JPH0433787B2 - - Google Patents

Description

[Detailed description of the invention]

Industrial Application Field The present invention is based on the following formula The present invention relates to novel substituted benzamides having the following formula: wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and A are as defined below. The benzamide is used in the treatment of emesis, especially emesis induced by chemotherapy, such as cisplatin treatment in cancer patients.
and/or in the treatment of gastric motility disorders such as delayed gastric emptying, dyspepsia, flatulence, reflux in the esophagus and the like. BACKGROUND OF THE INVENTION Vomiting is both common and a serious problem in patients receiving cancer therapeutics. In a significant number of patients, nausea and vomiting are so severe that the chemotherapy course is stopped before the chemotherapy is complete. Although there is no known antiemetic agent that is fully effective in suppressing chemotherapy-related emesis, there are a number of compounds (many of which are based on substituted benzamide structures) that have good antiemetic activity. Effective antiemetics are generally dopaminergic antagonists, although their mechanism of action is not completely known. In fact, screening for potential anti-emetic agents is typically accomplished by tests involving the determination of dopaminergic blocking properties, such as the in vitro spiperone binding test and the apomorphine emesis test in dogs. As a result of the phenomenon of topaminergic antagonism and/or as a result of central nervous system depression, known antiemetic agents have undesirable side effects such as sedation, ataxic reactions, diarrhea and akathisia. Surprisingly, a group of substituted benzamide antiemetics has a high degree of specificity; they are not dopaminergic antagonists; and they do not have the undesirable side effects of currently known antiemetics. This was discovered by the present invention. Excellent recent reports on various substituted benzamides and their pharmacological activities can be found in academic books.
Chemical Regulation of Biological
Mechanisms”, AMCreighton and S.Turner,
editors, Royal Society of London (1982), in
the chapter entitled Substituted
Benzamidesas Dopamine Antagonists”，by
MS Hadley (Pages 140-153)]. According to it, this class of compounds has the following formula

[Formula] and

[Formula] (However, the aryl ring in the formula is generally a phenyl ring, and "the methoxy group is present almost always at the ortho position to the benzamide moiety")
Defined by The journal also points out that the various effects of substituted benzamides are believed to be a result of the compounds being dopamine antagonists. Representative prior art patent documents disclosing N-substituted benzamides with various substituents on the phenyl ring include the following documents. U.S. Patent No. 3,219,528 (inventor: MLThominet,
(published on November 23, 1965) The specification is as follows: [However, during the ceremony

[Formula] or

[Formula], R ¹ and R ² are alkyl, L is oxygen,
methylene or NR, where R is hydrogen, alkyl, or alkylsulfamoyl; W is alkylene; A is alkyl; B is sulfur or oxygen; and X, Y, and Z are hydrogen,
halogen, alkoxy, nitro, amino, alkylamino, dialkylamino, (lower) acyl,
(lower) acylamino, cyano, alkylmercapto, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or halomethyl. This compound is an apomorphine antagonist and is defined as an anti-emetic agent. U.S. Patent No. 3177252 (published April 6, 1965) and U.S. Patent No. 3312739 (published April 4, 1967)
Each specification similarly discloses similar subject matter. US Patent No. 1500105 (published February 8, 1978) The specification is as follows: [However, in the formula, A is hydrogen, C _1-5 alkyl or C _2-5 alkenyl; X is hydrogen, C _1-5 alkoxy,
C _2-5 alkyl, C _2-5 alkenyloxy or C _2-5 alkenyl; Y is hydrogen, halogen, nitro,
is C _1-5 alkyl, C _1-5 alkoxy, amino or substituted amino; Z is hydrogen, halogen, C _1-5 alkoxy, C _1-5 alkylsulfonyl or -SO ₂ NR ¹
R ² group, and R ¹ and R ² are the same or different and are hydrogen or C _1-5 alkyl group, or -NR ¹
R ² is a heterocycle, optionally with other heteroatoms; W is a C _1-5 straight or branched alkylene group; B is -NR ³ R ⁴ and R ³ is C _{1- 5} alkyl and R ⁴ is C _1-5 hydroxyalkyl, or B is a nitrogen-attached heterocycle optionally containing a second nitrogen atom and optionally having one substituent; B is a racemic, dextrorotatory or levorotatory heterocycle, and is of the following formula (wherein R is C _1-5 alkyl and has a reactive functional group such as hydroxy, mercapto, oxo, thioxo, oxa or thia; and m is 1, 2 or 3)] Substituted benzamides and their acid addition salts, oxides and quaternary ammonium salts are disclosed. It has been established that this compound is an apomorphine antagonist and has various therapeutic properties, making it particularly useful as an anti-emetic agent. US Patent No. 4207327 (published on June 10, 1980, inventor CD Lunsford et al.) The specification is as follows: (wherein R is alkyl, cycloalkyl or phenylalkyl; R ¹ is alkyl, cycloalkyl or phenylalkyl; R ² is hydrogen, alkyl or phenyl; and R ³
discloses compounds having hydroxy, cyano, nitro, amino, fluoro, chloro, bromo, trifluoromethyl, alkyl, alkoxy, sulfamoyl or acetamide, each R ³ being the same or different. These compounds have been described as having antiemetic and gastric emptying properties. U.S. Patent No. 3966957 (published June 29, 1976, inventor Cale, Jr., etc.) The specification is as follows: (However, in the formula, R is cycloalkyl, phenyl, or phenylalkyl; R ¹ is hydrogen, C _1-8 alkyl, or phenyl; R ² is hydrogen, alkyl,
alkoxy, amino, nitro, alkylamino,
dialkylamino, mercaptomethyl, acetamide, sulfamoyl, cyano, hydroxy, benzyloxy or trifluoromethyl; and n is 0 to 3; (However, R is cycloalkyl; R ¹ is hydrogen or C _1-8 alkyl; R ² is nitro, amino,
halogen, fluoramoyl or alkoxy; and n is 0-3) and pharmaceutically acceptable acid addition salts thereof. The invention of US Pat. No. 3,963,745 relates to and discloses substantially the same disclosure. It is described that the compound is an apomorphine antagonist and is useful as an anti-emetic agent. It has also been described that some of the compounds alleviate catalepsy in rats. Means for solving the problems The present invention is based on the following formula [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
Alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or

[Formula], or R ⁴ and R ⁵ together are -HN-N=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ teeth

[Formula] or

[Formula], in which n is a numerical value of 1 to 4; R ⁷ and R ⁸ are the same or different, and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl,

[Formula] or

[Formula], R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy, and A is oxygen or

[Formula]; R ² is

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

[Formula] or

[Formula]; X is oxygen, sulfur or =NOR ¹⁶ , Z is -(CH ₂ ) _P -, O, N or

[Formula] the law of nature; B is

【formula】 【formula】

【formula】

【formula】

[Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value of 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
Alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl,

[Formula] or

[Formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together

[Formula] or

[Formula]; Alternatively, R ¹² and R ¹³ together with the carbon atoms attached to them form a saturated ring having 5 to 7 carbon atoms, and the ring is a saturated ring selected from the group consisting of oxygen, sulfur, and nitrogen. optionally having one heteroatom; or R ¹² and R ¹⁴ together with the carbon atoms attached to them form a saturated or unsaturated ring having 5 to 7 atoms, the ring containing oxygen , sulfur and nitrogen; or R ¹⁴ and R ¹⁵ together with the carbon and oxygen atoms attached to them are oxygen-containing saturated 3- to 7-membered atoms; or a pharmaceutically acceptable non-toxic salt, hydrate, solvate, or quaternary ammonium salt thereof. A more preferable group of compounds among the compounds of the formula is the following formula: (However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ¹ is

[Formula] or

[Formula]; n is a numerical value from 1 to 4; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, or (lower alkynyl); R ¹⁰ is is hydrogen or (lower) alkoxy; R ² is

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

【formula】

[Formula] or

[Formula]; X is oxygen, sulfur or =NOR ¹⁶ , Z is -(CH ₂ ) _P -, O, N or

[Formula] the law of nature; B is

【formula】 【formula】

【formula】

【formula】

[Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower alkynyl), (lower) alkoxy (lower) alkyl or cycloalkyl having 5 to 7 carbon atoms, provided that when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is oxygen or nitrogen. Not directly attached to an atom; ^R14 is hydrogen, halogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, (lower) alkoxy,
Hydroxy, (lower) alkenyloxy, hydrazino, (lower) alkoxycarbonyl (lower) alkenyl, acetylhydrazino, thienyl, phenyl, phenyl (lower) alkyl or and R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together

[Formula] or

[Formula]; Alternatively, R ¹² and R ¹⁴ together with the carbon atoms attached to them form a saturated or unsaturated ring having 5 to 7 atoms, and the ring is selected from the group consisting of oxygen, sulfur, and nitrogen. optionally having at least one heteroatom selected; or R ¹⁴ and R ¹⁵ together with the carbon and oxygen atoms attached to them are saturated oxygen-containing 3-7
or a non-toxic pharmaceutically acceptable salt, hydrate, solvate, or quaternary ammonium salt thereof. A more preferable group of compounds among the compounds of the formula is the following formula: [However, in the formula, R ⁷ and R ⁸ are the same or different and are ethyl or methyl; R ² is -CH ₂ OCH ₂ CH ₂ OR ¹¹ , -CH ₂ CH ₂ OR ¹¹ ,

【formula】

【formula】

【formula】

【formula】

[Formula] or

^{[ Formula ] ; _ _} (lower) alkyl, (lower) alkenyl,
(lower) alkynyl, (lower) alkoxy (lower)
Alkyl or cycloalkyl having 5 to 7 carbon atoms, provided that when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is an oxygen atom or a nitrogen atom. Not directly attached; R ¹⁴ is hydrogen, halogen, (lower) alkyl, (lower) alkoxy, hydroxy, hydrazino, (lower) alkoxycarbonyl (lower) alkenyl,
acetylhydrazino, thienyl, phenyl, phenyl (lower) alkyl or and R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or methyl; or R ¹² and R ¹⁴ together with the carbon atoms attached to them are saturated rings or unsaturated rings having 5 to 7 atoms. forming a saturated ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ are the carbon atoms to which they are attached; and a non-toxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt thereof. It is. A particularly preferred compound having the formula is: 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxyethoxy)
-benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydroxyethoxy)-benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl ]-2-(2,2-dimethoxy)-
Benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyethoxy)
-Methyloxy]benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-propanon-1-yl)-oxybenzamide, 4-amino-2-benzoylmethyloxy -5
-Chloro-N-[2-(diethylamino)ethyl]
-benzamide, 4-amino-2-(butan-2-one-3-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]-benzamide, 4-amino-5-chloro-2-( cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(5-hexen-2-one- 3-yl)-oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-hydroxyimino)
-propan-1-yl]oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyimino)-
Propan-1-yl]oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydroxypropan-1-yl)oxybenzamide, 4-amino-5 -chloro-2-cyanomethyloxy-N-[2-(diethylamino)ethyl]-benzamide, 4-amino-2-(carboxamidomethyloxy)-5-chloro-N-[2-(diethylamino)
ethyl]-benzamide acetate, 4-amino-2-(2-butyn-1-yl)oxy-5-chloro-N-[2-(diethylamino)
ethyl]-benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methylsulfinyl)-ethoxy]benzamide, 4-amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(pentan-2-one-3
-yl)-oxybenzamide, 4-amino-2-(2-butanon-1-yl)
Oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(pentan-2-one-1)
-yl)-oxybenzamide, 4-amino-5-chloro-2-(pentane-3
-on-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydrazino-2-oxo -ethoxy)benzamide, threo-4-amino-5-chloro-N-[2-
(diethylamino)ethyl]-2-(2-hydroxybut-3-yl)oxybenzamide, erythro-4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-(2-hydroxybut-3-yl)oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methylamino) )-2
-oxoethoxy]benzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(ethyl-3-methoxy-
croton-4-yl)oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1,3-dioxolane-
2-yl)oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(oxazolidine)-2-
on-5-yl-methyl)oxybenzamide, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-pyridinomethyl)oxybenzamide, 4-amino-5-chloro- N-[2-(diethylamino)ethyl]-2-tetrahydrofurfuryl-oxybenzamide, and 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxyethoxy-
ethyl)oxybenzamide, and non-toxic pharmaceutically acceptable salts thereof;
Hydrates, solvates and quaternary ammonium salts. It should be understood that within the scope of the present invention are included all possible optical and geometric isomers and tautomers, if any, of the compounds of formula. In other aspects, the invention relates to processes for preparing compounds of the formula and to anti-emetic compositions and/or gastric motility compositions containing at least one compound of the formula as an active ingredient. Compounds of formula are prepared in several steps. In a preferred reaction method, a compound of formula R ² -L (where L is a conventional residue) is reacted with a compound of formula R 2 -L (where L is a conventional residue) in the presence of a base as an acid carrier, as shown in the reaction formula below. Manufacture a compound. Suitable residues L are those well known to those skilled in the art, such as chloro, bromo, iodo, methanesulfonyl, toluenesulfonyl and the like. The base is a mild one such as K ₂ CO ₃ , Na ₂ CO ₃ ,
MgSO ₄ or quaternary ammonium hydroxides such as tetrabutylammonium hydroxide or benzyltriethylammonium hydroxide or mixtures thereof. The reaction is carried out in an inert organic solvent such as acetone, acetonitrile, methylene chloride, dimethylformamide, dimethylacetamide, methanol, ethanol, isopropanol, diglyme, or the like. It is also possible to use sodium hydride or potassium hydride as the base in an anhydrous, aprotic organic solvent, or a strong base such as NaOH or KOH.
as a highly concentrated solution in a phase change solvent system e.g. _CH2
Quaternary ammonium halides, sulfates or hydroxides as phase transfer catalysts in Cl ₂ /H ₂ O,
For example, this can be accomplished by adding tetrabutylammonium chloride, cetyltrimethylammonium bromide, benzyltriethylammonium chloride, or the like. The reaction of the formula involves the attachment of substituents R ³ , R ⁴ and/or R ⁵ into the compound of the formula as a final step (or conversion from a precursor group) in place of the substituents present in the compound of the formula. It is also possible to change it so that That is, for example, a compound in which R ⁵ is hydrogen is chlorinated to produce a compound in which R ⁵ is chloro. Similarly, if R ⁴ of the compound is, for example -
It can be NO ₂ , -NHCOR or -N=CHN(R) ₂ and R can be (lower) alkyl. -
The NO ₂ groups are reduced to amino groups in the next step or -
NHCOR or -N=CHN(R) ₂ is hydrolyzed to an amino group. In the present invention, the use of organic solvent soluble tetra-substituted ammonium salts is preferred as an example for one of the preferred compounds of the formula. In the first step, compound a is dissolved in aqueous sodium hydroxide and treated with 1 equivalent of tetrabutylammonium bromide. The quaternary ammonium salt a precipitated from the solution is collected by filtration. This is then reacted with the desired alkylating agent in an inert organic solvent such as dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, CHCl ₃ , dimethylsulfoxide or diglyme to produce the desired product a. An intermediate of formula a may be, for example, the commercially available metoclopramide having the formula (Metoclopramide) may be demethylated by methods well known to those skilled in the art. Suitable reaction methods include thioalkoxides or thioaryloxides such as NaSC ₂ H ₅ , in inert solvents such as dimethylformamide or dimethylsulfoxide,
KSC ₂ H ₅ , LiSC ₂ H ₅ or or by reaction with NaOH or KOH in a solvent such as ethylene glycol, propylene glycol or diglyme or by reaction with 48% aqueous hydrobromic acid. Preferred in the present invention is dimethylformamide.
Demethylation _{using NaSC2H5} . It will be appreciated that direct addition of certain 2-substituents to compound a is difficult without a protecting group introduction and deprotection scheme. On the other hand, the 2-substituents added initially can be modified in the next step. By way of example only, various conversions can be carried out using compound b of the following formula (another preferred compound of the invention) (see the formula below). In an alternative method for the preparation of compounds of the formula, the reaction is carried out to introduce the desired substituted carboxamide group in the 1-position of the compound of the formula with the desired 2-substituents. There are several variations to this reaction procedure, as shown in steps 2a to 2h in Reaction Scheme 2 below. The above reaction is described in detail in British Patent No. 1449524 (published September 15, 1976) using various disulfide and phosphorus compounds. heating the starting material and the amine to about 100°C;
If P ₂ O ₅ is added at that temperature, the temperature will drop to about
The temperature rises to 150℃. This operation is covered by British Patent No. 1441352
No. (published June 30, 1976) in the specification. In the above reaction, the amino substituent at position 4 must be protected by a suitable amide group, such as acetamide hair sylation. After introduction of the 1-substituent, the 4-acetamide group is converted to an amino group by alkaline hydrolysis. Variations on this operation are described in British Patent No. 1395132 (published 21 May 1975). There is a modification of (d) above for this reaction, which is described in British Patent No.
It is described in No. 1395131 (published on May 21, 1975). The above operating method and its variations are covered by British Patent No. 1409686.
issue (published October 15, 1975). The above operating method is described in Japanese Patent Application Publication No. 51-026840 (published on March 5, 1976). In the procedure described above, the 4-amino substituent is protected by acylation, e.g., by formation of an acetamide group, and then hydrolyzed to the free amino group in the final target compound. Regarding the method and its modifications, Japanese Patent Application Publication No. 47-18652 (published September 16, 1972)
There is a description in the official bulletin. The above operating method and its variations are covered by Belgian patent no.
It is described in the specification of No. 692670 (published on July 17, 1967). Effects of the Invention The physiology and neuropharmacology of emesis, and especially chemotherapy-induced emesis, are still not completely understood.
The control mechanism of emesis consists of two specific units within the bone marrow: the emetic center and the chemoreceptor zone (CTZ). The emetic center is the ultimate general passageway for all emetic stimuli and lies within the reticular formation outside the fourth ventricle. CTZ also appears to be present in the floor of the fourth ventricle, the area postrema, and is activated by chemical irritants in the blood or cerebrospinal fluid. When stimulation occurs, receptors such as CTZ
Dopamine receptors within the body generate impulses that are transmitted to the vomiting center, causing vomiting. Reflex-induced emesis can also be caused by hypersensitivity of the gastrointestinal tract or stimulation of receptors within the central nervous system. The cerebral cortex is believed to be another source of vomiting. It is therefore clear that the well-known problem of anticipatory emesis in patients receiving chemotherapy is not related to exogenous chemical stimuli. Anticipatory emesis is believed to be mediated initially by the brain cortex, which then stimulates emetic centers within the bone marrow. There are currently a number of anti-emetic drugs such as metoclopramide, bromopride, alizapride,
Clebopride, domperidone and nabilone are commercially available. Metocloporamide is the most prominent compound and is widely used in combination with cisplatin, which is an effective chemotherapeutic agent but is highly emetic. Substituted benzamide antiemetics currently on the market are generally dopaminergic antagonists and are believed to exert antiemetic activity by blocking dopamine receptors within the CTZ. Screening tests for potential anti-emetic agents are historical methods that include tests to measure dopaminergic antagonists, such as the in vitro spiperone binding test and the attenuation test of apomorphine-induced emesis in dogs or cats. Ta. The various primary effects of known substituted benzamide antiemetics are based on their dopamine blocking effects and include akathisia, acute ataxia, parkinsonian signs, and tardive dyskinesia, often affecting the nervous system. Associated with depression. Although compounds of the formula of the present invention are effective anti-emetic agents, in vitro tests (spiperone binding test)
and is not a dopaminergic antagonist as demonstrated by in vivo studies (dog apomorphine emesis study). That is, the compound of the formula has good anti-emetic activity (especially anti-chemotherapy-induced emetic activity) with a high degree of specificity and is prone to side effects that are more likely to occur with dopaminergic antagonists of substituted benzamide anti-emetic agents. (For example, the trend as described above) is not shown. Commercially available substituted benzamide anti-emetics (e.g. metoclopramide) also have gastric motor activity and are used for the treatment of diseases associated with impaired gastrointestinal motility, such as delayed gastric emptying, dyspepsia, flatulence, reflux in the esophagus and similar conditions. It is useful for Some of the compounds of the formula have been shown to exhibit similar activity to metoclopramide in the stimulated guinea pig ileum test, which is a standard screening test for gastric motor activity (Table 2). Furthermore, because the compounds of formula are not dopaminergic antagonists, the compounds of formula do not have the aforementioned side effect tendencies of commercially available substituted benzamides such as metoclopramide or clebopride. Biological Test Method A 3H-Spirone Excursion This test method consists of homogenization of rat brain striatum.
It is used for the detection of compounds capable of deviating radioactive spiperone ligands in vitro using a radioactive spiperone ligand.
It is used to identify compounds that exhibit affinity for dopaminergic (D ₂ ) receptors. A rat (150±10 g; Charles River strain) was decapitated, and the striatum was cut out and frozen on dry ice. The tissue was stored at -180°C before use. Striatal homogenate (Brinkmann Polytron) in cold HEPES. KOH buffer (final pH = 7.4).
Centrifugation was performed at 39000×G. The supernatant was discarded and the pellet was resuspended in Hepes KOH buffer and centrifuged again as described above. The supernatant was discarded again and the pellet was washed with 0.1% (w/v) ascorbic acid, 10 μM pargyline, 120 mM NaCl, 5 mM
Contains KCl, 2mM _CaCl2 and 1mM _MgCl2
The pellet was suspended in a buffer consisting of 50 mM Hepes KOH (concentration of 1 g of wet tissue pellet per 100 ml of buffer mixture). A test to determine the inhibitory concentration 50 ( _IC50 ) of a compound of formula and a reference compound versus ^3H -spiperone was conducted as follows. 100 μL buffer mix (for total binding), 100 μL buffer mix plus 100 μL of ^10-4 MD
Each tube was set up with 100 μL of a buffer mixture containing (+)-butaclamol (for blinding, i.e., non-specific binding) or 10 ⁻⁷ , 10 ⁻⁶ or 10 ⁻⁵ M of the test compound. . Add 3H-spiperone (New England Nuclear) in a buffer mixture (2000 c.pm in a thermostatic mixture) to each test tube.
100 μL of the solution and 800 μL of the striatal tissue suspension were added. The contents of these test tubes were then diluted to 1 mL with a buffer mixture to give final concentrations of test compounds of 10 ^-8 , 10 ^-7 and 10 ^-6 M and approximately 100 pM of 3H-.
I gave him spiperone. These samples were heated to 37 °C for 15
Incubated for minutes, filtered under vacuum on a glass fiber filter and counted by liquid scintillation spectrometry. For each test compound, the IC ₅₀ did not reach the maximum concentration of the test compound (10 ^-6 μM = 1000 nM), so the results in Table 2 are > 1000 nM.
It is stated that. If the IC ₅₀ of the control compound reaches (or exceeds) the original concentration, the measured concentration is 1/4, 1/2, 1, 2 (from the original concentration).
The test was then repeated by multiplying by 4 to get closest to the IC ₅₀ to more accurately measure the IC ₅₀ . These latter results are shown in Table 2. All samples were tested in duplicate. B. Antagonism of apomorphine-induced emesis in dogs Non-fasted dogs of both sexes were used as test subjects. Each of the test compound and apomorphine was administered subcutaneously as an aqueous solution, and the test compound was administered 30 minutes before the apomorphine administration. Dogs were observed for vomiting or complete prevention of vomiting (quantitative response) after 60 minutes of apomorphine administration. The single dose of apomorphine was 0.3 mg/Kg. Since the test compound essentially lacks apomorphine antagonist, the dose was 3 mg/Kg. 50% antagonism (prevention of emesis) was not achieved at this dose. Control compounds such as metoclopramide,
Alizapride, klebopride, and domperidone have dopaminergic antagonists, so the ED ₅₀ was measured at low doses of the standards and is shown in Table 1. All tests were conducted on at least two dogs. C. Antagonism to cisplatin-induced emesis in white ferrets Adult male castrated white ferrets (1.0-1.5 Kg) were anesthetized with pentobarbital sodium (30 mg/Kg, ip). The ventral and vertebral areas of the neck were shaved and a 3 cm incision was made. The left jugular vein was exposed and ligated at the cranial end with silk suture. The endogenous catheter is 18 cm long.
2 cm of polymeric silicone (Silastic) tubing (0.020 inch (0.05 cm) ID x 0.037 inch (0.09 cm) outside diameter) filled with heparin (1000 units/ml).
polyethylene sleeve
[0.045 inch (0.114 cm) inner diameter x 0.062 inch (0.157 cm) outer diameter], 23 gauge (guage) on both ends
A 1 inch (2.54 cm) needle was used to seal the exposed end. The jugular vein was slightly incised, the catheter was inserted, and the free end was placed through a subcutaneous 13 gauge x 5 cm trochar and attached to the scruff of the neck using silk sutures. Tested white weasels were placed in individual cages and allowed to recover for 2-4 days prior to testing. 5 minutes before and after administration of cisplatin on the day of the test.
After 90 minutes, the test compound (3 mg/
ml or 1 ml/Kg) was given by intravenous injection. A cisplatin solution was prepared by adding physiological saline at 70°C, stirring, and dissolving it by sonication. The obtained solution (4 mg/ml) was kept at 40 °C,
Intravenous injection (12ml/Kg) was given via catheter.
After administration of cisplatin, the white weasel was observed continuously for 4 hours and the state of vomiting (episode) was recorded. 1
Two or more episodes of vomiting within minutes were considered a single episode. At the end of the experiment, the albino was euthanized by intravenous injection of T-61 to confirm normal placement of the catheter. The test results are shown in Table 1 as % prevention (graded response) with saline treatment as a control. D. Testing of gastric motor activity A number of compounds of the invention were found to increase contractions in guinea pig region-stimulated ileal specimens. This activity is believed to correlate with gastrokinetic (prokinetic) activity, ie gastric motility and gastric emptying in vivo. Healthy male guinea piglet (Hartly; Charles River)
(weighing 300-400 g) were killed by cervical dislocation.
The distal ileum was removed after discarding the 10 cm long segment closest to the ileocecal border. 3
Sections ~4 cm long were placed in a 20 ml organ bath containing Krebs' physiological buffer.
I put it in the bath). Add this buffer to 95% O ₂ -5
Bubbled with % _CO2 and held at 37°C. The resting tension was adjusted to 1.0 g and allowed to equilibrate for 15 minutes without stimulating the tissue. Platinum wire (cathode) through the lumen to provide electrical stimulation
was pulled, another platinum wire (anode) was attached to the glass rod, and the muscle was suspended from the glass rod. The amount of voltage required to reach the maximum twitch in one delivery every 10 seconds, lasting 0.5 msec, with a single pulse.
Tissues were stimulated coaxially at 1.5x volume. After a 15 minute equilibration period (without stimulation), the stimulator (Grass S88 Stimulator) was activated to allow the tissue to stabilize for approximately 1 hour or until the twitch height remained steady; Washing was performed every 20 minutes. Force displacement device (force displacement transmission device) that controls ileal contractions
isometrically recorded using a transducer (Grass ETO3C) and expressed (displayed) on a dynograph recorder.
did. Some of the compounds of the formula showed increased contractions in regionally stimulated guinea pig ileal specimens. These are shown in Table 2. The table includes average maximum increase rate %, minimum effective shrinkage (μm), effective concentration ₃₀ (EC ₃₀ ) and, in some cases,
The effective concentration ₃₀ (EC ₃₀ ) (μM) is listed.

【table】

[Table] (Note) * Number of animals = 4

Tables 1 and 2 show that the compounds of the formula have useful antiemetic and gastric motor activity, and Table 1 shows that the compounds exhibit essentially no dopaminergic antagonism. This shows that it does not have the tendency to cause side effects of the substituted benzamide anti-emetic and gastric motility agents currently on the market. Compounds of formula may be administered orally, parenterally or by suppository. For use as an anti-emetic in patients taking cancer treatment chemicals such as cisplatin, large amounts of parenteral solutions (e.g. dextrose - 5% in water, dextrose - 0.45% in saline, Ringer's injection or lactate) are recommended. It is preferably administered as an intravenous infusion diluted in Ringer's Injection (5%). When used as a gastric motility imparting agent, it is preferable to administer the compound orally if the symptoms are not severe. If the symptoms are severe, it is preferable to start treatment with intramuscular or intravenous injection until the serious symptoms subside, and then oral administration should be investigated. The dosage of the compound of the formula depends on the intended use (anti-emetic or gastric motility), the particular compound to be administered, the age, weight and general health of the patient, and the severity of the disease. It is within the scope of the doctor's judgment. If taken for gastric motility, the compound of formula may be administered in doses of 1 to 100 mg, preferably 5 to 50 mg, 2 to 5 times a day, preferably 4 times a day, e.g. before meals and at bedtime. It is generally administered occasionally. For the prevention of nausea and vomiting associated with emetic chemical cancer treatments, compounds of the formula
mg/Kg, preferably at a dosage of 0.5-10 mg/Kg.
It is generally administered several times a day (diluted with a large volume of parenteral solution). The particular dosage used will depend on the factors mentioned above, as well as on the emetic properties of the chemical cancer treatment. Typically, the first dose is given, for example, 30 minutes before administration of the chemical cancer treatment;
It is then administered until nausea and vomiting subside or are alleviated, eg, 12 to 24 hours or more, 2 to 8 hours after each administration of the chemotherapeutic agent. Preferred for oral administration are tablets and capsules in single dosage form with the addition of conventional excipients such as binders, fillers, tabletting lubricants, disintegrants, wetting agents and the like. Good too. If desired, the tablets may be coated with a film according to conventional techniques. Oral solutions may be in the form of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or as dry products for reconstitution with water or other suitable vehicle before use. could be. Liquid products may contain conventional additives such as suspending agents, emulsifying agents, non-aqueous media (including edible oils), preservatives and flavoring and/or coloring agents. For parenteral administration, the compound of the formula is combined with a sterile excipient. Depending on the excipient and active ingredient concentration, the dosage form can be a solution or a suspension. The excipient is usually sterile water, at least in large part, but saline solutions, glucose solutions and the like may also be used. Injectable suspensions may also be employed, in which case conventional suspending agents may be employed. Conventional preservatives, buffers and the like may also be added to parenteral preparations. For solid dosage forms, the free base or salt of a compound of formula may be used. In the case of aqueous solutions, whether oral or parenteral, the use of salts of compounds of formula is often preferred since the solubility of the salts in aqueous solutions is usually greater. It is particularly advantageous for the above-described pharmaceutical compositions to be formulated in unit dosage form for ease of administration and uniformity of dosage. Unit dosage form refers to physiologically discrete units suitable for single administration, each unit containing a predetermined amount of active ingredient metered to produce the desired efficacy in association with the desired pharmaceutical carrier. The present invention also includes pharmaceutical compositions for alleviating nausea and vomiting, which compositions include an anti-emetic effective amount of at least one compound of formula plus a salt, hydrate or solvate thereof. Contains a pharmaceutically acceptable carrier. The present invention also includes pharmaceutical compositions for the treatment of diseases associated with impaired gastric motility, the compositions comprising at least one compound of formula or a salt, hydrate or solvent thereof. and a pharmaceutically acceptable carrier. The present invention also relates to a method for alleviating nausea and vomiting in a warm-blooded mammal, where necessary, the method comprising administering to the animal at least one compound of the formula or a salt, hydrate or salt thereof. comprises an anti-emetic effective amount of the solvate in a pharmaceutically acceptable carrier. The present invention also relates to a method of treating diseases related to impaired gastric motility in warm-blooded mammals, the method comprising: The method includes administering to the animal an effective amount of gastric motility facilitation in a pharmaceutically acceptable carrier. As used herein, the term "(lower) alkyl" refers to a straight or branched alkyl chain having 1 to 6 carbon atoms, and "(lower) alkynyl" refers to a straight or branched alkyl chain having 1 to 6 carbon atoms.
~6 alkenyl or alkynyl chains. All temperatures are expressed in degrees Celsius. Production example 1 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide A 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxy Benzamide Hydrochloride Sodium hydride (60%) in DMF (1275ml)
A stirred suspension of (57.44 g, 1.436 mol) was cooled (<
10°) To this was added dropwise a cold solution of ethanethiol (89.22 g, 1.436 mol) in DMF (250 ml). After hydrogen generation has finished, 4-amino-5-
Chloro-N-[2-(diethylamino)ethyl]-
2-methoxybenzamide (287.0g, 0.957mol)
(manufactured according to US Pat. No. 3,357,978 [1965]) and the mixture was heated at 100-105°C in an oil bath for 90°C.
It was heated for a minute. The solvent was removed under reduced pressure and the residue was partitioned between methylene chloride (800ml) and water (400ml). The aqueous layer was further washed with methylene chloride and the organic extracts were combined and washed once again with water (150ml).
The aqueous layers were combined, cooled in an ice bath, and treated with concentrated hydrochloric acid (200ml). After 20 minutes, the precipitate was collected by filtration, sucked for a while, made into a slurry with methanol (500 ml), and filtered again. When the product is vacuum dried, it weighs 302.3g.
(98%) of the title compound was obtained as a pale beige solid (mp 235-237°C). Analysis Calculated value for C ₁₃ H ₂₀ ClN ₃ O ₂・HCl: C, 48.46; H, 6.57; N, 13.04; Cl, 22.00 Experimental value: C, 47.67; H, 6.73; N, 12.84; Cl, 21.43 B 4 -Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride ( 3.0 g, 0.0093 mol) was added to concentrated ammonium hydroxide (6 ml) with stirring and the mixture was stirred for a further 5 minutes before 3-4 ml of water was added and then stirred for 5 minutes. After filtration, the solid was washed twice with 3 ml of water and dried to yield 2.37 g of the listed compound (mp134~
136℃) was obtained. The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values δ: 7.26 (s, 1H); 6,90 (s, 1H);
6.14 (s, 1H); 4.39 (s, 2H); 3.40 (s, 2H);
2.60 (multiplet, 6H); 1.06 (t, 6H) was given. Production Example 2 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (alternative method) 4-amino-5-chloro-N-[2-(diethylamino)ethyl]- 2-methoxybenzamide (29.5 g, 0.1 mol), sodium hydroxide tablets (4.0 g,
0.1 mol) and 1,2-propanediol (70 ml)
The mixture was stirred and heated under reflux for 20 hours, then concentrated under vacuum. The residue was treated with 1NHCl (100ml) and concentrated again under vacuum. The residue was chromatographed on silica using a solvent system of methylene chloride (90), methanol (10), ammonia (0.5). Appropriate fractions were collected and concentrated under vacuum and the residue was crystallized from ether to yield 9.3 g of product. This was dissolved in hot water and the solution was filtered over activated carbon. When the filtrate was cooled and filtered, a yellow-brown compound (mp 126-7°C) was obtained.
). Analysis Calculated value for C ₁₃ H ₂₀ ClN ₃ O ₂ : C, 54.64; H, 7.75; N, 14.70 Experimental value: C, 54.44; H, 7.15; N, 14.65 Production example 3 4-amino-5-chloro-N -[2-(diethylamino)ethyl]-2-hydroxybenzamide tetra-n-butylammonium salt 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride ( Tetra-n
-Butylammonium hydrogen sulfate (10.6g, 0.031
mmol) under stirring. The crystals were collected, washed with water, and dried (14.7 g, 87%). Reconsolidation from ethyl acetate produces the listed compound containing 0.5 moles of water (mp136.5
~138.5°C) was obtained. Analysis Calculated value for C ₂₉ H ₅₅ ClN ₄ O ₂・0.5H ₂ O: C, 64.95; H, 10.53; N, 10.44; H ₂ O, 1.71 Experimental value: C, 65.06; H, 10.42; N, 10.40; H ₂ O, 1.41 Example 1 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxyethoxy)
-Benzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (2.50 g, 7.76 mmol), 2-chloroethyl methyl ether (1.47 g, 15.5 mmol), A mixture of potassium carbonate (2.14 g, 15.5 mmol) and sodium bromide (0.80 g, 7.76 mmol)
ml of dimethylformamide (DMF) under reflux for 4 hours. The DMF was distilled off under vacuum and the residue was redissolved in methylene chloride and washed with water and dilute sodium hydroxide solution. After evaporation of the solvent, the product was chromatographed using a gradient elution with methanol-methylene chloride containing 0.25% _NH4OH . By collecting appropriate fractions and evaporating them,
2.34g (87.6%) of a cream solid was obtained. Recrystallization of the residue from ethyl acetate gave the title compound as a white solid (mp 108-110.5°).
NMR spectrum (90MHz) in CDCl ₃ gave the following resonance values: δ8.19 (s, 1H); 6,35 (s,
1H); 4.5 (bs, 2H); 4.2 (m, 2H); 3.8 (m,
2H); 3.5 (m, 2H); 3,49 (s, 3H); 2.59 (m,
6H); 1.02 (t, 6H). Analysis Calculated value for C ₁₆ H ₂₆ ClN ₃ O ₃ : C, 55.89; H, 7.62; N, 12.22; Cl, 10.31 Experimental value: C, 55.66; H, 7.66; N, 12.15; Cl, 10.35 Example 2 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2(2-hydroxyethoxy)
-Benzamide The general procedure described in Example 1 was repeated, but using 1.50 (18.62 mmol) of 2-chloroethanol instead of 2-chloroethyl methyl ether. The crude product was transferred onto 50 g of silica gel (230-400 mesh).
Purification was by flash chromatography using a methanol-methylene chloride gradient elution containing 0.25% ammonia. After collecting the appropriate fractions and reconsolidating the solid residue from acetonitrile,
1.30g (42.5%) of listed compound (mp144-146.5
°C) was obtained. NMR spectrum (90MHz) in DMSO/ _CDCl3 gave the following resonance value: δ8.1
(s, 1H); 6,4 (s, 1H); 4.75 (bs, 2H);
4.05 (m, 4H); 3.6 (m, 2H); 2.7 (m, 6H); 1.1
(t, 6H). Analysis Calculated value for C ₁₅ H ₂₄ ClN ₃ O ₃ : C, 54.62; H, 7.33; N, 12.74; Cl, 10.31 Experimental value: C, 54.67; H, 7.88; N, 12.92; Cl, 10.69 Example 3 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2,2-dimethoxyethoxy)benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxy Benzamide hydrochloride (8.06 g, 0.025 mol), chloroacetaldehyde dimethyl acetal (6.23 g; 0.05 mol),
A mixture of potassium carbonate (6.91 g, 0.05 mol) and sodium bromide (2.57 g, 0.025 mol) was stirred in 100 ml of dry DMF under reflux for 8 hours. After refluxing for 4 hours, alkylating agent (6.23 g, 0.05
mole) was added. Filter this mixture under vacuum
DMF was distilled off. The oily residue was redissolved in methylene chloride and washed sequentially with water, 1.0N aqueous NaOH, water, and saturated NaCl solution. The solvent was evaporated and the product was further purified by chromatography using a methanol-methylene chloride gradient containing 0.25% ammonia. Appropriate fractions were collected and evaporated to give a yellow residue. Reconsolidation from ethyl acetate-petroleum ether gave the title compound as a white solid (5.5 g (59.8%), mp 64-67°C).
NMR spectrum (90MHz) in CDCl ₃ gave the following resonance values: δ8.19 (s, 1H); 6,32 (s,
1H); 4.83 (t, 2H); 4.42 (bs, 2H); 4.08 (d,
2H); 3.55 (m, 2H); 3.50 (m, 2H); 2.41 (m,
6H); 1.1 (t, 6H). Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₄ : C, 54.61; H, 7.55; N, 11.24; Cl, 9.48 Experimental value: C, 54.21; H, 7.42; N, 11.07; Cl, 10.34 Example 4 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyethoxy)
-Methyloxy]benzamide Sodium hydride (60%) in 5 ml dry DMF
(0.34 g, 0.014 mol) suspension was stirred well, and 15 ml of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.57 g, 0.012 mol) was added to the suspension. was dissolved in dry DMF and added over a period of 18 minutes at room temperature. The mixture was then stirred for an additional hour until it became an essentially clear liquid. To this was added dropwise a solution of 2-methoxyethoxymethyl chloride (1.74 g, 0.014 mol) in 5 ml of dry DMF. After stirring for a further 4 hours at ambient temperature the mixture was concentrated in vacuo and the residue partitioned between water (200ml) and methylene chloride (75ml). The aqueous phase was extracted twice with 75 ml of methylene chloride. The organic phase is collected, washed three times with 50 ml of 10% aqueous sodium hydroxide and three times with brine, dried over sodium sulfate, filtered and concentrated under vacuum to give 4.26
A residue of g was obtained. This was reconstituted from ether to yield 2.53 g of the title compound (mp 79-81°C). NMR spectrum in CDCl ₃ (90MHz)
gave the following resonance value: δ8.18(s,2H); 6.61
(s, 1H); 5.40 (s, 2H); 4.40 (s, 2H); 3.84
(m, 2H); 3.50 (m, 4H); 3.44 (s, 3H); 2.56
(m, 6H); 1.04 (t, 6H). Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₄ : C, 54.60; H, 7.56; N, 11.24 Experimental value: C, 54.16; H, 7.75; N, 11.16 Example 5 4-Amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(2-propanon-1-yl)-oxybenzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride A stirred suspension of potassium carbonate (5.0 g, 1.6 mmol) and potassium carbonate (10.62 g, 77 mmol) in DMF (25 ml) was added to chloroacetone (90%
After stirring vigorously for 5 hours, the mixture was poured into water (130 ml), filtered and dried to yield 4.57 g of crude product. This was dissolved in methylene chloride, filtered through a short alumina column, concentrated and the residue reconsolidated from toluene to give 4.16 g (78%) of the title compound as a white solid (mp 105-106.5°C). . in CDCl ₃
NMR spectrum (90MHz) gave the following resonance values: δ8.44 (s, 1H); 8.24 (s, 1H); 6.16 (s,
1H); 4.72 (s, 2H); 4.4 (s, 2H); 3.6 (m,
2H); 2.68 (m, 6H); 2.28 (s, 3H); 1.08 (t,
6H). Analysis Calculated value for C ₁₆ H ₂₄ ClN ₃ O ₃ : C, 56.21; H, 7.08; N, 12.29; Cl, 10.37 Experimental value: C, 56.14; H, 6.97; N, 12.29; Cl, 10.29 Example 6 4- Amino-2-(2-phenyl-2-oxoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide Sodium hydride (320 mg of 60%, 8 mmol, washed with n-pentane) ) to DMF (15
ml) was stirred, and 4-amino-5-chloro-N-[2-(diethylamino)
Ethyl]-2-hydroxybenzamide hydrochloride (1.289 g, 4 mmol) was added and the mixture was stirred for 20 minutes before chloroacetophenone (619 mg, 4 mmol) was added.
mmol) was added. The mixture was stirred for 4 hours and poured into ice-cold water (50ml) to precipitate a solid.
This was isolated by filtration, dried and reconstituted from methanol to give 810 mg (50%) of the title compound as a white solid (mp 105-4°C). CDCl ₃
The middle NMR spectrum (90MHz) gave the following resonance values: δ8.64 (bs, 1H); 8.2 (s, 1H); 8
(m, 2H); 7.6 (m, 3H); 6.22 (s, 1H); 5.36
(s, 2H); 4.4 (s, 2H); 3.52 (m, 2H); 2.64
(m, 6H); 1.01 (m, 6H). Analysis Calculated value for C ₂₁ H ₂₆ ClN ₃ O ₃ : C, 62.45; H, 6.49; N, 10.40; Cl, 8.78 Experimental value: C, 62.54; H, 6.39; N, 10.83; Cl, 8.68 Example 7 A 4 -amino-2-(butan-2-one-3-
Sodium hydride (40 mg of 60%, 1 mmol, washed with n-pentane) in DMF
The 4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-(2-propan-1-yl)-oxybenzamide (0.349 g,
1 mmol) was added under nitrogen flow. The mixture was stirred until hydrogen evolution ceased, then iodomethane (0.07 ml, 160 mg, 1.1 mmol) was added.
Stirring was continued for an additional hour. The mixture was partitioned between water and methylene chloride, the organic phase was washed with water, dried, concentrated and the residue was dissolved on inert silica in methylene chloride (100), methanol (4.5), ammonia (0.5). Chromatography was performed using a solvent system. Collection of appropriate fractions gave 160 mg of the title compound as a viscous oil. in CDCl ₃
The NMR spectrum (90 MHz) gave the following resonance values: δ 8.24 (s, overlapping a wide singlet, 2H); 6.08 (s, 1H); 4.70 (q, J = 5.4
Hz, 1H); 4.44 (s, 2H); 3.56 (m, 2H); 2.62
(m, 6H); 2.2 (s, 3H); 1.6 (d, J=5.4Hz,
3H); 1.04 (t, 6H). B 4-amino-2-(butan-2-one-3-
yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.94g , 6 mmol) and potassium carbonate (4.16 g, 30 mmol) in DMF (10 ml) were stirred and 3-chloro-2-butanone (0.95 g, 8.9 mmol) was added to the mixture. The mixture was stirred for 3 hours, poured into water, and extracted with methylene chloride. The extract was washed with water, dried and concentrated under reduced pressure. Dissolve the residue in 1-propanol and 2NHCl
Treatment with and concentration gave an oily residue. This product was crystallized with acetone and 2-
Recrystallization from propanol gave 1.4 g of the title compound (mp 98°C) as a hemihydrate. Analysis Calculated value for C ₁₇ H ₂₆ CIN ₃ O ₃・HCl・0.5H ₂ O: C, 51.00; H, 6.80; N, 10.50; Cl17.71 Experimental value: C, 51.26; H, 6.86; N, 10.51; Cl, 17.38 C 4-amino-2-(butan-2-one-3-
yl)oxy-5-chloro-N-[2-(diethylamino)-ethyl]benzamide hydrochloride 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (19.4 g, 60 mmol) and potassium carbonate (41.6 g, 0.3 mol) and sodium iodide (10
g) was stirred and suspended in DMF (100 ml), and 3-chloro-2-butanone (9.5 g, 89 mmol) was added to this.
and stirred the mixture vigorously for 2 hours.
Heat to ˜80° C. then cool and partition between water and methylene chloride. The organic phase was washed with water, dried and concentrated. Treatment of the residue with 2NHCl, azeotrope with n-propanol and crystallization from acetone yielded 19.0 g (81%) of the title compound (mp 177-179°C).
was gotten. Example 8 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(3-methyl)-5-hexen-2-one-3-yl)oxybenzamide Sodium hydride (60 0.2 g, 5 mmol, washed with n-pentane) was stirred and suspended in DMF (10 ml), and 4-amino-2-(butan-2-one-3-yl)oxy-5- Chloro-N
A solution of -[2-(diethylamino)ethyl]benzamide (1.78 g, 5 mmol) in DMF (10 ml) was added dropwise. After hydrogen evolution had ceased, allyl bromide (690 g, 5.7 mmol) was added and the mixture was stirred for 72 hours before being partitioned between water and methylene chloride. The organic phase was washed with water, dried,
Concentrated. The residue was purified on inert silica with methylene chloride (100), methanol (4), ammonia (0.5).
It was subjected to chromatography using Collection of appropriate fractions gave 0.58 g of crude product as a viscous oil. This was crystallized from ether to give the title compound as a white solid (mp 138-140°C). The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ8.24 (s, 1H); 8.0 (bs, 1H); 5.92
(s, 1H); 5.9-5.0 (m, 4H); 4.38 (bs, 2H);
3.58 (m, 2H); 3.0-2.3 (m, 8H); 2.28 (s,
3H); 1.62 (s, 3H) 1.04 (t, 6H) was given. Analysis Calculated value for C ₂₀ H ₃₀ ClN ₃ O ₃ : C, 60.67; H, 7.68; N, 10.61 Experimental value: C, 60.34; H, 7.67; N, 10.54 Example 9 4-Amino-5-chloro-2- (Cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (6.4 g, 20 mmol) and potassium carbonate (13.8 g, 0.1 mol) in DMF (34 ml) and 2-chlorocyclohexanone (3.8 g,
28.6 mmol) was stirred for 4 days and then partitioned between water and methylene chloride. The organic phase was washed thoroughly with water, dried and concentrated. The residue was chromatographed on inert silica using methylene chloride (100), methanol (4), ammonia (0.5) as the solvent system. Appropriate fractions were collected and further purified by low pressure liquid chromatography to yield 1.0 g of the title compound as a colorless foam.
NMR spectrum (90MHz) in CDCl ₃ gave the following resonance values: δ8.4 (bs, 1H); 8.16 (s,
1H); 6.14 (s, 1H); 4.7 (m, 4H); 4.3 (s,
2H); 3.56 (q, J = 7.2Hz, 2H); 2.62 (m,
6H); 2.3-1.4 (m, 8H); 1.04 (t, J=7.2Hz,
6H) was given. Analysis Calculated value for C ₁₉ H ₂₈ ClN ₃ O ₃ : C, 59.75; H, 7.39; N, 11.00; Cl, 9.29 Experimental value: C, 59.40; H, 7.32; N, 10.94; Cl, 8, 99 Example 10 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-hydroxyimino)
-propan-1-yl]oxybensamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2- in methanol (20 ml)
Propanon-1-yl)oxybenzamide (1.0
g, 2.9 mmol) and hydroxylamine hydrochloride (0.3 g, 4.3 mmol) was heated under reflux for 10 minutes and then concentrated under vacuum. The residue was partitioned between aqueous sodium carbonate and methylene chloride. The organic phase was dried and concentrated, the residue was dissolved in methanol, treated with activated carbon and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from ethyl acetate-n-pentane to yield 0.58 g (56%) of the title compound (containing 0.25 mole water of crystallization) (mp 112-113°C). . NMR spectrum in CDCl ₃ (90M
Hz) is the following resonance value: δ9.16 (s, 1H); 8.32 (s,
1H); 6.36 (s, 1H); 4.72 (s, 2H); 4.36 (s,
2H); 3.68 (m, 2H); 2.68 (m, 6H); 1.92 (s,
Overlay on wide absorption: 4H); 1.12 (t;
6H) was given. Analysis Calculated value for C ₁₆ H ₂₅ ClN ₄ O ₃ 1/4 H ₂ O: C, 53.18; H, 7.11; N, 15.50; Cl, 9.80 Experimental value: C, 53.18; H, 7.01; N, 15.36; Cl ,9,52 Example 11 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyimino)-
Propan-1-yl]oxybenzamide The general procedure described in Example 10 is repeated, but using methoxyamine hydrochloride instead of hydroxylamine hydrochloride, and carrying out the reaction at ambient temperature (16 hours), the title compound is Obtained in 70% yield as a white solid (mp 121-123°C) from n-pentane.
NMR spectrum (90MHz) in CDCl ₃ is example 10
similar to the NMR spectrum of but with an additional δ3.92
A singlet in (3H) was added. Analysis Calculated value for C ₁₇ H ₂₇ ClN ₄ O ₃ : C, 55.05; H, 7.34; N, 15.11; Cl, 9.56 Experimental value: C, 54.69; H, 7.48; N, 14.92; Cl, 9, 47 Example 12 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydroxypropan-1-yl)oxybenzamide 4-Amino-5- in absolute ethanol (15 ml)
Chloro-N-[2-(diethylamino)ethyl]-
A mixture of 2-(2-propanon-1-yl)oxybenzamide (1.28 g, 3.7 mmol) and sodium borohydride (80 mg, 2.1 mmol) was added to
After refluxing for a minute, an additional 50 mg (1.3 mmol) of sodium borohydride was added and the mixture was refluxed for 10 minutes. The mixture was acidified with 2NHCl and concentrated under vacuum. The residue was partitioned between water and ether and the ether layer was discarded. The aqueous layer was made basic with Na ₂ CO ₃ and the solid was filtered off to give 0.80 g (77%) of the title compound (mp 149-150° C.). NMR in CDCl ₃
The spectrum (90MHz) has the following resonance value: δ8.48
(bs, 1H); 8.16 (s, 1H); 6.28 (s, 1H); 4.4~
3.4 (m, 7H); 2.64 (m, 6H); 1.26 (d, J = 7.5
Hz, 3H); 1.08 (t; 3H) was given. Analysis Calculated value for C ₁₆ H ₂₆ ClN ₄ O ₃ : C, 55.88; H, 7.62; N, 12.22; Cl, 10.31 Experimental value: C, 56.08; H, 7.65; N, 12.05; Cl, 9, 80 Example 13 4-Amino-5-chloro-2-cyanomethoxy-N-[2-(diethylamino)ethyl]benzamide Stirred suspension of sodium hydride (420 mg of 60%, 10.5 mmol, washed with n-pentane) in 10 ml DMF 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, 5 mmol) was added;
The mixture was stirred for 20 minutes, then cooled in an ice bath and chloroacetonitrile (418 mg, 5.5 mmol) and sodium bromide (100 mg) were added. The mixture was stirred in the cold for 1 hour and then at ambient temperature for 16 hours before the mixture was poured into ice water and the resulting solid was filtered. The product was dissolved in methylene chloride, filtered over alumina, and concentrated under vacuum to give the crude product. This was reconstituted from methanol to give 930 mg (57%) of the title compound as a white crystalline solid (mp 188-189°C).
The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ8.1 (s, 1H); 7.78 (bs, 1H); 6.44
(s, 1H); 4.84 (s, 2H); 4.60 (s, 2H); 3.43
(m, 2H); 2.59 (m, 6H); 1.02 (t; 6H) were given. Analysis Calculated values for C ₁₅ H ₂₁ ClN ₄ O ₂ : C, 55.47; H, 6.52; N, 17.25; Cl, 10.92 Experimental values: C, 55.85; H, 6.59; N, 16.95; Cl, 10, 97 Example 14 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1-cyano)ethoxybenzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2- A mixture of hydroxybenzamide hydrochloride (4.036 g, 12.5 mmol), potassium carbonate (8.56 g, 62 mmol), 2-chloropropionitrile (1.57 g, 17.54 mmol) and sodium iodide (300 mg) was added to DMF (18 ml). Stir in a container and heat at 50℃ for 20 hours, then pour into ice water.
Filtration gave a crude solid. This was dissolved in methylene chloride and filtered over a short alumina column. The filtrate was concentrated and the residue was recrystallized from methylene chloride-ether to yield 3.57 g (84.4%) of the title compound (mp 139-140°C). in CDCl ₃
The NMR spectrum (90MHz) has the following resonance values:
δ8.2 (s, 1H); 7.75 (bs, 1H); 6.28 (1, 1H);
4.97 (q, J=7.0Hz, 1H); 4.5 (bs, 2H); 3.54
(m, 2H); 2.6 (m, 6H); 1.88 (d, J=7.0Hz,
3H); 1.02 (t; 6H) was obtained. Analysis Calculated value for C ₁₆ H ₂₃ ClN ₄ O ₂ : C, 56.71; H, 6.84; N, 16.53; Cl, 10.46 Experimental value: C, 56.63; H, 6.96; N, 16.53; Cl, 9, 64 Example 15 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxy-2-oxoethoxy)benzamide sodium hydride (420 mg of 60%, 10.5 mmol) in DMF (10 ml) 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (1.612 g, 5 mmol) was added to the stirred suspension in
After stirring for 20 minutes, the mixture was cooled with ice water and methyl bromoacetate (832 mg, 5.44 mmol) was added. This mixture was heated in the cold for 20 minutes and then at ambient temperature.
Stir for 10 minutes and then pour into 70 ml of ice-cold water.
The separated solid was filtered and dried to yield 1.58 g of crude product (mp 92-94°C). When this material is reconstituted from methylene chloride-ether, it becomes 1.21 g.
(67.6%) of the title compound was obtained as a white crystalline solid (mp 94-95°C). in CDCl ₃
The NMR spectrum (90MHz) has the following resonance values:
δ8.2 (s, 1H); 6.16 (s, 1H); 4.7 (s, 2H);
4.40 (bs, 2H); 3.86 (s, 3H); 3.54 (m, 2H);
2.6 (m, 6H); 1.04 (t; 6H) was given. Analysis Calculated value for C ₁₆ H ₂₄ ClN ₃ O ₄ : C, 53.70; H, 6.76; N, 11.47; Cl, 9.82 Experimental value: C, 53.57; H, 6.78; N, 11.48; Cl, 9, 91 Example 16 4-Amino-2-(2-amino-2-oxoethoxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide acetate monohydrate 4-amino-5-chloro-N-[2-( diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (2.0 g, 6.2 mmol), potassium carbonate (2.57
g, 18.6 mmol), sodium iodide (0.93 g,
6.8 mmol) and 2-chloroacetamide (0.64
g, 6.8 mmol) was stirred well and heated to 75° C. for 3 hours. The mixture was then concentrated under vacuum and the residue was partitioned between water and methylene chloride. The aqueous phase was extracted twice with methylene chloride and the extracts were combined, washed with excess acetic acid and concentrated under vacuum. The semi-solid residue was treated with methylene chloride (150ml) and filtered to give a colorless solid. When this material is recondensed from acetonitrile, 1.04g (41
%) of the listed compound is an off-white solid (mp116~125
℃) was obtained. The NMR spectrum (90MHz) in D ₂ O has the following resonance value: δ7.8 (s, 1H); 6.26
(1H, s); 4.8 (s, 2H); 3.8 (m, 2H); 3.3 (m
，
6H); 1.95 (s, 3H); 1.3 (t; 6H). Analysis Calculated value for C ₁₆ H ₂₃ ClN ₄ O ₃・CH ₃ CO ₂ H・H ₂ O: C, 48.51; H, 6.94; N, 13.31; Cl, 8.43 Experimental value: C, 48.37; H, 6.88; N , 13.26 ; Cl, 8.32 Example 17 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide The method of Preparation Example 1A was repeated, but 4-amino-
4-Amino-5-chloro-N-[2-(dimethylamino)ethyl]-2-methoxybenzamide (US) was used instead of 5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide. Special No. 1793771
(manufactured by the method described in the specification) was used. The solvent (DMF) was evaporated under vacuum and the residue was treated with carbon dioxide saturated water and methylene chloride, concentrated and extracted with ethanol to give the crude product in 89% yield. This material was washed on a silica gel column with methylene chloride (97), methanol (3),
Chromatography was performed using a solvent system of ammonia (0.3). Appropriate fractions were collected and concentrated under vacuum. Crystallization of the residue from methanol gave the title compound as a colorless solid (mp 163-165°C). Analysis Calculated value for C ₁₁ H ₁₆ ClN ₃ O ₂ : C, 51.26; H, 6.62; N, 16.31; Cl, 13.76 Experimental value: C, 51.46; H, 6.35; N, 16.12; Cl, 13.60 Example 18 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2,2-dimethyl-1,
3-Dioxalan-4-yl)methoxybenzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (3.22 g, 10 mmol), 4-chloromethyl- 2,2-dimethyl-1,3-dioxalan (1.65 g, 10 mmol), potassium carbonate (2.76 g,
20 mmol), sodium bromide (1.03 g, 10 mmol) and 40 ml of DMF was heated under reflux for 20 hours. The DMF was distilled off under vacuum, the residue was treated with water,
Extraction with methylene chloride gave a gummy material. This substance was analyzed using HPLC (High Performance Liquid Chromatography) [Waters Prep].
500, silica cartridge, methylene chloride-2-
Elution with propanol-concentrated ammonia (100:1:0.5)] was used. When appropriate fractions are combined, the listed compound is obtained as a crystalline solid (1.8 g, mp76-78
℃) was obtained. Analysis Calculated values for C ₁₉ H ₃₀ ClN ₃ O ₄ : C, 57.06; H, 7.56; N, 10.51; Cl, 8.87 Experimental values: C, 56.65; H, 7.69; N, 10.46; Cl, 8, 53 Example 19 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(3-methylisoxazol-5-yl)methoxybenzamide 4-amino-5-chloro-N-[2-( 5-Bromomethyl-3-methylisoxazole was added to a solution of the tetrabutylammonium salt of diethylamino)ethyl]-2-hydroxybenzamide (4.82 g, 9.14 mmol) dissolved in 50 ml of acetonitrile, and the mixture was stirred for 1.5 hours. The crystalline product was collected and dried (2.53g). The filtrate was concentrated and the residue was crystallized from ethyl acetate to obtain second crystals (0.51 g) (yield: 87%). Analytical samples were reconsolidated from ethyl acetate. mp109~111℃. Analysis Calculated value for C ₁₈ H ₂₅ ClN ₄ O ₃ : C, 56.76; H, 6.62; N, 14.71; Cl, 9.31 Experimental value: C, 56.78; H, 6.90; N, 14.97; Cl, 9, 40 Example 20 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylthio)-ethoxy]benzamide 4-Amino-5-chloro-N-[2 in dry DMF (60 ml) -(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (10.0 g, 31.06 mmol) (from Preparation 1A), anhydrous potassium carbonate (12.84 g, 93.16 mmol), sodium iodide (4.66 g, 31.06 mmol) and A mixture consisting of 2-chloroethyl methyl sulfide (3.70 ml, 4.10 g, 37.26 mmol) was stirred and refluxed for 10 hours. The solvent was evaporated under reduced pressure and the dark semi-solid was partitioned between water and methylene chloride. The pH of the aqueous layer was brought to 14 by adding sodium hydroxide solution. The mixture was shaken well and separated. The aqueous layer was diluted with methylene chloride.
Extracted twice. The organic solvents were collected, dried over MgSO ₄ and evaporated. The resulting solid was dissolved in 100 ml of warm acetonitrile and added to Darco G-60.
evaporated to 30 ml and stored at -15°C.
Filtration of the solid gave 3.56 g of the title compound as off-white crystals (mp 118-120°C). Analysis Calculated value for C ₁₆ H ₂₆ ClN ₃ O ₂ S: C, 53.76; H, 7.28; N, 11.67; Cl, 9.85; S, 8.91 Experimental value: C, 53.60; H, 7.39; N, 11.69; Cl, 9,47;S,9.43 Example 21 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-methylsulfinyl)ethoxy]benzamide 4-amino-5-chloro-N -[2-(diethylamino)ethyl]-2-[2-methylthio)ethoxy]benzamide (1.0 g, 2.28 mmol) (prepared in Example 20) and 1.4NHCl solution (3.97 ml,
A solution of 5.56 mmol) dissolved in 15 ml of water is
The mixture was stirred at 5° C. and sodium metaperiodate (0.625 g, 2.92 mmol) was added thereto. The mixture, which began to darken after a while, was stirred at 0-5°C for 2 hours. This mixture was then diluted to 50 ml with NaOH
The solution was made alkaline (PH=12). Methylene chloride (50 ml) was added and the mixture was shaken well to separate the layers. The aqueous layer was extracted three times with methylene chloride and the combined organic solutions were dried (over anhydrous _MgSO4 ) and evaporated.
A dark oil (0.96g) was obtained which solidified on standing. The crude product was flash chromatographed on silica, eluting with the solvent CH ₂ Cl ₂ :CH ₃ OH:NH ₄ OH (80:20:0.5).
When appropriate fractions are collected and evaporated, 0.80g (77%)
The compound described above was obtained as a yellow resinous material, which crystallized on standing. mp110~114
℃. Analysis Calculated value for C ₁₆ H ₂₆ ClN ₃ O ₃ S: C, 51.12; H, 6.97; N, 11.18; Cl, 9.43; S, 8.53 Experimental value: C, 50.42; H, 6.94; N, 10.91; Cl, 9.94; S, 8.30 Example 22 4-Amino-2-(2-butanon-3-yl)
Oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride Tetra-n-butylammonium of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide Salt (0.53g,
A solution of 1.0 mmol) in acetonitrile (6 ml) was dissolved in 3-chloro-2-butanone (0.11
ml, 0.12 g, 1.1 mmol) and stirred at 20°C for 16 hours. After distilling off the acetonitrile under reduced pressure, the residue was treated with 10 ml of water and extracted with ethyl acetate. Wash the extract with dilute sodium carbonate solution,
After drying and concentrating, an oily substance remains, which is 1.0ml.
This salt, which was converted to the monohydrochloride salt with 1N hydrochloric acid, was crystallized from 2-propanol-ethyl acetate to give the title compound (mp 176-179°C).
This material was the same as that made in Example 7C. Example 23 A 4-amino-5-chloro-2-(cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl ]-2-Hydroxybenzamide hydrochloride (15 g, 47 mmol) (from Preparation Example 1A), tetrabutylammonium bromide (15 g, 47 mmol), anhydrous potassium carbonate (34.32 g, 0.234 mmol) and 2-chloro-cyclohexanone ( 8.9
g, 67 mmol) in DMF (60 ml).
The mixture was stirred for several days. The reaction mixture was partitioned between water and ethyl acetate. Ethyl acetate solution 0.4NNaOH
and water, and extracted with 1NHCl (50ml). The acidic extract was made basic with saturated sodium carbonate solution and extracted with methylene chloride. The extract is dried, filtered through silica, the filtrate is concentrated,
The concentrate was diluted with pentane. The oily precipitate solidified on standing and was crystallized from toluene (30ml) to give the title compound (mp 96-99°C). Analysis Calculated value for C ₁₉ H ₂₈ ClN ₃ O ₃ : C, 59.75; H, 7.39; N, 11.00; Cl, 9.29 Experimental value: C, 59.65; H, 7.34; N, 10.68; Cl, 9.03 B 4-Amino -5-chloro-2-(cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide hydrochloride 4-amino-5-chloro-2-(cyclohexanon-2-yl)oxy-N- Dissolve [2-(diethylamino)ethyl]benzamide (190 mg, 0.5 mmol) in 25 ml of 2-propanol and add 1 ml of
Treated with 1N sulfuric acid. This solution was concentrated under reduced pressure to obtain the title compound (mp. decomposed at 175°C). Analysis Calculated value for C ₁₉ H ₃₀ ClN ₃ O ₃ S: C, 47.54; H, 6.30; N, 8.75; Cl, 7.39; S, 6.68 Experimental value: C, 47.52; H, 6.39; N, 8.46; Cl, 7.26; S, 6.80 C 4-Amino-5-chloro-2-(cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl]benzamide hydrochloride Use 1N hydrochloric acid as in the case of sulfate. manufactured by. mp150-153℃ decomposition. Analysis Calculated value for C ₁₉ H ₂₉ Cl ₂ N ₃ O ₃ : C, 54.54; H, 6.99; N, 10.04 Experimental value: C, 54.54; H, 7.03; N, 9.95 Example 24 4-Amino-5-chloro- N-[2-(diethylamino)ethyl]-2-(5-hexen-2-one-3-yl)oxybenzamide hydrochloride Sodium hydride (400 mg of 60%, 10 mmol, washed with n-pentane) of 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-(2-propanon-1-yl)oxybenzamide (3.4 g, 10
mmol) (prepared in Example 5) was added under a stream of nitrogen. The mixture was stirred until hydrogen evolution ceased. Allyl bromide (0.9 ml, 1.26 g, 10.5 mmol) was added and stirring continued for 18 hours. The mixture was partitioned between water and methylene chloride, the organic phase was washed with water, dried, concentrated and the residue was washed on inert silica with a solvent of methylene chloride (100), methanol (4) and ammonia (0.5). chromatography using the system. Collection of appropriate fractions yielded 1.14 g of free base. This was dissolved in 1-propanol, treated with 7 ml of 2NHCl and concentrated to give an oily residue. This was crystallized from acetone-ether and the product was recrystallized from 2-propanol to give 0.53 g of the title compound (mp 171-173°C). The NMR spectrum in D ₂ O has the following resonance value: δ7.88 (s, 1H); 6.42
(s, 1H); 6.12-4.88 (m, 3H); 3.76 (bd,
2H); 3.28 (m, 6H); 2.88 (bt, 2H); 2.4 (s,
3H); 1.35 (t; 6H). Analysis Calculated value for C ₁₉ H ₂₉ Cl ₂ N ₃ O ₃ : C, 54.55; H, 6.99; N, 10.04; Cl, 16.95 Experimental value: C, 54.22; H, 7.11; N, 9.90; Cl, 16.51 Example 25 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(pentan-2-one-3
-yl)oxybenzamide The tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.5 g, 20 mmol) (from Preparation Example 3) was dissolved in acetonitrile. (150ml)
The solution dissolved in 3-bromo-2-pentanone (3.3 g of 80%, 20 mmol, 15
% of 1-bromo-2-pentanone) [ETBorrows, Holland (DO
Hollannd and J. Kenyon, Journal of the Chemical Society (J, Chem.
Soc), p. 1083, (1946)]. After 3 hours the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic phase was washed with water, dried and the solvent was evaporated. Relaxation of the semi-solid residue with ether gave a solid which was reconsolidated from ether-petroleum ether to give 1.5 g of the title compound (mp. 75-78 DEG C.). CDCl ₃
The middle NMR spectrum (90MHz) has the following resonance values: δ8.26 (s, 1H); 8.14 (bs, 1H); 6.1 (s,
1H); 4.5 (t, 1H); 4.4 (s, 2H); 3.69 (q,
2H); 2.64 (m, 6H); 2.1 (s, 3H); 2.1~1.7
(m; 2H); 1.05 (m; 9H) was given. Analysis Calculated value for C ₁₈ H ₂₈ ClN ₃ O ₃ : C, 58.45; H, 7.63; N, 11.36; Cl, 9.59 Experimental value: C, 58.30; H, 7.61; N, 11.20; Cl, 9.20 Example 26 4- Amino-2-(2-butanon-1-yl)
Oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide Tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.3 g, A solution of 10 mmol) in acetonitrile (100 ml) was treated with 1-bromo-2-butanone (1.5 g, 10 mmol) and stirred at 20°C for 2 hours. The residue after concentration was treated with water and extracted with ethyl acetate and methylene chloride-2-propanol (5:1). The undissolved solid material was collected and combined with the organic extract. The mixture was concentrated to a sticky crystalline material, which was recondensed from acetonitrile-water (4:1) to give the title compound (3.1 g, 86%).
mp103.0～104.5℃ Analysis Calculated value for C ₁₇ H ₂₆ ClN ₃ O ₃ : C, 57.37; H, 7.37; N, 11.81; Cl, 9.96 Experimental value: C, 57.21; H, 7.34; N, 11.76; Cl ,9.67 Example 27 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(pentan-2-one-1
-yl)oxybenzamide The tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (10.54 g, 20 mmol) was dissolved in acetonitrile (150 ml). 1-Bromo-2-pentanone (3.3 g of 45% purity, by Borows, Holland and Kenyon,
Journal of Chemical Society (J.chem.
Soc.) p. 1083 (1946) as a by-product in the bromination of 2-pentanone;
[confirmed by NMR] was added and stirring was continued for 16 hours. After evaporating the solvent, the residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried and the solvent was evaporated. The residue was chromatographed on inert silica using a solvent system of methylene chloride (100), methanol (2), ammonia (0.5). Collecting the appropriate fractions yielded a solid, which was reconsolidated from ethyl acetate to yield 0.8 g.
The listed compound (mp 112-115°C) was obtained.
The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ8.48 (bs, 1H); 8.24 (s, 1H); 6.14
(s, 1H); 4.7 (s, 2H); 4.4 (s, 2H); 3.56
(q, 2H); 2.66 (m, 8H); 1.7 (m, 2H); 1.06
(t; 9H) was given. Analysis Calculated for C ₁₈ H ₂₈ ClN ₃ O ₃ : C, 58.45; H, 7.63; N, 11.36 Experimental: C, 58.16; H, 7.66; N, 11.28 Example 28 4-Amino-5-chloro-2- (Pentane-3
-on-1-yl)oxy-N-[2-(diethylamino)ethyl]-benzamide hydrochloride 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride ( 4.83 g, 0.015 mmol) (from Preparation Example 1A),
2-Bromo-3pentanone (2.72 g, 0.0165 mmol) [JMMclntosh and CMMasse, Journal of Organic Chemistry (J.Org.Chem) Vol. 40]
1294 (1975)] and potassium carbonate (4.14 g, 0.030 mmol).
Stirred in 80ml dry DMF and heated to 90-95° for 2 hours. The mixture was filtered and the DMF was distilled off under reduced pressure. The oily residue was redissolved in methylene chloride and washed sequentially with water, 1.0 N NaOH aqueous solution, and water.
Dry _{over Na2SO4} . After evaporation of the solvent, the crude oil was flash chromatographed on 86 g of silica gel (230-400 meshes) using a gradient elution containing 0.25% _NH4OH . Appropriate fractions were collected and evaporated to yield 4.31 g (77.7%) of a pale yellow gum. 75 g of this free base (4.30 g, 0.0116 mmol)
Dissolve in 2.90ml of isopropyl alcohol.
Add 4.0NHCl aqueous solution, concentrate the solution to about 30ml, cool, filter and dry in vacuo to give 3.85g.
(63.2%) of crude product was obtained. This was reconstituted from acetonitrile to give the above compound as a white solid (mp 100-112°C). Analysis Calculated value for C ₁₈ H ₂₈ ClN ₃ O ₃ : C, 53.20; H, 7.19; N, 10.34; Cl, 17.45 Experimental value: C, 53.24; H, 7.17; N, 10.26; Cl, 17.47 Example 29 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(3-methyl)-butane-
2-one-1-yl]oxybenzamide 4-Amino-5-chloro-N in DMF (30 ml)
-[2-(diethylamino)ethyl]-2-hydroxybenzamide hydrochloride (5.82 g, 18 mmol),
A mixture of anhydrous potassium carbonate (12.48 g; 90 mmol) and 1-bromo-3-methyl-2-butanone (4.5 g, 27 mmol; M. Gaudry and A. Marquet, Organic Synthesis) Org. Syn.), Vol. 55, p. 24 (1976)] was stirred for 20 hours under a stream of nitrogen. The mixture was poured into water (150 ml) and the solid was collected. When dried and reconstituted from toluene, the listed compound (4.86g, 73%; mp109-110
°C) was obtained. The NMR spectrum (90MHz) has the following resonance values: δ8.56 (bt, 1H); 8.24 (s, 1H); 6.18 (s,
1H); 4.8 (s, 2H); 4.44 (s, 2H); 3.56 (m,
2H); 2.62 (m, 7H); 1.2 (d, 6H); 1.06 (t;
6H) was given. Analysis Calculated value for C ₁₈ H ₂₈ ClN ₃ O ₃ : C, 58.45; H, 7.63; N, 11.36 Experimental value: C, 58.38; H, 7.63; N, 11.25 Example 30 4-Amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(3-phenyl-2-propanon-1-yl)oxybenzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenza A solution of the tetrabutylammonium salt of mido (3.45 g, 6.5 mmol) and 1-chloro-phenyl-2-propanone (1.1 g, 6.5 mmol) in acetonitrile was stirred at 20 DEG C. for 18 hours. After distilling off the acetonitrile under reduced pressure, the residue was treated with water and extracted with methylene chloride. After concentrating the extract, the residue was chromatographed on alumina (active) using ethyl acetate as eluent. Combining the appropriate fractions gave 1.1 g of product, which was reconstituted from ethyl acetate to give the title compound (mp 138-139°C). Analysis Calculated value for C ₂₂ H ₂₈ ClN ₃ O ₃ : C, 63.22; H, 6.71; N, 10.05; Cl, 8.48 Experimental value: C, 63.23; H, 6.71; N, 9.92; Cl, 8.28 Example 31 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(3-methyl)butane-
2-one-3-yl)oxybenzamide hydrate Tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (15.81 g, 30 mmol ) in DMF, add 3-bromo-3
-Methyl-2-butanone [4.95 g, 30 mmol (80% purity), prepared by Gaudry and Marquette, Tetrahedrom, Vol. 26, p. 5611 (1970)] was added. . After stirring for 20 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. Ethyl acetate layer
Washed with 0.4N NaOH, water, dried and the solvent was evaporated. The residue was chromatographed on deactivated silica using a solvent system of methylene chloride (100), methanol (2), ammonia (0.5). Collecting the appropriate fractions yielded 4.86 g of oil.
When a part (3.86 g) of this was crystallized from acetonitrile-water and re-crystallized from methanol-water, 1.23
g of the title compound (mp 84-88°C) was obtained.
The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ8.24 (s, 1H); 8.08 (s, 1H); 5.92
(s, 1H); 4.34 (s, 2H); 3.58 (q, 2H); 2.6
(q, 6H); 2.32 (s, 3H); 1.66 (s, 2H); 1.64
(s, 6H); 1.04 (t; 6H) was given. Analysis Calculated value for C ₁₈ H ₂₈ ClN ₃ O ₃ · H ₂ O: C, 55.73; H, 7.80; N, 10.83; Cl, 9.14; H ₂ O, 4.67 Experimental value: C, 55.75; H, 7.83; N , 10.72; Cl, 8.74; H ₂ O, 4.62 Example 32 4-Amino-2-(2-butanon-3-yl)
Oxy-5-chloro-N-[2-(dimethylamino)ethyl]benzamide 4-Amino-5-chloro-N-[2-(dimethylamino)ethyl]-2-hydroxybenzamide (1.90 g, 7.37 mmol) (prepared in Example 17), potassium carbonate (3.06 g, 2.21 mmol), sodium iodide (1.11 g, 7.37 mmol) and 91
A solution of % 3-bromo-2-butanone (1.81 g, 12 mmol) in DMF (30 ml) was stirred for 1.5 hours. The solvent was removed under vacuum and the residue was partitioned between water and methylene chloride. The aqueous layer was extracted twice more with methylene chloride. The extracts were combined, dried and concentrated under vacuum. The residue was purified on a silica gel column with methylene chloride (99.5), methanol (0.5),
Chromatography was performed using a solvent system of ammonia (0.2). Appropriate fractions were collected and concentrated under vacuum to give a solid. Reconsolidation of this from acetonitrile gave 1.85 g of the title compound as a colorless solid (mp 124-125°). Analysis Calculated value for C ₁₅ H ₂₂ ClN ₃ O ₃ : C, 54.96; H, 6.76; N, 12.82; Cl, 10.82 Experimental value: C, 55.17; H, 6.86; N, 12.80; Cl, 10.83 Example 33 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(2-hydroxy-
3-phenylpropyl)]oxybenzamide Tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (2.64 g, 5 mmol) and 1-chloro -2-Hydroxy-3-phenylpropane (0.85 g, 5 mmol) in 10 ml
The solution in DMF was heated under reflux for 2 hours. The mixture was concentrated under reduced pressure. The residue was taken up in methylene chloride, washed with dilute sodium hydroxide, and diluted with Na ₂
Dry over _SO4 and concentrate. When the product is reconstituted from ethyl acetate, the listed compound (1.05g, mp155~
157℃) was obtained. Analysis Calculated value for C ₂₂ H ₃₀ ClN ₃ O ₃ : C, 62.92; H, 7.20; N, 10.01; Cl, 8.44 Experimental value: C, 62.71; H, 7.26; N, 10.01; Cl, 8.27 Example 34 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydroxyiminobut-3-yl)oxybenzamide 4-Amino-2-(2-butanon-3-yl)
Oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide hydrochloride (1.14 g, 2.9 mmol) (prepared in Example 7C) and hydroxylamine hydrochloride (0.3 g, 4.3 mmol) were dissolved in methanol (20 ml). The solution was refluxed for 15 minutes. The solvent was evaporated and the residue was partitioned between methylene chloride and saturated sodium carbonate. The organic phase was washed with water, dried and the solvent was evaporated. The residue was crystallized from ethyl acetate and petroleum ether to give the title compound (mp 113-115°C, 0.37g).
The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ9.8 (bs, 1H); 8.16 (s, 1H); 6.4 (s,
1H); 4.96 (q, 1H); 4.4 (s, 2H); 4.02-3.08
(bm, 3H); 2.66 (m, 6H); 1.84 (s, 3H); 1.6
(d, 3H); 1.08 (t; 6H) was given. Analysis Calculated value for C ₁₇ H ₂₇ ClN ₄ O ₃ : C, 55.05; H, 7.34; N, 15.11; Cl, 9.56 Experimental value: C, 54.91; H, 7.34; N, 14.97; Cl, 9.45 Example 35 α- {3-amino-4-chloro-6-

[N-[2
-(diethylamino)ethyl]] carbamoylphenoxy}phenyl acetic acid ethyl ester Sodium hydride (0.36 g of 60%, 9 mmol, washed with n-pentane) in 5 ml of dry DMF
Stir well to suspend the mixture, and add 4-amino-5-
Chloro-N-[2-(diethylamino)ethyl]-
A solution of 2-hydroxybenzamide (2.28 g, 8 mmol) (from Preparation Example 1B) in 10 ml of dry DMF was added. After hydrogen generation has finished, ethyl α-bromophenyl acetate (2.12
g, 8.7 mmol) in 5 ml of dry DMF was added dropwise. After stirring for a further 18 hours at ambient temperature, the mixture was concentrated under vacuum and the residue was partitioned between water (200ml) and methylene chloride (75ml). The aqueous phase was extracted twice with 75 ml of methylene chloride. The organic phases were combined and washed three times with 50 ml of 10% aqueous sodium hydroxide and three times with brine, dried over sodium sulfate, filtered and concentrated in vacuo to give 3.5 g of an oil, which gradually crystallized. Relaxation with pentane gave 3.4 g of the title compound (mp 84-87°C). in CDCl ₃
The NMR spectrum (90MHz) has the following resonance values:
δ8.55 (bt, 1H); 8.20 (s, 1H); 7.50 (m, 5H);
6.09 (s, 1H); 5.65 (s, 1H); 4.25 (m, 4H);
3.55 (m, 2H); 2.60 (m, 6H); 1.05 (m, 9H) were given. Analysis Calculated for C ₂₃ H ₃₀ ClN ₃ O ₄ : C, 61.66; H, 6.76; N, 9.38 Experimental: C, 61.75; H, 6.76; N, 9.27 Example 36 4-Amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(2-hydrazino-2-oxoethoxy)benzamide trihydrate 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2- Methoxy-2-oxoethoxy)benzamide (3.58 g, 10 mmol)
(prepared in Example 15) was suspended in 64% hydrazine hydrate in water (0.6 g, 12 mmol) and methanol (3 ml) and stirred for 1 hour to form a clear solution. The mixture was concentrated under vacuum and the residue was reconstituted from water and dried to 3.65 g.
(88.6%) of the listed compounds are trihydrate (mp130-131
℃) was obtained. Analysis Calculated value for C ₁₅ H ₂₄ N ₅ ClO ₃・3H ₂ O: C, 43.73; H, 7.34; N, 17.00; Cl, 8.60; H ₂ O, 13.12 Experimental value: C, 44.07; H, 7.46; N , 17.19; Cl, 8.77; _H2O , 11.60 Example 37 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(2-acetylhydrazino)-2-oxoethoxy ]Benzamide acetate 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydrazino-2-oxoethoxy)benzamide trihydrate (1.0 g,
2.43 mmol) (prepared in Example 36) to 110
Drying for 3 hours at °C/0.02 mm gave the corresponding anhydride (865 mg). To this, acetic anhydride (248 mg, 2.428 mmol) was added to methylene chloride (5 ml).
The solution dissolved in the solution was used until a clear solution was obtained. Concentrating this solution under vacuum yields 1.115
g (100%) of the title compound was obtained as a white absorbent solid. Analysis Calculated value for C ₁₉ H ₃₀ N ₅ ClO ₆ : C, 49.62; H, 6.58; N, 15.23; Cl, 7.71 Experimental value: C, 48.86; H, 6.67; N, 14.87; Cl, 8.20 Example 38 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[3-(phthalimido)-propoxy]benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2- Tetra-n-butylammonium salt of hydroxybenzamide (15.8 g, 30
mmol) (prepared in Preparation Example 3) was suspended in acetonitrile (50 ml) and added with N
-(3-bromopropyl)phthalimide is added;
This mixture was kept at ambient temperature for 16 hours, then for 1 hour.
Stir at 65-70°C. This was concentrated under vacuum and the residue was partitioned between water and a 1:1 mixture of ether and methylene chloride. The organic phase was washed several times with water, dried and concentrated to a small volume to give crystals. This was filtered and the solid was washed with ether to give 12.3g (86.7%) of the title product as a white solid (mp 141-143°C). Analysis Calculated value for C ₂₄ H ₂₉ N ₄ ClO ₄ : C, 60.94; H, 6.18; N, 11.85; Cl, 7.5 Experimental value: C, 61.05; H, 6.43; N, 11.80; Cl, 7.63 Example 39 4- Amino-2-(3-aminopropoxy)-5
-Chloro-N-[2-(diethylamino)ethyl]
Benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[3-phthalimido)propoxy]benzamide (4.73 g, 10 mmol) (e.g.
A mixture of 64% hydrazine hydrate (800 mg, 16 mmol) and absolute ethanol (15 ml) was briefly heated under reflux until a clear solution was obtained. The solution was heated to 55-57°C for 16 hours and then refluxed for 2 hours. After cooling, the solid was filtered off and washed with ethanol. The filtrate and washings were combined and concentrated under vacuum. The residue was dissolved in methylene chloride and the undissolved solids were filtered off. The filtrate was washed with water, dried and concentrated under vacuum to give a solid product. When this was reconstituted from methylene chloride-n-pentane, 2.96 g (86.3%) of the title compound was obtained as a white solid (mp 119-121°C). Analysis Calculated value for C ₁₆ H ₂₇ N ₄ ClO ₂ : C, 56.05; H, 7.94; N, 16.34; Cl, 10.34 Experimental value: C, 56.05; H, 7.92; N, 16.10; Cl, 10.47 Example 40 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(methylamino)-2
-Oxoethoxy]benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxy-2-oxoethoxy)benzamide (1.074 g, 3 mmol)
(prepared in Example 15) was suspended in 1N methylamine in toluene (10ml), to which 3ml of methanol was added and the mixture was stirred for 16 hours. This was concentrated in vacuo and the residue was crystallized from methanol-ether to give 815 mg (76%) of the title compound as a white solid (mp 149-151°C). Analysis Calculated value for C ₁₆ H ₂₅ N ₄ ClO ₃ : C, 53.85; H, 7.06; N, 15.70; Cl, 9.94 Experimental value: C, 53.85; H, 7.16; N, 15.63; Cl, 10.00 Example 41 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-hydroxy)but-3-yl]oxybenzamide (mixture of threo and erythro isomers) 4-amino-2-( 2-butanon-3-yl)
oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide [obtained by treating 1.2 g (3.1 mmol) of the corresponding hydrochloride salt prepared in Example 7C with saturated sodium carbonate solution] and A mixture of sodium borohydride (100mg) was heated under reflux in ethanol (20ml) for 1 hour. Concentrate this solution, dilute with water, 2N
The mixture was made acidic with hydrochloric acid and then made basic with saturated sodium carbonate solution. This mixture was extracted with methylene chloride to yield 1.16 g of foam. This was chromatographed on deactivated silica using methylene chloride (100), methanol (2), ammonia (0.5) as the solvent system. Collection of appropriate fractions gave the title compound (470 mg) as a foamy mixture of diastereoisomers. The NMR spectrum (90MHz) in CDCl ₃ has the following resonance values: δ8.54 (bd, 1H); 8.2, 8.15 (2s,
1H); 6.32, 6.35 (2s, 1H); 4.36 (s, 2H); 4.24
~4 (m, 1H); 4 ~ 2.12 (m, 3H); 2.8 ~ 2.52
(m, 6H); 1.41 to 0.96 (m, 12H) was given. Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₃ : C, 57.05; H, 7.89; N, 11.74; Cl, 9.91 Experimental value: C, 56.34; H, 7.79; N, 11.55; Cl, 9.65 Example 42 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(ethyl-3-methoxycroton-4-yl)oxybenzamide The general procedure of Example 35 was repeated but for α-bromophenyl acetate. Instead, an equimolar amount of ethyl 3-methoxy-4-chlorocarbonate (prepared by the method of US Pat. No. 4,348,333) was used. The solvent (DMF) was distilled off under vacuum and the residue was treated with water and methylene chloride. The organic layer was washed with 10% sodium hydroxide, water and brine, then dried over sodium sulfate, filtered and concentrated. Recrystallization of the crude solid from ether/methylene chloride gave the title compound (mp 109-111°C). Analysis Calculated value for C ₂₀ H ₃₀ ClN ₃ O ₅ : C, 55.99; H, 7.06; N, 9.80 Experimental value: C, 55.96; H, 7.14; N, 9.77 Example 43 4-Amino-5-chloro-N- [2-(Diethylamino)ethyl]-2-(1,3-dioxolan-2-yl)-oxybenzamide The general procedure described in Example 35 was repeated, but in place of ethyl α-bromophenyl acetate, the equimolar amount 2-
Bromoethyl-1,3-dioxalan was used and the reaction mixture was heated to 80°C for 30.5 hours. The solvent (DMF) was removed in vacuo, the residue was treated with brine and methylene chloride, the organic layer was washed with 10% sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated. . Recrystallization from methylene chloride/hexane gave the title compound (mp 93-95°C). Analysis Calculated value for C ₁₇ H ₂₆ ClN ₃ O ₄ : C, 54.90; H, 7.06; N, 11.30 Experimental value: C, 54.98; H, 7.07; N, 11.40 Example 44 4-Amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(oxazolidin-2-one-5ylmethyl)oxybenzamide fumarate An equimolar amount (6 mmol) of 4-amino-5-chloro-N-[2-(diethylamino) )ethyl]-2
- Tetra-n-butylammonium salt of hydroxybenzamide (prepared in Preparation Example 3) and 5-chloromethyl-2-oxazolidinone at 15
ml of DMF for 3 hours under stirring and reflux.
After distilling off the solvent, the residue was dissolved in methylene chloride and washed with water. After drying over MgSO ₄ and concentration, 2.7 g of crude product was obtained. This was purified by chromatography on active alumina using ethyl acetate containing 5 and 10% ethanol as eluent. Treatment of the partially purified product (1.1 g) in 1-propanol with fumaric acid (0.33 g) gave 0.81 g (30.5%) of crystalline fumarate salt (mp. 165-167 °C). . Analysis [C ₁₇ H ₂₅ ClN ₄ O ₄ ] ₂・C ₄ H ₄ O ₄ Calculated value: C, 51.52; H, 6.15; N, 12.65; Cl, 8.01 Experimental value: C, 51.21; H, 6.18; N , 12.40 ; Cl, 7.99 Example 45 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-pyridinomethyl)oxybenzamide 4-Amino-5-chloro-N-[2- (diethylamino)ethyl]-2-hydroxybenzamide tetra-n-butylammonium salt (2.64 g,
0.005 mol) (produced in Preparation Example 3) at 30
2-chloromethylpyridine (0.01 mol of the corresponding hydrochloride salt) in solution in ml of acetonitrile.
(prepared by neutralization with K ₂ CO ₃ ) was added. The resulting reaction mixture was stirred for 18 hours and then concentrated. Chromatography of the residue on active alumina using ethyl acetate and ethyl acetate-ethanol (100:2) as eluents gave 1.8 g of purified product, which was divided into 2:
1 was recrystallized from ethyl acetate-n-hexane.
1.45 g (77%) of the title compound (mp 84-85°C) was obtained. Analysis Calculated value for C ₁₉ H ₂₅ ClN ₄ O ₂ : C, 60.55; H, 6.69; N, 14.87; Cl, 9.41 Experimental value: C, 60.62; H, 6.76; N, 14.81; Cl, 9.34 Example 46 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxyethoxyethyl)oxybenzamide The general procedure described in Example 35 was repeated but in place of ethyl α-bromophenyl acetate. A molar amount of 1-bromo-2-(2-methoxyethoxy)ethane was used. The solvent (DMF) was distilled off under vacuum, the residue was treated with brine and methylene chloride, and the organic layer was diluted with
% sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated. Reconsolidation from ether gave the above compound (mp 49-51°C). Analysis Calculated value for C ₁₈ H ₃₀ ClN ₃ O ₄ : C, 55.72; H, 7.81; N, 10.83 Experimental value: C, 55.50; H, 7.69; N, 10.78 Example 47 4-amino-2-(2-amino ethoxy)-5-
Chloro-N-[2-(diethylamino)ethyl]-
Benzamide A teaspoon of Raney nickel (washed well with methanol) is suspended in methanol (130 ml) and 4-amino-5-chloro-2-cyanomethyl-N-[2-(diethylamino)ethyl]benzamide ( 12.05 g, 37.1 mmol) (prepared in Example 13) and the mixture was reduced to 2.8 Kg/cm ²
(40 psi) for 5 hours. The catalyst was filtered off under a stream of nitrogen and the filtrate was concentrated under vacuum. Dissolve the residue in methylene chloride and add 1N sodium hydroxide (4x
25ml). Extract the washing liquid with methylene chloride,
The organic phase is collected, dried and concentrated under vacuum to give 5.56
g of the title compound was obtained as a semi-solid. When this is recondensed from methanol-ether while cold,
An analytical sample with a mp of 97-99°C was obtained. Analysis Calculated value for C ₁₅ H ₂₅ ClN ₄ O ₂ : C, 54.78; H, 7.60; Cl, 10.78; N, 17.04 Experimental value: C, 54.71; H, 7.64; Cl, 10.91; N, 16.81 Example 48 2- (2-acetylaminoethoxy)-4-amino-5-chloro-N-[2-(diethylamino)ethyl]benzamide 4-amino-2-(2-aminoethoxy)-5-
To a solution of chloro-N-[2-(diethylamino)ethyl]benzamide (780 mg, 2.4 mmol) (prepared in Example 47) in methylene chloride was added acetic anhydride (245 mg, 2.4 mmol) and the mixture was stirred for 30 min. The mixture was stirred for a minute. This was concentrated under vacuum and the residue was partitioned between methylene chloride and sodium bicarbonate solution. The organic phase was concentrated and the residue was purified on silica with methylene chloride:methanol:ammonia (100:
It was subjected to flash chromatography using a solvent system of 4:0.5). Appropriate fractions were collected and concentrated under vacuum. Reconsolidation of the residue from methylene chloride-ether yielded 445 mg of the title compound as a white solid (mp143
~145°C). Analysis Calculated value for C ₁₇ H ₂₇ ClN ₄ O ₃ : C, 55.05; H, 7.37; Cl, 9.56; N, 15.11 Experimental value: C, 54.82; H, 7.28; Cl, 9.71; N, 14.54 Example 49 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[3-(methylthio)-propoxy]benzamide 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2- Tetrabutylammonium salt of hydroxybenzamide (10.54 g, 20 mmol) (prepared in Preparation Example 3) was added to DMF.
1-bromo-3-chloropropane (3.268 g, 2.2 ml, 20.76 mmol) was added to the solution in (100 ml) and the mixture was kept at ambient temperature for 2 hours and then for 30 minutes.
Stir at 40°C. The mixture was cooled to 0°C and sodium hydride (1.0 g of a 60% dispersion in mineral oil, 25
(washed with n-pentane) under a stream of nitrogen. The mixture was stirred under cooling and methyl mercaptan gas was passed through it until the evolution of hydrogen had ceased. The mixture was stirred at 35-40°C for 2 hours, poured into water (700 ml), left to stand for 1 hour, and the resulting solid was filtered with suction and air-dried to give 7.06 g (94%).
A crude product (mp 58-59°C) was obtained. This was dissolved in methylene chloride and filtered through a short column packed with silica and alumina. Concentrate the filtrate and crystallize the residue from ether to give 4.95
g (66%) of the listed compound as a white solid (mp79~
80°C). Analysis Calculated values for C ₁₇ H ₂₈ ClN ₃ O ₂ S: C, 54.61; H, 7.55; Cl, 9.48; N, 11.24; S, 8.56 Experimental values: C, 54.56; H, 7.52; Cl, 9.38; N, 11.10; S, 8.23 Example 50 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[3-(methyl-sulfinyl)propoxy]benzamide 2N hydrochloric acid (5.0 ml, 10 mmol) and water (20ml)
Sodium periodate (856 mg,
4.0 mmol) was added and the mixture was stirred for 2.5 hours. Next, add this to 4N sodium hydroxide (3 ml)
The mixture was made basic and extracted with methylene chloride (3 x 30 ml). The extract was concentrated in vacuo and the residue was flash chromatographed on an inert silica column using a solvent system of methylene chloride:methanol:ammonia (100:3.5:0.5). The appropriate fractions were collected and concentrated to give a yellow oil which crystallized from methylene chloride-ether to give 770 mg of the title compound as a pale yellow solid (mp 116-117°C). Analysis Calculated values for C ₁₇ H ₂₈ ClN ₃ O ₃ S: C, 52.37; H, 7.24; Cl, 9.09; N, 10.78; S, 8.21 Experimental values: C, 52.31; H, 7.25; Cl, 8.70; N, 10.68; S, 7.88 Example 51 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[1H-4,5-dihydro-imidazol-2-yl)methoxybenzamide Methanol (25 ml) 4-amino-5-chloro-2-cyanomethoxy-N-[2-(diethylamino)ethyl]benzamide (3.25 g, 10 mmol) (prepared in Example 13) and 1,2-diaminoethane (0.6 g, 10 mmol) was heated under reflux for 3 hours. The reaction mixture was concentrated to a crystalline residue, which was crystallized from ethyl acetate to give the title compound (2.78 g, 76%) (mp 144-145°C).
gave. Analysis Calculated value for C ₁₇ H ₂₆ ClN ₅ O ₂ : C, 55.50; H, 7.12; Cl, 9.64; N, 19.04 Experimental value: C, 55.64; H, 7.21; Cl, 9.75; N, 18.94 Example 52 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-thienoylmethoxy)benzamide 2-thiophenecarboxylic acid (2.6 g, 20 mmol), thionyl chloride (2.4 g, 20 mmol) and toluene (15ml) was heated under reflux for 1 hour. The reaction was concentrated to give an oily residue (2.8 g).
A solution of this oil in diethyl ether (10 ml) was dissolved in diazomethane [N-methyl-N-nitrosourea (8.1 g, 80 mmol) in ether (200 ml).
A solution of [prepared from] was added. After stirring for 2 hours at 20°C, the reaction was treated with hydrochloric acid gas (excess) for 20 minutes. After stirring for an additional 1/2 hour, the reaction mixture was concentrated to give chloroacetyl-2-thiophene as a dark oil (3.2 g).
A portion (1.6 g) of this dark oil was taken into acetonitrile (25 ml) and 4-amino-5-chloro-N-
It was treated with the tetra-n-butylammonium salt of [2-(diethylamino)ethyl]-2-hydroxybenzamide (2.6 g, 5 mmol) (prepared in Preparation Example 3) and stirred for 18 hours. The residue after concentration was purified by chromatography on alumina (activity) using 2% ethanol in ethyl acetate as eluent to give the title compound, which was reconsolidated from acetonitrile (mp 135-139°C). . Analysis Calculated value for C ₁₉ H ₂₄ ClN ₃ O ₂ S: C, 55.67; H, 5.90; N, 10.25; S, 7.82 Experimental value: C, 55.86; H, 5.91; N, 10.18; S, 7.54 Example 53 4 -amino-5-chloro-2-(2-chloroethoxy)-N-[2-(2-diethylamino)ethyl]benzamide from the corresponding hydrochloride (5.0 g, 1.6 mmol) (prepared in Preparation Example 1) The produced 4-amino-5-chloro-N-[2-(diethylamino)
Sodium salt of ethyl]-2-hydroxybenzamide and sodium hydride (60 ml) in DMF (15 ml)
2-chloroethyl-p-toluenesulfonate (3.64 g, 16 mmol) was added to a stirred solution of 2-chloroethyl-p-toluenesulfonate (1.3 g, 32.6 mmol) and the mixture was heated at ambient temperature for 16 hours and further heated to 80-90°C. Stirred for 3 hours. The mixture was concentrated in vacuo and the residue was partitioned between brine and methylene chloride. The organic phase was washed with aqueous sodium hydroxide, brine, water, then dried and concentrated under vacuum. Reconsolidation of the residue from ether gave 2.02 g of the title compound (mp 153-154°C). Analysis Calculated value for C ₁₅ H ₂₃ Cl ₂ N ₃ O ₂ : C, 51.72; H, 6.67; N, 12.06 Experimental value: C, 51.76; H, 6.64; N, 11.42 Example 54 4-Amino-5-chloro- N-[2-(diethylamino)ethyl]-2-[2-methyl-2-(1,
3-Dioxolan)-4-yl]oxybenzamide Sodium hydride (washed with pentane) (1.26 g of 60%) in dry DMF (3 ml), 32
mmol) in DMF to a well-stirred suspension of
(12 ml) of 4-amino-5-chloro-N-[2-
(Diethylamino)ethyl]-2-hydroxybenzamide (8.57 g, 3 mmol) was added over 30 minutes. After stirring for 11/2 hours, 2-methyl-2
-(2-iodoethyl)-1,3-dioxolone (6.54 g, 27 mmol) [Journal of Organic Chemistry Vol. 48, pp. 5381-5382 (1983)
[prepared by the method described in 1999] was added for 8 minutes or more and then stirred for 24 hours. The mixture was then poured into 300 ml of saline and extracted four times with methylene chloride (100 ml each). The extracts were combined and the organic phase was washed twice with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate and concentrated under vacuum to give 9.44 g of an oil. 5 g of this product was purified by flash chromatography on a silica gel column to produce methylene chloride (93), methanol (7), and ammonia (0.2).
It was eluted with a solvent mixture consisting of: The appropriate fractions were combined and concentrated in vacuo to yield 2.68 g of the listed compound (mp84~
86℃). Analysis Calculated for C ₁₉ H ₃₀ ClN ₃ O ₄ : C, 57.05; H, 7.58; N, 10.51 Experimental value: C, 56.82; H, 7.55; N, 10.40 Example 55 4-Amino-5-chloro-2- [2-(dimethylamino)-2-oxoethoxy]-N-[2-(diethylamino)ethyl]benzamide The general procedure described in Example 40 was repeated using dimethylamine in place of methylamine. After 6 days of reaction, the mixture was concentrated under vacuum and the residue was partitioned between water and methylene chloride. The organic phase was dried and concentrated in vacuo, and the residue was crystallized from methanol-methylene chloride-ether to give the title compound as a white solid (1/
(containing 2 moles of water of crystallization) (mp 130-131°C). Analysis Calculated value for C ₁₇ H ₂₇ ClN ₄ O ₃・1/2H ₂ O: C, 53.74; H, 7.42; Cl, 9.33; N, 14.36 Experimental value: C, 54.09; H, 7.17; Cl, 9.02; N , 14.74 Example 56 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(4-diethylamino-4
-oxobutoxy)benzamide 4-Amino-5- Chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (3.43 g, 12
mmol) (prepared as in Example 58)
added. Add 10ml of DMF to this,
This mixture was stirred at ambient temperature for 40 minutes and then approx.
Warm to 50°C for 15 minutes, then 4-chloro-N,N-
Diethylbutyramide (1.92 g, 11 mmol) was added. This mixture was then heated to 60-70°C for 6 hours.
Stirred at room temperature for 2 days and further at 60-70°C for 4 hours. The cooled mixture was poured into 400 ml of brine and extracted with methylene chloride (4 x 100 ml). The extracts were combined and the organic phase was washed twice with 100 ml of 10% aqueous sodium hydroxide and brine, dried over sodium sulfate, filtered and concentrated in vacuo to give an oil (3.75
g) was given. When this substance is purified by flash chromatography on silica gel, it becomes 1.64 g.
The title compound was given as an oil. Analysis Calculated value for C ₂₁ H ₃₅ ClN ₄ O ₃ : C, 59.06; H, 8.28; N, 13.12 Experimental value: C, 57.71; H, 8.15; N, 12.71 Example 57 2-(2-acetoxyethoxy)-4 -Amino-
5-Chloro-N-[2-(diethylamino)ethyl]benzamide Tetrabutylammonium salt of 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (5.27 g, 10 mmol) ) (prepared in Preparation Example 3) in acetonitrile (100 ml) and 2-bromoethyl acetate (2 g, 12 mmol) was stirred for 48 hours. The residue after evaporation of the solvent was partitioned between ethyl acetate and water. The organic phase was washed with ice-cold 0.4N sodium hydroxide solution and then with water and, after drying, the solvent was evaporated. The residue was chromatographed on inert silica using a solvent system of methylene chloride (100), methanol (2), ammonia (0.5). Combining the appropriate fractions and evaporating the solvent gave a residue consisting of the title compound (3.18 g, 85%). Analytical sample (mp101) when crystallized from toluene
~102°C). Analysis Calculated value for C ₁₇ H ₂₆ ClN ₃ O ₄ : C, 54.91; H, 7.05; N, 11.30 Experimental value: C, 54.86; H, 7.01; N, 11.28 Example 58 4-Amino-5-chloro-N- [2-(diethylamino)ethyl]-2-[4-(methylsulfinyl)-butoxy)benzamide A 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[4-( methylthio)
butoxy]benzamide 4-Amino-5-chloro- in DMF (150 ml)
Tetrabutylammonium salt of N-[2-(diethylamino)ethyl]-2-hydroxybenzamide (15.82 g, 30 mmol) (prepared in Preparation Example 3) and 1,4-dibromobutane (6.48 g,
30 mmol) was stirred for 24 hours. The solution was cooled and poured into a 500 ml flask containing sodium hydride (1.5 g, 37.5 mmol, 60% emulsion washed with pentane). The suspension was ice-cooled, stirred, and methyl mercaptan was passed into the mixture until hydrogen evolution ceased.
The clear solution was heated to 35-50° C. for 5 hours, poured into 1400 ml of water and extracted with ethyl acetate. The organic layer was washed with water, dried and the solvent was evaporated. For the residue, methylene chloride (100), methanol (2),
Chromatography on deactivated silica using a solvent system of ammonia (0.5). Two compounds namely (1) 1,4-bis{4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2
-oxybenzamide}butane (mp172-176℃)
and (2) the listed compound (2.5 g) was obtained, the latter compound being crystallized from 2-propanol.
It showed mp101-103℃. Analysis Calculated value for C ₁₈ H ₃₀ ClN ₃ O ₂ S: C, 55.72; H, 7.79; N, 10.83; Cl, 9.14; S, 8.27 Experimental value: C, 55.59; H, 7.87; N, 10.81; Cl, 9.26;S, 8.19 B 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[4-(methyl-sulfinyl)butoxy]benzamide 4-amino-5-chloro-N-[2 -(diethylamino)ethyl]-2-[2-(methylthio)ethoxy]benzamide was replaced by the product obtained from step A above and the general procedure of Example 21 was repeated, chromatography on silica and methylene chloride - Crystallization from ether gave the title compound in 78% yield as a solid with mp 80-83°C. Analysis Calculated value for C ₁₈ H ₃₀ ClN ₃ O ₃ S: C, 53.51; H, 7.49; N, 10.40; Cl, 8.78; S, 7.94 Experimental value: C, 53.70; H, 7.72; N, 10.36; Cl, 8.40; S, 7.74 Example 59 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(1-pyrrolidinyl)
-2-Oxoethoxy]benzamide 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2- in methanol (10 ml)
[2-Methoxy-2-oxoethoxy)benzamide (1.07 g, 3 mmol) (prepared in Example 15) and pyrrolidine (0.952 g, 23 mmol)
The solution was refluxed overnight. The solvent was evaporated and the residue was chromatographed on deactivated silica using a solvent system of methylene chloride (100), methanol (2.5), ammonia (0.5). Combining the appropriate fractions, evaporating the solvent, and crystallizing the residue from 2-propanol and recrystallizing from methanol-ether gives the listed compound (0.86 g) (72%) (mp 160-162°C).
gave. Analysis Calculated value for C ₁₉ H ₂₉ ClN ₄ O ₃ ·1/4H ₂ O: C, 56.84; H, 7.40; N, 13.96 Experimental value: C, 56.89; H, 7.24; N, 13.67 Example 60 4-Amino- 5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(ethylsulfinyl)-ethoxy]benzamide A 4-amino-5-chloro-N-[2-(diethylamino)ethyl]- 2-[2-(ethylthio)-
ethoxy]benzamide 2 instead of 2-chloroethylmethyl sulfide
- By repeating the general procedure of Example 20 using 2-chloroethyl ethyl sulfide in place of chloroethyl methyl sulfide, the listed compound was obtained from acetonitrile as an off-white solid (mp 92-94°C).
Obtained in 61%. Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₂ S: C, 54.60; H, 7.55; N, 11.24; Cl, 9.48; S, 8.58 Experimental value: C, 54.14; H, 7.57; N, 10.97; Cl, 9.03; S, 8.58 B 4-Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[2-(ethyl-sulfinyl)ethoxy]benzamide Example using the product obtained from step A above 21 and reconsolidation from acetonitrile gave the title compound in 53% yield as bright yellow bright crystals (mp 140-142°C). Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₃ S: C, 52.36; H, 7.24; N, 10.78; Cl, 9.09; S, 8.22 Experimental value: C, 52.56; H, 7.38; N, 10.75; Cl, 8.89;S, 8.21 Example 61 cis-4-amino-5-chloro-N-{1-[3
-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-[2-(methylthio)ethoxy]benzamide monohydrate A cis-4-amino-5-chloro-N-{ 1-
[3-(4-fluorophenoxy)propyl]-
3-Methoxy-4-piperidinyl}-2-hydroxybenzamide Cis-4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-methoxybenzamide -N-{1-
[3-(4-fluorophenoxy)propyl]-3
-Methoxy-4-piperidinyl}-2-methoxybenzamide (2 g, 4.3 mmol) [produced by the method described in European Patent Application No. 76530 (1983)] Production Example 1 The general operation was repeated. Crystallization of the product from 2-propanol gives the title compound (mp146~) in 54% yield.
148℃). Analysis Calculated value for C ₂₂ H ₂₇ ClFN ₃ O ₄ : C, 58.34; H, 6.01; N, 9.28; Cl, 7.83 Experimental value: C, 58.31; H, 6.19; N, 9.12; Cl, 7.88 B Cis-4 -amino-5-chloro-N-{1-
[3-(4-fluorophenoxy)propyl]-
3-methoxy-4-piperidinyl}-2-[2-
(Methylthio)ethoxy]benzamide monohydrate Product from step A above (0.45 g, 1 mmol)
was added to a stirred suspension of sodium hydride (40 mg, 1 mmol of 60%, washed with petroleum ether) in acetonitrile (10 ml), to which was added tetrabutylammonium bromide (0.32 g,
1 mmol) was added. The reaction mixture was heated to 40°C for 15 minutes before adding 2-chloro-ethylmethylsulfide (0.44g, 4mmol) and potassium iodide (50°C).
mg) was added. This mixture was heated at reflux for 2 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate (containing 10% methylene chloride) and water. The organic layer was dried and the solvent was evaporated to obtain a residue. This residue was crystallized from 2-propanol to yield 0.26 g (50
%) of the listed compound (mp 58-60°C). Analysis Calculated value for C ₂₅ H ₃₃ ClFN ₃ O ₄ S・H ₂ O: C, 55.18; H, 6.48; N, 7.72 Experimental value: C, 55.46; H, 6.42; N, 7.47 Example 62 Cis-4-amino -2-(amino-2-oxoethoxy)-5-chloro-N-{1-[3-(4-fluorophenoxy)propyl]-3-methoxy-
4-piperidinyl}benzamide sesquihydrate cis-4-amino-5-chloro-N-{1-[3
-(4-Fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-hydroxybenzamide (1.35 g, 3 mmol) (prepared in Example 61 Step A) was dissolved in acetonitrile (20 ml). To a stirred suspension of sodium hydride (0.12 g, 3 mmol of a 60% emulsion, washed with petroleum ether) was added followed by tetrabutylammonium bromide (0.96 g, 3 mmol). reaction mixture
It was heated to 40° C. for 15 minutes and then treated with methyl bromoacetate (0.92 g, 6 mmol). After 2 days of stirring, the reaction mixture was partitioned between water and ethyl acetate. The organic phase was dried, concentrated in vacuo and the residue was chromatographed on deactivated silica using a solvent system of methylene chloride (100), methanol (2), ammonia (0.5). Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in methylene chloride by addition of methanol and the solution was saturated cold with ammonia gas. After 30 minutes, the solvent was evaporated and the residue was crystallized from ethanol-water to yield 0.3 g of the title compound as the sesquihydrate (19%) (mp 173-175°C). Analysis C ₂₄ H ₃₀ ClFN ₄ O ₅・1-1/2For H ₂ O Calculated value: C, 53.78; H, 6.20; N, 10.45 Experimental value: C, 53.59; H, 6.21; N, 10.36 The above compound is as follows. It can also be produced by other methods. cis-4-amino-5-chloro-N-{1-[3
-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl}-2-hydroxybenzamide (0.68 g, 1.5 mmol) (Example 61, Step A
(prepared in 0.48 g, 1.5 mmol) was added. The reaction mixture was heated to 40° C. for 15 minutes to give a clear solution, then treated with chloroacetamide (0.56 g, 6 mmol) and potassium iodide (0.25 g) and heated to reflux. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The residue from the organic layer was chromatographed on deactivated silica using a solvent system of methylene chloride (100), methanol (2), ammonia (0.5). Combine the appropriate fractions and divide the remainder (0.2
Crystallization of g) from ethanol-water produced the title compound as (60 mg) (mp 173-175°C). Example 63 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxypropane-
1-yl)oxybenzamide The title compound is obtained by repeating the general procedure of Example 31 using an equimolar amount of 1-chloro-2-methoxypropane in place of 3-bromo-3-methyl-2-butanone. It was done. Purity after repeat chromatography was >95% (HPLC). Analysis Calculated value for C ₁₇ H ₂₈ ClN ₃ O ₃ : C, 57.05; H, 7.89; N, 11.74; Cl, 9.91 Experimental value: C, 56.85; H, 7.92; N, 11.56; Cl, 9.90 Example 64 4- Amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-hydroxy-2-
methyl)propan-1-yl]oxybenzamide An equimolar amount of 1-chloro-2,3-epoxy-2 instead of 3-bromo-3-methyl-2-butanone
- The general procedure of Example 31 was repeated using methylpropane and the intermediate thus obtained was reduced with sodium borohydride according to the procedure described in Example 41 to give the title compound (mp 87-89°C). . Example 65 Instead of 1-chloro-2,3-epoxy-2-methylpropane, an equimolar amount of 2-chloro-3,4-
By repeating the general procedure of Example 64 using epoxy-3-methyl-butane, 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-
[(2-Hydroxy-2-methyl)but-3-yl]oxybenzamide was produced. Example 66 Threo- and erythro-4 were prepared by using equimolar amounts of 2-chloro-3-methoxybutane and 2-chloro-3-methoxy-3-methylbutane in place of 1-chloro-2-methoxypropane, respectively. -Amino-5-chloro-N-[(2-diethylamino)ethyl]-2-[(2-methoxy)buto-
3-yl]oxybenzamide, and 4-amino-
5-chloro-N-[(2-diethylamino)ethyl]-2-[(2-methoxy-2-methyl)buto-
A mixture of 3-yl]oxybenzamide was prepared.

Claims (1)

[Claims] 1 Formula 1 [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower) alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl, or [Formula], or R ⁴ and R ⁵ are Together -NH-N
=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [Formula] or [Formula], in which n is a number of 1 to 4; Yes; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [formula] or [formula], and R ¹⁰ is hydrogen or (lower) alkoxy and R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or is a quaternary ammonium salt. 2 The compound has the formula (However, R ¹ is [Formula] or [Formula]; n is a numerical value of 1 to 4; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, or ( R ¹⁰ is hydrogen or (lower) alkoxy; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or [ X is oxygen, sulfur or =NOR ¹⁶ , Z is -(CH ₂ ) _P -, O, N or [formula]; B is [formula] ] [Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower alkynyl), (lower) Alkoxy (lower) alkyl or cycloalkyl having 5 to 7 carbon atoms, provided that when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is oxygen or Not directly attached to the nitrogen atom; ^R14 is hydrogen, halogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, (lower) alkoxy,
Hydroxy, (lower) alkenyloxy, hydrazino, (lower) alkoxycarbonyl (lower) alkenyl, acetylhydrazino, thienyl, phenyl, or R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together [formula] or [formula] or R ¹² and R ¹⁴ together with the carbon atoms attached to them form a saturated or unsaturated ring having 5 to 7 atoms, and the ring is a ring selected from the group consisting of oxygen, sulfur, and nitrogen. both optionally have one heteroatom; or ^R14 and ^R15 together with the carbon and oxygen atoms attached to them are saturated oxygen-containing 3-7
The compound according to claim 1, which is a non-toxic pharmaceutically acceptable salt, hydrate, solvate, or quaternary ammonium salt thereof. . 3 The compound has the formula [However, in the formula, R ⁷ and R ⁸ are the same or different and are ethyl or methyl; R ² is -CH ₂ OCH ₂ CH ₂ OR ¹¹ , -CH ₂ CH ₂ OR ¹¹ ,
[Formula] [Formula] [Formula] [Formula] [Formula] or [Formula]; X is oxygen or =NOR ¹⁶ ; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl,
(lower) alkynyl, (lower) alkoxy (lower)
Alkyl or cycloalkyl having 5 to 7 carbon atoms, provided that when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is an oxygen atom or a nitrogen atom. Not directly attached; R ¹⁴ is hydrogen, halogen, (lower) alkyl, (lower) alkoxy, hydroxy, hydrazino, (lower) alkoxycarbonyl (lower) alkenyl,
acetylhydrazino, thienyl, phenyl, phenyl (lower) alkyl or and R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or methyl; or R ¹² and R ¹⁴ together with the carbon atoms attached to them are saturated rings or unsaturated rings having 5 to 7 atoms. forming a saturated ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ are the carbon atoms to which they are attached; and a non-toxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt thereof. The compound according to claim 1, which is 4 The compound is 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-(2,2-dimethoxyethoxy)benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof Compound according to item 1. 5 The compound is 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-[(2-methoxyethoxy)methyloxy]benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. A compound according to scope 1. 6 The compound is 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-(2-propanon-1-yl)oxybenzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof A compound according to item 1 in the range. 7 The compound is 4-amino-2-(butan-2-one-3-yl)oxy-5-chloro-N-[2-
The compound according to claim 1, which is (diethylamino)ethyl]benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 8 The compound is 4-amino-5-chloro-2-(cyclohexanon-2-yl)oxy-N-[2-
The compound according to claim 1, which is (diethylamino)ethyl]benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 9 The compound is 4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-[(2-hydroxyimino)propan-1-yl]oxybenzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof The compound according to claim 1, which is 10 The compound is 4-amino-5-chloro-N-
A patent claim that is [2-(diethylamino)ethyl]-2-hydroxypropan-1-yl)oxybenzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof A compound according to item 1 in the range. 11 The compound is 4-amino-5-chloro-2-cyanomethyloxy-N-[2-(diethylamino)
The compound according to claim 1, which is ethyl]benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 12 The compound is 4-amino-2-(carboxamidomethyloxy)-5-chloro-N-[2-(diethylamino)ethyl]benzamide acetate or its non-toxic pharmaceutically acceptable salt, hydrate, or ester Alternatively, the compound according to claim 1, which is a quaternary ammonium salt. 13 The compound is 4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-[2-(methylsulfinyl)ethoxy]benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof A compound according to claim 1. 14 The compound is 4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-(pentan-2-one-3-yl)oxybenzamide or its non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt The compound according to claim 1, which is 15 The compound is 4-amino-2-(2-butanon-1-yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]benzamide or a non-toxic pharmaceutically acceptable salt thereof, hydrated The compound according to claim 1, which is a compound, an ester, or a quaternary ammonium salt. 16 The compound is 4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-(pentan-2-one-1-yl)oxybenzamide or its non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt The compound according to claim 1, which is 17 The compound is 4-amino-5-chloro-2-
(pentan-3-one-2-yl)oxy-N-
2. The compound according to claim 1, which is (2-diethylaminoethyl)benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 18 The compound is 4-amino-5-chloro-N-
Patent for [2-(diethylamino)ethyl]-2-(2-hydrazino-2-oxoethoxy)benzamide or its non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt A compound according to claim 1. 19 The compound is threo-4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2
2. The compound according to claim 1, which is hydroxybut-3-yl)oxy-benzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 20 The compound is erythro-4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-
(2-hydroxybut-3-yl)oxy-benzamide or a non-toxic pharmaceutically acceptable salt thereof;
The compound according to claim 1, which is a hydrate, an ester, or a quaternary ammonium salt. 21 The compound is 4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-(ethyl 3
-methoxycroton-4-yl)-oxybenzamide or a non-toxic pharmaceutically acceptable salt, hydrate, ester or quaternary ammonium salt thereof. 22. In a pharmaceutical composition for alleviating nausea and vomiting, the formula 1 [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower) alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl, or [Formula], or R ⁴ and R ⁵ are Together -NH-N
=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [Formula] or [Formula], in which n is a number of 1 to 4; Yes; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [formula] or [formula], and R ¹⁰ is hydrogen or (lower) alkoxy and R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ is at least one compound or a salt thereof that forms an oxygen-containing saturated 3- to 7-membered ring with the carbon atoms and oxygen atoms attached to it;
The above composition, characterized in that it contains an anti-emetic effective amount of the hydrate or solvate and a pharmaceutically acceptable carrier. 23. In a pharmaceutical composition for treating diseases associated with gastric motility disorders, the formula 1 [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower) alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl, or [Formula], or R ⁴ and R ⁵ are Together -NH-N
=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [Formula] or [Formula], in which n is a number of 1 to 4; Yes; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
[Formula] or [Formula], R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pinidyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ is at least one compound or a salt thereof that forms an oxygen-containing saturated 3- to 7-membered ring with the carbon atoms and oxygen atoms attached to it;
The above-mentioned composition, characterized in that it contains an effective amount of a hydrate or solvate for facilitating gastric motility and a pharmaceutically acceptable carrier. 24 formula 1 [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower) alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl, or [Formula], or R ⁴ and R ⁵ are Together -NH-N
=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [Formula] or [Formula], in which n is a number of 1 to 4; Yes; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl,
[Formula] or [Formula], R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula (wherein R ¹ , R ³ , R ⁴ and R ⁵ are as defined above) and a compound of formula R ² -L (where R ² is as defined above and L is a conventional residue) (a) in the presence of a base as a carrier for the acid to produce a compound of the formula, optionally a non-toxic pharmaceutically acceptable salt, hydrate or solvent. A method characterized by converting it into a hydrate or a quaternary ammonium salt. 25 formula [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower) alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl, or [Formula], or R ⁴ and R ⁵ are Together -NH-N
=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [Formula] or [Formula], in which n is a number of 1 to 4; Yes; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [formula] or [formula]; R ¹⁰ is hydrogen or (lower) alkoxy and R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula (where R ¹ is as defined above) and a compound of formula R ² -L (where R ² is as defined above and L is a conventional residue) are combined with a base as a carrier for the acid. When reacted in the presence of the formula The compound is prepared and the substituents are then added by conventional methods.
Obtaining a compound of the preceding formula by introducing R ³ , R ⁴ and/or R ⁵ into the compound of the formula or converting a precursor group into a substituent R ³ , R ⁴ and/or R ⁵ A method characterized by: 26 formula To produce the compound of The compound, namely metoclopramide, is treated with a thioalkoxide or thioaryloxide in an inert organic solvent or with NaOH or KOH in an organic solvent.
By reacting with or with 48% aqueous hydrobromic acid, the formula A compound of the formula is prepared, and then a compound of the formula is reacted with tetrabutylammonium bromide in an aqueous sodium hydroxide solution to obtain a compound of the formula 25. The process according to claim 24, wherein the compound of the formula is prepared and finally the compound of the formula is reacted with the compound of the formula in an inert organic solvent to obtain the compound of the formula. 27 formula... (However, R is NOH, NOCH ₃ , R ¹ is CH ₃ ,
CH ₂ −CH=CH ₂ ) in the method for producing a compound of formula is reacted with chloroacetone in an inert solvent and in the presence of a base to form the formula A compound of the formula is prepared, and then a compound of the formula and H ₂
Compounds of formula are prepared by reacting with NOH or H ₂ NOCH ₃ or NaBH ₄ or by reacting a compound of formula with BrCH ₂ CH=CH ₂ or CH ₃ in the presence of sodium hydride. It is characterized by producing a compound of the formula or reacting the compound of the formula (wherein R ₁ is CH ₃ ) with BrCH ₂ CH=CH ₂ in the presence of sodium hydroxide to produce the compound of the formula How to do it. 28 formula [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
is alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or [Formula], or R ⁴ and R ⁵ together are -HN-N=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [formula], in which n is a numerical value of 1 to 4; R ⁷ and R ⁸ are the same or different (lower) ) alkyl, (lower) alkenyl, (lower) alkynyl, [formula] or [formula], R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or _[ ^Formula _] ; ] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) Alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
Alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing a quaternary ammonium salt, a formula (wherein R ² , R ³ , R ⁴ and R ⁵ are as defined above) and a compound of formula H ₂ NR ¹ (wherein R ¹ is as defined above) are combined into triphenylphosphine. and di-(2-pyridyl)disulfide to obtain a compound of formula or b a compound of formula and a compound of formula H ₂ NR ¹ are reacted in the presence of P ₂
heating in the presence of O ₅ to obtain a compound of formula or c a compound of formula and a compound of formula H ₂ NR ¹ to form hexahalo-2,2,4,4,6,6-hexahydro-1,3 . acceptable salt,
A process characterized by conversion into a hydrate, solvate or quaternary ammonium salt. 29 formula [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
is alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or [Formula], or R ⁴ and R ⁵ together are -HN-N=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is and in the formula, n is a numerical value of 1 to 4; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [Formula] or [ R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl; m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula (where R ² , R ³ , R ⁴ and R ⁵ are as defined above) and formula H ₂ NR ¹ (where R 1 is as defined above) are reacted to form a compound of formula H 2 NR 1 (where R ¹ is as defined above). preparing, optionally converting a compound of said formula into its non-toxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt according to any of the above methods. How to characterize it. 30 formula [However, in the formula, R ³ is hydrogen; R ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
is alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or [Formula]; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is and in the formula, n is a numerical value of 2; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [Formula] or [Formula] R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula By reacting the compound with ethyleneamine, the formula A compound of the formula is prepared, and then a compound of the formula and the formula
By reacting with a compound of HNX ₂ (where X ₂ is R ⁷ and R ⁸ ), the formula and finally hydrolyzing a compound of formula c to produce a compound of formula c, optionally preparing a compound of formula c according to any of the above methods to obtain a non-toxic pharmaceutically acceptable compound of formula c. A process characterized by converting it into a salt, hydrate, solvate or quaternary ammonium salt. 31 formula [However, in the formula, R ³ is hydrogen, or when R ⁴ and R ⁵ are each hydrogen, R ³ is (lower) alkoxy; R ⁴ is hydrogen, amino, or (lower) alkoxy; ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
is alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or [Formula], or R ⁴ and R ⁵ together are -HN-N=N-; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [formula], in which n is a numerical value of 1 to 4; R ⁷ and R ⁸ are the same or different (lower) ) alkyl, (lower) alkenyl, (lower) alkynyl, [formula] or [formula], R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula By reacting the compound with lower alkanol in the presence of hydrochloric acid, the formula A compound of the formula is prepared, and then a compound of the formula and
H ₂ NR ¹ (wherein R ¹ is as defined above) is reacted with a compound of the formula preparing a compound of formula and then hydrolyzing the compound of formula with an acid to obtain a compound of formula;
A process characterized in that a compound of the formula is optionally converted into its non-toxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt according to any of the above processes. . 32 formula [However, in the formula, R ³ is hydrogen; R ¹ is and in the formula, n is a numerical value of 2; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [Formula] or [Formula] and R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or ^[ _{Formula ]} ; Formula] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula By reacting the compound with ethanolamine, the formula and then reacting the compound of the formula with thionyl chloride to produce the corresponding chloride, and then reacting the chloride with HNX ₂ (wherein X ₂ is R ₇ and R ₈ ). React the formula and finally alkaline hydrolysis of a compound of formula to obtain a compound of formula, optionally converting said compound of formula to a non-toxic pharmaceutically acceptable salt thereof according to any of the aforementioned methods. , a hydrate, a solvate, or a quaternary ammonium salt. 33 formula [However, in the formula, R ³ is hydrogen; R ⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower) alkylthio, (lower)
is alkanesulfinyl, (lower) alkanesulfonyl, sulfamyl or [formula]; R ⁶ is (lower) alkyl, (lower) alkenyl or (lower) alkynyl; R ¹ is [formula] and the formula where n is a numerical value of 2; R ⁷ and R ⁸ are the same or different and are (lower) alkyl, (lower) alkenyl, (lower) alkynyl, [Formula] or [Formula]; R ¹⁰ is hydrogen or (lower) alkoxy; R ¹⁷ is hydrogen, halogen, hydroxy, (lower)
is alkyl or (lower) alkoxy; A is oxygen or [formula]; R ² is [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] [formula] or [Formula]; X is oxygen, sulfur, or =NOR ¹⁶ ; Z is -(CH ₂ ) _P -, O, N, or [Formula]; Formula] [Formula] is pyridyl or oxazolidinyl, m is 2 or 3; p is 0, 1 or 2; q is a numerical value from 0 to 4; r is 2 or 3; R ⁹ is hydrogen or (lower) alkyl; R ¹¹ , R ¹² , R ¹³ , R ¹⁵ and R ¹⁶ are the same or different and are hydrogen, (lower) alkyl, (lower) alkenyl, (lower) alkynyl, (lower) ) alkoxy (lower) alkyl, cycloalkyl having 5 to 7 carbon atoms, or However, when R ¹¹ , R ¹⁵ or R ¹⁶ is (lower) alkenyl or (lower) alkynyl, the unsaturated carbon atom is not directly attached to the oxygen atom or nitrogen atom; R ¹⁴ is hydrogen, halogen , (lower) alkyl, (lower) alkenyl, (lower) alkynyl, cycloalkyl having 5 to 7 carbon atoms, hydroxy, (lower)
Alkoxy, (lower) alkenyloxy, (lower)
alkoxycarbonyl (lower) alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, [formula] or [formula]; R ¹⁸ and R ¹⁹ are the same or different and are hydrogen or (lower) alkyl; R ²⁰ and R ²¹ are each hydrogen or together represent [Formula] or [Formula]; or R ¹² and R ¹³ together with the carbon atoms attached to them are saturated hydrogen atoms having 5 to 7 carbon atoms; forming a ring, said ring optionally having at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹² and R ¹⁴ together with the carbon atoms attached to them contain from 5 to forming a saturated or unsaturated ring having 7 atoms, optionally containing at least one heteroatom selected from the group consisting of oxygen, sulfur and nitrogen; or R ¹⁴ and R ¹⁵ forms an oxygen-containing saturated 3- to 7-membered ring together with the carbon and oxygen atoms attached to them], or its pharmaceutically acceptable non-toxic salts, hydrates, solvates, or In the method for producing quaternary ammonium salt, the formula By reacting the compound with H ₂ NCH ₂ CH ₂ Cl, the formula
and then reacting a compound of the formula with HNX ₂ (wherein X ₂ is R ⁷ and R ⁸ ) to obtain the formula
preparing a compound of the formula and finally performing alkaline hydrolysis of the compound of the formula to obtain a compound of the formula;
A process characterized in that the compound of said formula is optionally converted into its non-toxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt according to any of the above processes. 34 Compounds numbered 1 to 30 below, namely 1 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-methoxyethoxy)-benzamide, 2 4-amino-5-chloro -N-[2-(diethylamino)ethyl]-2-(2-hydroxyethoxy)-benzamide, 3 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2,2- dimethoxy-ethoxy)-benzamide, 4 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyethoxy)-methyloxy]benzamide, 5 4-amino-5-chloro -N-[2-(diethylamino)ethyl]-2-(2-propanone-1
-yl)-oxybenzamide, 6 4-amino-2-benzoylmethyloxy 5
-chloro-N-[2-(diethylamino)ethyl]-benzamide, 7 4-amino-2-(butan-2-one-3-
yl)oxy-5-chloro-N-[2-(diethylamino)ethyl]-benzamide 8 4-Amino-5-chloro-2-(cyclohexanon-2-yl)oxy-N-[2-(diethylamino)ethyl] Benzamide, 9 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(5-hexene-2-
on-3-yl)-oxybenzamide, 10 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-hydroxyimino)-propan-1-yl)-oxybenza Mido, 11 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methoxyimino)-propan-1-yl)-oxybenzamide, 12 4-amino-5- Chloro-N-[2-(diethylamino)ethyl]-2-(2-hydroxypropan-1-yl)oxybenzamide, 13 4-amino-5-chloro-2-cyanomethyloxy-N-[2-( diethylamino)ethyl]
-benzamide, 14 4-amino-2-(carboxamidomethyloxy)-5-chloro-N-[2-(diethylamino)ethyl]-benzamide acetate, 15 4-amino-2-(2-butyn-1-yl )
Oxy-5-chloro-N-[2-(diethylamino)ethyl]-benzamide, 16 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2-methylsulfinyl) -ethoxy]benzamide, 17 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(pentan-2-one-3-yl)-oxybenzamide, 18 4-amino-2- (2-butanon-1-yl)
Oxy-5-chloro-N-[2-(diethylamino)ethyl]-benzamide, 19 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(pentan-2-one-1- yl)-oxybenzamide, 20 4-amino-5-chloro-2-(pentane-
3-on-2-yl)oxy-N-[2-(diethylamino)ethyl]-benzamide, 21 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-hydrazino- 2
-oxo-ethoxy)benzamide, 22 threo-4-amino-5-chloro-N-[2
-(diethylamino)ethyl]-2-(2-hydroxybut-3-yl)oxybenzamide, 23 erythro-4-amino-5-chloro-N-
[2-(diethylamino)ethyl]-2-(2-hydroxybut-3-yl)oxybenzamide, 24 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-[(2 -(Methylamino)-2-oxoethoxy]benzamide, 25 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(ethyl-3-methoxy-croton-4-yl)oxybenza Mido, 26 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(1,3-dioxolan-2-yl)oxybenzamide, 27 4-amino-5-chloro-N- [2-(diethylamino)ethyl]-2-(oxazolidine)-
2-one-5-yl-methyl)oxybenzamide, 28 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2-pyridinomethyl)oxybenzamide, 29 4-amino- 5-chloro-N-[2-(diethylamino)ethyl]-2-tetrahydrofurfuryl-oxybenzamide, and 30 4-amino-5-chloro-N-[2-(diethylamino)ethyl]-2-(2 -methoxyethoxy-ethyl)oxybenzamide, and optionally converted into their non-toxic pharmaceutically acceptable salts, hydrates, solvates or quaternary ammonium salts. The method according to paragraph 24.