
  • a base sodium hydride, potassium tertiary butoxide
  • Lithium diisopropylamide, butyl lithium, pyridine triethylamine, potassium carbonate, sodium carbonate, sodium hydrogen carbonate Obtained by reacting in the presence at a temperature from 1 O'C to the boiling point of the solvent used, or by reacting with an aldehyde in the presence of a reducing agent such as sodium borohydride or sodium cyanoborohydride .
  • the compound of the general formula (XlXb) is prepared by adding water or water and an organic solvent (methanol, ethanol, getyl ether, tetrahydro) in the presence of a base (eg, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide). Furan, dioxane, etc. are preferable.
  • the hydrolysis reaction is carried out at a temperature from C to the boiling point of the solvent used, and the resulting reaction solution is acidified using an acid such as hydrochloric acid, sulfuric acid, hydrobromic acid, trifluoroacetic acid, and trifluoromethanesulfonic acid.
  • hydrazine is added to a suitable solvent (water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixed solvent thereof) in a suitable solvent (from 0 to the boiling point of the solvent used).
  • a suitable solvent water, methanol, ethanol, isopropyl alcohol, tetrahydrofuran, dioxane or a mixed solvent thereof.
  • a suitable solvent from 0 to the boiling point of the solvent used.
  • the compound represented by the general formula (XXb) is obtained by deprotection at a temperature of, and the alkyl halide of the general formula (XVI I lb) is further converted to a suitable solvent (getyl ether, dibutyl propyl ether, tetrahydrofuran).
  • the compound of general formula (Xinb) is converted to N-oxide with a peracid such as metabenzo-perbenzoic acid, hydrogen peroxide, or peracetic acid in an inert solvent such as chloroform, carbon tetrachloride, dichloroethane, benzene, or toluene.
  • a peracid such as metabenzo-perbenzoic acid, hydrogen peroxide, or peracetic acid
  • an inert solvent such as chloroform, carbon tetrachloride, dichloroethane, benzene, or toluene.
  • the compound in which a is 1 to 6 is obtained by introducing an alkoxycarbonyl group at the 3-position of the compound of the general formula (XIIIb) in the same manner as described above.
  • R ′ represents alkyl such as methyl and ethyl, and other symbols are as defined above.
  • the compound in which a is 1 to S can be obtained by converting the compound of the general formula (Xlllb) to an inactive compound such as tetrahydrofuran, dioxane, getyl ether, benzene, toluene, dimethylformamide, etc.
  • a base (hydrogenated In the presence of thorium, potassium tertiary butoxide, lithium diisopropylamide, butyl lithium, etc.), the formula: Q— (CH 2 ) a NPh th or the formula: Q- (CH 2 ) a OCOR ' Has the same meaning as defined above.) Can also be directly obtained.
  • This reaction usually proceeds from 0 to 150, and the resulting compound is deprotected and hydrolyzed, respectively, to synthesize a one-branch (lib) or (Vb) compound.
  • the compound of the general formula (VUIb) can be synthesized by the following synthetic route.
  • the compound of the general formula (XXVIb) is prepared by adding water or water and a suitable solvent (methanol) in the presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogen carbonate, barium hydroxide.
  • the compound of the general formula (VI IIb) is obtained by acidifying with an acid such as an acid to carry out a decarboxylation reaction.
  • the compound of the general formula (I) thus obtained can be separated and purified from the reaction mixture by a method known per se such as recrystallization, column chromatography and the like.
  • Compounds of the general formula (I) can be obtained by conventional methods without acid-free (hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, etc.), organic acids (acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, lingic acid) , Tartaric acid, cunic acid, maleic acid, fumaric acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, ascorbic acid, etc.), inorganic bases (sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, Zinc hydroxide, ammonium hydroxide, etc.), organic bases (methylamine, getylamine, triethylamine, dicyclohexylamine, triethanolamine, ethylendiamine, trishydroxymethylaminoaminomethane, quinine, guanidine, cinchonine, etc.
  • the compound of the present invention When the compound of the present invention has a chiral carbon atom, it is usually obtained as a racemic form.
  • the racemate can be separated into optical isomers by a conventional method.
  • Various optical isomers can also be produced by using optically active starting materials.
  • the individual diastereomers can be refined by fractional crystallization or chromatography.
  • the compound of the present invention and a salt thereof have excellent cholecystokinin and gastrin antagonism, and also have a potent and long-lasting effect on the ophthalmic enzyme and gastric acid secretion. It is also useful as a prophylactic or therapeutic agent for hepatic disorders and gastrointestinal ulcers. Further, the compound of the present invention can be expected to have an anxiolytic effect based on cholecystokinin antagonistic activity, and is also useful as an anxiolytic. Next, a pharmacological test method of the compound of the present invention will be described.
  • the rat cerebral cortex is homogenized (Bolitron, 15,000 rpm for 60 seconds) with 20 volumes of ice-cold 0.32M sucrose solution, and centrifuged at 1,000 g for 10 minutes. The supernatant is further centrifuged at 40,000, 15 minutes. 1 0 mM HEPES buffer in order to wash the obtained Bere' bets (pH7. 4, 1 3 OmM NaC l, 5m MgC 1 2 inclusive) to homogenization (Polytron, 15, 1 000 r pm 0 Byo ⁇ ) Single Centrifuge (40,000 g, 10 minutes) twice.
  • the pellet obtained finally was mixed with a 30-fold amount of buffer for Atsushi (13 OmM NaCl, 5 mM MgC 1 j 0.02% bacitracin, lmgZ phenylmethanesulfonyl fluoride containing 5 mM HEPES, pH 6.5) ) And homogenize (Bolitron, 15, OOO rpm for 20 seconds ⁇ ) to prepare a synaptic membrane specimen.
  • H-CCK «(0.5 nNO 50 ⁇ final concentration and test solution or solvent 50) react at 22 for 40 minutes, and aspirate glass fiber filter paper (Pittman GFZB). after ⁇ immediately ice cold 1 Omm HEPES buffer. (:. pH7 4) was washed three times with 3m, measuring the radioactivity concentration on ⁇ non-specific binding amount bound in the presence of 1 MCC K 8
  • Atsushi 13 OmM NaCl, 5 mM MgC 1 j 0.02% bacitracin, l
  • the finally obtained pellet is diluted with a 60-fold amount of buffer for Atsushi (130 mM NaC 5 mM MgCl 2 , 0.02% bacitracin, 1 mg / phenyl methanesulfonyl fluoride containing 1 OmM HEPES, pH 7.4) Then homogenize (Polytron, 15,000 rpm for 20 seconds) to prepare a synaptic membrane specimen. Synaptic membrane preparations 0. 9PiP this S H- CCK 8 (final concentration 0.
  • test compound in the CCK receptor binding test in Experimental Example 1 and Experimental Example 2 is determined by the following formula, and evaluated at the concentration (IC i0 ) that suppresses specific binding by 50%.
  • the compound of the general formula (I) of the present invention has an action of inhibiting leukocyte adhesion to vascular endothelial cells by suppressing the expression of CD18 on leukocytes, and also has an effect on leukocyte infiltration in vivo. Also suppress.
  • the present compound is expected to be useful as a therapeutic or prophylactic agent for various inflammatory diseases, allergic diseases, etc., in which cell adhesion is involved in the onset and progression of the disease. It can also be used to prevent or treat rejection during organ transplantation and to prevent metastasis of tumor cells.
  • the pharmacological test method is shown below.
  • HUVEC fetal calf serum (20%), bovine brain-derived vascular endothelial cell growth factor (20 / g / m £) and heparin (100 ⁇ g / m 2) were suspended in 199 medium and added to a 96-well tissue culture plate coated with collagen. Incubate underneath. When cells reach confluence, add interleukin 1 (1 OU / m) and incubate for an additional 24 hours.
  • CD18 antigen which constitutes the ⁇ chain of LFA-1 (lymphocyte function associated antigen-1), one of the adhesion molecules expressed on the surface of most leukocyte cells
  • LFA-1 lymphocyte function associated antigen-1
  • the acute toxicity of the compound of the present invention was examined using ⁇ male mice.
  • the test compound was administered orally and observed for 5 days, no death occurred at a dose of 100 mg / kg.
  • pharmaceutically acceptable additives such as carriers, excipients, diluents, and solubilizing agents (lactose, corn starch, talc, kaolin) are usually used. , Physiological saline, sterile water, etc.) and safely to patients in the form of tablets (including sugar-coated tablets, film-coated tablets), capsules, powders, injections, infusions, suppositories, patches, etc. Can be administered.
  • the dosage may vary depending on the sex, age, weight or condition of the patient, but is usually preferably in the range of about 1 to 50 mg orally per adult per day.
  • the solvent was distilled off under reduced pressure, 50m of water was added, the pH was adjusted to 2 with 1N hydrochloric acid, and the mixture was stirred for 1 hour, neutralized with an aqueous solution of sodium hydrogen carbonate, and extracted twice with chloroform. I do.
  • the organic layer is dried over anhydrous magnesium sulfate, the solvent is distilled off under reduced pressure, the residue is dissolved in ethanol 5 Om ⁇ , and 1.25 g of hydrazine hydrate is added and refluxed for 3 hours. After the reaction, ethanol is distilled off under reduced pressure. The residue is added with chloroform and water, and the precipitated crystals are filtered off. The chloroform layer is washed with saturated aqueous sodium hydrogen carbonate.
  • 6-Amino-4-1 (2-chloro-phenyl) 1-9-six-hexyl 2-H-ethyl-6 H-thieno [3,2-f) [1,2,4] triab ⁇ (4, 3-a) [1,) Dissolve 0.6 g of diazebine, add 0.2 m of 4-methoxyphenylisocyanate, and stir for 30 minutes.
  • the reaction solution was poured into cold water, extracted with ethyl acetate, washed with water, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography. After that, the target fraction was concentrated under reduced pressure, and the concentrated residue was suspended in a mixture of 9 Om of ethanol and 3 Om of water, and 0.65 g of barium hydroxide octahydrate was added while stirring at room temperature. After stirring at room temperature for 10 hours, the mixture was subjected to low pressure S, water was added to the residue, and ethyl acetate was added.
  • the aqueous layer is adjusted to pH 2 with 6N hydrochloric acid and left at room temperature overnight
  • the reaction mixture is neutralized with sodium bicarbonate, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and filtered. Is concentrated under reduced pressure, and the residue is crystallized by adding isopropyl ether to give light brown crystals (4- (4-chlorophenyl) -12-ethyl-9-methyl-6H-thieno [3,2-f) (3,2-f) ( 1,2,4] triazolo (4,3-a) [1,4] diazepine-1-yl) Acetic acid 0.15 g, melting point 1998 ⁇ 202'C
  • reaction solution is poured into water, neutralized by adding sodium hydrogen carbonate, and extracted with ethyl acetate.
  • the organic layer is washed with an aqueous solution of sodium hydrogen carbonate and further with water, and dried over anhydrous magnesium sulfate.
  • the base solution is concentrated under reduced pressure, and the residue is dissolved in 4 Om of methanol.
  • a solution of sodium hydroxide and 62 dissolved in 1 Om of water is added, and the mixture is stirred at room temperature for 3 hours.
  • the reaction mixture was concentrated under reduced pressure, added with 5 Om of water, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Pressure concentration.
  • the above compound (I) was well mixed with 0.5 part, lactose 25 parts, crystalline cellulose 35 parts and corn starch 3 parts, and then kneaded well with a binder made with corn starch 2 parts.
  • the kneaded product was passed through 16 mesh, dried in an oven at 50, and then sieved through 24 mesh.
  • the kneaded powder obtained here is thoroughly mixed with 8 parts of corn starch, 11 parts of crystalline cellulose and 9 parts of talc, and then pressed to give a tablet containing 0.5 active ingredient per tablet. .

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)

Abstract

Composé de thiénodiazépine représenté par la formule générale (I), ou sel de ce composé, et son utilisation comme médicament, formule dans laquelle R3 représente formule (1), (2): (CH¿2?)aN(R?4)COR7¿, (3): (CH¿2?)aN(R?8)SO¿2R9, (4): (CH¿2?)aN(R?8)COOR10¿, (5): (CH¿2?)aOCON(R?11)(R12¿), (6): (CH¿2?)aCON(R?13)(R14¿), (7): (CH¿2?)aOCOR?15¿, (8): (CH¿2?)aOSO2R?16¿, (9): (CH¿2?)aCOR?17¿, ou (10): (CH¿2?)aS(O)nR?19¿, a valant 0 ou un nombre entier de 1 à 6, et Z représente oxygène ou soufre; X représente oxygène ou soufre, ou, selon une variante, X et Y représentent en combinaison =N-N=C(R20)- ou =N-CH=C(R20)-. Ce composé agit comme antagoniste de cholécystokinine (CCK), comme antagoniste de gastrine, et comme inhibiteur d'adhésion cellulaire, ce qui lui permet d'être utilisé comme médicament.
PCT/JP1992/001198 1990-05-23 1992-09-18 Compose de thienodiazepine et son utilisation comme medicament Ceased WO1994006801A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
PCT/JP1992/001198 WO1994006801A1 (fr) 1990-05-23 1992-09-18 Compose de thienodiazepine et son utilisation comme medicament
CA002144985A CA2144985A1 (fr) 1992-09-18 1993-09-16 Derives de la thienodiazepine et leur utilisation en pharmacie

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP13490590 1990-05-23
PCT/JP1992/001198 WO1994006801A1 (fr) 1990-05-23 1992-09-18 Compose de thienodiazepine et son utilisation comme medicament

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011111A1 (fr) * 1996-09-13 1998-03-19 Yoshitomi Pharmaceutical Industries, Ltd. Composes de thienotriazolodiazepine et leurs utilisations a des fins medicinales
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0228181A (ja) * 1987-12-22 1990-01-30 Yoshitomi Pharmaceut Ind Ltd チエノジアゼピン化合物
JPH03223290A (ja) * 1989-12-01 1991-10-02 Yoshitomi Pharmaceut Ind Ltd チエノジアゼピン化合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0228181A (ja) * 1987-12-22 1990-01-30 Yoshitomi Pharmaceut Ind Ltd チエノジアゼピン化合物
JPH03223290A (ja) * 1989-12-01 1991-10-02 Yoshitomi Pharmaceut Ind Ltd チエノジアゼピン化合物

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998011111A1 (fr) * 1996-09-13 1998-03-19 Yoshitomi Pharmaceutical Industries, Ltd. Composes de thienotriazolodiazepine et leurs utilisations a des fins medicinales
CN1109037C (zh) * 1996-09-13 2003-05-21 三菱制药株式会社 噻吩并－三唑并二氮杂䓬化合物及其医药用途
US8796261B2 (en) 2010-12-02 2014-08-05 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9249161B2 (en) 2010-12-02 2016-02-02 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9522920B2 (en) 2010-12-02 2016-12-20 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9422292B2 (en) 2011-05-04 2016-08-23 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9328117B2 (en) 2011-06-17 2016-05-03 Constellation Pharmaceuticals, Inc. Bromodomain inhibitors and uses thereof
US9493483B2 (en) 2012-06-06 2016-11-15 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9624244B2 (en) 2012-06-06 2017-04-18 Constellation Pharmaceuticals, Inc. Benzo [B] isoxazoloazepine bromodomain inhibitors and uses thereof
US9925197B2 (en) 2012-06-06 2018-03-27 Constellation Pharmaceuticals, Inc. Benzo [C] isoxazoloazepine bromodomain inhibitors and uses thereof
US9969747B2 (en) 2014-06-20 2018-05-15 Constellation Pharmaceuticals, Inc. Crystalline forms of 2-((4S)-6-(4-chlorophenyl)-1-methyl-4H-benzo[C]isoxazolo[4,5-e]azepin-4-yl)acetamide

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