Specification
DESCRIPTION
Title of the Invention:
NITROGENOUS-RING ACYLGUANIDINE DERIVATIVE
Technical Field
[0001]
The present invention relates to pharmaceuticals, particularly to nitrogenous-ring acylguanidine derivatives with 5-HT5A receptor modulating action, useful as an agent for treating or preventing dementia, schizophrenia, and the like.
Background Art
[0002]
In recent years, it has been suggested that the 5-HTSA receptor which is one of the subtypes of serotonin receptors plays an important role in dementia and schizophrenia. For example, it has been reported that new exploratory behaviors are increased in the 5-HT5A receptor knock-out mice, and hyperactivity by LSD is inhibited in the 5-HT5A receptor knock-out mice (Neuron 22, 581-591,1999). From the results of gene expression analysis, it has been reported that the 5-HTSA receptor is highly expressed in human and rodent brain, and in brain, it is highly expressed in hippocampal CA1 and CA3 pyramidal cells which are related to memory, and frontal lobe (cerebral cortex) which is deeply related to schizophrenia (Molecular Brain Research 56, 1-8,1998). Furthermore, it has been reported that gene polymorphism of the 5-HTsA receptor relates to schizophrenia (Neuroreport 11,2017-2020,2000; Mol. Psychiatr. 6,217-219,2001; and J. Psychiatr. Res. 38, 371-376,2004). Accordingly, it is suggested that regulation of 5-HTSA receptor action leads to the improvement of dementia and schizophrenia and compounds with such function are needed.
[0003]
Hitherto, several kinds of compounds having affinity for a 5-HTSA receptor have been reported.
For example, it is described that bicyclic acylguanidine derivatives represented by the following general formula bind to the 5-HTSA receptor, and are thus used for treating dementia, schizophrenia, and the like (Patent Document 1).
[Chem. 1]
(A represents phenyl or the like, R1, R2, and R3 each represent H, lower alkyl, halogen, or the like, R7 and R8 each represent H, lower alkyl, or the like, X represents O, S, or CR "R , R a and R each represent H or the like, the dotted line represents a bond or absence, m represents 0, 1, or 2, L1 and L2 each represent a bond or the like, and R4, R5, and R6 each represent H or the like. For details, refer to the publication.)
In the publication, there is no disclosure on those in which the bicyclic ring group has a N atom containing ring.
[0004]
In addition, it is reported that compounds having a tricyclic acylguanidine structure (Patent Document 2) and compounds having a structure in which the ring is directly bonded to the guanidine (Patent Document 3) each bind to the 5-HT5A receptor, and are used for treating dementia, schizophrenia, and the like.
Furthermore, it is described that quinoline derivatives represented by the following general formula bind to a 5-HTSA receptor, and are used for treating dementia, schizophrenia, and the like (Patent Document 4).
[Chem. 2]
(R1 represents -QCONR'CHi-Ar1 or the like, R2 represents -Ar2, -CHRd-Ar2, -CHaCFfcO-Ar2, or the like, R3 represents phenyl or pyridinyl, which may be substituted, Ar1 and Ar2 each represent aryl or heteroaryl, which may be substituted, and Rc and Rd each represent a hydrogen atom or Ci.7-alkyl. For details on these, refer to the publication.)
In the publication, there is no disclosure on those having acylguanidine as R1.
Hitherto, there is no report for a 5-HTSA receptor modulator which has a structure in which the guanidine is bonded to a bicyclic nitrogen-containing ring via a carbonyl group.
[0005]
In addition, naphthalene ring derivatives substituted with an acylguanidino group have been reported in Patent Document 5. This document relates to a naphthylacylguanidine derivative, but does not disclose the quinoline derivative of the present invention. Further, the application of the compound of this document is an antiviral agent.
List of the Documents Patent Documents
[0006]
Patent Document 1: WO 2009/022633 pamphlet
Patent Document 2: WO 2008/096791 pamphlet
Patent Document 3: WO 2005/082871 pamphlet
Patent Document 4: WO 2009/040290 pamphlet
Patent Document 5: WO 2006/135978 pamphlet
Summary of the Invention
Problem that the Invention is to Solve
[0007]
The object of the present invention is to provide excellent agents for treating or preventing dementia, schizophrenia, and the like, based on 5-HTSA receptor modulating action.
Means for Solving the Problem
[0008]
The present inventors have extensively studied compounds having 5-HTSA receptor modulating action, and as a result, it has been found that acylguanidine derivatives which have the characteristic structure in which the guanidine is bonded to one ring of the quinoline or isoquinoline via a carbonyl group, and a cyclic group is bonded to the other ring, exhibit potent 5-HT5A receptor modulating actions and excellent pharmacological actions based on said 5-HT5A receptor modulating action, and thus can be excellent agents for treating or preventing dementia, schizophrenia, and the like, thereby completing the present invention.
Compound of formula (I) is characterized by the quinoline or isoquinoline structure, good metabolism profile and safety.
That is, the present invention relates to compound of formula (I) or pharmaceutically acceptable salts thereof.
[0009]
[Chem. 3]
(wherein the symbols have the following meanings: [Chem. 4]
: aryl, cycloalkyl, cycloalkenyl or monocyclic nitrogen-containing heterocyclic group,
Z , Z , Z , Z and Z : one of any of them is a nitrogen atom, and the others are carbon atoms, in which the nitrogen atom is optionally oxidized to form an N-oxide,
R , R and R : each independently represents H, lower alkyl, halogen, halogeno-lower alkyl, -CN, -NO2, -OR", -S-lower alkyl, -O-halogeno-lower alkyl, -CO2Ra, -C(O)NRbRc, -S02-lower alkyl, or -lower alkylene-OR8,
R4, R5 and R6: each independently represents H, lower alkyl, cycloalkyl, halogen, halogeno-lower alkyl, -CN, -NO2, -ORa, -S-lower alkyl, -O-halogeno-lower alkyl, -CO2Ra, -C(O)NRbRc, -S02-lower alkyl, or lower alkylene-ORa,
RB, Rb and Rc: each independently represents H or lower alkyl, and
R7 and R8: each independently represents H or lower alkyl.)
Unless otherwise specifically noted, in the present specification, when a symbol in a chemical formula is used in another chemical formula same symbols have the same meanings.
Furthermore, atoms from Z1 to Z5 in formula (I), that are carbon atoms and do not bond to any ofR4,R5,andR6 are substituted with H.
[0010]
Furthermore, the present invention relates to pharmaceutical compositions containing a compound of the above formula (I) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, and, for example, the above pharmaceutical composition which is a 5-HTSA receptor modulator. In another example, the present invention relates to the above pharmaceutical composition, which is an agent for preventing or treating dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder; and further as another example, it relates to the above pharmaceutical composition which is an agent for preventing or treating dementia or schizophrenia.
In another embodiment, the present invention relates to 5-HT5A receptor modulators, for example, agents for preventing or treating dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder; further as another example, it relates to use of compound of the above formula (I) or a pharmaceutically acceptable salt thereof for prevention or treatment of dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder; further as another example, it relates to use of compound of the above formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of an agent for preventing or treating dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder or a method for preventing or treating dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder, or a method for preventing or treating dementia or schizophrenia in which the method includes administering a therapeutically effective amount of compound of the above formula (I) or a pharmaceutically acceptable salt thereof to a mammal. The above said schizophrenia includes positive symptoms, negative symptoms, cognitive impairment, and mood disorders.
Effects of the Invention
[0011]
Compounds of formula (I) have the advantage of potent 5-HTSA receptor modulating action and excellent pharmacological action based thereon. The pharmaceutical compositions of the present invention are useful for treatment or prevention of 5-HT5A receptor-related diseases, particularly for treatment or prevention of dementia, schizophrenia, bipolar disorder, or attention deficit hyperactivity disorder.
Mode for Carrying out the Invention
[0012]
Hereinafter, the present invention is described in detail.
In the present specification, the "5-HTSA receptor modulator" is a generic term referring to a compound that inhibits activation of the 5-HTSA receptor by antagonizing with an endogenous ligand (5-HTSA antagonist), and a compound that shows function by activation of the 5-HT5A receptor (5-HT5A agonist). Examples of the "5-HT5A receptor modulating action" include a 5-HTSA antagonist.
The "lower alkyl" means a linear or branched alkyl group having 1 to 6 carbon atoms (hereinafter abbreviated as Ci.6), specifically, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl group, or the like. In another embodiment, it is CM alky1' and in a still another embodiment, methyl, ethyl, n-propyl, or isopropyl.
The "lower alkylene" is a linear or branched C^ alkylene, for example, methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, propylene, methylmethylene, ethylethylene, 1,2-dimethylethylene, 1,1,2,2-tetramethylethylene, and the like. In another embodiment, it is CM alkylene, in a still another embodiment, methylene or ethylene, and in a further still another embodiment, methylene.
The "cycloalkyl" is a C3.10 saturated hydrocarbon ring group, which may have a bridge. Specifically, it is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group, or the like, in another embodiment, C3.6 cycloalkyl group, and in a still another embodiment, cyclopropyl group.
The "cycloalkenyl" is a C5.10 cycloalkenyl, in another embodiment, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cycloheptenyl group, or the like, and in a still another embodiment, cyclopentenyl or cyclohexenyl group.
[0013]
The "halogen" means F, CI, Br, or I. In a certain embodiment, it is F or CI.
The "halogeno-lower alkyl" is a C« alkyl group substituted with one or more halogen atoms. In a certain embodiment, it is a Ct-6 alkyl group substituted with 1 to 5 halogen atoms, and in another embodiment, difluoromethyl or trifluoromethyl group.
The "aryl" is a C^-u monocyclic to tricyclic aromatic hydrocarbon ring group, and in a certain embodiment, it is phenyl or naphthyl group, and in another embodiment, a phenyl group.
The "monocyclic nitrogen-containing heterocyclic group" means a 5- to 8-membered monocyclic heterocyclic group that contains one nitrogen atom, and may further contain one or two heteroatoms selected from nitrogen, oxygen, and sulfur. The "monocyclic nitrogen-containing heterocyclic group" is a generic term referring to a "monocyclic nitrogen-containing saturated heterocyclic group" that is a saturated or partially unsaturated ring group and a "monocyclic nitrogen-containing heteroaryl" that is an aromatic ring group. Sulfur or nitrogen which is a ring atom is optionally oxidized to form an oxide or a dioxide. The "monocyclic nitrogen-containing saturated heterocyclic group" is specifically azetidinyl, pyrrolidinyl, piperidyl, piperazinyl, azepanyl, diazepanyl, azocanyl, morpholinyl, thiomorpholinyl, tetrahydropyridinyl group, or the like. In another embodiment, it is pyrrolidinyl, piperidyl, or piperazinyl group, and in a still another embodiment, pyrrolidinyl group. The "monocyclic nitrogen-containing heteroaryl" is specifically pyridyl, pyrimidinyl, thiazolyl, pyrazolyl, oxadiazolyl group, or the like. In another embodiment, it is pyridyl or pyrimidinyl group, and in a still another embodiment, pyridyl group.
The expression "optionally substituted" means unsubstituted or substituted with 1 to 5 substituents. When plural substituents, these may be the same or different each other.
[0014]
Some embodiments of compound of formula (I) are shown below.
(1) A compound wherein Z1 is nitrogen atom, and Z2, Z3, Z4, and Z5 are carbon atoms.
(2) A compound wherein Z3 is nitrogen atom, and Z1, Z2, Z4, and Z5 are carbon atoms.
(3) A compound wherein
[Chem. 5]
1 is phenyl group, pyridyl, cyclopropyl, cyclohexenyl, cyclopentenyl, or pyrrolidinyl group, and in another embodiment, phenyl or pyridyl group. (The present ring group is hereinafter referred as ring group A.)
(4) A compound wherein R1, R2, and R3 are each H, lower alkyl, halogen, halogeno-lower alkyl, -CN, or -OR8; in another embodiment, H, lower alkyl, F, CI, trifluoromethyl, -CN, or -ORa; and in a still another embodiment, H, F, CI, or -ORa group.
(5) A compound wherein R4, R5, and R6 are each H, lower alkyl, cyclopropyl, halogen, halogeno-lower alkyl, -CN, or -C(O)NRbRc; in another embodiment, H, lower alkyl, F, CI, halogeno-lower alkyl, -CN, or -C(O)NRbRc; and still in another embodiment, H, lower alkyl, F, CI, or halogeno-lower alkyl group.
(6) A compound wherein both R7 and R8 are H.
(7) A compound which combines two or more groups described in the above (1) to (6).
Examples of specific embodiments of (7) above include the following compounds.
(8) A compound as described in the aforesaid (3), wherein both R7 and R8 are H.
(9) A compound as described in the aforesaid (3) or (8), wherein R , R , and R are as described in the aforesaid (4).
(10) A compound as described in any one of the aforesaid (3), (8), (9), wherein R4, R5, and R6 are as described in the aforesaid (5).
(11) A compound as described in the aforesaid (3), wherein Z1 is a nitrogen atom, and Z2, Z3, Z4, and Z5 are carbon atoms.
(12) A compound as described in the aforesaid (3), wherein Z3 is a nitrogen atom, and Z1, Z2, Z4, and Z5 are carbon atoms.
(13) A compound as described in the aforesaid (11) or (12), wherein both R7 and
R8 are H.
(14) A compound as described in any one of the aforesaid (11) to (13), wherein R , R2, and R3 are as described in the aforesaid (4).
(15) A compound as described in any one of the aforesaid(l 1) to (14), wherein R4, R5, and R6 are as described in (5) above.
[0015]
(16) A compound wherein Z1 is a nitrogen atom; Z2, Z3, Z4, and Z5 are carbon atoms; the ring group A is phenyl, pyridyl, cyclopropyl, cyclohexenyl, cyclopentenyl, or pyrrolidinyl group; R1, R2, and R3 are each H, lower alkyl, halogen, halogeno-lower alkyl, -CN, or -OR8; R4, R5, and R6 are each H, lower alkyl, cyclopropyl, halogen, halogeno-lower alkyl, -CN, or -C(O)NRbRc; and R7 and R8 are both H.
(17) A compound wherein Z3 is a nitrogen atom; Z1, Z2, Z4, and Z5 are carbon atoms; the ring group A is phenyl, pyridyl, cyclopropyl, cyclohexenyl, cyclopentenyl, or pyrrolidinyl group; R1, R2, and R3 are each H, lower alkyl, halogen, halogeno-lower alkyl, -CN, or -OR8; R , R , and R6 are each H, lower alkyl, cyclopropyl, halogen, halogeno-lower alkyl, -CN, or -C(O)NRbRc; and both R7 and R8 are H.
(18) A compound wherein Z1 is a nitrogen atom; Z2, Z3, Z4, and Z5 are carbon atoms; the ring group A is phenyl or pyridyl group; R1, R2, and R3 are each H, F, CI, or a -OR8 group; R4, R5, and R6 are each H, lower alkyl, F, CI, or a halogeno-lower alkyl group; and both R7 and R8 are H.
(19) A compound wherein Z3 is a nitrogen atom; Z1, Z2, Z4, and Z5 are carbon atoms; the ring group A is phenyl or pyridyl group; R1, R2, and R3 are each H, F, CI, or -OR8 group; R4, R5, and R6 are each H, lower alkyl, F, CI, or a halogeno-lower alkyl group; and both R7 and R8 are H.
[0016]
(20) A compound or a salt thereof, which is selected from the group consisting of: N-(diaminomethylene)-2-methyl-4-(2,4,6-trifluorophenyl)quinoline-6-carboxamide, l-(2-cliloro-6-fiuorophenyl)-N-(diammometnylene)-4-fluoroisoquinoline-7-carboxamide,
N-(diaminomethylene)-1 -(2,6-difluorophenyl)-4-fluoroisoquinoline-7-carboxamide, l-(2-cMoro-4-fluorophenyl)-N-(diaminomethylene)-4-fluoroisoquinoline-7-carboxamide,
N-(diaminomethylene)-4-methyl-l-(2,4,6-trifluorophenyl)isoquinoline-7-carboxamide,
N-(diaminomethylene)-2,3-dimethyl-4-(2,4,6-trifluorophenyI)quinoline-6-carboxamide,
N-(diaminomethylene)-l-(3,5-difluoropyridin-4-yl)-4-fluoroisoquinoline-7-carboxamide,
N-CdjammoraethyleneH-fluo,.-, ,, . hloro-N 4"flUOroiSOI'ufao«ne-7^boxamid; wboxamide, ne) ''0Phenyi)iS0quinoiine_7_
l-C3-ch]oro-5-fluoropyridin-l vn xi ,.,• wboxamide, ° (dlaminometliylene)-4-flllnmi . M . ' ' Huoro"soqumoline.7- (diaminomethylene)-l-rt A J „ carboxde, °} ( ' d,flUOr0phen^™,hyliSoquinoline.7. chJoro-N-Cdiaminomethylene)-! o 4 ,,-x, carboxamide. y D6) PhenyDisoquinoline-?-
[0017]
Furthermore, compound of formni* m confonnational isomers or optical , M 0ther tautoms5 isomers, yet the present invemion J^£»* ta d~ in only one form mixtures. Forexamnle flm_ ™ °UW1 lsomers»m^ Elated forms or their arrangement in the guanidine moietv n,. • geometrical guamume moiety. The present mvention includes all
Furthermore, pharmaceutical^ accentable n™H mers- compounds which have a group that can be convened into a, an^o grouP%H, CO H the like by solvolysis or under physiological conditions. Examples of groups forming prodrugs include the groups described in "Prog. Med., 5,2157-2161 (1985), and "fyakuhin no Kaihatsu (Development of Medicines)" (Hirokawa Publishing company, 1990), vol. 7 Bunshi Sekkei (Molecular Design)", 163-198.
[0018]
Furthermore, compound of formula (I) may form an acid addition salt, or may form a salt with a base depending on the kind of substituents, and the salts are included in the present invention as long as they are pharmaceutically acceptable salts. Specifically, examples of these salts include acid addition salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, and with organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, and glutamic acid, salts with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum, and organic bases such as methylamine, ethylamine, ethanolamine, lysine, and ornithine, and ammonium salts.
In addition, compound of formula (I) and pharmaceutically acceptable salts thereof include hydrates, solvates, and crystal polymorphs. Also, compound of formula (I) and pharmaceutically acceptable salts thereof include the compounds labeled with radioactive or non-radioactive isotopes.
[0019]
(Production Processes)
Compound of formula (I) and pharmaceutically acceptable salts thereof can be produced by applying known synthetic methods, according to its basic skeleton or kind of substituents. Protection of the functional groups with suitable protecting groups (groups which can be easily converted into the original functional group) may be effective in technical means, depending on the kind of the functional group, in any step from starting materials to intermediates. Examples of functional groups include amino group, hydroxyl group, and carboxyl group, and examples of the protecting group include those described in "Greene's Protective Groups in Organic Synthesis (4th Edition, 2006)", edited by P. G. M. Wuts and T. W. Greene, which can beselected and used depending on the reaction conditions. In this way, the object compound can be obtained by introducing a protecting group during the reaction, and then, by optionally removing it.
In addition, prodrugs of compound of formula (I) can be produced by introducing a specific group during any step from starting materials to intermediates, in a similar way to the aforementioned protecting groups, or by carrying out further reactions using the obtained compound of formula (I). The reaction can be carried out by employing known methods to a skilled person in the art, such as usual esterification, amidation, and dehydration reactions.
Hereinbelow, representative production processes of compound of formula (I) are described. Each production process can be carried out according to the references cited in the description. Further, production processes of the present invention are not limited to the examples as shown below. (Production Process 1)
[Chem. 6]
(Lv1 represents -OH or a leaving group.)
Compound of formula (1) can be produced by the reaction of a carboxylic acid or a reactive derivative thereof (1) with guanidine (2) or a salt thereof.
The reaction can be carried out by using the carboxylic acid or a reactive derivative thereof (1) and guanidine (2) in equivalent amounts, or guanidine in an excess amount. It can be carried out under cooling to under heating, and preferably at -20°C to 80°C, in a solvent inert to the reaction, such as aromatic hydrocarbons such as benzene, toluene, xylene, and the like; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, chloroform, and the like; ethers such as diethylether, tetrahydrofuran (THF), dioxane, dimethoxyethane (DME), and the like; N,N-dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP), ethyl acetate, acetonitrile, water, and the like, or a mixtures thereof.
When a carboxylic acid wherein Lv1 is -OH is used as the carboxilic acid or a reactive derivative thereof (1), it is desirable to carry out the reaction in the presence of a condensing agent. In this case, examples of the condensing agent include N,N'-dicyclohexylcarbodiimide (DCC), l-[3-(dimethyiamino)propyl]-3-ethylcarbodiimide (WSC), l,l'-carbonyldiimidazole (CDI), 2-(lH-benzotriazol-l-yl)-l,1,3,3-tetramethyluronium hexafluorophosphate (HBTU), diphenylphosphoryl azide (DPPA), and phosphorous oxychloride. In some cases, it is preferable to further use additive agents (e.g., N-hydroxysuccinimide (HONSu), 1-hydroxybenzotriazole (HOBt) and the like). The condensing agent is usually used in an equivalent amount or excess to the carboxylic acid.
When a reactive derivative of the carboxylic acid wherein Lv is a leaving group is used as the carboxylic acid or a reactive derivative thereof (1), acid halides (acid chloride, acid bromide, or the like), acid anhydrides (mixed acid anhydrides obtained by the reaction flcarboxylic acid with phenyl chlorocarbonate, p-toluenesulfonic aci^ o I like- or symmetric acid anhydrides), active esters (esters which can be prepared from a fluorine atom, and the like), lower alkyl esters, and the uke group such as a m*o ^ , from carboxylic M using reactions OependmgonthekindofthereactiveMtissometimes advantageous for quick progress of the reaction to carry out the reaction in presence of a base (organic bases such as triethylamine, diisopropylethylamine (DIPEA), N-methylmorpholine, pyridine, 4-(N,N-dimethylamino)pyridine, and the like, or inorganic bases such as sodium hydrogen carbonate and the like). Pyridine can also serve as a solvent Further, when a lower alkyl ester is used as the reactive derivative, it is preferable to carry out the reaction under from room temperature to heating under reflux.
[0020]
(Production Process 2)
[Chem. 7]
(Lv2 represents a leaving group such as pyrazol-1-yl optionally substituted with lower alkyl, or -S-lower alkyl, -O-phenyl, -Br, -CI, and the like, and R8a represents lower alkyl.)
Compound (la) having lower alkyl as R8 among compounds of formula (I) can be produced by reaction of an amidine compound (3) having a leaving group with an amine compound (4).
This reaction can be carried out using compound (3) and compound (4) in equivalent amounts, or in an excess amount of one of them, in which their mixture is stirred under from cooling to heating under reflux, and preferably from 0°C to 80°C, usually for 0.1 hours to 5 days, in a solvent inert to reaction or without solvent. Examples of solvents used herein are not limited, but include aromatic hydrocarbons, ethers, halogenated hydrocarbons, DMF, DMSO, ethyl acetate, acetonitrile, and a mixture thereof. It is sometimes advantageous for smooth progress of the reaction to carry out the reaction in the presence of organic bases such as triethylamine, N,N-diisopropylethylamine, N-methylmorpholine, and the like, or inorganic bases such as potassium carbonate, sodium carbonate, potassium hydroxide, and the like.
[0021]
Carboxylic acid or a reactive derivative thereof (1) of the above Production Process 1 can be produced by known methods or any variation thereof. For example, starting compound (1 a) can be produced by the reaction route shown below (Production Process of Starting Compound).
(Production Process of Starting Compound) [Chem. 8]
(In the formula, X1 represents halogen, methanesulfonyloxy group, p-toluenesulfonyloxy group, or trifluoromethanesulfonyloxy group, R11 represents a protecting group of carboxyl group such as lower alkyl, benzyl, or the like, and X represents an active group such as -B(OH)2, -B(0 Y)0 W, and the like. Here, Y and W are the same or different from each other and represent lower alkyl, or Y and W are combined together to form lower alkylene.)
Compound (la) can be obtained by coupling reaction of compound (5) and compound (6) to first obtain compound (7),followed by its hydrolysis.
Synthesis of compound (7) is carried out by using a mixture of compound (5) and compound (6) in equivalent amounts or in an excess of one of them, and stirring the mixture under from room temperature to heating under reflux, usually for 0.1 hours to 5 days, in a reaction inert solvent in the presence of a base and palladium catalyst. The present reaction is preferably carried out under an inert gas atmosphere. Examples of solvents used herein include, but not particularly limited to, aromatic hydrocarbons, ethers, halogenated hydrocarbons, alcohols such as methanol, ethanol, and the like, DMF, DMSO, and mixed solvents thereof. As bases, inorganic bases such as sodium carbonate ToLTium carbonate, sodium hydroxide, and the like are preferred. Examples of the palladium catalyst include tetrakiS(triphenylphosphine)palladium, S Sadl ligands, tert-bu
Documents
Application Documents
| # |
Name |
Date |
| 1 |
1162-CHENP-2012 POWER OF ATTORNEY 06-02-2012.pdf |
2012-02-06 |
| 2 |
1162-CHENP-2012 FORM-5 06-02-2012.pdf |
2012-02-06 |
| 3 |
1162-CHENP-2012 FORM-3 06-02-2012.pdf |
2012-02-06 |
| 4 |
1162-CHENP-2012 FORM-2 06-02-2012.pdf |
2012-02-06 |
| 5 |
1162-CHENP-2012 FORM-13 06-02-2012.pdf |
2012-02-06 |
| 6 |
1162-CHENP-2012 FORM-1 06-02-2012.pdf |
2012-02-06 |
| 7 |
1162-CHENP-2012 CORREPONDENCE OTHERS 06-02-2012.pdf |
2012-02-06 |
| 8 |
1162-CHENP-2012 PCT 06-02-2012.pdf |
2012-02-06 |
| 9 |
1162-CHENP-2012 FORM-13 106-02-2012.pdf |
2012-02-06 |
| 10 |
1162-CHENP-2012 ENGLISH TRANSLATION 06-02-2012.pdf |
2012-02-06 |
| 11 |
1162-CHENP-2012 DESCRIPTION (COMPLETE) 06-02-2012.pdf |
2012-02-06 |
| 12 |
1162-CHENP-2012 CLAIMS 06-02-2012.pdf |
2012-02-06 |
| 13 |
1162-CHENP-2012 ABSTRACT 06-02-2012.pdf |
2012-02-06 |
| 14 |
1162-CHENP-2012 CORRESPONDENCE OTHERS 27-07-2012.pdf |
2012-07-27 |
| 15 |
1162-CHENP-2012 FORM-3 27-07-2012.pdf |
2012-07-27 |
| 16 |
1162-CHENP-2012 CORRESPONDENCE OTHERS 12-11-2012.pdf |
2012-11-12 |
| 17 |
abstract1162-CHENP-2012.jpg |
2013-04-11 |
| 18 |
1162-CHENP-2012-FER.pdf |
2017-08-29 |
| 19 |
1162-CHENP-2012-AbandonedLetter.pdf |
2018-03-15 |
Search Strategy
| 1 |
1162CHENP2012_20-06-2017_STN_Search_28-08-2017.pdf |
| 2 |
1162CHENP2012-Surechem_StructureSearchandResults_28-08-2017.pdf |
| 3 |
1162CHENP2012-GoogleSearch_28-08-2017.pdf |