HK1140197B

HK1140197B - (aza)indole derivative and use thereof for medical purposes

Info

Publication number: HK1140197B
Application number: HK10106337.7A
Authority: HK
Inventors: 和夫清水; 靖泷川; 秀纪藤仓; 雅人饭塚; 正博平枥; 纪彦菊地
Original assignee: 橘生药品工业株式会社
Priority date: 2007-04-11
Filing date: 2008-04-10
Publication date: 2014-03-07

Description

(Aza) indole derivatives and medicinal use thereof

Technical Field

The present invention relates to (aza) indole derivatives useful as medicaments.

More specifically, the present invention relates to an (aza) indole derivative, a prodrug thereof, or a pharmaceutically acceptable salt thereof, which has xanthine oxidase inhibitory activity and is useful as a prophylactic or therapeutic agent for a disease associated with abnormality of serum uric acid level.

Background

Uric acid is the end product of human purine metabolism. In many mammals, unlike humans, uric acid is further broken down by urate oxidase (uricase) in the liver to form allantoin, which is excreted through the kidney. In humans, the main pathway of uric acid excretion is the kidney, where about two thirds of uric acid is excreted in the urine. The remainder is excreted in the feces. Hyperuricemia is caused when excessive uric acid production or low uric acid excretion occurs. Hyperuricemia is classified into a uric acid overproduction type, a uric acid excretion hypo type and a mixed type thereof. This classification of hyperuricemia is clinically important. In order to reduce the side effects of therapeutic agents, therapeutic agents are selected according to each classification (for example, see non-patent document 1).

In hyperuricemia with excessive uric acid production, the urinary excretion of uric acid increases, and when the urinary excretion of uric acid is further increased by using a uricosuric agent, there is a possibility that urinary calculi may occur. Therefore, uric acid production inhibitors (or uric acid synthesis inhibitors, hereinafter simply referred to as "uric acid production inhibitors") are used in uric acid overproduction types in principle.

Uric acid is produced from the diet and via endogenously synthesized purines, ultimately by oxidation of xanthine by xanthine oxidase. Allopurinol has been developed as a xanthine oxidase inhibitor and is the only uric acid production inhibitor in medical practice. However, although allopurinol is reported to be effective in hyperuricemia and various diseases resulting therefrom, serious side effects such as toxic syndrome (hypersensitivity vasculitis), sjogren's syndrome, exfoliative dermatitis, aplastic anemia, liver dysfunction and the like have also been reported (for example, see non-patent document 2). As one of the reasons, allopurinol has been suggested to have a nucleic acid-like structure and to inhibit the pyrimidine metabolic pathway (for example, see non-patent document 3).

On the other hand, in hyperuricemia with low uric acid excretion, uric acid excretion is low. It has been reported that when allopurinol is used, allopurinol is metabolized into oxypurinol, which is excreted through the kidney by the same mechanism as uric acid, the excretion of oxypurinol is also low, and the incidence of liver disorders is increased (for example, see non-patent document 4). Therefore, in principle, uricosuric drugs such as probenecid, benzbromarone, and the like are used in the uricosuric hypostyle. However, these uricosuric drugs also have side effects such as gastrointestinal dysfunction, urinary calculi, and the like. In particular, benzbromarone is known to be likely to cause severe hepatitis in a idiosyncratic patient (for example, see non-patent document 5).

Therefore, it can be said that the existing uric acid production-inhibiting drugs and uric acid excretion-promoting drugs have limited use or serious side effects on patients. Therefore, development of a therapeutic agent for hyperuricemia which is easy to use is urgently desired.

Uric acid is excreted mainly through the kidney, and uric acid kinetics in the kidney have been examined so far in some experiments using Brush Border Membrane Vesicles (BBMV) prepared from the renal cortex (for example, see non-patent documents 6 and 7). In human bodies, it is known that uric acid freely passes through the glomerulus of the kidney, and a mechanism of reabsorption and secretion of uric acid exists in the proximal tubule (for example, see non-patent document 8).

In recent years, a gene encoding human renal uric acid transporter (SLC22a12) has been identified (for example, see non-patent document 9). The transporter protein (transporter 1, hereinafter referred to as "URAT 1") encoded by this gene is a 12-transmembrane type molecule belonging to the OAT family. URAT1 mRNA was specifically expressed in the kidney, and URAT1 localization on the proximal tubule lumen side was observed on human kidney tissue sections. In experiments using xenopus oocytes expression system, uric acid uptake mediated by URAT1 was shown. In addition, it can be shown that uric acid uptake is transported by exchange with organic anions such as lactic acid, pyrazinecarboxylic acid (PZA), nicotinic acid, and the like, and that uric acid uptake mediated by URAT1 is inhibited by the uricosuric drugs probenecid and benzbromarone. Therefore, as expected from experiments with membrane vesicles, it is strongly suggested that URAT1 is a urate/anion exchanger (urate/anion exchanger). That is, URAT1 can be shown to be a transporter that plays an important role in uric acid reabsorption in the kidney (for example, see non-patent document 9).

In addition, the relationship between URAT1 and disease is clear. Idiopathic renal hypouricemia is a disease in which uric acid excretion is increased and serum uric acid level is lowered due to uric acid kinetic abnormality in the kidney. The disease is known to be often complicated by urinary calculi or acute renal failure after exercise. URAT1 is identified as a causative gene of renal hypouricemia (for example, see non-patent document 9). These all strongly suggest that URAT1 is involved in the regulation of uric acid level in blood.

Therefore, a substance having an inhibitory activity of URAT1 can be used as a therapeutic agent and a prophylactic agent for diseases associated with high blood uric acid level, i.e., hyperuricemia, tophus, gouty arthritis, renal disorder associated with hyperuricemia, urinary calculi, and the like.

In the treatment of hyperuricemia, it is reported that the combined use of allopurinol, which is a uric acid production inhibitor, and an agent having a uricosuric action lowers the serum uric acid level more strongly than the use of allopurinol alone (for example, see non-patent documents 10 and 11). Therefore, when a treatment using a single existing agent cannot exert a sufficient effect, it is expected that a higher therapeutic effect is achieved by using a uric acid production inhibitory drug in combination with a uric acid excretion promoting drug. In addition, in hyperuricemia with low uric acid excretion, it is considered that since the amount of uric acid excretion in urine can be reduced by lowering the blood uric acid level, the risk of urinary calculi caused by the treatment with a uricosuric agent alone can be reduced. In addition, a high therapeutic effect is expected for the mixed hyperuricemia. Therefore, it is expected that an agent having both an inhibitory effect on uric acid production and an effect of promoting uric acid excretion is a very useful prophylactic or therapeutic agent for hyperuricemia.

As a compound having both xanthine oxidase inhibitory activity and URAT1 inhibitory activity, morin (morin), which is a natural product, is known (see non-patent document 12). In addition, as a compound having an uricosuric action, a diaryl compound or diaryl ether compound is known (see patent document 1).

It has been reported that 1-phenylindole derivatives have a stem cell differentiation inhibitory effect (see patent documents 2 to 4). It is also reported that a 1-pyrimidine-indole derivative has a sodium channel inhibitory effect (see patent document 5). However, the (aza) indole derivatives of the present invention have different structures from the compounds described in the above documents, and neither description nor suggestion that they have xanthine oxidase inhibitory effects or can be used for the prevention or treatment of diseases associated with abnormal serum uric acid level such as gout, hyperuricemia, and the like.

Patent document 1: japanese patent laid-open No. 2000-001431 (JPA2000-001431)

Patent document 2: international publication 2005/007838 pamphlet

Patent document 3: japanese patent laid-open No. 2006-180763 (JPA2006-180763)

Patent document 4: japanese patent laid-open No. 2006-204292 (JPA2006-204292)

Patent document 5: international publication 2005/003099 pamphlet

Non-patent document 1: atsuo Taniguchi and 1, Modern Physician, 2004, Vol.24, No. 8, p.1309-1312

Non-patent document 2: kazuhide Ogino and 2, Nihon Rinsho (Japan clinical), 2003, Vol.61, journal number 1, pp.197-201

Non-patent document 3: hideki Horiuchi and 6, Life Science, 2000, vol 66, No. 21, pp 2051-2070

Non-patent document 4: hisashi Yamanaka and 2, Konyusankessyo to Tsufu (hyperuricemia and gout), Medical Review Co. Press, 1994, Vol.2, No. 1, p.103-

Non-patent document 5: konyasankessyo, tsufu no Chiryo guidelinesakeeiikai (Committee for therapeutic guidelines for hyperuricemia and gout), which is published for the treatment of hyperuricemia and gout (guidelines for hyperuricemia), 1 st edition, Nihon tsuhu kakusan tai gakkai (Japan society for gout and nucleic acid metabolism), 2002, pages 32 to 33

Non-patent document 6: francoise Roch-Ramel and 2, am.J. Physiol, 1994, volume 266(Renal Fluid Electrolysis Physiol, volume 35), F797-F805

Non-patent document 7: francoise Roch-Ramel and 2, J.Pharmacol.Exp.Ther., 1997, vol.280, p.839-845

Non-patent document 8: hiroaki Kimura and 3, Nihon rinsyo (Japanese clinical practice), 2003, volume 61, supplement No. 1, page 119-

Non-patent document 9: atsushi Enomoto and 18, Nature 2002, volume 417, pages 447-

Non-patent document 10: takahashi and 5, Ann. Rheum. Dis., 2003, vol.62, page 572-575

Non-patent document 11: feher and 4, Rheumatology, 2003, Vol.42, pp.321-325

Non-patent document 12: zhifeng Yu and 2, j.pharmacol. exp. ther., 2006, volume 316, page 169-

DISCLOSURE OF THE INVENTION

Problems to be solved by the invention

The present invention provides a prophylactic or therapeutic agent for a disease associated with abnormal serum uric acid level, which has an inhibitory activity on uric acid production.

Technical scheme for solving technical problem

The present inventors have intensively studied to solve the above problems. As a result, they have found that (aza) indole derivatives represented by the following general formula (I) exhibit an excellent xanthine oxidase inhibitory action and significantly lower serum uric acid levels, and thus are useful as preventive or therapeutic agents for diseases associated with abnormal serum uric acid levels, and thus form the basis of the present invention.

That is, the present invention relates to:

(aza) indole derivatives represented by the following general formula:

[ chemical formula 1]

Wherein T represents nitro, cyano or trifluoromethyl;

ring J represents an aryl or heteroaryl ring;

q represents carboxy, lower alkoxycarbonyl, carbamoyl, mono (di) (lower alkyl) carbamoyl, sulfo, sulfamoyl or 5-tetrazolyl;

y represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a nitro group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group, provided that two or more Y are optionally present on the ring J and these Y are optionally the same as or different from each other;

X¹，X²and X³Independently represent CR²Or N, provided that all X¹，X²And X³Does not simultaneously represent N, and when two or more R are present²When then these R' s²Optionally identical or different from each other; and

R¹and R²Independently represents a halogen atom, cyano, perfluoro (lower alkyl group), -A^A-A-D-E-G or-N (-D-E-G)₂Provided that the two (-D-E-G) are optionally different from each other; or with the proviso that when R bound to an adjacent atom is present¹And R²Or two R²When R is equal to¹And R²Or two R²Optionally joined together to form a ring;

in the above formula, A^ARepresents a hydrogen atom, a hydroxyl group, a thiol group, -CHO, a carboxyl group, -CONHR³，-NHR³，-N(R³)CHO，-N(R³)CONHR⁴or-SO₂NHR³；

A represents a direct bond, -O-, -S-, -CO-, -COO-, -CON (R)³)-，-SO₂-，-SO₂N(R³)-，-N(R³)-，-N(R³)CO-，-N(R³)COO-，-N(R³)SO₂-or-N (R)³)CONR⁴-, wherein R³And R⁴Independently represents a hydrogen atom or a lower alkyl group;

d represents optionally substituted lower alkylene, optionally substituted lower alkenylene, optionally substituted lower alkynylene, optionally substituted cycloalkylene, optionally substituted heterocycloalkylene, optionally substituted arylene or optionally substituted heteroarylene, with the proviso that D is optionally further substituted by-E-G;

e represents a direct bond, -O-, -N (R)⁵)-，-S-，-CO-，-COO-，-CON(R⁵)-，-SO₂-，-SO₂N(R⁵)-，-N(R⁵)CO-，-N(R⁵)COO-，-N(R⁵)SO₂-or-N (R)⁵)CON(R⁶) Provided that R is⁵And R⁶Independently represents a hydrogen atom or a lower alkyl group; and

g represents a hydrogen atom, an optionally substituted lower alkyl group, an optionally substituted lower alkenyl group, an optionally substituted lower alkynyl group, an optionally substituted cycloalkyl group, an optionally substituted heterocycloalkyl group, an optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group (lower alkyl group), an optionally substituted heterocycloalkyl group (lower alkyl group), an optionally substituted aryl group (lower alkyl group) or an optionally substituted heteroaryl group (lower alkyl group), with the proviso that when G is a hydrogen atom, E is a direct bond, -O-, -N (R)⁵)-，-S-，-COO-，-CON(R⁵)-，-N(R⁵)CO-，-N(R⁵)CON(R⁶) -or-SO₂N(R⁵) When is, or G is optionally substituted with R⁵And R⁶Joined together to form a ring;

above-mentioned [1]Or a prodrug thereof,or a pharmaceutically acceptable salt thereof, wherein X¹，X²And X³Independently represent CR²Provided that when two or more R's are present²When R is equal to²Optionally identical or different from each other;

(aza) indole derivative of the above [1] or [2], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein T represents cyano;

(aza) indole derivative of any of the above [1] to [3], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Q represents a carboxyl group;

(aza) indole derivative of any of the above [1] to [4], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y represents a hydrogen atom, a hydroxyl group or a halogen atom;

(aza) indole derivative of the above [5], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Y represents a hydroxyl group;

(aza) indole derivative of any of the above [1] to [6], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein ring J represents a benzene ring;

the (aza) indole derivative of the above [4], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein a group represented by the following general formula:

[ chemical formula 2]

Is a group represented by the following general formula (IIa):

[ chemical formula 3]

In the formula (I), the compound is shown in the specification,

Z¹，Z²and Z³Independently represent CR⁷Or N; and

Y¹and R⁷Independently represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a lower alkyl group or a lower alkoxy group, provided that when two or more R's are present⁷When R is equal to⁷Optionally identical or different from each other;

above-mentioned [8]Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein Z is¹And Z³Represents CH, and Z²Represents CR⁸Or N; and

Y¹and R⁸Independently represents a hydrogen atom, a hydroxyl group or a halogen atom;

(aza) indole derivative of any of the above [4] to [6], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein ring J represents a 5-membered heteroaryl ring containing 1 to 3 different or identical heteroatoms selected from an oxygen atom, a nitrogen atom and a sulfur atom in the ring, with the proviso that the oxygen atom and the sulfur atom are not present next to each other; and Y represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group, provided that two or more Y are optionally present on the ring J and these Y are optionally the same as or different from each other;

the (aza) indole derivative of the above [10], or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein a group represented by the following general formula:

[ chemical formula 4]

Is a group represented by the following general formula (IIb):

[ chemical formula 5]

In the formula (I), the compound is shown in the specification,

Z⁴，Z⁵and Z⁷Represents an oxygen atom, a nitrogen atom, a sulfur atom or CR⁹Provided that Z is⁴And Z⁵Both not being atoms selected from oxygen and sulfur atoms, wherein R⁹Represents a hydrogen atom, a hydroxyl group, an amino group, a halogen atom, a lower alkyl group or a lower alkoxy group, provided that when two or more R's are present⁹When R is equal to⁹Optionally identical or different from each other; z⁶Represents a carbon atom; and Z⁴，Z⁵，Z⁶And Z⁷Taken together with the carbon atom to which the carboxy is attached to form a 5-membered heteroaryl ring;

[ chemical formula 6]

Is a group represented by the following general formula (IId):

[ chemical formula 7]

R¹Represents a hydrogen atom; x¹Represents CR¹⁰Wherein R is¹⁰Represents lower alkyl or-O- (lower alkyl) -; x²Represents CR¹¹Wherein R is¹¹Represents a halogen atom orA lower alkyl group; and X³Represents CH;

above [12 ]]Or a prodrug thereof, or a pharmaceutically acceptable salt thereof, wherein R is¹⁰Represents a methyl group or a methoxy group; and R¹¹Represents a fluorine atom, a chlorine atom or a methyl group.

A xanthine oxidase inhibitor comprising the (aza) indole derivative of any one of the above [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof as an active ingredient;

a pharmaceutical composition comprising as an active ingredient the (aza) indole derivative of any of the above [1] to [13] or a prodrug thereof or a pharmaceutically acceptable salt thereof;

the pharmaceutical composition according to the above [15], which is a prophylactic or therapeutic agent for a disease selected from the group consisting of hyperuricemia, tophus, gouty arthritis, renal disorder associated with hyperuricemia and urinary calculi;

the pharmaceutical composition according to the above [16], which is a prophylactic or therapeutic agent for hyperuricemia;

the pharmaceutical composition according to the above [15], which is a serum uric acid level-lowering agent.

The pharmaceutical composition of the above [15], which is an inhibitor of uric acid production.

The pharmaceutical composition of any one of the above [15] to [19], which comprises a further combination with at least one drug selected from colchicine, non-steroidal anti-inflammatory drugs, steroids and urine alkalinizing agents as an active ingredient; and so on.

In the (aza) indole derivative represented by the above general formula (I) of the present invention, each term has the following meaning.

The term "halogen atom" means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The term "lower" refers to straight or branched chain hydrocarbon groups containing up to 6 carbon atoms. For example, as the lower alkyl group, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, tert-pentyl, hexyl and the like can be illustrated, as the lower alkenyl group, vinyl, allyl, 1-propenyl, isopropenyl, 1-butenyl, 2-methylallyl and the like can be illustrated, and as the lower alkynyl group, ethynyl, 2-propynyl and the like can be illustrated. Examples of the lower alkylene group include methylene, methylmethylene, dimethylmethylene, ethylene, 1-methylethylene, 2-methylethylene, propane-1, 3-diyl, 1-methylpropane-1, 3-diyl, 1, 1-dimethylpropane-1, 3-diyl, 2-methylpropane-1, 3-diyl, 2, 2-dimethylpropane-1, 3-diyl, 3-methylpropane-1, 3-diyl, 3, 3-dimethylpropane-1, 3-diyl, butane-1, 4-diyl, 1-methylbutane-1, 4-diyl, 1, 1-dimethylbutane-1, 4-diyl, 2, 2-dimethylbutane-1, 4-diyl, 3, 3-dimethylbutane-1, 4-diyl, 4-methylbutane-1, 4-diyl, 4, 4-dimethylbutane-1, 4-diyl, pentane-1, 5-diyl, 1-methylpentane-1, 5-diyl, 2-methylpentane-1, 5-diyl, 3-methylpentane-1, 5-diyl, 4-methylpentane-1, 5-diyl, 5-methylpentane-1, 5-diyl, hexane-1, 5-diyl and the like, as the lower alkenylene group, vinylene, propene-1, 3-diyl, 1-butene-1, 4-diyl, 2-butene-1, 4-diyl, 1, 3-butadiene-1, 4-diyl, 1-pentene-1, 5-diyl, 2-pentene-1, 5-diyl, 1, 3-pentadiene-1, 5-diyl, 1-hexene-1, 6-diyl, 2-hexene-1, 6-diyl, 3-hexene-1, 6-diyl, 1, 3-hexadiene-1, 6-diyl, 1,3, 5-hexatriene-1, 6-diyl and the like, and as the lower alkynylene group, ethynylene, 2-propynylene and the like can be exemplified. As the lower alkoxy group, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, hexyloxy and the like can be illustrated, and as the lower alkoxycarbonyl group, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl, isopentyloxycarbonyl, neopentyloxycarbonyl, tert-pentyloxycarbonyl, hexyloxycarbonyl and the like can be illustrated.

The term "perfluoro (lower alkyl)" means the above-mentioned lower alkyl group substituted with a fluorine atom, preferably a methyl group substituted with 1 to 3 fluorine atoms or an ethyl group substituted with 1 to 5 fluorine atoms.

The term "cycloalkyl" refers to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl, and the term "cycloalkylene" refers to a divalent radical derived from a cycloalkyl group as described above.

The term "heterocycloalkyl" refers to a3 to 8 membered aliphatic monocyclic hydrocarbon group containing any 1 or 2 heteroatoms selected from oxygen atom, sulfur atom and nitrogen atom in the ring and optionally having 1 or 2 oxo groups, such as aziridinyl, azetidinyl, 4-morpholinyl, 2-morpholinyl, thiomorpholinyl, 1-pyrrolidinyl, 1-piperidinyl, 4-piperidinyl, 1-piperazinyl, 1-pyrrolyl, tetrahydrofuranyl, tetrahydropyranyl and the like, or a 5 to 6 membered aliphatic monocyclic hydrocarbon group as defined above fused to a benzene ring, for example, 1, 3-dioxoisoindol-2-yl and the like, and the term "heterocycloalkylene" refers to a divalent group derived from the heterocycloalkyl described above.

The term "aryl" refers to phenyl or naphthyl, and the term "arylene" refers to a divalent radical derived from an aryl group as described above.

The term "cycloalkyl (lower alkyl)" means the above-mentioned lower alkyl substituted with the above-mentioned cycloalkyl, the term "heterocycloalkyl (lower alkyl)" means the above-mentioned lower alkyl substituted with the above-mentioned heterocycloalkyl, the term "aryl (lower alkyl)" means the above-mentioned lower alkyl substituted with the above-mentioned aryl, and the term "heteroaryl (lower alkyl)" means the above-mentioned lower alkyl substituted with the above-mentioned heteroaryl. The substituent of the optionally substituted cycloalkyl (lower alkyl) group may be located on the cycloalkyl group or the lower alkyl group. The same holds true for optionally substituted heterocycloalkyl (lower alkyl), optionally substituted aryl (lower alkyl) and optionally substituted heteroaryl (lower alkyl).

The term "heteroaryl" refers to a 5 or 6 membered aromatic heterocyclic group containing any 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen atoms in the ring, derived from thiazole, oxazole, isothiazole, isoxazole, pyridine, pyrimidine, pyrazine, pyridazine, pyrrole, furan, thiophene, imidazole, pyrazole, oxadiazole, thiadiazole, triazole, tetrazole, furazan and the like, or a 5-or 6-membered aromatic heterocyclic group fused with a 6-membered ring containing any 1 to 4 hetero atoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which are derived from indole, isoindole, benzofuran, isobenzofuran, benzothiophene, benzoxazole, benzothiazole, benzisoxazole, benzisothiazole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline, cinnoline (sinoline), indolizine, naphthyridine, pteridine, and the like, and the term "heteroarylene" refers to a divalent group derived from the heteroaryl group described above.

The term "optionally substituted" means that it may have 1 to 3 substituents which may be the same or different.

As the substituent for the optionally substituted lower alkyl group, the optionally substituted lower alkenyl group, the optionally substituted lower alkynyl group, the optionally substituted cycloalkyl group or the optionally substituted heterocycloalkyl group, for example, a fluorine atom, perfluoro (lower alkyl group), -OW¹，-SW¹Carboxy, sulfo, lower alkyl, lower alkylsulfonyl, lower alkoxycarbonyl, -OCOW²，-N(W²)COW³，-OCOOW⁴，-N(W²)COOW⁴，-NHC(＝NH)-NW²W³，-NW²W³，-CONW²W³，-N(W⁵)CONW⁶W⁷，-N(W²)SO₂W⁵，-SO₂NW²W³，-SO₂W⁴(ii) a Aryl which may have any of 1 to 3 groups selected from a halogen atom, hydroxyl, lower alkyl, lower alkoxy and trifluoromethyl; and heteroaryl group which may have any of 1 to 3 groups selected from halogen atom, hydroxy group, lower alkyl group, lower alkoxy group and trifluoromethyl groupA group of (1). As the substituent for the optionally substituted lower alkyl group in Y, a fluorine atom, perfluoro (lower alkyl), lower alkyl, hydroxy and lower alkoxy are preferable.

As the substituent for the optionally substituted lower alkoxy group, a fluorine atom, perfluoro (lower alkyl), lower alkyl, hydroxy and lower alkoxy are preferable.

As the substituents for the optionally substituted aryl group and the optionally substituted heteroaryl group, there may be illustrated, for example, a halogen atom, perfluoro (lower alkyl group), cyano group, nitro group, -OW⁸，-SW⁸Carboxy, lower alkyl, lower alkylsulfonyl, lower alkoxycarbonyl, -OCOW²，-N(W²)COW³，-OCOOW⁴，-N(W²)COOW⁴，-NHC(＝NH)-W²W³，-NW²W³，-CONW²W³，-N(W⁵)CONW⁶W⁷，-N(W²)SO₂W⁵，-SO₂NW²W³，-SO₂W⁴(ii) a Aryl, which may have any 1-3 groups selected from: halogen atom, hydroxy group, lower alkyl group, lower alkoxy group and trifluoromethyl group; and heteroaryl, which may have any 1-3 groups selected from: halogen atom, hydroxy group, lower alkyl group, lower alkoxy group and trifluoromethyl group.

In the above definition, W¹Represents a hydrogen atom, a lower alkyl group, a perfluoro (lower alkyl group); aryl, which may have any 1-3 groups selected from: halogen atom, hydroxy group, alkyl group, lower alkoxy group and trifluoromethyl group; aryl (lower alkyl); or lower alkyl having 2 to 6 carbon atoms having a group selected from the group consisting of amino, mono (di) (lower alkyl) amino and lower alkylsulfonamide, with the proviso that with W¹Bound oxygen or sulfur atoms and W¹The nitrogen atom in (1) is bound to a different carbon atom;

W²，W³，W⁵，W⁶and W⁷Independently represents a hydrogen atom, a lower alkyl group, an aryl group (lower)Alkyl) or W²And W³And W⁵And W⁶Or W is⁶And W⁷An alicyclic amino group containing a bonded nitrogen atom may be formed;

W⁴represents lower alkyl, or W²And W⁴An alicyclic amino group containing a bonded nitrogen atom may be formed;

and W⁸Represents a hydrogen atom, a lower alkyl group, a perfluoro (lower alkyl group); aryl, which may have any 1-3 groups selected from: halogen atom, hydroxy group, alkyl group, lower alkoxy group and trifluoromethyl group; aryl (lower alkyl); or lower alkyl having 2 to 6 carbon atoms having a group selected from the group consisting of amino, mono (di) (lower alkyl) amino and lower alkylsulfonamide, with the proviso that with W⁸Bound oxygen or sulfur atoms and W⁸Wherein the nitrogen atom is bound to different carbon atoms and when two-OW are present on adjacent carbon atoms in the aryl ring⁸When these W are present⁸May be joined together to form a methylene chain which may be substituted by 1 or 2 fluorine atoms or an ethylene chain which may be substituted by 1 to 4 fluorine atoms, respectively.

The term "mono (di) (lower alkyl) amino" means an amino group mono-or di-substituted with the above-mentioned lower alkyl group, and the term "mono (di) (lower alkyl) carbamoyl" means a carbamoyl group mono-or di-substituted with the above-mentioned lower alkyl group. The two lower alkyl groups in the disubstituted group may be different from each other.

The term "alicyclic amino group" means a 3-to 8-membered cyclic amino group optionally having a heteroatom selected from an oxygen atom, a sulfur atom and a nitrogen atom in addition to a nitrogen atom at a bonding position in the ring, such as aziridinyl, azetidinyl, 4-morpholinyl, thiomorpholinyl, 1-pyrrolidinyl, 1-piperidinyl, 1-piperazinyl, 1-pyrrolyl and the like, optionally having 1 or 2 oxo groups and optionally having 1 or 2 double bonds in the ring, for example, 2-oxo-1-pyrrolidinyl and the like.

Ring G and R⁵Or R⁶Or R is¹And R²Or two R²Optionally joined together to form an optionally substituted cycloalkyl or optionally substituted heterocycloalkyl, each of which may have 1 to 3 oxo groups on the ring and 1 or 2 double bonds within the ring, respectively.

In the formula (I), as R¹Preferably a halogen atom, a cyano group, a hydrogen atom, a hydroxyl group, -O- (optionally substituted lower alkyl group), optionally substituted lower alkyl group, optionally substituted aryl group and the like, more preferably a halogen atom, a hydrogen atom, a hydroxyl group, a lower alkoxy group, a lower alkyl group and the like. At X¹Or X²In (b) as CR²Preferably a halogen atom, cyano group, trifluoromethyl group, a hydrogen atom, hydroxy group, carboxy group, mono (di) (lower alkyl) amino group, optionally substituted lower alkyl group, optionally substituted lower alkenyl group, cycloalkyl group (lower alkoxy group), optionally substituted aryl group, optionally substituted heteroaryl group, -O- (optionally substituted lower alkyl group), -CO- (optionally substituted heterocycloalkyl group), -CON (R)³) - (optionally substituted lower alkyl), -N (R)³)SO₂- (lower alkyl), -O- (lower alkylene) -N (R)⁵) COO- (optionally substituted lower alkyl), wherein R³And R⁵The meaning of (1)]The same as in (1), etc., more preferably a halogen atom, a hydrogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, etc.; and in X³Among them, a halogen atom, a hydrogen atom, a lower alkyl group and the like are preferable, and a halogen atom or a hydrogen atom is more preferable.

In the (aza) indole derivative represented by the general formula (I), when the group represented by the above formula (II) is a group represented by the following formula (IIc), wherein Q^CRepresents a carboxyl group or a 5-tetrazolyl group; x¹And X²Independently represent CR²(ii) a And at R¹And two R²Wherein any two of them represent a hydrogen atom, and the other one represents a hydrogen atom, a lower alkyl group, a perfluoro (lower alkyl group), a halogen atom, a cyano group or a lower alkoxy group, as Y, preferably a hydroxyl group, an amino group, a halogen atom, a nitro group, an optionally substituted lower alkyl group or an optionally substituted lower alkoxy group,provided that there are optionally two or more Y on ring J and these Y are optionally different from each other, and more preferably hydroxy or amino.

[ chemical formula 8]

The preferred compounds of the (aza) indole derivatives represented by the above general formula (I) of the present invention also have URAT1 inhibitory effect. Therefore, this compound exerts a uric acid excretion promoting action in addition to a uric acid production inhibiting action, and exhibits an excellent serum uric acid level lowering action. Examples of the compound having a URAT1 inhibitory activity include indole derivatives represented by the following general formula (IA).

[ chemical formula 9]

In the formula, R¹The definitions of (a) are the same as those described above.

In other respects, as a preferable compound having URAT1 inhibitory action and exerting excellent pharmacokinetics, for example, an indole derivative represented by the following general formula (IB) can be exemplified.

[ chemical formula 10]

In the formula, R^2bRepresents lower alkyl or lower alkoxy, preferably methyl or methoxy. R^2cRepresents a halogen atom or a lower alkyl group, preferably a fluorine atom, a chlorine atom or a methyl group.

The (aza) indole derivative represented by the above general formula (I) of the present invention can be produced, for example, by the method described below or a method analogous thereto, or by a method described in the literature or a method analogous thereto, or the like. Further, when a protecting group is necessary, the introduction of the protecting group and the deprotection operation may be carried out in combination according to a general method

[ Synthesis method 1]

[ chemical formula 11]

In the formula, L represents a halogen atom, and T, ring J, Q, Y, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 1

The (aza) indole derivative represented by the above general formula (I) of the present invention can be produced by conducting a coupling reaction of the compound (2) and the compound (3) in an inert solvent or in the absence of any solvent in the presence of a base, and optionally removing a protecting group. As the inert solvent, N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, 1, 2-dimethoxyethane, dimethylsulfoxide, 1, 2-diethoxyethane, 1, 4-dioxane, a mixed solvent thereof and the like can be illustrated. As the base, sodium hydride, potassium carbonate, cesium carbonate, sodium hydroxide, potassium hydroxide, sodium methoxide and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

The (aza) indole derivative represented by the above general formula (I) of the present invention can also be prepared by subjecting compound (2) and compound (3) to a coupling reaction in an inert solvent in the presence of a base, a catalytic amount of copper iodide and a ligand, and optionally removing the protecting group. As the inert solvent, N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, 1, 2-dimethoxyethane, dimethylsulfoxide, a mixed solvent thereof and the like can be illustrated. As the base, potassium phosphate, potassium carbonate, cesium carbonate and the like can be illustrated. As the ligand, N, N-dimethylethylenediamine, (1R, 2R) - (-) -N, N '-dimethylcyclohexane-1, 2-diamine, (1S, 2S) - (+) -N, N' -dimethylcyclohexane-1, 2-diamine, proline, N, N-dimethylaminoglycine and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

The above reaction can also be carried out by the method described in the following document (a).

(a) Hui Zhang,; qian Cai,; and Dawei Ma, j.org.chem, volume 70, No. 13, 2005, 5173.

[ chemical formula 12]

In the formula, R^aRepresents a hydrogen atom or a lower alkyl group, provided that two R are^aMay be different and two R^aMay be joined together to form a ring, and T, ring J, Q, Y, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 2

The (aza) indole derivative represented by the above general formula (I) of the present invention can also be prepared by conducting a coupling reaction of compound (2) and compound (4) in an inert solvent in the presence of a base and a catalytic amount of copper acetate, and optionally removing the protecting group. As the inert solvent, there can be exemplified dichloromethane, 1, 2-dichloroethane, N, N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, 1, 2-dimethoxyethane, a mixed solvent thereof and the like. As the base, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

Among the (aza) indole derivatives represented by the above general formula (I) of the present invention, the compound (Ia) wherein Q represents a carboxyl group can also be produced by, for example, synthesis method 2.

[ Synthesis method 2]

[ chemical formula 13]

In the formula, T, ring J, Y, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 3

The (aza) indole derivative (Ia) of the present invention can also be prepared by reacting the aldehyde compound (5) with an oxidizing agent in an inert solvent in the presence or absence of a base. As the inert solvent, there can be exemplified methylene chloride, 1, 4-dioxane, acetonitrile, acetone, hexane, cyclohexane, t-butanol, water, a mixed solvent thereof and the like. As the base, there can be exemplified sodium hydroxide, potassium hydroxide, lithium hydroxide and the like. As the oxidizing agent, potassium permanganate, barium permanganate, silver oxide, and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

Among the (aza) indole derivatives represented by the above general formula (I) of the present invention, the compound (Ib) wherein T represents a cyano group can also be prepared by, for example, synthesis method 3.

[ Synthesis method 3]

[ chemical formula 14]

In the formula, ring J, Q, Y, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 4

The aldehyde compound (7) can be produced by subjecting the compound (6) to formylation in an inert solvent in the presence of N, N-dimethylformamide and phosphorus oxychloride. As the inert solvent, N-dimethylformamide, acetonitrile, benzene, toluene, chlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, a mixed solvent thereof, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

Process 5

The (aza) indole derivative (Ib) of the present invention can also be prepared by subjecting the aldehyde compound (7) to a cyanation reaction using hydroxylamine or its hydrochloride in an inert solvent in the presence or absence of a base in the presence or absence of a condensing agent. As the inert solvent, N, N-dimethylformamide, acetonitrile, benzene, toluene, chlorobenzene, dichloromethane, 1, 2-dichloroethane, chloroform, N-methylpyrrolidone, a mixed solvent thereof, and the like can be illustrated. As the base, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [ 5.4.0 ] -7-undecene, potassium carbonate, sodium carbonate and the like can be illustrated. As the condensing agent, acetic anhydride, thionyl chloride, phosphorus pentachloride, N, N '-dicyclohexylcarbodiimide, N, N' -carbonyldiimidazole and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

The above-mentioned cyanation reaction can also be carried out by reacting the aldehyde compound (7) and hydroxylamine or its hydrochloride with sodium formate in a formic acid solvent. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

Among the (aza) indole derivatives represented by the above general formula (I) of the present invention, one may also prepare a compound wherein R is represented by the following general formula (I), for example, by synthetic method 4¹Or R²Represents A-D-E-G (provided that A represents-O-, -S-or-N (R)³) -) or-N (-D-E-G)₂(provided that D represents lower alkylene, and E, G and R³The same as defined above) is used. In Synthesis Process 4, for example, use is made of a catalyst in which R¹represents-O-D^A-E-G (wherein D)^ARepresents lower alkylene); x¹-X³An example of CH is illustrated.

[ Synthesis method 4]

[ chemical formula 15]

In the formula, L²Represents a halogen atom, a methanesulfonyloxy group, a p-toluenesulfonyloxy group or a trifluoromethanesulfonyloxy group, and D^AE, G, T, ring J, Q and Y are as defined above.

Process 6-1

The (aza) indole derivative (Ic) of the present invention can also be prepared by alkylating the hydroxyindole compound (8) with the compound (9) in an inert solvent in the presence of a base and optionally in the presence of a phase transfer catalyst. As the inert solvent, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, benzene, toluene, methylene chloride, a mixed solvent thereof and the like can be illustrated. Examples of the base include inorganic bases such as sodium carbonate, potassium carbonate, cesium carbonate and sodium hydride, and organic bases such as triethylamine, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine and 1, 8-diazabicyclo [5, 4, 0] -7-undecene. As the phase transfer catalyst, tetra-n-butylammonium chloride, tetra-n-butylammonium bromide, 18-crown-6, and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

[ chemical formula 16]

In the formula, D^AE, G, T, ring J, Q and Y are as defined above.

Process 6-2

The (aza) indole derivative (Ic) of the present invention can also be produced by alkylating the compound (10) with the hydroxy compound (11) in an inert solvent in the presence of a condensing agent and a phosphorus compound. As the inert solvent, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, N, N-dimethylformamide, dimethyl sulfoxide, N-methylpyrrolidone, benzene, toluene, methylene chloride, a mixed solvent thereof and the like can be illustrated. As the condensing agent, ethyl azodicarboxylate, isopropyl azodicarboxylate, 1, 1' - (azodicarbonyl) dipiperidine, and the like can be illustrated. As the phosphorus compound, triphenylphosphine and the like can be illustrated. The reaction temperature is usually from room temperature to reflux temperature, and the reaction time is usually from 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

In the (aza) indole derivative represented by the above general formula (I) of the present invention, wherein R is¹Or R²Compounds (Id) representing-A-D-E-G (provided that A represents a direct bond and D represents an optionally substituted alkenylene group (provided that a double bond is present next to A), an optionally substituted arylene group or an optionally substituted heteroarylene group, and E and G are as defined above) can also be prepared by, for example, synthetic method 5. In Synthesis Process 5, for example, use is made of a catalyst in which R¹Is represented by the formula-A^B-D^B-E-G (wherein A)^BDenotes a direct bond, D^BRepresents an optionally substituted alkenylene group, an optionally substituted arylene group or an optionally substituted heteroarylene group); and X¹-X³An example of CH is illustrated.

[ Synthesis method 5]

[ chemical formula 17]

In the formula, L⁴Represents a halogen atom or a trifluoromethanesulfonyl group, D^BRepresents an optionally substituted lower alkenylene group, an optionally substituted arylene group or an optionally substituted heteroarylene group, and E, G, T, ring J, Q and Y are as defined above.

Process 7[ method 1]

The (aza) indole derivatives (Id) of the present invention can also be prepared by performing the Suzuki-Miyaura coupling of compound (12) using the corresponding arylboronic acid reagent or heteroarylboronic acid reagent in an inert solvent in the presence of a base and a palladium catalyst. As the inert solvent, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, dichloromethane, 1, 2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, water, a mixed solvent thereof, and the like can be illustrated. As the base, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium fluoride, cesium fluoride, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [5, 4, 0] -7-undecene, and the like can be illustrated. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

Process 7[ method 2]

The (aza) indole derivative (Id) of the present invention can also be prepared by carrying out the Mizorogi-Heck reaction of compound (12) using the corresponding alkene in an inert solvent in the presence of a base and a palladium catalyst. As the inert solvent, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, dichloromethane, 1, 2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, water, a mixed solvent thereof, and the like can be illustrated. As the base, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [ 5.4.0 ] -7-undecene, and the like can be illustrated. As the palladium catalyst, palladium acetate, palladium chloride, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and the like can be illustrated. In addition, the reaction can also be carried out using a ligand depending on the type of the palladium catalyst, and as the ligand, triphenylphosphine, tri-o-tolylphosphine, tri-t-butylphosphine tetrafluoroborate, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

The arylation or heteroarylation reaction of Process 7 (method 1) can also be carried out by, for example, the methods described in the following documents (b) to (f).

(b)Anderson，K.W.；Buchwald，S.L.Angew Chem，Int Ed.2005，44(38)，6173-6177。

(c) Appukkuttan, p.; van Der Eycken, E. et al, Synlett 2005, (1), 127-.

(d) Wang, w.; xiong, C et al Tetrahedron Lett.2001, 42(44), 7717-.

(e)Yang，Y.；Martin，A.R.Synth Commun 1992，22(12)，1757-1762。

(f)Billingsley，K.L.；Anderson，K.W.；Buchwald，S.L.Angew Chem，Int Ed 2006，45(21)，3484-3488。

The olefination reaction of the process 7 (method 2) can also be carried out by, for example, the methods described in the following documents (g) to (i).

(g) Hassner, a.; loew, d. et al, J Org chem.1984, 49(14), 2546.

(h) Leclerc, j. -p.; andre, M. et al, J Org chem.2006, 71(4), 1711-.

(i) Harrison, C. -A.; jackson, P.M. et al, J Chem Soc, Perkin Trans 1, 1995, (9), 1131-.

Among the starting materials (2) used in the above-mentioned process, the compound (2a) wherein T represents a cyano group may be commercially available or prepared by a known method or a method similar thereto. In addition, it can be prepared according to the following method or a similar method thereof, and the like.

[ chemical formula 18]

In the formula, L⁵Represents a halogen atom, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 8

The amide compound (15) can be produced by subjecting the carboxylic acid compound (14) and ammonia to amidation using an additive such as 1-hydroxybenzotriazole or the like in an inert solvent in the presence or absence of a condensing agent in the presence or absence of a base. As the inert solvent, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, benzene, toluene, xylene, methylene chloride, 1, 2-dichloroethane, chloroform, a mixed solvent thereof, and the like can be illustrated. As the condensing agent, acetic anhydride, thionyl chloride, oxalyl chloride, N, N ' -carbonyldiimidazole, N, N ' -dicyclohexylcarbodiimide, diisopropylcarbodiimide, N-ethyl-N ' -3-dimethylaminopropylcarbodiimide and hydrochloride thereof, diphenylphosphoryl azide and the like can be illustrated. As the base, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [ 5.4.0 ] -7-undecene, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

Process 9

The nitrile compound (2a) can also be produced by dehydrating the amide compound (15) in an inert solvent in the presence of a dehydrating agent. As the inert solvent, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, N, N-dimethylformamide, acetonitrile, benzene, toluene, xylene, dichloromethane, 1, 2-dichloroethane, chloroform, a mixed solvent thereof and the like can be illustrated. As the dehydrating agent, acetic anhydride, thionyl chloride, phosphorus oxychloride, methanesulfonylimidazole, p-toluenesulfonyl chloride, N, N' -dicyclohexylcarbodiimide, phosphorus pentoxide, triphosgene and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

Process 10

The aldehyde compound (17) can also be produced by subjecting the compound (16) to formylation reaction by a method similar to that described in the above-mentioned process 4.

Process 11

The nitrile compound (2a) can also be produced by subjecting the aldehyde compound (17) to a cyanation reaction by a method similar to that described in the above-mentioned process 5.

Process 12

Halogenated compound (18) can be prepared by subjecting compound (16) to halogenation reaction in an inert solvent in the presence of a halogenating agent. As the inert solvent, tetrahydrofuran, 1, 4-dioxane, acetic acid, dichloromethane, 1, 2-dichloroethane, chloroform, a mixed solvent thereof, and the like can be illustrated. As the halogenating agent, bromine, N-bromosuccinimide, bromopyridine perbromide, iodine, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

Process 13

The nitrile compound (2a) can also be produced by subjecting the halogenated compound (18) to a cyanation reaction in an inert solvent in the presence of a cyanating reagent, a base and a palladium catalyst. As the inert solvent, benzene, toluene, xylene, diethyl ether, tetrahydrofuran, 1, 4-dioxane, 1, 2-dimethoxyethane, dichloromethane, 1, 2-dichloroethane, chloroform, methanol, ethanol, 2-propanol, butanol, N-dimethylformamide, N-methylpyrrolidone, dimethylsulfoxide, water, a mixed solvent thereof, and the like can be illustrated. As the cyanating agent, there may be exemplified sodium cyanide, potassium cyanide, copper cyanide, zinc cyanide, trimethylsilyl cyanide. As the base, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium ethoxide, sodium methoxide, potassium fluoride, cesium fluoride, triethylamine, N, N-diisopropylethylamine, pyridine, 2, 6-dimethylpyridine, 1, 8-diazabicyclo [5, 4, 0] -7-undecene, and the like can be illustrated. As the palladium catalyst, tetrakis (triphenylphosphine) palladium, dichlorobis (triphenylphosphine) palladium, [1, 1' -bis (diphenylphosphino) ferrocene ] dichloropalladium and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 30 minutes to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used. In addition, in the present method, the reaction may optionally be carried out using a pressure-resistant reaction vessel.

The cyanation reaction of Process 13 can also be carried out by, for example, a method described in the following document (j) or a similar method thereto, and the like.

(j)Sakamoto，T.；Ohsawa，K.；J Chem Soc，Perkin Trans 11999，(16)，2323-2326。

The raw material (16) used in the above-mentioned process may be commercially available or prepared by, for example, a method described in the following documents (k) to (n) or a method similar thereto, or the like.

(k)Rege，Pankaj D.；Tian，Yuan；Corey，E.J.Organic Letters，2006，8(14)，3117-3120。

(l) Wang, Jianji; soundarajan, nacimutu; et al Tetrahedron Letters, 2005, 46(6), 907-.

(m)Cacchi，Sandro；Fabrizi，Giancarlo；Parisi，Luca M.OrganicLetters，2003，5(21)，3843-3846。

(n) Bosco, Marcella; dalpozzo, Renato; bartoli, et al, Journal of the chemical Society, Perkin Transactions 2: physical Organic Chemistry, 1991, (5), 657-63.

Further, the starting material (16) can also be prepared according to the method shown in the following synthetic method 6 or a similar method thereof, or the like.

[ Synthesis method 6]

[ chemical formula 19]

In the formula, X¹-X³And R¹The definitions of (a) are the same as those described above.

Process 14

The indole compound (16) can also be produced by reacting the nitrobenzene derivative (19) or (20) in an inert solvent under normal pressure or under pressure in a hydrogen atmosphere using a metal catalyst. As the inert solvent, methanol, ethanol, N-butanol, acetic acid, ethyl acetate, tetrahydrofuran, N-dimethylformamide, acetonitrile, water, a mixed solvent thereof, and the like can be illustrated. As the metal catalyst, palladium on carbon, rhodium on carbon, platinum (IV) oxide, and the like can be illustrated. The reaction temperature is usually 0 ℃ to reflux temperature, and the reaction time is usually 1 hour to 7 days, depending on the starting materials, the solvent, the reaction temperature, and the like used.

As the protecting group to be used in the present invention, various protecting groups generally used in organic reactions can be used. For example, as the protecting group of a hydroxyl group, in addition to p-methoxybenzyl, benzyl, methoxymethyl, acetyl, pivaloyl, benzoyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, allyl and the like, when two hydroxyl groups are adjacent, isopropylidene, cyclopentylidene, cyclohexylidene and the like can be exemplified. As the protecting group of the thiol group, p-methoxybenzyl, benzyl, acetyl, pivaloyl, benzoyl, benzyloxycarbonyl and the like can be illustrated. As the protecting group of amino group, benzyloxycarbonyl, t-butoxycarbonyl, benzyl, p-methoxybenzyl, trifluoroacetyl, acetyl, phthaloyl and the like can be illustrated. As the protecting group of the carboxyl group, there may be illustrated methyl, ethyl, benzyl, t-butyldimethylsilyl, allyl and the like.

The compound represented by the above general formula (I) of the present invention can be isolated or purified by a conventional separation technique such as fractional recrystallization, chromatographic purification, solvent extraction, solid phase extraction, and the like.

The (aza) indole derivatives represented by the above general formula (I) of the present invention can be converted into pharmaceutically acceptable salts thereof in a conventional manner. As such a salt, there can be exemplified an acid addition salt formed with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid and the like, acid addition salts with organic acids such as formic acid, acetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, propionic acid, citric acid, succinic acid, tartaric acid, fumaric acid, butyric acid, oxalic acid, malonic acid, maleic acid, lactic acid, malic acid, carbonic acid, benzoic acid, glutamic acid, aspartic acid, etc., inorganic salts such as sodium salt, potassium salt, magnesium salt, zinc salt, lithium salt, aluminum salt, etc., salts with organic amines such as N-methyl-D-glucamine, N' -dibenzylethylenediamine, 2-aminoethanol, tris (hydroxymethyl) aminomethane, arginine, lysine, piperidine (piperadine), choline, diethylamine, 4-phenylcyclohexane, and the like.

Among the (aza) indole derivatives represented by the above general formula (I) of the present invention, among the compounds having an unsaturated bond, compounds having two geometric isomers, i.e., a cis (Z) configuration and a trans (E) configuration. In the present invention, any one compound may be used, and a mixture thereof may also be used.

In the (aza) indole derivative represented by the above general formula (I) of the present invention, in the compound having a chiral carbon atom, for each chiral carbon, there are a compound of the R form and a compound of the S form. In the present invention, any one of optical isomers may be used, and a mixture of optical isomers thereof may also be used.

In the (aza) indole derivative represented by the above general formula (I) of the present invention, there may be some tautomers, and the compound of the present invention also includes these tautomers.

In the present invention, the term "prodrug" refers to a compound modified from a parent compound by a pharmaceutically acceptable group commonly used in prodrugs, which, for example, gives properties such as improved stability, persistence, oral absorbability and the like, and can be expected to be converted into the parent compound in vivo (in the liver, intestine and the like) to exert an effect. The prodrug of the compound represented by the above general formula (I) of the present invention can be prepared as follows: the prodrug-forming group is appropriately introduced into one or more groups selected from hydroxyl group, amino group, carboxyl group and others which can form a prodrug of the compound represented by the above general formula (I) using a conventional method using a corresponding reagent to form a prodrug, such as a halide or the like, and then, when necessary, is appropriately isolated and purified using a conventional method. Gekkan-Yakuji iyakuhitekiseisiyouu no tameno rinsyou yakubutudoutai (journal of medicine, clinical pharmacokinetics for appropriate use of pharmaceuticals), temporary journal addition 3 months in 2003, volume 42, phase 4, page 669-. As the prodrug-forming group used in a hydroxyl group or an amino group, for example, (lower alkyl) -CO-such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl and the like; aryl-CO-such as benzoyl; (lower alkyl) -O- (lower alkylene) -CO-; (lower alkyl) -OCO- (lower alkylene) -CO-; (lower alkyl) -OCO-such as methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl and the like; (lower alkyl) -O- (lower alkylene) -OCO-; (lower alkyl) -COO- (lower alkylene) such as acetoxymethyl, pivaloyloxymethyl, 1- (acetoxy) ethyl, 1- (pivaloyloxy) ethyl and the like; (lower alkyl) -OCOO- (lower alkylene) such as methoxycarbonyloxymethyl, 1- (methoxycarbonyloxy) ethyl, ethoxycarbonyloxymethyl, 1- (ethoxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, t-butyloxycarbonyloxymethyl, 1- (t-butyloxycarbonyloxy) ethyl and the like; cycloalkyl-OCOO- (lower alkylene) such as cyclohexyloxycarbonyloxymethyl, 1- (cyclohexyloxycarbonyl) ethyl and the like; esters or amides with amino acids such as glycine and the like; and so on.

As the prodrug-forming group used in the carboxyl group, for example, lower alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl and the like; (lower alkyl) -COO- (lower alkylene) such as pivaloyloxymethyl, acetoxymethyl, 1- (pivaloyloxy) ethyl, 1- (acetoxy) ethyl and the like; (lower alkyl) -OCOO- (lower alkylene) such as ethyloxycarbonyloxymethyl, 1- (ethyloxycarbonyloxy) ethyl, isopropyloxycarbonyloxymethyl, 1- (isopropyloxycarbonyloxy) ethyl, tert-butyloxycarbonyloxymethyl, 1- (tert-butyloxycarbonyloxy) ethyl and the like; cycloalkyl-OCOO- (lower alkylene) such as cyclohexyloxycarbonylmethyl, 1- (cyclohexyloxycarbonyl) ethyl and the like; and so on.

(aza) indole derivatives represented by the general formula (I), or prodrugs thereof, or pharmaceutically acceptable salts thereof, may be sometimes obtained as hydrates or solvates thereof in the course of purification or salt formation thereof. The (aza) indole derivative represented by the general formula (I) of the present invention, or a prodrug thereof, or a pharmaceutically acceptable salt thereof includes a hydrate thereof or a solvate with a pharmaceutically acceptable solvent. As the pharmaceutically acceptable solvent, ethanol and the like can be illustrated.

The pharmaceutical composition of the present invention is useful as a prophylactic or therapeutic agent for diseases associated with high blood uric acid level such as hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, urinary calculi, and the like, particularly hyperuricemia.

When the pharmaceutical composition of the present invention is used in actual prevention or treatment, the dose of the compound represented by the above general formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof as an active ingredient is appropriately determined depending on the age, sex, body weight and degree of symptoms of each patient and the difference in treatment, for example, in the case of oral administration, the dose is about 1 to 2,000 mg/day/adult, and the daily dose may be divided into one to several doses per day and administered.

When the pharmaceutical composition of the present invention is used in actual prevention or treatment, various dosage forms are used orally or parenterally depending on the application thereof, for example, preparations for oral administration such as powder, fine granules, tablets, capsules, dry syrup and the like are preferable.

These pharmaceutical compositions can be prepared by optionally mixing with appropriate pharmaceutical additives such as excipients, disintegrants, binders, lubricants, etc., and formulating the mixture according to a conventional method.

For example, powders may be formulated by intimately mixing the active ingredient with appropriate excipients, lubricants, and the like, if necessary. For example, tablets can be formulated by tableting the active ingredient with an appropriate excipient, disintegrant, binder, lubricant or the like according to a conventional method, and, if necessary, appropriately coated to provide film-coated tablets, sugar-coated tablets, enteric-coated tablets or the like. For example, capsules can be formulated by thoroughly mixing the active ingredient with appropriate excipients, lubricants, and the like, or by formulating it into fine particles, granules, and filling it into appropriate capsules according to a conventional method. In addition, in the case of, for example, orally administered drugs, they may also be formulated into a rapid-release or sustained-release preparation depending on the prophylactic or therapeutic method.

The compound represented by the above general formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof of the present invention can be further used in combination with any other therapeutic agent for hyperuricemia or therapeutic agent for gout. As the hyperuricemia treating agent which can be used in the present invention, for example, urine alkalifying agents such as sodium hydrogen carbonate, potassium citrate, sodium citrate and the like can be illustrated. In addition, as the therapeutic agent for gout, colchicine or a nonsteroidal anti-inflammatory drug such as indomethacin, naproxen, fenbufen, pranoprofen, oxaprozin, ketoprofen, etoxib, tenoxicam, and the like, and a steroid and the like can be exemplified. In the present invention, the active ingredient of the present invention may be further used in combination with at least one of these drugs, and the pharmaceutical composition comprising the combination with at least one of these drugs includes any dosage form including not only a single formulation together with the active ingredient of the present invention but also a combined formulation consisting of a pharmaceutical composition comprising the active ingredient of the present invention and a pharmaceutical composition separately prepared for administration at the same time or at different dosage intervals. In addition, when used in combination with a drug other than the active ingredient of the present invention, the dose of the compound of the present invention may be reduced depending on the dose of the other drug used in combination, and as the case may be, a favorable effect exceeding the additional effect may be obtained in the prevention or treatment of the above-mentioned diseases, or side effects of the other drug used in combination may be avoided or alleviated.

Effects of the invention

The (aza) indole derivative represented by the above general formula (I) of the present invention exhibits an excellent xanthine oxidase inhibitory effect and inhibits uric acid production. In addition, preferred compounds of the present invention may also exert excellent URAT1 inhibitory effects and increase uric acid excretion. Therefore, the (aza) indole derivative represented by the general formula (I) of the present invention or a prodrug thereof or a pharmaceutically acceptable salt thereof can significantly inhibit the rise in serum uric acid level and can be used as a prophylactic or therapeutic agent for a disease associated with abnormal serum uric acid level such as hyperuricemia.

Preferred forms of carrying out the invention

The present invention will be further described in more detail with reference to the following reference examples, examples and test examples. However, the present invention is not limited by these examples.

Reference example 1

4-fluoro-2-hydroxy-benzoic acid ethyl ester

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0g) in ethanol (40mL) was added thionyl chloride (5.61mL) at 0 deg.C, and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. The residue was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (3.5 g).

Reference example 2

4-fluoro-2-methoxymethyloxybenzoic acid ethyl ester

To a solution of ethyl 4-fluoro-2-hydroxybenzoate (3.5g) in dichloromethane (30ml) were added N, N-diisopropylethylamine (5.0g) and (chloromethyl) methyl ether (2.3g) at 0 deg.C, and the reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).

Reference example 3

4-fluoro-2-methoxymethyloxybenzoic acid methyl ester

To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0g) in N, N-dimethylformamide (5mL) was added sodium hydride (60% 1.0g) and (chloromethyl) methyl ether (2.1g) at room temperature, and the mixture was stirred at the same temperature for 48 hours. The reaction mixture was poured into 2mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.22 g).

Reference example 4

5, 6-difluoro-1H-indole-3-carbaldehyde

To a solution of 5, 6-difluoro-1H-indole (1.0g) in N, N-dimethylformamide (10mL) was added phosphorus oxychloride (1.2g) at 0 deg.C, and the mixture was stirred at room temperature for 4 hours. To the mixture was added a 2mol/L aqueous solution of sodium hydroxide (5mL), and the resulting mixture was stirred at 70 ℃ for 0.5 hour. After cooling to ambient temperature, the mixture was poured into 1mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (1.1 g).

Reference example 5

5, 6-difluoro-1H-indole-3-carbonitrile

To a solution of 5, 6-difluoro-1H-indole-3-carbaldehyde (1.0g) in tetrahydrofuran (15ml) were added hydroxylamine hydrochloride (0.81g) and pyridine (1.9g), and the mixture was stirred at 80 ℃ for 8 hours. Acetic anhydride was added to the reaction mixture, and the mixture was stirred at 80 ℃ for 8 hours. After cooling to ambient temperature, a 2mol/L aqueous solution of sodium hydroxide was added to the mixture, and the resulting mixture was stirred for 30 minutes. The mixture was poured into 2mol/L hydrochloric acid, and the precipitated solid was collected by filtration and washed with water and n-hexane. The solid was dissolved in ethyl acetate, and the residue was subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate) to obtain the title compound (0.95 g).

Reference example 6

6-fluoro-1H-indoline-3-carbonitrile

To a solution of 6-fluoro-1H-indole-3-carbaldehyde (0.97g) in 90% formic acid (25mL) were added hydroxylamine (0.65g) and sodium formate (0.81g), and the mixture was stirred at 100 ℃ for 3 hours. After cooling to ambient temperature, water was added to the reaction mixture, and the precipitated solid was collected by filtration, washed with water, and dried to give the title compound (0.57 g).

Reference example 7

5-phenyl-1H-indole-carbonitriles

The title compound was prepared using a similar method to reference example 5, using the corresponding starting materials.

Reference example 8

3-formyl-1H-indole-5-carboxylic acid benzyl ester

To a solution of benzyl 1H-indole-5-carboxylate (3.5g) in N, N-dimethylformamide (30mL) was added phosphorus oxychloride (2.6g) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 2mol/L aqueous sodium hydroxide solution until the pH became 6, and the mixture was stirred at 70 ℃ for 30 minutes. After cooling to ambient temperature, the precipitated solid was collected by filtration, washed with water and methanol, and dried to give the title compound (3.9 g).

Reference example 9

3-cyano-1H-indole-5-carboxylic acid benzyl ester

To a solution of benzyl 3-formyl-1H-indole-5-carboxylate (4.3g) and pyridine (4.8g) in tetrahydrofuran (60ml) was added hydroxylamine hydrochloride (1.6g) at room temperature, and the mixture was stirred at 80 ℃ overnight. Acetic anhydride was added to the reaction mixture at the same temperature and the mixture was stirred for 8 hours. After cooling to ambient temperature, 1mol/L sodium hydroxide solution (20mL) was added to the mixture, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (2.8 g).

Reference example 10

3-benzyloxy-4-methylbenzoic acid benzyl ester

To a solution of 3-hydroxy-4-methylbenzoic acid (5.0g) in N, N-dimethylformamide (100mL) were added cesium carbonate (32g) and bromobenzyl (12g) at the same temperature, and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (7.5 g).

Reference example 11

(3-benzyloxy-4-methylphenyl) methanol

To a suspension of lithium aluminum hydride in diethyl ether (50mL) was added dropwise a solution of benzyl 3-benzyloxy-4-methyl-benzoate (7.5g) in diethyl ether (11mL) at 0 ℃ under an argon atmosphere, and the mixture was stirred at room temperature for 6 hours. To the reaction mixture was added water (3.2mL) dropwise, and then celite was added to the mixture and filtered. The filtrate was concentrated to give the title compound as a mixture of benzyl alcohols (7.0 g).

Reference example 12

3-benzyloxy-4-methylbenzaldehyde

To a solution of (3-benzyloxy-4-methylphenyl) methanol (1.0g) in dichloromethane (50mL) was added manganese dioxide (2.5g), and the mixture was stirred at room temperature for 2 days. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39 g).

Reference example 13

5-benzyloxy-2-bromo-4-methylbenzaldehyde

To a solution of 3-benzyloxy-4-methylbenzaldehyde (0.39g) in a mixed solvent of dichloromethane (1mL) and methanol (1mL) was added a solution of bromine (0.410g) in dichloromethane (0.2mL) at 0 deg.C, and the mixture was stirred at room temperature for 2 hours. The mixture was poured into water, and the resulting mixture was extracted with dichloromethane. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.39 g).

Reference example 14

(Z) -3- (5-benzyloxy-2-bromo-4-methylphenyl) -2-benzyloxycarbonylamino acrylic acid methyl ester

To a solution of 5-benzyloxy-2-bromo-4-methylbenzaldehyde (0.39g) and trimethyl N- (benzyloxycarbonyl) - α -phosphonoglycine (0.38g) in dichloromethane (2mL) was added 1, 1,3, 3-tetramethylguanidine (0.18g) at room temperature, and the mixture was stirred at room temperature for 2 days. To the reaction mixture was added 1mol/L hydrochloric acid, and the precipitated solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (0.34 g).

Reference example 15

5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid methyl ester

To a solution of methyl (Z) -3- (5-benzyloxy-2-bromo-4-methylphenyl) -2-benzyloxycarbonyl aminoacrylate (0.2g) and copper (I) iodide (0.075g) in dimethyl sulfoxide (8mL) was added cesium acetate (0.38g) at room temperature, and the mixture was stirred at 90 ℃ for 5 hours under an argon atmosphere. To the reaction mixture was added an aqueous ammonia solution (28%) and the precipitated solid was collected by filtration, washed with water and dried under reduced pressure to give the title compound (0.073 g).

Reference example 16

5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid

To a solution of methyl 5-benzyloxy-6-methyl-1H-indole-2-carboxylate (1.3g) in a mixed solvent of 1, 4-dioxane (40mL) and water (20mL) was added lithium hydroxide monohydrate at room temperature, and the mixture was stirred at 50 ℃ for 1 hour. After the reaction mixture was cooled to room temperature, 1mol/L hydrochloric acid was added. The title compound (1.0g) was obtained by collecting the precipitated solid, washing with water and drying under reduced pressure.

Reference example 17

5-benzyloxy-6-methyl-1H-indole

To a solution of 5-benzyloxy-6-methyl-1H-indole-2-carboxylic acid (0.6g) in quinoline (6mL) was added copper powder (0.15g), and the mixture was stirred at 220 ℃ for 20 minutes. The reaction mixture was poured into 1mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.21 g).

Reference example 18

5-benzyloxy-6-methyl-1H-indole-3-carbaldehyde

The title compound (0.48g) was prepared using a similar method to reference example 4, using the corresponding starting material.

Reference example 19

5-benzyloxy-6-methyl-1H-indole-3-carbonitrile

The title compound (0.10g) was prepared using a similar method to reference example 5, using the corresponding starting material.

Reference example 20

4- (6-Nitroindol-1-yl) benzoic acid ethyl ester

To a solution of 6-nitro-1H-indole (0.5g) in N, N-dimethylformamide (10mL) were added cesium carbonate (1.2g) and ethyl 4-fluorobenzoate (0.62g), and the mixture was stirred at 75 ℃ overnight. The reaction mixture was poured into water and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure to give the title compound (0.64 g).

Reference example 21

1- (5-Formylfuran-2-yl) -1H-indole-3-carbonitrile

A suspension of 3-cyanoindole (0.14g), 5-bromo-2-furancarbaldehyde (0.18g) and cesium carbonate (0.39g) in N, N-dimethylformamide (3mL) was stirred at room temperature for 3 hours. The reaction mixture was stirred at 50 with heating for 2 hours. After cooling to ambient temperature, water was added to the reaction mixture. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate 2/1) to give the title compound (0.086g).

Reference example 22

4- (6-Formylindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a similar method to reference example 20 using the corresponding starting materials.

Reference example 23

4- (6-acetoxymethyl-indol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (6-formylindol-1-yl) benzoate in a mixed solvent of tetrahydrofuran (3mL) and methanol (10mL) was added sodium borohydride (0.075g) at 0 ℃ and the mixture was stirred at room temperature for 0.5 hours. The reaction mixture was poured into a saturated aqueous ammonium chloride solution and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give ethyl 4- (6-hydroxymethyl-indol-1-yl) benzoate (0.38 g). To a solution of ethyl 4- (6-hydroxymethyl-indol-1-yl) benzoate (0.09g) in dichloromethane (1mL) were added acetic anhydride (0.093g) and pyridine (0.024g), and the mixture was stirred at room temperature for 2 days. The mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate) to obtain the title compound (0.068g).

Reference example 24

4-fluoro-2-methylphenylcarbonate methyl ester

To a solution of 4-fluoro-2-methylphenol (2.0g) in 1, 4-dioxane (20mL) were added methyl chloroformate (3.0g) and pyridine (2.5g) under ice-cooling, and the mixture was stirred at room temperature overnight. Insoluble matter was removed by filtration, and 1mol/L hydrochloric acid was added to the filtrate. The mixture was extracted with ethyl acetate, and the organic layer was washed with water twice and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound.

Reference example 25

4-fluoro-2-methyl-5-nitrophenol

Fuming nitric acid (1.1mL) was added dropwise to a solution of methyl 4-fluoro-2-methylphenyl carbonate (2.9g) in concentrated sulfuric acid (11mL) over 10 minutes under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in methanol, sodium hydrogencarbonate (2.6g) and potassium carbonate (2.2g) were added to the solution at room temperature, and the mixture was stirred for 2 hours. To the reaction mixture was added 1mol/L hydrochloric acid until the pH became 1, and the organic solvent was removed under reduced pressure. The residue was extracted with ethyl acetate, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (1.5g).

Reference example 26

1-fluoro-4-methoxy-5-methyl-2-nitrobenzene

To a solution of 4-fluoro-2-methyl-5-nitrophenol (0.5g) in N, N-dimethylformamide (5mL) were added potassium carbonate (0.44g) and methyl iodide (0.46g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added water and the precipitated solid was collected by filtration, washed with water and n-hexane to give the title compound (0.44 g).

Reference example 27

Cyano- (4-methoxy-5-methyl-2-nitrophenyl) acetic acid methyl ester

To a suspension of sodium hydride (0.86g) in N, N-dimethylformamide (5mL) was added dropwise a solution of methyl cyanoacetate (0.35g) in N, N-dimethylformamide (3mL) under ice-cooling, and the mixture was stirred for 15 minutes. To the reaction mixture was added dropwise a solution of 1-fluoro-4-methoxy-5-methyl-2-nitrobenzene (0.44g) under ice-cooling, and the mixture was stirred at room temperature for 30 minutes and then at 70 ℃ overnight. After cooling to ambient temperature, 1mol/L hydrochloric acid (5mL) was added to the reaction mixture. The resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.45 g).

Reference example 28

(4-methoxy-5-methyl-2-nitrophenyl) acetonitrile

To a solution of methyl cyano- (4-methoxy-5-methyl-2-nitrophenyl) acetate in methanol (1.7mL) was added 6mol/L hydrochloric acid (1.7mL), and the mixture was heated under reflux for 9 hours. After cooling to ambient temperature, the organic solvent was removed under reduced pressure and the resulting mixture was extracted with ethyl acetate. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.25 g).

Reference example 29

6-methoxy-5-methylindole

To a solution of (4-methoxy-5-methyl-2-nitrophenyl) acetonitrile (0.24g) in a mixed solvent of tetrahydrofuran (2mL) and n-butanol (2mL) was added palladium-carbon powder (0.043g) under an argon atmosphere, and the mixture was stirred at 60 ℃ for 36 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.13 g).

Reference example 30

3-cyano-6-methoxy-5-methylindole

The title compound (0.070g) was prepared using a similar method to that of reference example 4 and reference example 5, using the corresponding starting materials.

Reference example 31

1-methoxy-2-methyl-4-nitrobenzene

To a solution of 1-hydroxy-2-methyl-4-nitrobenzene (1.0g) in N, N-dimethylformamide (10mL) were added potassium carbonate (1.8g) and iodomethane (1.3g) at room temperature and the mixture was stirred at the same temperature for 24 hours. The reaction mixture was poured into water and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.95 g).

Reference example 32

(5-methoxy-4-methyl-2-nitrophenyl) acetonitrile

To a solution of 1-methoxy-2-methyl-4-nitrobenzene (0.4g) and (4-chlorophenoxy) acetonitrile (0.4g) in N, N-dimethylformamide (10mL) was added potassium tert-butoxide (0.3g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.2g).

Reference example 33

5-methoxy-6-methyl-1H-indole

The title compound (0.065g) was prepared using a similar method to that of reference example 29, using the corresponding starting material.

Reference example 34

5-methoxy-6-methyl-1H-indole-3-carbonitrile

The title compound (0.05g) was prepared using a similar method to that of reference example 4 and reference example 5, using the corresponding starting materials.

Reference example 35

5-benzyloxy-6-chloro-1H-indole

To a solution of (5-benzyloxy-4-chloro-2-nitrophenyl) acetonitrile (4.170g) in ethanol (70mL) was added platinum (IV) oxide (0.344g) at room temperature, and the mixture was stirred under an atmosphere of hydrogen (30-35psi) for 12 hours. To the reaction mixture were added acetic acid (7mL) and water (7mL), and the mixture was stirred under the same conditions for 24 hours. After the reaction mixture was replaced with an argon atmosphere, insoluble materials were removed by filtration. To the filtrate was added water, and the resulting mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 75/25) to give the title compound (0.629 g).

Reference example 36

5-benzyloxy-6-chloro-1H-indole-3-carbaldehyde

The title compound (0.270g) was prepared using a similar method to that of reference example 4, using the corresponding starting material.

Reference example 37

5-benzyloxy-6-chloro-1H-indole-3-carbonitrile

The title compound (0.267g) was prepared using a similar method to reference example 5, using the corresponding starting material.

Reference example 38

Benzyl cyano- (4-fluoro-5-methyl-2-nitrophenyl) acetate

A suspension of 1, 4-difluoro-2-methyl-5-nitrobenzene (1.00g), benzyl cyanoacetate (1.01g) and potassium carbonate (1.76g) in N, N-dimethylformamide (20.0mL) was stirred at 60 ℃ for 1 day. To the reaction mixture was added 1mol/L hydrochloric acid (25.4mL), and the mixture was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was washed with ethanol to give the title compound (1.54 g).

Reference example 39

6-fluoro-5-methyl-1H-indoles

To a solution of benzyl cyano- (4-fluoro-5-methyl-2-nitrophenyl) acetate (1.54g), acetic acid (7mL), and water (7mL) in ethanol (15mL) under an argon atmosphere was added 10% palladium-on-charcoal (0.154 g). The reaction mixture was stirred at room temperature under a hydrogen atmosphere for 60 hours. After water was added to the reaction mixture, hydrogen was replaced with argon. Insoluble matter was removed by filtration, and the filtrate was extracted with diethyl ether. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 75/25) to give the title compound (0.536 g).

Reference example 40

6-fluoro-5-methyl-1H-indole-3-carbaldehyde

The title compound (0.577g) was prepared using a similar method to that of reference example 4, using the corresponding starting material.

Reference example 41

6-fluoro-5-methyl-1H-indole-3-carbonitrile

The title compound (0.544g) was prepared using a similar method to that of reference example 5, using the corresponding starting material.

Reference example 42

6-benzyloxy-5-methoxy-1H-indole

4-benzyloxy-3-methoxybenzaldehyde (4.85g) was added dropwise to nitric acid (d ═ 1.42, 20mL) at room temperature over 1 hour, and the mixture was stirred for 1 hour. The reaction mixture was poured into ice water and the precipitated solid was collected by filtration. The solid was washed with water and dried under reduced pressure at 50 ℃ to give 4-benzyloxy-5-methoxy-2-nitrobenzaldehyde (4.99 g). To the product was added acetic acid (50mL), followed by nitromethane (3.19g) and ammonium acetate (5.36g), and the mixture was stirred at 100 ℃ for 5 hours. The reaction mixture was concentrated under reduced pressure. To the residue was added water and the precipitated solid was collected by filtration, which was washed with methanol and dried to give 1-benzyloxy-2-methoxy-5-nitro-4- (2-nitrovinyl) benzene (4.03 g). To the compound were added benzene (96mL), acetic acid (72mL) and cyclohexane (24mL), followed by silica gel (18g) and iron powder (10.2g), and the mixture was stirred at 100 ℃ for 1 hour. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: ethyl acetate/n-hexane 75/25) to give the title compound (1.06 g).

Reference example 43

6-benzyloxy-5-methoxy-1H-indole-3-carbaldehyde

The title compound was prepared using a similar method to reference example 4 using the corresponding starting materials.

Reference example 44

6-benzyloxy-5-methoxy-1H-indole-3-carbonitrile

Reference examples 45 to 47

The title compound was prepared using a similar method to reference example 29 using the corresponding starting materials.

Reference example 48

Dimethyl- (4-nitro-2-trifluoromethylphenyl) amine

To a solution of 1-fluoro-4-nitro-2-trifluoromethylbenzene (2.0g) in tetrahydrofuran (20mL) was added dimethylamine (0.64g) and sodium hydride (0.34g) at room temperature, and the mixture was stirred at 50 ℃ for 16 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: n-hexane/ethyl acetate) to obtain the title compound (0.94 g).

Reference example 49

(5-dimethylamino-2-nitro-4-trifluoromethylphenyl) acetonitrile

To a solution of dimethyl- (4-nitro-2-trifluoromethylphenyl) amine (0.95g) in N, N-dimethylformamide (20mL) were added (4-chlorophenoxy) acetonitrile (0.75g) and 1mol/L potassium tert-butoxide (4.5mL in tetrahydrofuran solution) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate) to give the title compound (0.11 g).

Reference example 50

Dimethyl- (6-trifluoromethyl-1H-indol-5-yl) amine

To a solution of (5-dimethylamino-2-nitro-4-trifluoromethylphenyl) acetonitrile (0.058g) in a mixed solvent of ethanol (1mL), acetic acid (0.1mL) and water (0.1mL) was added palladium-carbon powder (0.0058g), and the mixture was stirred at 35 ℃ for 16 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.058 g).

Reference example 51

4- (5-dimethylamino-6-trifluoromethylindol-1-yl) benzoic acid ethyl ester

Reference example 52

4- (3-formyl-5-methylamino-6-trifluoromethylindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (5-dimethylamino-6-trifluoromethylindol-1-yl) benzoate (0.054g) in N, N-dimethylformamide (2mL) was added phosphorus oxychloride (0.026g) under ice-cooling, and the mixture was stirred at room temperature for 16 hours. To the mixture was added 2mol/L aqueous sodium hydroxide solution (5mL), and the resulting mixture was stirred at 50 ℃ for 30 minutes. After cooling to ambient temperature, 1mol/L hydrochloric acid (10mL) was added to the mixture, and the precipitated solid was collected by filtration. The solid was washed with water and dried under reduced pressure at 50 ℃ to give the title compound (0.026 g).

Reference example 53

The title compound was prepared in a similar manner to referential example 29 using (3-benzyloxy-2, 4-dimethyl-6-nitrophenyl) acetonitrile instead of (4-methoxy-5-methyl-2-nitrophenyl) acetonitrile.

Reference examples 54 to 55

Indole obtained in a similar manner to referential example 31 using the compound of referential example 53 and the corresponding starting material, and the title compound was prepared in a similar manner to example 5 using the indole.

Reference examples 56 to 63

Example 1

4- (3-cyano-5, 6-difluoroindol-1-yl) -2-methoxymethyloxybenzoic acid ethyl ester

To a solution of 3-cyano-5, 6-difluoroindole (0.25g) in N, N-dimethylformamide (10mL) was added cesium carbonate (0.91g), ethyl 4-fluoro-2-methoxymethylbenzoate (0.32g), and the mixture was stirred at 75 ℃ overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 10/90-75/25) to give the title compound (0.12 g).

Example 2

4- (3-cyano-5, 6-difluoroindol-1-yl) -2-hydroxybenzoic acid ethyl ester

To a solution of ethyl 4- (3-cyano-5, 6-difluoroindol-1-yl) -2-methoxymethoxybenzoate (0.12g) in a mixed solvent of tetrahydrofuran (1.5mL) and ethanol (3mL) was added 2mol/L hydrochloric acid (1.0mL), and the mixture was stirred at 70 ℃ overnight. After cooling to ambient temperature, the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 40 ℃ to give the title compound (0.074 g).

Example 3

4- (3-cyano-5, 6-difluoroindol-1-yl) -2-hydroxybenzoic acid

To a solution of ethyl 4- (3-cyano-5, 6-difluoroindol-1-yl) -2-hydroxybenzoate (0.074g) in a mixed solvent of tetrahydrofuran (3.0mL) and ethanol (0.75mL) were added 0.1g/mL of an aqueous lithium hydroxide solution (0.62mL) and water (1.0mL), and the mixture was stirred at room temperature for 26 hours. To the reaction mixture was added 2mol/L hydrochloric acid (5mL), and the organic solvent was removed under reduced pressure. The resulting mixture was extracted with ethyl acetate, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure to give the title compound (0.06 g).

Example 4

4- (6-benzyloxy-3-cyanoindol-1-yl) -2-methoxymethyloxybenzoic acid ethyl ester

The title compound (3.4g) was prepared using a similar method to example 1, using the corresponding starting material.

Example 5

4- (6-benzyloxy-3-cyanoindol-1-yl) -2-hydroxybenzoic acid

The title compound was prepared using procedures analogous to examples 2 and 3, using the corresponding starting materials.

Example 6

4- (3-cyano-6-hydroxyindol-1-yl) -2-methoxymethyloxybenzoic acid ethyl ester

To a solution of ethyl 4- (6-benzyloxy-3-cyanoindol-1-yl) -2-methoxymethoxybenzoate in a mixed solvent of ethyl acetate (60mL) and methanol (60mL) at 0 ℃ under an argon atmosphere was added palladium-carbon powder (0.61g), and the mixture was stirred at 40 ℃ for 3 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (2.5 g).

Example 7

4- [6- (2-Benzyloxycarbonylaminoethyloxy) -3-cyanoindol-1-yl ] -2-methoxymethyloxybenzoic acid ethyl ester

To a solution of ethyl 4- (3-cyano-6-hydroxyindol-1-yl) -2-methoxymethoxybenzoate (0.37g) in N, N-dimethylformamide (10mL) were added benzyl (2-bromoethyl) carbamate (0.39g) and potassium carbonate (0.28g), and the mixture was stirred at 50 overnight. The reaction mixture was poured into water and the precipitated solid was collected by filtration. The solid was washed with methanol and dried to give the title compound (0.40 g).

Example 8

4- [6- (2-Benzyloxycarbonylaminoethyloxy) -3-cyanoindol-1-yl ] -2-hydroxybenzoic acid

To a solution of ethyl 4- [6- (2-benzyloxycarbonylaminoethyloxy) -3-cyanoindol-1-yl ] -2-methoxymethoxybenzoate (0.14g) in a mixed solvent of ethanol (2.5mL), tetrahydrofuran (5mL) and water (2.5mL) was added lithium hydroxide monohydrate (0.03g), and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added 2mol/L hydrochloric acid (0.75mL), and the mixture was stirred at 50 ℃ for 5 hours. The reaction mixture was treated with 1mol/L hydrochloric acid (5mL), and the mixture was concentrated under reduced pressure until the solvent volume became one third, and the precipitated solid was collected by filtration, washed with water, methanol and ether to give the title compound (0.097 g).

Example 9

4- [6- (2-aminoethyloxy) -3-cyanoindol-1-yl ] -2-hydroxybenzoic acid

To a solution of 4- [6- (2-benzyloxycarbonylaminoethyloxy) -3-cyanoindol-1-yl ] -2-hydroxybenzoic acid (0.087g) in a mixed solvent of ethyl acetate (2mL) and methanol (2mL) was added palladium-carbon powder (0.016g) at 0 ℃ under an argon atmosphere, and the mixture was stirred at 40 ℃ for 3 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting pale yellow solid was washed with diethyl ether and dried to give the title compound (0.058 g).

Example 10

4- [6- (2-Aminoethyloxy) -3-cyanoindol-1-yl ] -2-methoxymethyloxybenzoic acid ethyl ester

To a solution of ethyl 4- [6- (2-benzyloxycarbonylaminoethoxy) -3-cyanoindol-1-yl ] -2-methoxymethoxybenzoate (0.27g) in a mixed solvent of ethyl acetate (5mL) and methanol (5mL) was added palladium-carbon powder (0.05g) under an argon atmosphere at 0 ℃ and the mixture was stirred under a hydrogen atmosphere at 40 ℃ for 3 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The resulting pale yellow solid was washed with diethyl ether and dried to give the title compound (0.20 g).

Example 11

4- [6- (2-Acetylaminoethyloxy) -3-cyanoindol-1-yl ] -2-methoxymethyloxybenzoic acid ethyl ester

To a solution of ethyl 4- [6- (2-aminoethyloxy) -3-cyanoindol-1-yl ] -2-methoxymethoxybenzoate (0.10g) and triethylamine (0.076g) in dichloromethane (5mL) was added acetyl chloride (0.049g) at room temperature, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane: methanol ═ 10: 1) to give the title compound (0.083 g).

Example 12

4- [6- (2-Acetylaminoethyloxy) -3-cyanoindol-1-yl ] -2-hydroxybenzoic acid

The title compound (0.039g) was prepared using a similar method to example 8 using the corresponding starting material.

Example 13

4- (5-bromo-3-cyanoindol-1-yl) benzoic acid ethyl ester

To a solution of 5-bromo-3-cyanoindole (2.0g) in N, N-dimethylformamide (50mL) were added cesium carbonate (7.4g) and ethyl 4-fluorobenzoate (3.0g), and the mixture was stirred at 80 ℃ for 48 hours. The reaction mixture was poured into water and the precipitated solid was collected by filtration. The solid was washed with water and dried under reduced pressure at 50 ℃ to give the title compound (1.8 g).

Example 14

4- [ 3-cyano-5- (4-methoxyphenyl) indol-1-yl ] benzoic acid ethyl ester

A mixture of ethyl 4- (5-bromo-3-cyanoindol-1-yl) benzoate (0.1g), 4-methoxyphenylboronic acid (0.066g), and potassium carbonate (0.09g) in a mixed solvent of 1, 2-dimethoxyethane (3mL), ethanol (0.5mL), and water (0.5mL) was stirred in the presence of tetrakis (triphenylphosphine) palladium catalyst at 90 ℃ for 18 hours. The reaction mixture was poured into water and the precipitated solid was collected by filtration. The solid was washed with water and dried under reduced pressure at 50 ℃ to give the title compound (0.098 g).

Example 15

4- [ 3-cyano-5- (4-methoxyphenyl) indol-1-yl ] benzoic acid

The title compound (0.081g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 16

4- {5- [ (E) -2-ethoxycarbonylvinyl ] -3-cyanoindol-1-yl } benzoic acid

A solution of ethyl 4- (5-bromo-3-cyanoindol-1-yl) benzoate (0.1g), ethyl acrylate (0.11g) and triethylamine (0.082g) in N, N-dimethylformamide (2mL) was stirred in the presence of palladium (II) acetate (0.0061g) and triphenylphosphine (0.014g) at 100 ℃ for 30 hours. The reaction mixture was poured into water, and the resulting mixture was extracted twice with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 10/90-75/25) to give the title compound (0.035 g).

Example 17

4- [5- ((E) -2-carboxyvinyl) -3-cyanoindol-1-yl ] benzoic acid

The title compound was prepared using a method analogous to example 3, using the corresponding starting material.

Example 18

4- (4-benzyloxy-3-cyanoindol-1-yl) benzoic acid ethyl ester

The title compound (0.16g) was prepared using a similar method to example 13 using the corresponding starting material.

Example 19

4- (4-benzyloxy-3-cyanoindol-1-yl) benzoic acid

To a solution of ethyl 4- (4-benzyloxy-3-cyanoindol-1-yl) benzoate (0.16g) in ethanol (2mL) was added 2mol/L aqueous sodium hydroxide solution (0.4mL), and the mixture was stirred at 50 ℃ overnight. Ethanol was removed under reduced pressure, and 2mol/L hydrochloric acid (3mL) was added to the reaction mixture. The precipitated solid was collected by filtration, and the solid was washed with water and n-hexane to give the title compound (0.11 g).

Example 20

4- (3-cyano-6-nitroindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (6-nitroindol-1-yl) benzoate (0.53g) in N, N-dimethylformamide (6mL) was added phosphorus oxychloride (0.31g) under ice-cooling, and the mixture was stirred at 70 ℃ overnight. After cooling to ambient temperature, a 2mol/L aqueous sodium hydroxide solution was added to the reaction mixture and the mixture was stirred for 30 minutes. The reaction mixture was poured into 1mol/L hydrochloric acid, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 40 ℃ to give ethyl 4- (3-formyl-6-nitroindol-1-yl) benzoate (0.46 g). To a solution of the aldehyde (0.46g) in tetrahydrofuran (10mL) were added hydroxylamine hydrochloride (0.19g) and pyridine (0.43g) at room temperature, and the mixture was stirred at 80 ℃ for 8 hours. Acetic anhydride (0.42g) was added to the reaction mixture at 80 ℃ and the mixture was stirred at the same temperature overnight. After cooling to ambient temperature, 1mol/L hydrochloric acid was added to the reaction mixture, and the precipitated solid was collected by filtration. The solid was washed with water, n-hexane and diethyl ether to give the title compound (0.13 g).

Example 21

4- (6-amino-3-cyanoindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (3-cyano-6-nitroindol-1-yl) benzoate (0.11g) in a mixed solvent of tetrahydrofuran (2mL) and methanol (2mL) was added palladium-carbon powder (0.04g) under an argon atmosphere, and the mixture was stirred at room temperature for 7 hours under a hydrogen atmosphere. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.070 g).

Example 22

4- (3-cyano-6-methanesulfonylaminoindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (5-amino-3-cyanoindol-1-yl) benzoate (0.070g) in dichloromethane (2mL) was added methanesulfonyl chloride (0.035g) and pyridine (0.036g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1mol/L hydrochloric acid, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 10/90-75/25) to give the title compound (0.046 g).

Example 23

4- (3-cyano-6-methanesulfonylaminoindol-1-yl) benzoic acid

The title compound (0.040g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 24

4- (5-benzyloxy-3-cyanoindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a method analogous to example 13 using the corresponding starting materials.

Example 25

4- (5-hydroxy-3-cyanoindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a method analogous to example 6, using the corresponding starting material.

Example 26

4- [ 3-cyano-5- (thien-2-ylmethyloxy) indol-1-yl ] benzoic acid ethyl ester

To a solution of ethyl 4- (5-hydroxy-3-cyanoindol-1-yl) benzoate and thiophene-2-methanol (0.057g) and triphenylphosphine (0.012g) in tetrahydrofuran (2.5mL) was added diisopropylcarbodiimide (40% in toluene, 0.18mL) at room temperature, and the mixture was stirred for 3 hours. The reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 1/3) to give the title compound (0.10 g).

Example 27

4- [ 3-cyano-5- (thien-2-ylmethyloxy) indol-1-yl ] benzoic acid

The title compound (0.01g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 28

4- (3-cyano-5-benzyloxycarbonylindol-1-yl) benzoic acid ethyl ester

The title compound (0.24g) was prepared using a similar method to example 13 using the corresponding starting material.

Example 29

4- (5-carboxy-3-cyanoindol-1-yl) benzoic acid

The title compound (0.050g) was prepared using a similar method to example 3, using the corresponding starting materials.

Example 30

4- (5-carboxy-3-cyanoindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (3-cyano-5-benzyloxycarbonylindol-1-yl) benzoate (0.16g) in a mixed solvent of methanol (5mL) and tetrahydrofuran (5mL) at 0 ℃ under an argon atmosphere was added palladium-carbon powder (0.03g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (0.057 g).

Example 31

4- (3-cyano-5-hydroxymethylindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (5-carboxy-3-cyanoindol-1-yl) benzoate (0.057g) in tetrahydrofuran (2mL) was added borane-tetrahydrofuran complex (1.2mol/L in tetrahydrofuran, 0.2mL) at 0 deg.C, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate, and the mixture was extracted with diethyl ether. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 1/1) to give the title compound (0.032 g).

Example 32

4- (3-cyano-5-hydroxymethylindol-1-yl) benzoic acid

The title compound (0.029g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 33

4- (3-cyano-5-dimethylaminocarbonylindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (5-carboxy-3-cyanoindol-1-yl) benzoate (0.084g), dimethylamine hydrochloride (0.061g), triethylamine (0.13g) and 4-dimethylaminopyridine (0.006g) in dichloromethane (2.5mL) was added N-ethyl-N' -3-dimethylaminopropylcarbodiimide (0.058g) at room temperature, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 1mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated solution of sodium hydrogencarbonate and water, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 1/2) to give the title compound (0.020 g).

Example 34

4- (3-cyano-5-dimethylaminocarbonylindol-1-yl) benzoic acid

The title compound (0.0025g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 35

5- (3-cyanoindol-1-yl) furan-2-carboxylic acid

To a suspension of 1- (5-formylfuran-2-yl) -1H-indole-3-carbonitrile (0.085g) in methanol (4mL) and tetrahydrofuran (4mL) were added silver oxide (0.1g) and 2mol/L aqueous sodium hydroxide solution (0.27mL), and the mixture was stirred at room temperature for 6 hours. Insoluble matter of the reaction mixture was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added water (15mL) and 2mol/L hydrochloric acid (2mL), and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: dichloromethane/methanol-10/1) to give the title compound (0.023 g).

Example 36

3- (3-Cyanoindol-1-yl) benzoic acid ethyl ester

To a solution of 1H-indole-3-carbonitrile (0.28g) in dimethyl sulfoxide (3mL) were added ethyl 3-iodobenzoate (0.61g), cesium carbonate (0.65g), copper iodide (0.038g), and N, N-dimethylglycine (0.041g), and the mixture was stirred at 75 ℃ for 3 days. To the reaction mixture was added ethyl acetate, insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue was added water, and the precipitated solid was collected by filtration, washed with water and n-hexane, and dried under reduced pressure at 40 ℃ to give the title compound (0.38 g).

Example 37

3- (3-cyanoindol-1-yl) benzoic acid

The title compound (0.30g) was prepared using a similar method to example 3, using the corresponding starting material.

Example 38

2- (3-Cyanoindol-1-yl) isonicotinic acid ethyl ester

A mixture of 1H-indole-3-carbonitrile (0.1g), ethyl 2-bromoisonicotinate (0.16g), potassium phosphate (0.27g), (1R, 2R) - (-) -N, N' -dimethylcyclohexane-1, 2-diamine (0.017g), copper iodide (0.006g) and toluene (0.7mL) was stirred at 110 ℃ for 38 hours. Insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane 10/90 to 66/34) to give the title compound (0.061 g).

Example 39

2- (3-cyanoindol-1-yl) isonicotinic acid

The title compound (0.038g) was prepared using a similar method to example 8 using the corresponding starting material.

Example 40

4- (3-Cyanoindol-1-yl) -2-nitrobenzoic acid methyl ester

The title compound was prepared using a method analogous to example 1, using the corresponding starting materials.

EXAMPLE 41

4- (3-cyanoindol-1-yl) -2-nitrobenzoic acid

Example 42

2-amino-4- (3-cyanoindol-1-yl) benzoic acid

To a solution of 4- (3-cyanoindol-1-yl) -2-nitrobenzoic acid (0.012g) in a mixed solvent of ethanol (1mL), water (0.5mL) and tetrahydrofuran (0.5mL) were added zinc powder (0.041g) and ammonium chloride (0.004g) at room temperature, and the mixture was stirred at 80 ℃ for 2.5 hours. After cooling to ambient temperature, ethyl acetate was added to the reaction mixture. Insoluble materials were removed by filtration, and the filtrate was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.003 g).

Example 43

2-acetoxy- (3-cyanoindol-1-yl) benzoic acid

To a suspension of 4- (3-cyanoindol-1-yl) -2-hydroxybenzoic acid in pyridine (0.5mL) at 0 deg.C was added acetic anhydride (0.1mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 1mol/L hydrochloric acid, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (0.047 g).

Example 44

2- (3-Cyanoindol-1-yl) nicotinic acid ethyl ester

The title compound was prepared in a similar manner to referential example 13 using ethyl 6-chloronicotinate instead of ethyl 4-fluorobenzoate.

Example 45

2- (3-cyanoindol-1-yl) nicotinic acid

Example 46

2- (3-Cyanoindol-1-yl) -4-methylthiazole-5-carboxylic acid ethyl ester

The title compound was prepared in a similar manner to referential example 13 using ethyl 2-chloro-4-methylthiazole-5-carboxylate instead of ethyl 4-fluorobenzoate.

Example 47

2- (3-cyanoindol-1-yl) -4-methylthiazole-5-carboxylic acid

Examples 48 to 55

The compounds of examples 48 to 55 were prepared using a similar method to that of example 13, using the corresponding starting materials.

Examples 56 to 65

The compounds of examples 56 to 65 were prepared using analogous methods to example 7 using the corresponding starting materials.

Examples 66 to 76

The compounds of examples 66 to 76 were prepared using a similar method to example 14 using the corresponding starting materials.

Examples 77 to 81

The compounds of examples 77 to 81 were prepared using analogous methods to example 33 using the corresponding starting materials.

Examples 82 to 84

The compounds of examples 82 to 84 were prepared using a similar method to that of example 26, using the corresponding starting materials.

Examples 85 to 86

The compounds of examples 85 to 86 were prepared using a similar method to that of example 44, using the corresponding starting materials.

Example 87

The compound of example 87 was prepared using a similar procedure to example 13 using the corresponding starting materials.

Example 88

The compound of example 88 was prepared using a similar method to example 20 using the corresponding starting materials.

Examples 89 to 107

The compounds of examples 89 to 107 were prepared using a similar method to example 1 using the corresponding starting materials.

Examples 108 to 109

The compounds of examples 108 to 109 were prepared using a similar method to that of example 6, using the corresponding starting materials.

Examples 110 to 134

The compounds of examples 110 to 134 were prepared using a similar method to that of example 7, using the corresponding starting materials.

Examples 135 to 136

The compounds of examples 135 to 136 were prepared using a similar method to that of example 26, using the corresponding starting materials.

Example 137

The compound of example 137 was prepared using a similar method to example 10 using the corresponding starting materials.

Examples 138 to 140

The compounds of examples 138 to 140 were prepared using analogous methods to example 11 using the corresponding starting materials.

Examples 141 to 187

The compounds of examples 141 to 187 were prepared using a similar method to example 3, using the corresponding starting materials.

Examples 188 to 225

The compounds of examples 188 to 225 were prepared using analogous methods to those of example 2 and example 3, using the corresponding starting materials.

Examples 226 to 227

The compounds of examples 226 to 227 were prepared using a similar procedure to example 8 using the corresponding starting materials.

Examples 228 to 234

The compounds of examples 228 to 234 were prepared using analogous methods to those of examples 2 and 3, using the corresponding starting materials.

Example 235

The compound of example 235 was prepared using a similar method to example 8 using the corresponding starting materials.

Examples 236 to 237

The compounds of examples 236 to 237 were prepared using analogous methods to those of example 2 and example 3, using the corresponding starting materials.

Examples 238 to 240

The compounds of examples 238 to 240 were prepared using a similar method to example 8 using the corresponding starting materials.

Example 241

The compound of example 235 was prepared using a similar method to example 3, using the corresponding starting materials.

Example 242

4- (3-cyano-5-methoxy-6-methylindol-1-yl) benzoic acid ethyl ester

Example 243

4- (5-benzyloxy-6-chloro-3-cyanoindol-1-yl) benzoic acid ethyl ester

The title compound (0.31g) was prepared using a similar method to example 13 using the corresponding starting material.

Example 244

4- (6-chloro-3-cyano-5-hydroxyindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (5-benzyloxy-6-chloro-3-cyanoindol-1-yl) benzoate (0.310g) in dichloromethane (7mL) was added boron tribromide (1mol/L dichloromethane solution) (0.860mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and filtered. The filtrate was removed under reduced pressure. The residue was washed with diethyl ether to give the title compound (0.181 g).

Example 245

4- (6-chloro-3-cyano-5-methoxyindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a method analogous to that of example 31, using the corresponding starting materials.

Example 246

4- (6-chloro-3-cyano-5-trifluoromethanesulfonyloxyindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (6-chloro-3-cyano-5-hydroxyindol-1-yl) benzoate (0.079g) and pyridine (0.056mL) in dichloromethane (2.3mL) was added trifluoromethanesulfonic anhydride (0.058mL) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added 1mol/L hydrochloric acid (0.370mL) and water. After separation of the organic layer, the organic solvent was removed under reduced pressure to give the title compound (0.103 g).

Example 247

4- (6-chloro-3-cyano-5-methylindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (6-chloro-3-cyano-5-trifluoromethanesulfonyloxyindol-1-yl) benzoate (0.103g), trimethylboroxine (0.033g) and tripotassium phosphate (0.070g) in dioxane (2.0mL) was added tetrakis (triphenylphosphine) palladium catalyst (0.038g), and the mixture was stirred at 80 ℃ for 1 day. The reaction mixture was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 75/25) to give the title compound (0568 g).

Example 248

4- (3-cyano-6-fluoro-5-methylindol-1-yl) benzoic acid ethyl ester

The title compound (0.117g) was prepared using a similar method to example 13 using the corresponding starting material.

Example 249

6- (3-cyano-6-fluoro-5-methylindol-1-yl) nicotinic acid ethyl ester

The title compound (0.152g) was prepared using a similar method to example 44, using the corresponding starting material.

Example 250

4- (3-cyano-6-fluoro-5-methylindol-1-yl) -2-methoxymethyloxybenzoic acid ethyl ester

The title compound (0.116g) was prepared using a similar method to example 1, using the corresponding starting material.

Example 251

4- (6-benzyloxy-3-cyano-5-methoxyindol-1-yl) benzoic acid ethyl ester

Example 252

4- (3-cyano-6-hydroxy-5-methoxyindol-1-yl) benzoic acid ethyl ester

Example 253

4- (3-cyano-6-cyclopropyl-5-methoxyindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (3-cyano-6-hydroxy-5-methoxyindol-1-yl) benzoate (0.195g) and pyridine (0.138g) in dichloromethane (2.3mL) was added trifluoromethanesulfonic anhydride (0.246g) under ice-cooling, and the mixture was stirred at the same temperature for 1 hour. To the reaction mixture were added 1mol/L hydrochloric acid (0.370mL) and water, and the organic layer was separated. The organic solvent was concentrated under reduced pressure to give ethyl 4- (3-cyano-5-methoxy-6-trifluoromethanesulfonyloxyindol-1-yl) benzoate (0.238 g). After toluene (1.5mL) was added to the product (0.070g), cyclopropylboronic acid (0.016g), potassium carbonate (0.031g) and tetrakis (triphenylphosphine) palladium (0) (0.026g) were added to the mixture, and the mixture was stirred at 80 ℃ for 1 day. The reaction mixture was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane 75/25) to give the title compound (0.037 g).

Example 254

4- (cyano-5-hydroxy-6-methylindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a method analogous to example 244 using ethyl 4- (3-cyano-5-methoxy-6-methylindol-1-yl) benzoate.

Example 255

4- (3-cyano-5, 6-dimethylindol-1-yl) benzoic acid ethyl ester

The title compound was prepared using a method analogous to that of examples 246 and 247 using ethyl 4- (cyano-5-hydroxy-6-methylindol-1-yl) benzoate.

Example 256

Example 257

4- (3-cyano-6-fluoro-5-hydroxyindol-1-yl) benzoic acid

To a solution of ethyl 4- (3-cyano-6-fluoro-5-methoxyindol-1-yl) benzoate (1.2g) in dichloromethane (20mL) was added boron tribromide (1.0mol/L dichloromethane solution) (10mL) dropwise under ice-cooling, and the mixture was stirred at room temperature for 12 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure to give the title compound (0.44 g).

Example 258

4- [ 3-cyano-6-fluoro-5- (2-methoxyethoxy) indol-1-yl ] benzoic acid 2-methoxyethyl ester

To a solution of 4- (3-cyano-6-fluoro-5-hydroxyindol-1-yl) benzoic acid (0.06g) in N, N-dimethylformamide (2mL) were added 1-bromo-2-methoxyethane (0.14g) and potassium carbonate (0.13g) at room temperature, and the mixture was stirred at the same temperature for 16 hours. The reaction mixture was poured into water, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was subjected to silica gel column chromatography (eluent: ethyl acetate/n-hexane) to give the title compound (0.79 g).

Examples 259 to 264

Example 265

The title compound was prepared using a method analogous to that of example 245, using the corresponding starting material.

Example 266

The title compound was prepared using a method analogous to that of example 252, using the corresponding starting materials.

Examples 267 to 270

Example 271

The title compound was prepared using a method analogous to that of example 244, using the corresponding starting materials.

Examples 272 to 277

Example 278

Example 279

The title compound was prepared in a similar manner to example 1 using ethyl 2, 4-difluoro-6-methoxymethoxybenzoate instead of ethyl 4-fluoro-2-methoxymethoxybenzoate.

Examples 280 to 282

The title compound was prepared using a method analogous to example 258 using the corresponding starting material. And s.

Example 283

4- (3-cyano-5-dimethylamino-6-trifluoromethylindol-1-yl) benzoic acid ethyl ester

To a solution of ethyl 4- (3-formyl-5-methylamino-6-trifluoromethylindol-1-yl) benzoate (0.026g) in tetrahydrofuran (1mL) were added hydroxylamine hydrochloride (0.0067g) and pyridine (0.02g), and the mixture was stirred at 60 for 4 hours. After cooling to ambient temperature, acetic anhydride (0.013g) was added to the reaction mixture and the mixture was stirred at 60 ℃ for 12 hours. The reaction mixture was poured into water and the precipitated solid was collected by filtration. The solid was washed with water and n-hexane, and dried under reduced pressure at 50 ℃ to obtain the title compound (0.026 g).

Examples 284 to 291

Example 292

The title compound was prepared using a method analogous to that of example 257 using the corresponding starting material.

Examples 293 to 308

Example 309

After the corresponding carboxylic acid was produced in a similar manner to example 3, 2mol/L hydrochloric acid was added to the product until the pH became 1, and the mixture was stirred overnight. The precipitated solid was collected by filtration to give the title compound.

Examples 310 to 321

The title compound was prepared using a method analogous to example 309, using the corresponding starting materials.

Example 322

Example 323

Example 324

The title compound was prepared in a similar manner to example 309 using the corresponding starting material, followed by alkylation in a similar manner to example 7.

Example 325

Example 326

The title compound was prepared using a method analogous to that of example 324, using the corresponding starting materials.

Example 327

Example 328

The title compound was prepared using procedures analogous to examples 41 and 21, using the corresponding starting materials.

Tables 1 to 3 and 42 to 45 show the above reference examples 1 to 23 andchemical structural formula of compounds 24 to 53 and¹H-NMR data, Table 46 shows the chemical structural formulae of reference examples 54 to 63, and tables 4 to 41, 47 to 49 and 53 to 59 show the chemical structural formulae and¹H-NMR data, tables 50 to 52 show the chemical structures of examples 259 to 283.

Abbreviations in these tables: "Ref No.", "Ex No.", "Strc" and "Solv" indicate reference example number, chemical structural formula and¹measurement of H-NMR solvent.

[ Table 1]

[ Table 2]

[ Table 3]

[ Table 4]

[ Table 5]

[ Table 6]

[ Table 7]

[ Table 8]

[ Table 9]

[ Table 10]

[ Table 11]

[ Table 12]

[ Table 13]

[ Table 14]

[ Table 15]

[ Table 16]

[ Table 17]

[ Table 18]

[ Table 19]

[ Table 20]

[ Table 21]

[ Table 22]

[ Table 23]

[ Table 24]

[ Table 25]

[ Table 26]

[ Table 27]

[ Table 28]

[ Table 29]

[ Table 30]

[ Table 31]

[ Table 32]

[ Table 33]

[ Table 34]

[ Table 35]

[ Table 36]

[ Table 37]

[ Table 38]

[ Table 39]

[ Table 40]

[ Table 41]

[ Table 42]

[ Table 43]

[ Table 44]

[ Table 45]

[ Table 46]

[ Table 47]

[ Table 48]

[ Table 49]

[ Table 50]

[ Table 51]

[ Table 52]

[ Table 53]

[ Table 54]

[ Table 55]

[ Table 56]

[ Table 57]

[ Table 58]

[ Table 59]

Test example 1

Xanthine oxidase inhibitory Activity

(1) Preparation of test Compounds

Test compounds were dissolved in dmso (wako) at a concentration of 40mM and then diluted with Phosphate Buffered Saline (PBS) to the planned concentration.

(2) Measuring method

Xanthine oxidase (obtained from cow's milk, Sigma) was prepared using Phosphate Buffered Saline (PBS) at 0.02 units/ml, and the solution was added to a 96-well plate at 50 μ L/well. In addition, test compounds diluted with PBS were added at 50. mu.L/well. 200 μ M xanthine (Wako) prepared with PBS was added at 100 μ L/well, and the reaction was allowed to proceed at room temperature for 10 minutes. The absorbance at 290nm was measured using a microplate reader SpectraMax Plus 384(Molecular device). The absorbance in the absence of xanthine was 0%,the absorbance of the control without test compound was 100%. The 50% Inhibitory Concentration (IC) of the test compound was calculated₅₀) (Table 60). Ex.no in the table indicates the example number.

[ Table 60]

Ex.No	IC₅₀(nM)
		3	6.5
5	33.6
		8	41.5
9	12.5
		12	7.0
15	15.5
		17	12.1
19	96.0
		27	14.6
29	43.3
		32	91.1
34	48.3
		42	175.3
45	72.9
		47	58.6
143	24.4
		149	38.0
150	20.6
		151	22.4
152	15.8
		153	12.2
154	19.0
		155	111.7
156	11.9
		157	14.1
158	9.5
		159	14.4
160	11.3
		161	49.8
162	16.5
		165	111.2
166	7.2
		167	10.9
170	20.0
		171	10.9
172	8.0
		174	24.4
175	22.2
		176	18.3
177	16.4
		178	12.9

Ex.No	IC₅₀(nM)
		179	8.0
180	29.0
		181	17.2
182	16.3
		183	7.5
184	138.3
		185	40.2
186	49.7
		187	16.4
188	5.0
		189	13.9
190	5.4
		191	3.9
192	4.3
		193	4.6
194	8.3
		195	14.5
196	6.7
		197	9.0
198	54.6
		199	49.2
200	39.4
		201	5.5
202	61.8
		203	7.1
205	27.6
		206	7.2
207	7.3
		208	6.0
209	11.0
		210	7.0
211	6.2
		212	5.1
213	7.2
		214	11.0
215	10.5
		216	7.4
217	6.0
		218	6.0
219	8.3
		220	9.4

Ex.No	IC₅₀(nM)
		221	71.5
222	41.8
		223	7.5
224	9.7
		225	4.6
226	10.0
		227	10.4
228	7.5
		229	7.1
230	67.1
		231	29.1
232	42.5
		233	7.2
234	86.5
		235	14.2
237	12.6
		238	8.3
239	6.5
		240	9.8
286	58
		287	16
288	10
		293	14
295	9
		298	12
300	96
		303	10
307	13
		308	45
316	10
		318	12

Test example 2

Uric acid transport inhibitory Activity Using Brush-border Membrane vesicles (BBMV)

The uric acid transport inhibitory activity of the test compounds was carried out according to the method described in the literature (am.J. Physiol.266(Renal Fluid Electrolyte Physiol.35): F797-F805, 1994), with some modifications.

(1) Preparation of BBMV derived from human renal cortex

BBMV from human renal cortex was purchased from KAC. The renal cortex was dissected from the human kidney and cut into small pieces. The skin layer was then homogenized in 5 volumes of ice-cold isotonic buffer (300mM mannitol, 5mM ethylene glycol-bis- (β -aminoethyl ether) -N, N' -tetraacetic acid (EGTA), 12mM Tris (hydroxymethyl) aminomethane (Tris) · HCl, pH 7.4). After addition of 1M magnesium chloride to a final concentration of 12mM, the suspension was then mixed and placed on ice for 15 minutes. The homogenized solution was centrifuged at 2,500Xg for 15 minutes at 4 ℃ and the supernatant was centrifuged at 30,000Xg for 30 minutes at 4 ℃. The pellet was resuspended in ice-cold buffer 1(150mM mannitol, 2.5mM EGTA, 6mM Tris & HCl, pH 7.4). After addition of 1M magnesium chloride to a final concentration of 12mM, the suspension was then mixed and placed on ice for 15 minutes. The supernatant was centrifuged again at 2,500Xg for 15 minutes at 4 ℃ and 30,000Xg for 30 minutes at 4 ℃. The pellet was resuspended in ice-cold buffer 2(100mM mannitol, 100mM potassium gluconate, 20mM 2- [4- (2-hydroxyethyl) -1-piperazinyl ] ethanesulfonic acid (Hepes) -Tris, pH 7.4). After centrifugation at 30,000Xg for 30 minutes at 4 ℃, the pellet was resuspended in buffer 2 and the protein concentration was then determined.

(2) Preparation of test Compounds

Test compounds were dissolved in DMSO (Wako) at a concentration of 40mM, followed by the use of Cl^-This was diluted to 2-fold the desired concentration with a running buffer (100mM mannitol, 100mM potassium gluconate, 20mM hepes-Tris, pH 7.4). Cl without test compound^-The catch buffer was used as a control. In addition, equal amounts will be included¹⁴C-labelled uric acid (Moravek) and propanesulfonic acidShu (Wako) Cl^-The test buffer containing 40 μ M uric acid and 5 μ M probenecid was finally prepared by adding the conjugate buffer to the test compound and the control. To measure with Cl^-In a hook-and-match independent manner¹⁴Uptake of C-labelled uric acid with Cl^-Equilibration buffer (100mM mannitol, 60mM potassium gluconate, 40mM potassium chloride, mM Hepes-Tris, pH 7.4) in place of Cl^-Assay buffer was prepared by spiking buffer.

(3) Measuring method

BBMV was thawed on ice. After 8mL of an intracapsular buffer (100mM mannitol, 60mM potassium gluconate, 40mM potassium chloride, 20mM Hepes-Tris, pH 7.4) was added to 200. mu.L of the prepared BBMV (protein concentration: 16mg/mL), the BBMV was suspended by a 25-gauge needle and allowed to equilibrate at room temperature for 60 minutes. After centrifugation at 30,000Xg for 30 minutes at 4 ℃, the pellet was resuspended in 1.2mL of intracapsular buffer. The suspension was kept on ice until the measurement was started. Uric acid uptake by BBMV was measured by rapid filtration techniques. The necessary amount of BBMV (20. mu.L/1 reaction) was warmed up for 20 minutes at room temperature. Uptake of uric acid was initiated by mixing with 100 μ L of assay buffer. After 20 seconds of incubation at room temperature, 3mL of ice-cold stop solution (300mM mannitol, 60mM sodium sulfate, 100. mu.M probenecid (Wako), 5mM Tris-H) was added₂SO₄pH 7.4) and then the solution was rapidly filtered through a nitrocellulose filter (0.65 μm pore size, Sartorius) which was kept under suction. In addition, the filter was washed twice with 3mL stop solution and dissolved in 10mL of filter-count (PerkinElmer) and the radioactivity was calculated in a liquid scintillation counter (PerkinElmer). The radioactivity associated with the filter in the absence of BBMV was used as a correction value. In addition, the% inhibition of the test compound at 10 μ M was calculated according to the following formula (table 61). The ex.no., conc.and inhibition% in the table represent the example number, the concentration (μ M) of the test compound and the percentage (%) of inhibition, respectively.

Percent (%) inhibition ═ 1- (B-C)/(a-C) ] X100

A: radioactivity of control

B: radioactivity with addition of test Compound

C：Cl^-Radioactivity of equilibration buffer

[ Table 61]

Ex.No	Conc.(μM)	inhibition％
			237	10	64

Test example 3

Uric acid transport inhibitory Activity Using human URAT 1-expressing cells

(1) Preparation of human URAT1 transient expression cell

The full-length human URAT1cDNA (NCBI accession No. NM-144585) was subcloned into the expression vector pcDNA3.1 (Invitrogen). Human URAT1 expression vector was transfected into COS7 cells (RIKEN CELL BANK RCB0539) using Lipofectamine 2000. COS7 cells were plated at 2X 10 onto collagen-coated 24-well plates (Asahi Techno Glass)⁵One/well in D-MEM medium (Invitrogen) containing 10% fetal bovine serum (Sanko Junyaku) at 37 ℃ and 5% CO₂Cultured for 2 hours under the conditions of (1). For 1 well, 2. mu.L of Lipofectamine 2000 was diluted in 50. mu.L of OPTI-MEM (Invitrogen) and kept at room temperature forThe reaction time was 7 minutes (hereinafter referred to as Lipo 2000-OPTI). For 1 well, 0.8 μ g of human URAT1 expression vector was diluted in 50 μ L of OPTI-MEM (Invitrogen) and gently combined with Lipo 2000-OPTI. After being kept at room temperature for 25 minutes, the mixture was added to COS7 cells at 100. mu.L/well. In addition, COS7 cells were incubated at 37 ℃ and 5% CO₂Was cultured for 2 days and used to measure the inhibitory activity on uptake.

(2) Preparation of test Compounds

Test compounds were dissolved in dmso (wako) at a concentration of 10mM, and then diluted to a concentration 2-fold higher than desired using a pretreatment buffer (125mM sodium gluconate, 4.8mM potassium gluconate, 1.2mM potassium dihydrogen phosphate, 1.2mM magnesium sulfate, 1.3mM calcium gluconate, 5.6mM glucose, 25mM Hepes, pH 7.4). Pretreatment buffer without test compound was used as control. In addition, equal amounts will be included¹⁴Pre-treatment buffer of C-labeled uric acid (Moravek) was added to test compounds and controls, and finally test buffer containing 20 μ M uric acid was prepared.

(3) Measuring method

All tests were carried out on a hot plate at 37 ℃. The pretreatment buffer and assay buffer were incubated at 37 ℃ and then used for the assay. The medium was removed from the plate and 700. mu.L of pretreatment buffer was added and the cells were pre-incubated for 10 minutes. After repeating the same procedure, the pre-treatment buffer was removed and assay buffer was added at 400 μ L/well. The uptake reaction took 5 minutes. After termination of the reaction, the assay buffer was quickly removed and the cells were washed twice with 1.2 mL/well of ice cold pre-treatment buffer. Then, cells were lysed by adding 0.2N sodium hydroxide at 300. mu.L/well. The cell lysis solution was transferred to Picoplate (Perkinelmer) and Microscinti 40(Perkinelmer) was added at 600. mu.L/well. After mixing, radioactivity was calculated in a liquid scintillation counter (PerkinElmer). Radioactivity in COS7 cells not transfected with URAT1 expression vector was also counted under the same conditions as a control. In addition, the% inhibition of the test compound at 10 μ M was calculated according to the following formula (table 62). The ex.no., conc.and inhibition% in the table represent the example number, the concentration (μ M) of the test compound and the percentage (%) of inhibition, respectively.

Percent (%) inhibition ═ 1- (B-C)/(a-C) ] X100

A: radioactivity of control

B: radioactivity with addition of test Compound

C: radioactivity in COS7 cells not transfected with URAT1 expression vector

[ Table 62]

Ex.No	Conc.(μM)	inhibition％
			193	10	47
194	10	64

Test example 4

Serum uric acid lowering action

(1) Measuring method

Test compounds at 3 mg/kg suspended in 0.5% methylcellulose solution were orally administered to overnight fasted male cd (sd) IGS rats (5 weeks old, Charls River Japan). After 2 hours after the administration, blood was collected from the abdominal aorta under ether anesthesia, and serum was separated according to a general method. Serum Uric acid values were determined using Uric acid measurement kit (Uric acid C-Test Wako: Wako), and percent Uric acid reduction was calculated according to the following formula.

Percent uric acid reduction (%) — (serum uric acid value of control animals-serum uric acid value of animals given test compound) x 100/serum uric acid value of control animals.

(2) Results

The compounds of examples 3, 188, 191 and 192 had a uric acid lowering effect of 60% or more 2 hours after oral administration. The above results confirm that the compounds of the present invention have a potent serum uric acid lowering effect.

Industrial applicability

The (aza) indole derivative represented by the above general formula (I), or a prodrug thereof, or a pharmaceutically acceptable salt thereof of the present invention exhibits an excellent xanthine oxidase inhibitory action, and therefore can exhibit an inhibitory action on uric acid production and a reduction in uric acid level in blood. Accordingly, the present invention can provide a prophylactic or therapeutic agent for hyperuricemia, tophus, gouty arthritis, renal disorder associated with hyperuricemia, urinary calculi, and the like.

Claims

1. An indole derivative represented by the following general formula:

[ chemical formula 1]

Wherein:

t represents a cyano group;

ring J represents a benzene ring, a pyridine ring or a thiazole ring;

q represents a carboxyl group;

y represents a hydroxyl group, an amino group, a lower alkyl group or a lower alkoxy group optionally substituted with a lower alkoxy group when ring J is a benzene ring, or a hydrogen atom, a hydroxyl group, an amino group, a lower alkyl group or a lower alkoxy group optionally substituted with a lower alkoxy group when ring J is a pyridine ring or a thiazole ring;

X¹，X²and X³Represents CR²Provided that R is²Optionally identical or different from each other; and

R¹and R²Independently represents a halogen atom, cyano group, perfluoro lower alkyl group, -A^A-A-D-E-G or-N (-D-E-G)₂Provided that the two (-D-E-G) are optionally different from each other;

in the above formula, A^ARepresents a hydrogen atom, a hydroxyl group or a carboxyl group;

a represents a direct bond, -O-, -CON (R)³) -or-N (R)³)SO₂-, wherein R³Represents a hydrogen atom or a lower alkyl group;

d represents lower alkylene, lower alkenylene, phenylene optionally substituted with a halogen atom, thienylene or pyridinylene;

e represents a direct bond, -O-, -N (R)⁵)-，-CO-，-COO-，-SO₂-，-N(R⁵)CO-，-N(R⁵) COO-or-N (R)⁵)SO₂Provided that R is⁵Represents a hydrogen atom or a lower alkyl group;

g represents a hydrogen atom, a lower alkyl group, a cycloalkyl group, a phenyl group optionally substituted with a halogen atom or a lower alkylsulfonyl group, a thiophene or a phenyl lower alkyl group, with the proviso that when G is a hydrogen atom, E is a direct bond, -O-, -N (R)⁵) -, -COO-or-N (R)⁵) CO-or with the proviso that when there are two R's bound to adjacent atoms²When two R are present²Optionally joined together to form a ring, an

"lower" means a straight or branched chain hydrocarbon group containing up to 6 carbon atoms.

2. The indole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y represents a hydroxyl group when ring J is a benzene ring, or a hydrogen atom or a hydroxyl group when ring J is a pyridine ring or a thiazole ring.

3. The indole derivative according to claim 2, or a pharmaceutically acceptable salt thereof, wherein Y represents hydroxy.

4. The indole derivative of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein ring J represents a benzene ring.

5. The indole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the group is represented by the following general formula:

[ chemical formula 2]

Is a group represented by the following general formula (IIa):

[ chemical formula 3]

In the formula (I), the compound is shown in the specification,

Z¹and Z³Represents CH;

Z²represents CH or N; and

when Z is²When is CH, Y¹Represents hydroxy, amino, lower alkyl or lower alkoxy, or when Z is²When is N, Y¹Represents a hydrogen atom, a hydroxyl group, an amino group, a lower alkyl group or a lower alkoxy group.

6. The indole derivative of claim 5, or a pharmaceutically acceptable salt thereof, wherein

When Z is²When is CH, Y¹Represents hydroxy, or when Z²When is N, Y¹Represents a hydrogen atom or a hydroxyl group.

7. The indole derivative of claim 6, or a pharmaceutically acceptable salt thereof, wherein Z is²Represents CH.

8. The indole derivative of claim 7, or a pharmaceutically acceptable salt thereof, wherein Y is¹Represents a hydroxyl group.

9. The indole derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein ring J represents a thiazole ring.

10. The indole derivative of claim 9, or a pharmaceutically acceptable salt thereof, wherein the group is represented by the following general formula:

[ chemical formula 4]

Is a group represented by the following general formula (IIb):

[ chemical formula 5]

In the formula (I), the compound is shown in the specification,

R⁹represents a lower alkyl group.

11. The indole derivative of claim 1, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

4- (3-cyano-5, 6-difluoroindol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-5-methyl-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-6-chloro-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-5-fluoro-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-6-fluoro-indol-1-yl) -2-hydroxybenzoic acid,

4- (6-chloro-3-cyano-5-fluoro-indol-1-yl) -2-hydroxybenzoic acid,

4- (7-cyano-1, 3-dioxino [4,5-f ] -indol-5-yl) -2-hydroxybenzoic acid,

4- (3-cyano-6-trifluoromethyl-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-5-methoxy-indol-1-yl) -2-hydroxybenzoic acid,

4- (5-chloro-3-cyano-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-5-hydroxy-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-4-hydroxy-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-6-hydroxy-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-6-methoxy-indol-1-yl) -2-hydroxybenzoic acid,

4- (3-cyano-4-fluoro-indol-1-yl) -2-hydroxybenzoic acid, and

4- (3-cyano-6-isopropyl-indol-1-yl) -2-hydroxybenzoic acid.

12. A xanthine oxidase inhibitor comprising the indole derivative according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof as an active ingredient.

13. A pharmaceutical composition comprising as an active ingredient the indole derivative according to any one of claims 1 to 11 or a pharmaceutically acceptable salt thereof.

14. The pharmaceutical composition according to claim 13, which is a prophylactic or therapeutic agent for a disease selected from the group consisting of hyperuricemia, tophus, gouty arthritis, renal disorders associated with hyperuricemia, and urinary calculi.

15. The pharmaceutical composition according to claim 14, which is a prophylactic or therapeutic agent for hyperuricemia.

16. The pharmaceutical composition of claim 13, which is a serum uric acid level-lowering agent.

17. The pharmaceutical composition according to claim 13, which is an uric acid production inhibitor.

18. Pharmaceutical composition according to any one of claims 13 to 17, comprising a further combination with at least one drug selected from colchicine, non-steroidal anti-inflammatory drugs, steroids and urine alkalinizing agents as active ingredient.