WO2001079206A1 - Quinazolinediones tricycliques - Google Patents
Quinazolinediones tricycliques Download PDFInfo
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- WO2001079206A1 WO2001079206A1 PCT/JP2001/003104 JP0103104W WO0179206A1 WO 2001079206 A1 WO2001079206 A1 WO 2001079206A1 JP 0103104 W JP0103104 W JP 0103104W WO 0179206 A1 WO0179206 A1 WO 0179206A1
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- 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
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- C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
- C07D487/06—Peri-condensed systems
Definitions
- the present invention relates to a compound having an inhibitory action on poly (ADP-ribose) polymerase (PARP, also known as poly (ADP-ribose) synthetase).
- PARP poly (ADP-ribose) polymerase
- compounds that have a PARP inhibitory action include diseases caused by an increase in PARP activity, such as cerebral ischemic disorders (eg, stroke, sequelae after stroke (disorders associated with stroke and disorders that occur as sequelae after stroke (eg, motor disorders).
- Neurodegenerative diseases eg, Parkinson's disease, Alzheimer's disease, Huntington's chorea, etc.
- brain contusion head trauma, spinal injury, diabetes, ischemic heart disease (eg, Myocardial infarction, angina pectoris, arrhythmia, etc.), organ damage due to ischemia or reperfusion of ischemia (eg, myocardial ischemia-reperfusion, acute renal failure, renal ischemia, organ transplantation and percutaneous coronary angioplasty Disorders caused by surgical procedures such as surgery, etc., inflammation (eg, arthritis, rheumatoid arthritis, sepsis), inflammatory enteritis (eg, colitis, Crohn's disease) Etc.), cancer, cachexia (force hex), renal disorder, osteoporosis, acute and chronic pain (eg, neurogenic pain), sepsis (eg, endotoxin shock), skeletal muscle degeneration, muscular dystrophy It is useful as a therapeutic agent
- ischemic heart disease eg
- cerebral ischemic injury In particular, cerebral ischemic injury, stroke, sequelae after stroke, cerebral edema, neurodegenerative disease, Parkinson's disease, Alzheimer's disease, Huntington's chorea, cerebral contusion, head injury, spinal cord injury, diabetes mellitus, ischemic heart disease It is useful as a therapeutic drug for myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, skin aging, etc.
- Background art describes myocardial infarction, myocardial ischemia-reperfusion injury, angina, arrhythmia, arthritis, chronic rheumatoid arthritis, inflammatory bowel disease, sepsis, cancer, skin aging, etc.
- Compounds having a poly (AD P-ribose) polymerase inhibitory activity include, for example, dihydroisoquinolinone derivatives and isoquinolinone derivatives (for example, described in Anti-cancer Drug Design (1991), 7, 107-117), bis Monobenzamide derivatives (for example, international public Open (WO) No. 99/47494), tetracyclic compounds (for example, described in International Publication (WO) No. 99/11645), and J. Biol. Chem. (1992) , 267 (3), 1569-1575 describe the inhibition of poly (ADP-ribose) polymerase by compounds having various backbones. -Disclosure of the invention
- the present inventors have conducted intensive studies in order to achieve the above object, and as a result, have found that the compound represented by the general formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof (hereinafter referred to as the compound of the present invention as necessary) (Sometimes abbreviated) has excellent poly (ADP-ribose) polymerase inhibitory activity. That is, the present invention relates to the following.
- RR 2 and R 3 each independently represent a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, Or an unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, a substituted or unsubstituted acyl group, a halogen atom Or a nitro group, or a group represented by the formula: OR la , _NR la R lb, or — SR la (each is independently a hydrogen atom, or a substituted or unsubstituted Represents an alkyl group).
- n represents an integer of 0, 1 or 2
- R 6a represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted alkenyl group, a substituted or unsubstituted alkynyl group, a substituted or unsubstituted cycloalkyl group, Or an unsubstituted cycloalkylalkyl group, a substituted or unsubstituted arylalkyl group, a substituted or unsubstituted aromatic group, a substituted or unsubstituted saturated heterocyclic group, or a substituted or unsubstituted acyl group.
- R 6b represents a hydrogen atom, a substituted or unsubstituted alkyl group, or a substituted or unsubstituted arylalkyl group
- R 6e and R Sd each independently represent a hydrogen atom or a substituted or unsubstituted aryl group. Represents a good lower alkyl group).
- R 4 is a substituted or unsubstituted C 2-5 alkylene group (one CH 2 -group of the alkylene group is a group represented by the formula: — ⁇ , -S (O) n- , -N (R 6a )
- R 6a , R 6b , R 6 and R 6d represent the same meaning as in [1]), or a prodrug thereof or a pharmaceutically acceptable salt thereof according to [1]. .
- R 4 has at least one substituent, and at least one of the substituents has a formula: R 4a _R 4b — R 4c — Substituted alkyl group represented by R 4d
- R 4a is an alkylene group which may be substituted
- R 4b represents an optionally substituted aromatic group, a cycloalkyl group, or a single bond
- R 4c represents an optionally substituted alkylene group (one of the CH 2 — groups of the alkylene group may be replaced by an oxygen atom) or a single bond
- R 4d is a saturated heterocyclic group containing a hydrogen atom, an amino group or a nitrogen atom (one or two lower alkyl groups or amino groups on the nitrogen atom of the saturated heterocyclic group containing an amino group or a nitrogen atom) (The alkylalkyl tombs may be the same or different and may be substituted.)
- a medicament comprising the compound according to any one of [1] to [5] or a pro or drug thereof or a pharmaceutically acceptable salt thereof.
- a poly (ADP-ribose) polymerase inhibitor comprising the compound according to any one of [1] to [5], a prodrug thereof, or a pharmaceutically acceptable salt thereof.
- a patient comprising administering a compound according to any of [1] to [5] or a prodrug thereof or a pharmaceutically acceptable salt thereof to a patient in need of treatment; For inhibiting poly (AD P-ribose) polymerase in Escherichia coli.
- a brain disease comprising administering to a patient in need of treatment a compound according to any of [1] to [5] or a prodrug thereof or a pharmaceutically acceptable salt thereof.
- the compound represented by the general formula (1), a prodrug thereof, or a pharmaceutically acceptable salt thereof is abbreviated as the compound of the present invention, if necessary.
- Various groups in the present invention will be described below. Unless otherwise indicated, the following description also applies to the case where each group is a part of another group.
- the alkyl group include straight-chain or branched groups such as methyl, ethyl, propyl, 2-propyl, butyl, 2-butyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl, hexyl, heptyl, and octyl.
- Alkyl groups with 8 or less carbon atoms are mentioned.
- alkenyl group examples include alkenyl groups having 6 or less carbon atoms such as vinyl, aryl, propenyl, 2-propenyl, butenyl, pentenyl and hexenyl.
- alkynyl group examples include alkynyl groups having 6 or less carbon atoms such as ethynyl, propargyl, butynyl and pentynyl.
- cycloalkyl group examples include 3- to 8-membered cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl.
- Examples of the cycloalkenyl group include 3- to 8-membered rings such as 1-cyclopentenyl, 2-cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, and 3-cyclohexenyl.
- a cycloalkenyl group having one heavy bond is exemplified.
- Examples of the cycloalkylalkyl group include a group in which the above-mentioned alkyl group is substituted by the above-mentioned cycloalkyl group.
- aromatic group examples include an aryl group and a heteroaryl group.
- aryl group examples include aryl groups having 10 or less carbon atoms, such as a phenyl group and a naphthyl group.
- the heteroaryl group includes, for example, a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms, a 5- to 6-membered monocyclic group containing 1 to 2 nitrogen atoms and an oxygen atom;!
- saturated heterocyclic group examples include a 5- to 8-membered ring group having one nitrogen atom such as 1-piperidinyl and 1-pyrrolidinyl; a 6- to 8-membered ring group having two nitrogen atoms such as 1-piperazinyl; And a 6- to 8-membered ring group having one nitrogen atom and one oxygen atom, such as morpholino.
- Examples of the saturated heterocyclic group containing a nitrogen atom include a 5- to 8-membered ring group having one nitrogen atom such as 1-piberidinyl and 1-pyrrolidinyl, and a nitrogen atom having two nitrogen atoms such as 1-piperazinyl 6 to Examples thereof include an 8-membered ring group and a 6 to 8-membered ring group having one nitrogen atom and one oxygen atom such as morpholino.
- Examples of the substituent of the saturated heterocyclic group, the saturated heterocyclic group containing a nitrogen atom, and the saturated heterocyclic carbonyl group include a substituent on a carbon atom such as a hydroxyl group, a carboxyl group, a halogen atom, an alkoxycarbonyl group.
- Examples of the substituent on the nitrogen atom include an alkyl group, an arylalkyl group, and an alkoxycarbonyl group.
- acryl group examples include a formyl group, for example, an alkanoyl group having 2 to 6 carbon atoms such as acetyl and propanol, and a carbon atom having 4 to 7 carbon atoms such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, and cyclohexanecarbonyl.
- a formyl group for example, an alkanoyl group having 2 to 6 carbon atoms such as acetyl and propanol
- a carbon atom having 4 to 7 carbon atoms such as cyclopropanecarbonyl, cyclobutanecarbonyl, cyclopentanecarbonyl, and cyclohexanecarbonyl.
- Cycloalkanecarbonyl groups such as cyclopentenecarbonyl, cyclohexene Cycloalkenecarbonyl groups having 4 to 7 carbon atoms such as carbonyl, for example, aroyl groups having 7 to 11 carbon atoms such as benzoyl, toluoyl, and naphthoyl, such as 2-piperidinecarbonyl, 3-morpholinecarbonyl
- Heteroaromatic acyl groups having a 5- or 6-membered heteroaromatic ring containing one or two heteroatoms selected from nitrogen, oxygen, and sulfur, such as 3-, tenoyl, nicotinoyl, and isonicotinoyl Is mentioned.
- Alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkylalkyl, alkanoyl, cycloalkanecarbonyl, cycloalkenecarbonyl, and arylalkyl groups may have one or the same substituent (s).
- the substituent may be, for example, a halogen atom, a cyano group, a phenoxy group, a benzyloxy group, a trifluoromethyl group, a hydroxyl group, a lower alkoxy group, a lower alkanoyloxy group, or an amino group.
- the substituents on the aryl portion of the aromatic group, aryloyl group and heteroaromatic acyl group, and the aryl portion of the arylalkyl group may be one or more, and may be the same or different, for example, a halogen atom, a cyano group , Trifluoromethyl group, nitro group, hydroxyl group, methylenedioxy group, lower alkyl group, lower alkoxy group, benzyloxy group, lower alkanoyloxy group, amino group, mono-lower alkylamino group, di-lower alkylamino group, and carbamoyl group , Lower alkylaminocarbonyl group, di-lower alkylaminocarb Examples thereof include a bonyl group, a carboxyl group, a lower alkoxycarbonyl group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group,
- alkyl moiety of the substituent is a lower alkyl group.
- lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, and tert-butyl. And the like having 4 or less carbon atoms.
- alkylene group examples include alkylene groups having 10 or less carbon atoms, such as methylene, ethylene, trimethylene, tetramethylene, pentamethylene, and hexamethylene.
- alkylene group having 2 to 5 carbon atoms is used.
- the alkylene group may have one or more substituents, which may be the same or different and include, for example, an alkyl group, a substituted alkyl group, a hydroxyl group, a halogen atom, a cycloalkyl group, a cycloalkenyl group, a formino group, a carboxyl group, an alkoxycarbonyl group, and a saturated group.
- a heterocyclic group, an amino group (one or two lower alkyl groups or arylalkyl groups may be the same or different on the nitrogen atom of the amino group), and an aromatic group.
- Substituents on R 4 are substituted alkyl groups, especially
- R 4a —R 4b —R 4c —R 4d R 4a , R 4b , R 4e , and R 4d have the same meanings as described above.
- Preferred substituents for the lower alkyl group in R 6 e and R 6 d include a z atom and a lower alkoxy group.
- the compound represented by the general formula (1) can be synthesized from known compounds by combining known synthesis methods. For example, it can be synthesized by the following method. (A)
- R 1 R 2 , R 3 , R 4 and R 7 represent the same meaning as in the above [1].
- X 3 represents a hydrogen atom or a halogen atom
- R 1G represents a protecting group for an amino group, for example, Represents a hydroxyl group.
- the starting compound represented by the formula (3) is a known compound or can be synthesized from a known compound by combining known synthesis methods.
- Known methods include, for example, the following methods.
- n, R S a, R 6b, R S c, and R 6 d Represents the same meaning as in the above [1]. ]
- the amino group of the compound of the formula (3) is R 1 .
- the protecting group is t-butoxycarbonyl, di-tert-butyl dicarbonate is used, and a solvent such as benzene, toluene, or xylene is used.
- Aromatic hydrocarbon solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, ester solvents such as ethyl acetate, or In these mixed solvents, the method may be carried out from 0 ° C to the boiling point of the solvent.
- ether solvents such as tetrahydrofuran and 1,4-dioxane
- halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane
- ester solvents such as ethyl acetate
- the method may be carried out from 0 ° C to the boiling point of the solvent.
- Step (a) is a reaction in which a carboxylic acid is introduced into the ortho-position of the nitrogen atom to give a compound represented by the formula (5).
- Step (b) is a reaction in which the carboxylic acid represented by the formula (5) is amidated to give a compound represented by the formula (6).
- the carboxylic acid represented by the formula (5) and a compound represented by the formula: The compound can be obtained by reacting an amine represented by H 2 NR 7 with an condensing agent in an inert solvent at room temperature or under heating.
- the reaction is, for example, dicyclohexylcarposimide (D CC), disopropylcarbodiimide (DIPC), 1-ethyl-13- (3-dimethylaminopropyl) -carbodiimide (WSC), benzotriazole-1-yltris (dimethylamino) phosphonium hexafluorophosphoride (BOP) ), Diphenylphosphonyl azide (DPPA), N, N-carbonyldiimidazole (Angew. Chem. Int. Ed. Engl., Vol. 1, 351 (1962)).
- D CC dicyclohexylcarposimide
- DIPC disopropylcarbodiimide
- WSC 1-ethyl-13- (3-dimethylaminopropyl) -carbodiimide
- BOP benzotriazole-1-yltris (dimethylamino) phosphonium hexafluoro
- N-hydroxysuccinimide HONS u
- 1-hydroxybenzotriazole HOB t
- 3-hydroxy-14-oxo-1,3,4-dihydro-1,2,3-benzotriazine HO bt
- additives such as aromatic hydrocarbon solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran and 1,4-dioxane Solvents, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, etc., amide solvents such as dimethylformamide and dimethylacetamide, basic solvents such as pyridine, and mixed solvents thereof preferable.
- a method of obtaining a reactive derivative of a carboxylic acid as an intermediate compound and reacting the reactive derivative with an amine is a well-known method.
- the reactive derivative of the carboxylic acid include an acid halide, an acid anhydride (including a mixed acid anhydride) and an ester derivative.
- the acid halide include an acid chloride or an acid bromide, and a mixed acid.
- the anhydride include alkyloxycarbonyl chlorides such as ethyloxycarbonyl chloride and isobutyloxycarbonyl chloride, and ⁇ -carboxylic acids such as 2-ethyl-n-butylyl chloride and trimethylacetyl chloride.
- esters such as active esters such as ⁇ -ditrophenyl ester, ⁇ -hydroxysuccinimide ester, pentafluorophenyl ester, and methyl esters, ethyl esters, etc.
- active esters such as ⁇ -ditrophenyl ester, ⁇ -hydroxysuccinimide ester, pentafluorophenyl ester, and methyl esters, ethyl esters, etc.
- General esters can be mentioned.
- Such reactive derivatives of carboxylic acids can be readily obtained from the corresponding carboxylic acids according to commonly used general methods.
- the reaction can be carried out in a solvent under cooling or at room temperature in the presence of a base or excess amine.
- a base include inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and sodium hydrogen carbonate, and organic bases such as triethylamine and pyridine
- the solvent include aromatic hydrocarbons such as benzene, toluene, and xylene.
- Solvents such as tetrahydrofuran and 1,4-dioxane, halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane, amide solvents such as dimethylformamide and dimethylacetamide, pyridine etc. Or a mixed solvent thereof.
- an ester solvent such as tetrahydrofuran, 1,2-dimethoxyethane or dioxane
- an ester solvent such as ethyl acetate, dimethylformamide or a mixed solvent thereof may be used to prepare another ester.
- the reaction is preferably performed in an alcohol solvent such as methanol, ethanol, or isopropanol, an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, or dioxane, dimethylformamide, or a mixed solvent thereof.
- an alcohol solvent such as methanol, ethanol, or isopropanol
- an ether solvent such as tetrahydrofuran, 1,2-dimethoxyethane, or dioxane, dimethylformamide, or a mixed solvent thereof.
- Step (c) is a reaction in which the protecting group R 1 Q is removed to give a compound represented by the formula (7).
- the protecting group is t-butoxycarbonyl
- hydrogen chloride in dioxane is used.
- the method can be performed using hydrochloric acid in acetic acid at a temperature from room temperature to the boiling point of the solvent.
- the removal of various protecting groups from an amine can be carried out, for example, by the method described in Protective Groups in Organic Synthesis, JOHN WILLEY & SONS, 1991.
- Step (d) is a reaction for converting the compound of the formula (7) into a compound of the formula (21) by a ring-closure reaction, for example, N, N-carbonyldiimidazole, haemic acid ester,
- the reaction can be performed at a temperature from room temperature to the boiling point of the solvent using a reagent such as triphosgene in the presence of a suitable solvent, or using the reagent as a solvent.
- a solvent for example, aromatic hydrocarbon solvents such as benzene, toluene, and xylene, ether solvents such as tetrahydrofuran and 1,4-dioxane, and halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane It is preferable to carry out the reaction in a hydrocarbon solvent, an amide solvent such as dimethylformamide or dimethylacetamide, a basic solvent such as pyridine, or a mixed solvent thereof.
- aromatic hydrocarbon solvents such as benzene, toluene, and xylene
- ether solvents such as tetrahydrofuran and 1,4-dioxane
- halogenated solvents such as dichloromethane, chloroform, and 1,2-dichloroethane
- R 1 Q is an alkoxycarbonyl group or the like
- the compound represented by the formula (21) can be directly obtained by the ring closure reaction in the step (e).
- a base such as sodium hydride and potassium t-butoxy
- aromatic hydrocarbon solvents such as benzene, toluene, and xylene
- ether solvents such as tetrahydrofuran and 1,4-dioxane
- dimethylformamide dimethyla
- the reaction temperature include a temperature from 0 ° C. to the boiling point of the solvent.
- R 47 is a substituted or unsubstituted alkylene group (one CH 2 — group of the alkylene group has the formula:
- R 6a , R 6b , R 6c and R 6d represent the same meaning as in the above [1]. ]
- Step (f) is a reaction for ring-closing the carboxylic acid represented by the formula (22) to obtain a compound represented by the formula (23).
- a ring-closing reaction in polyphosphoric acid or polyphosphate ester for example, the method of heating to 140 C using pentachloride and phosphoric acid in a ratio of 2.5: 1 is described in Ctiem, Heterocycl. Compd. (1997), 33 (1), 96- 98, and can be carried out according to an equivalent method.
- the ⁇ [j method can be performed using a generally known Friedel-Crafts reaction.
- a carboxylic acid represented by the formula (22) is converted into an acid halide with thionyl chloride or pentachloroaniline, etc., and then converted into chloroanilide aluminum, pentachloroanilide antimony, iron trichloride, tin tetrachloride. Ring closing reaction using a Lewis acid such as titanium tetrachloride, zinc chloride and boron trifluoride. Solvents used in this step include nitrobenzene, 1,2-dichloroethane, chloroform, acetone, tetrahydrofuran, and ethyl acetate.
- Step (g) is carried out by reducing the compound represented by the formula (23) to obtain a compound represented by the formula (24), which can be carried out by a conventional method for reducing a ketone at the benzyl position.
- a method using triethylsilane in trifluoroacetic acid may be mentioned.
- a compound in which a carbonyl group is converted to a hydroxymethylene group can be synthesized by selecting reduction conditions, and the hydroxymethylene group can be converted to another substituent according to a conventional method.
- R 1 R 2 , R 3 , R 4 and R 8 represent the same meaning as in the above [1]. ]
- a compound represented by the formula (26) is obtained from a compound represented by the formula (25) (a compound in which R 7 is a hydrogen atom among the compounds represented by the formula (21))
- R 8 is NH 2
- N, N-getylaniline the intermediate compound obtained by refluxing in salted phosphorus is reacted in methanol saturated with ammonia at a temperature from room temperature to heated reflux, preferably at 60 ° C., preferably at 60 ° C. (Tetrahedron Letters (1994 ), 35 (3), 397-400).
- R 8 is a group represented by the formula: one OR 8 a , one NH 2 , -NHR 8 a , — NR 8 a R 8 b or one SR 8 a , it can be produced according to this.
- the compound in which R 8 is a halogen atom can be obtained, for example, by reacting with a phosphorus oxyhalide such as phosphorus oxychloride, or a phosphorus halide such as pentachloride or phosphoryl chloride.
- a group active in the reaction such as a hydroxyl group, an amino group or a carboxylic acid group
- these groups other than the site to be reacted as required Is protected with an appropriate protecting group in advance, and after performing each reaction or after carrying out some reactions, the protecting group is removed to obtain a desired compound.
- a protecting group for protecting a hydroxyl group, an amino group, a carboxyl group, or the like a normal protecting group used in the field of synthetic organic chemistry may be used, and such a protecting group may be introduced and removed according to a usual method. (Eg, the method described in Protective Groups in Organic Synthesis, JOHN WILLEY & SONS, 1991).
- a protecting group for a hydroxyl group includes a methoxymethyl group and a tetrahydroviranyl group
- a protecting group for an amino group includes a tert-butyloxycarbonyl group.
- Such a hydroxyl-protecting group can be removed, for example, by reacting in a solvent such as aqueous methanol, aqueous ethanol, or aqueous tetrahydrofuran in the presence of an acid such as a base, sulfuric acid, or acetic acid.
- the group can be removed by, for example, reacting in a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform, or aqueous methanol in the presence of an acid such as hydrochloric acid or trifluoroacetic acid.
- a solvent such as aqueous tetrahydrofuran, methylene chloride, chloroform, or aqueous methanol
- an acid such as hydrochloric acid or trifluoroacetic acid.
- the form of protection includes, for example, tert-butyl ester, orthoester, acid amide and the like.
- Removal of such protecting groups can be accomplished by tert
- the reaction is carried out in a solvent containing water in the presence of hydrochloric acid
- orthoester for example, aqueous methanol, hydrated tetrahydrofuran, hydrated 1,2-dimethoxyethane, etc.
- acid amide for example, water, hydrated methanol, hydrated tetrahydrofuran in the presence of an acid such as hydrochloric acid or sulfuric acid.
- the reaction can be carried out in a solvent such as
- the compounds represented by the formula (1) include those having an optically asymmetric center, and therefore, they may be in a racemic form or in an optically active form when an optically active starting material is used. Obtainable. If necessary, the racemates obtained can be physically or chemically resolved into their optical antipodes by known methods.
- a diastereomer is formed from a racemate by a reaction using an optically active resolving agent. Different diastereomers can be separated by known methods such as fractional crystallization.
- “Prodrugs” include those that are readily hydrolyzed in vivo and reproduce the compound of the formula (1). For example, in the case of a compound having a carboxyl group, the carboxyl group becomes an alkoxycarbonyl group. Or an alkylthiocarbonyl group, or a compound that has become an alkylaminocarbonyl group.
- a compound having an amino group a compound in which the amino group is substituted with an alkanoyl group to form an alkanoylamino group, a compound in which the amino group is substituted with an alkoxycarbonyl group to form an alkoxycarbonylamino group And a compound converted to an acyloxymethylamino group or a compound converted to hydroxylamine.
- a compound having a hydroxyl group a compound in which the hydroxyl group is substituted with the above-mentioned acyl group to form an acyloxy group, a compound which becomes a phosphoric ester, or a compound which becomes an acyloxymethyloxy group is used.
- alkyl moiety of the group used in these prodrugs examples include the above-mentioned alkyl groups, and the alkyl group is substituted (for example, an alkyl group having 1 to 6 carbon atoms). A alkoxy group or the like.
- Preferable examples include, for example, a compound in which a carboxyl group has become an alkoxycarbonyl group, for example, lower (for example, having 1 to 6 carbon atoms) alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl And lower (eg, having 1 to 6 carbon atoms) alkoxycarbonyl substituted with an alkoxy group such as 1,2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl, pivaloyloxymethoxycarbonyl, and the like.
- lower alkoxycarbonyl such as methoxycarbonyl and ethoxycarbonyl, methoxymethoxycarbonyl, ethoxymethoxycarbonyl
- alkoxycarbonyl substituted with an alkoxy group such as 1,2-methoxyethoxycarbonyl, 2-methoxyethoxymethoxycarbonyl
- the compound represented by the formula (1) or a prodrug thereof can be converted into a pharmaceutically acceptable salt, if necessary.
- salts include salts with mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid; formic acid, acetic acid, fumaric acid, maleic acid, oxalic acid, citric acid, malic acid, tartaric acid, and aspartic acid.
- a salt with an organic carboxylic acid such as glutamic acid
- a salt with a sulfonic acid such as methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, hydroxybenzenesulfonic acid, dihydroxybenzenesulfonic acid; and,
- alkaline metal salts such as sodium salt and potassium salt
- alkaline earth metal salts such as calcium salt and magnesium salt
- ammonium salt triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, dicyclohexane Xylamine salts, salts with N, N'-dibenzylethylenediamine and the like.
- the compound represented by the formula (1) or a prodrug thereof or a pharmaceutically acceptable salt thereof may be an anhydride, hydrate or solvate thereof.
- the compounds of the present invention can be administered orally or parenterally when using them as medicaments. That is, it can be orally administered in a commonly used dosage form, for example, a powder, granule, tablet, capsule, syrup, suspension or the like, or, for example, a solution, emulsion, or suspension thereof. Can be administered parenterally in the form of injections. It can also be administered rectally in the form of suppositories.
- Said suitable dosage form is, for example, It can be produced by mixing the compound of the present invention with an acceptable usual carrier, excipient, binder, stabilizer, and diluent.
- an acceptable buffer, solubilizing agent, or isotonic agent can be added.
- the dosage and the number of administrations vary depending on, for example, the target disease, symptoms, age, body weight, and administration form, but are usually 0.1 to 2000 mg, preferably 1 to 200 mg per day for an adult once or several times (for example, 2 to 4 times).
- Example 2 The compound shown in Example 2 was obtained according to Example 1.
- 1, 2, 3, 4-tetrahydro-2-quinolinylmethanol 1 8.60 g (0.1 14 mol), 8.54 g (0.125 mol) of imidazole and 10 ml of dimethylformamide were stirred under ice-cooling while stirring with 18.03 g of tert-butyldimethylsilyl chloride (0.120 mol). ) was added, and the mixture was heated. The ice bath was removed, and the mixture was stirred at room temperature overnight. To the reaction mixture was added a cold 2% aqueous potassium hydrogen sulfate solution, and the mixture was extracted with getyl ether.
- reaction mixture was poured into a 5% aqueous potassium hydrogen sulfate solution (Z ice), and extracted with geethyl ether.
- the organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated.
- tert-butyl 8- (aminocarbonyl) -12-( ⁇ [tert-butyl (dimethyl) silyl] oxy ⁇ methyl) 1,3,4-dihydro_1 (2H) -quinolinecarboxylate 5.04 g (12 . tetrahydrofuran 3 OML solution room temperature under stirring 0 mmol), 60% sodium hydride 1. 20 g of (30.0 mmol) Karoe, after addition, at the temperature was raised to 50 ° C and 50 ° C Stir for 1.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution (Z ice) and extracted with a black hole form. The organic layer was treated with sulfuric anhydride, After drying, the mixture was filtered and concentrated. The obtained residue is subjected to silica gel column chromatography.
- Example 4 The compound shown in Example 4 was obtained according to Example 3.
- Example 5 The compound shown in Example 5 was obtained according to Example 3.
- Example 6 The compound shown in Example 6 was obtained according to Example 3.
- Example 10 The compound shown in Example 10 was obtained according to Example 7.
- Example 1 Melting point of hydrochloride: 295-297 ° C. (decomposition) The compound shown in Example 1 was obtained according to Example 11.
- Example 13 The compound shown in Example 13 was obtained according to Example 11.
- Example 13 The compound shown in Example 13 was obtained according to Example 11.
- Example 13 Example 13
- Example 14 Melting point of hydrochloride: 300 ° C. or higher The compound shown in Example 14 was obtained according to Example 11.
- Example 15 The compound shown in Example 15 was obtained according to Example 11.
- Example 18 The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid aqueous solution and ethyl acetate were added to the obtained residue, and liquid separation was performed. The hydrochloric acid aqueous layer was concentrated under reduced pressure, and 6- (aminomethyl) -1,6,7-dihydro-1H, 5H-pyrido [3,2,1-ij] quinazoline-1,3 (2H) -dione hydrochloride 203.5 mg (98% yield). Melting point: 300 ° C. or higher The compound shown in Example 18 was obtained according to Example 17.
- Example 19 Melting point: 300 ° C. or higher The compound shown in Example 19 was obtained according to Example 17.
- Example 20 Melting point: 300 ° C. or higher The compound shown in Example 20 was obtained according to Example 1.
- Example 22 The compound shown in Example 22 was obtained according to Example 21.
- Example 22
- Example 24 N-[(1,3-dioxo-1,2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,1-ij] quinazoline-6-yl) methyl] isonicotinamide Melting point: 282 — 285 ° C.
- the compound shown in Example 24 was obtained according to Example 21.
- Example 25 Melting point: 247-250 ° C.
- the compound shown in Example 25 was obtained according to Example 21.
- Example 26 Melting point: 300 ° C. or higher The compound shown in Example 26 was obtained according to Example 21.
- Example 27 [(1,3-Dioxo-2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,11-ij] quinazoline-1-6-yl) methyl] -1-2-phenylacetate Amide Melting point: 275 ° C (decomposition) The compound shown in Example 27 was obtained according to Example 21.
- Example 28 The compound shown in Example 28 was obtained according to Example 21.
- Example 29 The compound shown in Example 29 was obtained according to Example 21.
- Example 30 The compound shown in Example 30 was obtained according to Example 21.
- Example 31 N-[(1,3-Dioxo-1,2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,1-ij] quinazoline-1-6-yl) methyl] cyclohexanecarboxami : 280-281 ° C (decomposition)
- the compound shown in Example 31 was obtained according to Example 21.
- Example 32 The compound shown in Example 32 was obtained according to Example 21.
- Example 33 The compound shown in Example 33 was obtained according to Example 21.
- Example 3 The compound shown in Example 3 was obtained according to Example 21.
- Example 35 The compound shown in Example 35 was obtained according to Example 21.
- Example 21 5- (aminomethyl) -1,5,6-dihydro-1H-pyro [3,2,1-ij] quinazoline-1,3 (2H) dione hydrochloride and N-Boc-dalicy The resulting product was deprotected to give the compound shown in Example 36.
- Example 39 Melting point: 300 ° C. or higher The reaction was carried out according to Example 36 to obtain the compound shown in Example 39.
- Example 42 The compound shown in Example 42 was obtained according to Example 41.
- Example 11 Tert-butyl 1,3-dioxo_2,3,6,7-tetrahydro-1H, 5H-pyrido [3,2,1-ij] quinazoline-1-6-ylcarbamate was prepared according to Example 1 (2). Obtained.
- reaction mixture was ice-cooled, and under ice-cooling stirring, di-tert-butyldicarbonate 8.35 mL (36.3 mmol) was added dropwise. After the addition, the ice bath was removed and the mixture was stirred at room temperature. One hour later, 50 mL of tetrahydrofuran was added, and the mixture was further stirred. The reaction mixture was slowly poured into a cold aqueous solution of ammonium chloride and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, filtered and concentrated.
- tert-Butyl 3-formyl-11H-indole-1-carboxylate 5.38 g (21.9 mmol) of methylene chloride in 15 OmL under ice-cooling and stirring, 70-75% m-chloroperbenzoic acid 5.64 g of the acid was added, and the mixture was stirred for 2 hours under ice cooling and stirred at room temperature overnight. Water and a 10% aqueous sodium sulfite solution were sequentially added to the reaction mixture, and the mixture was stirred at room temperature for 1 hour. The organic layer was washed sequentially with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate, filtered, and concentrated. The obtained residue is subjected to silica gel column chromatography.
- Example 48 Melting point: 300 ° C. or higher
- the compound shown in Example 48 was obtained according to Example 47.
- Example 50 the compound shown in Example 51 was obtained.
- Example 5 1
- NAD Nacalai Tesque
- NAD [adenine-2,8-3 ⁇ 4] -NAD) (EN (Wei trademark) Life Science Products, Inc. (USA), specific activity 1402 GBq / mmol)
- PARP human PARP recombinant, 660 units / mg
- a buffer (50% Tris-HCl (pH 8.0) / 25 mM MgCl 2 aqueous solution) was used for the preparation of each solution.
- each well of the plate was washed four times with 80% ethanol, and the washing solution was also passed through the glass fiber filter.
- Dara The fiber filter was heated and dried in a microwave oven for 3 to 4 minutes, and two sheets of the solid scintillator were stacked in a sample bag and sealed with a heat seal. This was placed on a heater at about 50 ° C to heat-melt the scintillator, penetrated through the filter, returned to room temperature, and cooled to a plate counter (1450 MicroBeta (registered trademark) TriLux,
- the inhibition rate for PARP activity was calculated using the following equation.
- the compound of the present invention has a PARP inhibitory action, and thus, for example, a disease caused by enhanced PARP activity, for example, cerebral ischemic injury, neurodegenerative disease, cerebral contusion, head injury, spinal injury, diabetes, ischemic heart Diseases, organ damage due to ischemia or ischemia reperfusion, inflammation, inflammatory bowel disease, cancer, cachexia, renal disorder, osteoporosis, acute and chronic pain, sepsis, skeletal muscle degeneration, muscular dystrophy, skin aging, It can be used as a therapeutic drug for aging of the immune system, AIDS, changes in gene expression of senescent cells, etc.
- a disease caused by enhanced PARP activity for example, cerebral ischemic injury, neurodegenerative disease, cerebral contusion, head injury, spinal injury, diabetes, ischemic heart Diseases, organ damage due to ischemia or ischemia reperfusion, inflammation, inflammatory bowel disease, cancer, cachexia, renal disorder, osteoporosis, acute and chronic pain, sepsis, skeletal muscle de
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Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2001246893A AU2001246893A1 (en) | 2000-04-18 | 2001-04-10 | Tricyclic quinazolinediones |
US10/258,026 US20030105118A1 (en) | 2000-04-18 | 2001-04-10 | Tricyclic quinazolinediones |
EP01919884A EP1288216A1 (en) | 2000-04-18 | 2001-04-10 | Tricyclic quinazolinediones |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2000-116577 | 2000-04-18 | ||
JP2000116577 | 2000-04-18 |
Publications (1)
Publication Number | Publication Date |
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WO2001079206A1 true WO2001079206A1 (fr) | 2001-10-25 |
Family
ID=18628024
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/JP2001/003104 WO2001079206A1 (fr) | 2000-04-18 | 2001-04-10 | Quinazolinediones tricycliques |
Country Status (4)
Country | Link |
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US (1) | US20030105118A1 (ja) |
EP (1) | EP1288216A1 (ja) |
AU (1) | AU2001246893A1 (ja) |
WO (1) | WO2001079206A1 (ja) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002102793A2 (en) * | 2001-06-19 | 2002-12-27 | Warner-Lambert Company Llc | Quinazolinediones as antibacterial agents |
WO2002100860A3 (fr) * | 2001-06-08 | 2003-11-20 | Aventis Pharma Sa | Composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens |
WO2004043959A1 (ja) * | 2002-11-12 | 2004-05-27 | Mochida Pharmaceutical Co., Ltd. | 新規parp阻害剤 |
US7365071B2 (en) | 2002-09-05 | 2008-04-29 | Branislav Musicki | Heterocyclic compounds, preparation process and intermediates, and use as medicaments, in particular as β-lactamase inhibitors and antibacterials |
US7612087B2 (en) | 2002-01-28 | 2009-11-03 | Novexel | Heterocyclic compounds as inhibitors of beta-lactamases |
US7960384B2 (en) | 2006-03-28 | 2011-06-14 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US8084605B2 (en) | 2006-11-29 | 2011-12-27 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
WO2013021363A1 (en) | 2011-08-11 | 2013-02-14 | Actelion Pharmaceuticals Ltd | Quinazoline-2,4-dione derivatives |
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3709887A (en) * | 1971-12-08 | 1973-01-09 | Sandoz Ag | 1-substituted-5,6-dihydro-7h-pyrido(3,2,1-ij)quinazolin-3(3h)-ones and their preparation |
US3872119A (en) * | 1973-03-26 | 1975-03-18 | Sandoz Ag | 1-Substituted-5,6-dihydro-pyrrolo(3,2,1-ij)quinazolin-3(3H)-ones |
WO1998033802A1 (en) * | 1997-02-01 | 1998-08-06 | Newcastle University Ventures Limited | Quinazolinone compounds |
-
2001
- 2001-04-10 AU AU2001246893A patent/AU2001246893A1/en not_active Abandoned
- 2001-04-10 EP EP01919884A patent/EP1288216A1/en not_active Withdrawn
- 2001-04-10 US US10/258,026 patent/US20030105118A1/en not_active Abandoned
- 2001-04-10 WO PCT/JP2001/003104 patent/WO2001079206A1/ja not_active Application Discontinuation
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3709887A (en) * | 1971-12-08 | 1973-01-09 | Sandoz Ag | 1-substituted-5,6-dihydro-7h-pyrido(3,2,1-ij)quinazolin-3(3h)-ones and their preparation |
US3872119A (en) * | 1973-03-26 | 1975-03-18 | Sandoz Ag | 1-Substituted-5,6-dihydro-pyrrolo(3,2,1-ij)quinazolin-3(3H)-ones |
WO1998033802A1 (en) * | 1997-02-01 | 1998-08-06 | Newcastle University Ventures Limited | Quinazolinone compounds |
Non-Patent Citations (2)
Title |
---|
BANASIK M. ET AL.: "Specific inhibitors of .. transferase", vol. 267, no. 3, 1992, pages 1569 - 1575, XP002040060 * |
GAMA Y. ET AL.: "Synthesis of glucosylamino ... amino acids", vol. 29, no. 9, 1999, pages 1493 - 1501, XP002942119 * |
Cited By (14)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002100860A3 (fr) * | 2001-06-08 | 2003-11-20 | Aventis Pharma Sa | Composes heterocycliques, leur preparation et leur utilisation comme medicaments, notamment comme anti-bacteriens |
US7288549B2 (en) * | 2001-06-08 | 2007-10-30 | Aventis Pharma S.A. | Heterocyclic compounds, method for preparing same and use thereof as medicines, in particular as antibacterial agents |
EP1798231A3 (fr) * | 2001-06-08 | 2008-02-27 | Novexel | Produits intermédiaires dans la préparation de composés anti-bactériens |
WO2002102793A3 (en) * | 2001-06-19 | 2003-04-10 | Warner Lambert Co | Quinazolinediones as antibacterial agents |
WO2002102793A2 (en) * | 2001-06-19 | 2002-12-27 | Warner-Lambert Company Llc | Quinazolinediones as antibacterial agents |
US7612087B2 (en) | 2002-01-28 | 2009-11-03 | Novexel | Heterocyclic compounds as inhibitors of beta-lactamases |
US7365071B2 (en) | 2002-09-05 | 2008-04-29 | Branislav Musicki | Heterocyclic compounds, preparation process and intermediates, and use as medicaments, in particular as β-lactamase inhibitors and antibacterials |
WO2004043959A1 (ja) * | 2002-11-12 | 2004-05-27 | Mochida Pharmaceutical Co., Ltd. | 新規parp阻害剤 |
US8906901B2 (en) | 2005-09-14 | 2014-12-09 | Takeda Pharmaceutical Company Limited | Administration of dipeptidyl peptidase inhibitors |
US8222411B2 (en) | 2005-09-16 | 2012-07-17 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US7960384B2 (en) | 2006-03-28 | 2011-06-14 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors |
US8084605B2 (en) | 2006-11-29 | 2011-12-27 | Kelly Ron C | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
WO2013021363A1 (en) | 2011-08-11 | 2013-02-14 | Actelion Pharmaceuticals Ltd | Quinazoline-2,4-dione derivatives |
US8916573B2 (en) | 2011-08-11 | 2014-12-23 | Actelion Pharmaceuticals Ltd. | Quinazoline-2,4-dione derivatives |
Also Published As
Publication number | Publication date |
---|---|
AU2001246893A1 (en) | 2001-10-30 |
US20030105118A1 (en) | 2003-06-05 |
EP1288216A1 (en) | 2003-03-05 |
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