CS271462B2 - Method of substituted benzamides production - Google Patents

Description

Hal, r! and R ² are as defined below, which are useful in the treatment of emesis, in particular emesis induced by chemotherapy, such as treatment for the cancer patient specimen cisplatin, and / or the treatment of disorders of gastric motility, such as delayed gastric emptying, dyspepsia, flatulence, esophageal reflux, etc.

Emesis is a common and serious problem for the incidence of patients treated. chemotherapeutics against malignant tumors. In a significant number of patients, nausea and vomiting are so severe that it is necessary to discontinue chemotherapy before discontinuation. While no known antiemetic agent is fully effective in alleviating the emesis associated with chemotherapy, there are nevertheless a large number of compounds (many of which are structurally substituted benzamides) showing good antiemetic activity.

Although the complete mechanism of action of antiemetic agents is unknown, potent antiemetic agents are generally dopaminergic antagonists. Indeed, screening for potential anti-emetic agents is usually performed using assays designed to detect dopaminergic blockade, such as in vitro spiperone binding assays and emesis induced apomorphine induced in dogs.

Due to their dopaminergic antagonism and / or depressive effect on the central nervous system, known antiemetic agents have undesirable side effects such as sedation, dystonic reactions, diarrhea and restlessness.

Surprisingly, a group of substituted amide-based antiemetic agents has now been found which have a highly specific effect, are not dopaminergic antagonists and do not have the undesirable side effects of prior art antiemetic agents.

An excellent modern review of variously substituted benzamides and their pharmacological efficacy can be found in the Chemical Regulation of Biological Mechanism " ed. AND.

M. Creighton and S. Turner, Royal Society of London (1982), in the chapter entitled Substituted Benzamides as Oopamine Antagonists, by M.S. Hadley (pp. 140-153). It is stated that this class of compounds is defined by the general formulas.

CS 271462 02 conh - nr ₂

¹ aryl 1 к / v ✓ / X

'aryl}

У in which the aryl ring is most commonly a phenyl ring and wherein the methoxy group is ortho-positively present in the ortho position to the benzamide moiety. It should be pointed out that the various effects of substituted benzamides can be considered as a result of these compounds being dopamine antagonists.

Representative prior art patents describing N-substituted benzamides with various substituents on the phenyl ring include the following:

U.S. Patent No. 3,219,526, issued Nov. 23, 65 (M.L. Thominet), describing substituted benzamides of the general formula

in which

Y

means the rest of the formula Z “ ¹ -N or -NL w

where

2

R and R are each alkyl and are oxygen, methylene or NR, wherein R is hydrogen, alkyl or alkylsulfamoyl,

W represents an alkylene group,

A is an alkyl group,

В is a sulfur or oxygen atom and

X, Y and Z are each hydrogen, halogen, alkoxy, nitro, amino, alkylamino, dialkylamino, lower acyl, lower acylamino, cyano, alkylmercapto, sulfamoyl, alkylsulfamoyl, dialkylsulfamoyl or haloalkylsulfamoyl.

These compounds are apomorphine antagonists and are reported to act as anti-emetic agents. The above-cited patent documents are related U.S. Patent Nos. 3,177,252 (issued April 06, 65) and 3,312,739 (issued April 4, 67), which also have similar content.

British Patent Specification No. 1,500,105, published Feb. 08, 78, describes substituted benzamides of the general formula

in which

A n is hydrogen, C 1 -C 5 alkyl or C 2 -C 5 alkenyl,

X is hydrogen, C 1 -C 5 alkoxy, C 2 -C 5 alkyl, C 2 -C 5 alkenyloxy or C 2 -C 5 alkenyl,

Y represents a hydrogen atom, a halogen atom, a nitro group, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms, an amino group or a substituted amino group,

Z is hydrogen, halogen, C 1 -C 5 alkoxy, C 1 -C 5 alkylsulfonyl, or a radical of formula

- SO ₂ NR ¹ R ² wherein

2

R @ 1 and R @ 2 are the same or different and each represents a hydrogen atom or a C1 -C5 alkyl group, or --NR @ 2 R @ ² represents a heterocyclic ring containing optionally another heteroatom,

W represents a straight or branched alkylene group having 1 to 5 carbon atoms,

V is -NR ³ R ⁴ where R * ⁵ is C 1 -C 5 alkyl and R ⁴ is C 1 -C 5 hydroxyalkyl,

CS 271462 В2

Or V represents a nitrogen-linked heterocyclic ring optionally containing a second nitrogen atom and optionally carrying a substituent, or V represents a racemic, dextrorotatory or left-handed heterocyclic ring of the general formula

where

R is a (C 1 -C 5) alkyl group containing a reactive function such as a hydroxyl group, a mercapto group,

- oxo, thioxo, oxo or thia, and m is 1, 2 or 3,

Z and their acid addition salts, oxides and quaternary ammonium salts. These compounds are said to be apomorphine antagonists and to have valuable therapeutic properties, in particular to act as antiemetics.

U.S. Patent No. 4,207,327, issued Jun. 10, 1987 to C. O. Lundsford et al.

in which

R is alkyl, cycloalkyl or phenylalkyl, represents alkyl, cycloalkyl or phenylalkyl, represents hydrogen, alkyl or phenyl and represents hydroxyl, cyano, nitro, amino, fluoro, chloro or bromo, trifluoromethyl , alkyl, alkoxy, sulfamoyl or acetamido, wherein the individual substituents of R ⁵ may be the same or different.

These compounds are said to have antiemetic properties and cause gastric emptying.

U.S. Pat. No. 3,966,957, issued May 29, 76 to Cale et al., Discloses substituted benzamides of the formula

in which

R represents a cycloalkyl group, a phenyl group or a phenylalkyl X group; represents a hydrogen atom, an alkyl group having 1 to 0 carbon atoms or a phenyl group,

R is halogen, alkyl, alkoxy, amino, nitro, alkylamino, dialkylamino, mercaptomethyl, acetamido, sulfamoyl, cyano, hydroxyl, benzyloxy or a trifluoromethyl group and n is an integer of 0-3 _tons and the substituted thiobenzamide ocecného formula

R ¹

in which

R

R ¹

R ² represents a cycloalkyl group, is hydrogen or alkyl having 1-0 carbon atoms, represents nitro, amino, halogen, sulfamoyl or alkoxy group and n is an integer of 0 to 3, the pharmaceutically acceptable addition salts thereof with acids.

U.S. Pat. No. 3,963,745 is related to the above cited patent and has substantially identical content. The above compounds are said to be apomorphine antagonists and useful as antiemerics. Some of these compounds are reported to reduce catalepsy in rats.

The invention relates to compounds of formula I

in which

Hal

R ¹ represents a halogen atom, represents a radical of formula

- (CH ₂ ) _n

^X R ⁸ or

where

R ⁷ _R 10

R ( ¹¹⁾ are the same or different (C1-C4) -alkyl, (C1-C4) -alkoxy and is a radical of formula

R ¹⁷

wherein n is an integer of 1 to 4; and

R ¹⁷ is hydrogen or halogen, and is a radical of formula

-CH ₂ CH ₂ Cl ₂ O. ^U ,

R ¹²

AND

-CHCH 0R-,

R

IX ^х -cc

R ¹²

-С -

where

X

В

R ¹² I R ¹² I 1 -CH (OH ₂ ) _q B, 1 -C-CN AND at

or

CH -

R ¹⁴

represents oxygen or a group = NOR ¹⁶ , O is -NHCR ⁹ , (0) ^fp 9 -S-R \ 0 R ⁹ -c - - (Ьн) \ n7 ^2r X 9 ir > pyridyl or

R ¹² and R ¹³

H is an oxazolidinyl residue, m is an integer of 2 or 3, p is an integer of 0, 1 or 2, q is an integer □ of 0 to 4, г is an integer of 2 or 3,

Q

R represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms, the same or different and each represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms, an alkenyl group having at most 4 carbon atoms, an alkoxyalkyl group containing in each alkoxy, alkyl moiety C 1 -C 4 or C 5 -C 7 cycloalkyl, with the proviso that when R 1 is an alkenyl as defined above

CS 271462 v2, the unsaturated carbon atom is not directly attached to the oxygen atom,

R is hydrogen, halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydrazino, arylhydrazino, thienyl, phenyl, C 1 -C 4 phenylalkyl, or amino,

16 18

R, R, R and R are the same or different and are each a hydrogen atom or a C 1 -C 4 alkyl group,

21

R and R either represent hydrogen atoms or together form a group

or R 12 _and together with the carbon atoms to which they are attached may form a saturated ring of 5 to 7 atoms, optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, or and together with a carbon and oxygen atom, to which they are attached may form a three to seven membered saturated oxygen ring, and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates or quaternary alkyl ammonium salts containing from 1 to 4 carbon atoms in each alkyl moiety.

A preferred group of compounds according to the invention are compounds of formula I

(AND)

- in which R ⁷ and R ⁸ they are the same or different and are each ethyl or methyl group and R ² represents the rest of the formula

-CH ₂ 0CH ₂ CH ₂ 0R

-CH ₂ CH ₂ OR

CS 271462 ^в2

-CHCN

О

wherein the individual general symbols are as defined above, and non-toxic, pharmaceutically acceptable salts, hydrates, solvates or the above-defined quaternary ammonium salts thereof.

Particularly preferred compounds of formula I are

4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N '

4-amino-5-chloro-N4-afnino-5-chloro-N [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl]

-2- (2'-methoxyethoxy) benzamide

-2- (2-hydroxyethoxy) benzamide,

-2- (2,2-dimethoxyethoxy) benzaniide,

-2 - [(2-methoxyethoxy) methyloxy] benzamide,

-2- (2-propanol-1-yl) oxybenzamide

4-amino-2-benzoylmetholoxy-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 '(cyclohexanone-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- (diethylamine) ethyl] -2 - [(2-hydroxyimino) propan-1-yl] oxybenzamide, 4-amino-5-chloro-N- [2- (diethylamine) 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-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-butanone-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- (pentan-3-one-2-yl) oxy-N- (2-diethylaminoethyl) benzamide;

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-hydrozino-2-oxoethoxy) 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-methoxycoton-4-yl) oxybenzamide,

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (1,3-dioxolan-2-yl) oxybenzamide,

4-Amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2 - (diethylamino) ethyl] [2- (diethylamino) ethyl] -2- (2-methoxyethoxyethyl) oxobenzamide

-2- (oxazolidin-2-one-5-ylmethyl) oxybenzamide,

-2- (2-pyridinomethyl) oxobenzamide,

-2-tetrahydrofurfuryloxybenzamide and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates and the above-defined quaternary ammonium salts.

The invention also encompasses all possible optical and geometric isomers of the compounds of Formula I as well as tautomeric forms where possible. Further, the invention includes a process for the preparation of compounds of formula I and antiemetic and / or gastrokinetic compositions comprising at least one compound of formula I as active ingredient. _E

In accordance with the invention, compounds of formula I are prepared by reacting a compound of formula II with a compound of formula R-L wherein L is a conventional leaving group in the presence of a base as an acid acceptor. The following reaction scheme illustrates this reaction.

Reaction Scheme 1

(II)

Suitable leaving groups L are well known to those skilled in the art and include, for example, chlorine, bromine, iodine, methanesulfonyl, toluenesulfonyl and the like. The base used may be a mild base such as potassium carbonate, sodium carbonate, magnesium sulfate or a quaternary ammonium hydroxide, 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, dimethyl ether, diethylene glycol and the like. It is also possible to use sodium hydride or potassium hydride as the base and work in anhydrous aprotic solvent. or use a strong base such as sodium hydroxide or potassium hydroxide as a highly concentrated solution and work in a phase transfer solvent system such as dichloromethane-water with the addition of a quaternary ammonium halide, -sulfate or -hydroxide as a phase transfer catalyst such as tetrobutylammonium chloride , cetoutrimethylammonium bromide, benzyltriethylammonium chloride and the like.

It will be appreciated by those skilled in the art that Reaction Scheme 1 may also be modified so that the substrates Hal and / or NH 2 may no longer be present in the compound of Formula II, but may be introduced as the final Qtupeff into the compound of Formula I (or a suitable precursor residue). For example, a compound of formula (I) in which a hydrogen atom is present instead of Hal may be chlorinated to give the corresponding compound of formula (I) in which Hal is a chlorine atom. Similarly, in the compound of formula I, for example, nitro, -NHCOR, or -N = CHN (R) 2, where R is lower alkyl, may be in place of the amino group. The nitro group can then be reduced to the amino group, or the -NHCOR or -N ^ CHNCR 4 moieties can be hydrolyzed to the amino group.

Preferably the tetrasubstituted amine salt soluble in an organic solvent is used in the process of the invention, as illustrated in the following scheme for one of the preferred compounds of formula (I).

(lila)

02

CHLCN —и ---- *

CH 2 Cl 2 CHCl 3

СИ ₃

In the first reaction step, the compound of formula IIIa is dissolved in aqueous sodium hydroxide and one equivalent of tetrabutylammonium bromide is added. The quaternary ammonium salt of formula IIIa precipitated from the solution is filtered off and then reacted with the desired alkylating agent in an inert organic solvent such as dimethylformamide, dimethylacetamide, acetonitrile, tetrahydrofuran, chloroform, dimethylsulfoxide or diethylene glycol dimethyl ether to give the desired product Ia.

The intermediate of formula (IIa) can be prepared, for example, by demethylation of a commercially available metoclopramide of formula

Metoclopramide can be demethylated by methods known in the art. Suitable processes include reaction with a thioalkoxide or thioaryloxide, such as sodium thioethoxide, potassium thioethoxide, lithium thioethoxide or sodium thiophenoxide in an inert organic solvent such as dimethylformamide or dimethylsulfoxide, or reaction with sodium hydroxide or potassium hydroxide in glycerol, ethylene glycol, or diethylene glycol dimethyl ether, or reaction with 48% aqueous hydrobromic acid. Demethylation using sodium thioethoxide in dimethylformamide is preferred.

It will be appreciated that certain substituents at the 2-position may be difficult to introduce directly into the compound of formula IIIa without carrying out the appropriate protecting measures and subsequent deprotection. In contrast, the originally introduced 2-substituent can be subsequently modified. Various conversions are set forth below using a compound of formula Ib, another preferred compound of the invention, which exemplifies herein.

(Ib)

Η ₂ Ν0Η

NaBH.

db) _____1

CS 271462 02

NaH

BrCH ₂ CH = CH ₂

(Ib)

NaH

BrCH ₂ CH = CH ₂

CONHCl 2 CH 2

CS 271462 В2

The physiology and neuropharmacology of emesis, and especially emesis resulting from chemotherapy, is not fully known. The emesis control mechanism consists of two distinct areas in the spinal cord, the emetic center and the chemoreceptor trigger zone (CPM). The emetic center, which is the ultimate common center for all emetic stimuli, is located in the lateral reticular formation of the fourth chamber. CTM is also located at the bottom of the fourth ventricle, in the postrema area, and appears to be activated by chemical stimuli in the blood and cerebrospinal fluid. emesis occurs. Reflex-induced vomiting can also be caused by irritation (and resulting stimuli) from the gastrointestinal tract or by stimulation of receptors in the central nervous system. It is believed that another source of emesis is the cerebral cortex. Indeed, the common problem of pre-vomiting in chemotherapy-treated patients is clearly not related to exogenous chemical stimuli. It is believed that pre-vomiting is initially mediated by the cerebral cortex, which can then stimulate the einetic center in the spinal cord.

There are currently a variety of commercially available anethiemotic agents such as metoclopramide, bromopride, alizapride, clebopride, domperidone and nabilone. The lead compound is metoclopramide, which is widely used in combination with cisplatin, which is a potent but highly emetogenic chemotherapeutic agent.

The currently available substituted benzamide-based anti-emetic agents are generally dopaminergic antagonists and are also believed to exert their anti-emetic activity by blocking dopamine receptors in CTZ. Screening assays for potential anti-emetic agents include assays for determining dopaminergic antagonist activity, such as in vitro spiperone binding assays and assays for suppressing apomorphine-induced vomiting in dogs or cats.

The principal adverse effects of known substituted benzamide-based anti-emetic agents are due to dopamine blocking activity and include restlessness, acute dystonia, Parkinson's syndrome and tardive dyskinesia, often together with nervous system depression.

The compounds of formula (I) of the present invention are potent antiemetic agents but are not dopaminergic antagonists as evidenced by both in vitro (spiperone binding) and in vivo (apomorphine-induced emesis in dogs) tests. Thus, the compounds of formula I exhibit good anti-emetic activity (particularly against emesis induced by the application of chemotherapeutic agents) with high specificity of action, but do not have the ability to produce side effects (as described above) characteristic of dopaminergic antagonists of the substituted benzamide-based anti-emetic agent.

Many of the commercially available substituted benzamide-based anti-emetic agents (such as metoclopramide) also have gastrokinetic activity and are useful in the treatment of disorders associated with impaired gastrointestinal motility such as delayed gastric emptying, dyspepsia, flatulence, esophageal reflux and the like. The compounds of formula (I) exhibit similar efficacy to metoclopramide in guinea pig stimulated ileum (see Table 2), one of the standard screening tests for substances with gastrokinetic activity. Even in this case, since they are not dopaminergic antagonists, the compounds of formula I do not tend to produce the above-mentioned side effects characteristic of commercially available substituted benzamides such as metoclopramide or clebopride.

The following section describes the biological tests and their results.

A) Displacement of 1 H-spiperone

This assay is for the detection of compounds capable of displacing radioactive spiperone ligand in vitro using rat brain striatum corpus homogenate. This assay is used to identify compounds exhibiting affinity for dopaminergic (D 1) receptors.

The rats weighing 150 + 10 g (Charles River) are decapitated, their corpus striatum removed and frozen in solid carbon dioxide. Tissues are pooled and stored at -80 ° C until use. The homogenates (Brinkmann Polytron) corpus striatum in cold HEPES.KOH buffer (final pH 7.4) are centrifuged at 39,000 x G, the supernatant discarded and the solid material is again centrifuged as above before resuspending in HEPES.KOH buffer. The supernatant is discarded again and the solid material is suspended in a buffer consisting of 50 mM HEPES.KOH containing 0.1% (w / v) ascorbic acid, 10 pmol pargylline, 120 mmol sodium chloride, 5 mmol potassium chloride, 2 mmol chloride of calcium chloride and 1 mmol of magnesium chloride at 20 ° C (final pH 7.4) at a concentration of 1 g wet solid tissue per 100 ml buffer.

The assays to determine the inhibitory concentration values of ((IC ₅₀ ) of compounds of formula I and comparative compounds against ³ H-spiperone are performed as follows. Tubes are prepared containing either 100 µl of buffer (to determine total binding) or 100 µl of buffer and 100 µl of 10 ~ ⁴ MD (+) - butaclamol (blank, ie, to determine non-specific binding), or 100 µl of buffer containing 10?, 10 10 or 10 mol of test substance. 100 µl of H-spiperone solution (New England Nuclear) in buffer (2000 pulses per minute in incubation mixture) and 800 µl of striatal tissue suspension are added to each of these tubes. The contents of the tubes are then diluted to 1 ml with the buffer to obtain a 10 M, 10 M or 10 ^µ M concentration of the test substance and about 100 µM ³ H-spiperone. The samples were incubated at 37 ° C for 15 minutes, then filtered under vacuum through a glass fiber filter and evaluated by liquid phase scintillation spectrometry.

For all test compounds were not even at the highest concentration (10 ^-6 PM = 1000 nM) IC _5Q achieved, so these results are in Table 2 identified as> 1000 nM. For comparison compound и which was the original concentration was reached values 1C _5O (or these values are exceeded), the к accurately determine ΙΟ ^ θ test was repeated using a quarter, half, equal, double and quadruple the concentration based on the concentration of which was found (using the original concentrations) to be closest to the IC 50 value. The latter values are given in Table 2. Each test is performed with two samples each.

B) Anatagonizing emesis induced in the dog by apomorphine

Dogs (beagles) of both sexes, which were not denied food, were used as test animals. Both test compounds and apomorphine are administered subcutaneously in aqueous solutions, the test substance being administered 30 minutes before apomorphine administration. Dogs are observed for 60 minutes after apomorphine administration to detect either emesis or complete suppression of emesis (quantitative response).

Apomorphine is administered at a dose of 0.3 mg / kg. Because the test compounds do not substantially antagonize apomorphine, they are administered at a dose of 3 mg / kg. If 50% antagonism (50% emesis suppression) is not achieved at this dose, this is recorded in Table 1 as> 3 mg / kg. Since comparative compounds such as metoclopramide, alizapride, clebopride and domperidone act as dopaminergic antagonists, they are administered at lower doses and the calculated ED $ q values are shown in Table 1. All tests should be performed on at least two dogs.

C) Antagonism of emesis induced in ferrets by sisplatin

Adult male ferrets weighing 1.0 to 1.5 kg are anesthetized by intraperitoneal administration of 30 mg / kg natriumpentobarbital. The ventral and dorsal parts of their neck are shaved and a 3 cm incision is made. The left jugular vein is dissected and ligated with silk at the head end. A 18 cm long plastic tube (Silastic) (0.51 mm ID, 0.94 mm OD) is made into a 2 inch (0.44 mm ID, 1.57 mm OD) insertion catheter. unclipped heparin and a 25 mm needle at the outer end. A small incision is made into the juCS 271462 B2 spherical vein, a catheter is inserted, the free end of which is inserted through a No. 13 trocar 5 cm under the skin and attached with a silk to the back of the neck. Ferrets are placed in individual cages and allowed to recover for 2-4 days prior to the test,

On the day of the test, the test compounds are administered via a 1 ml / kg intravenous catheter (3 mg / ml concentration) 5 minutes before and 90 minutes after cisplatin administration. The cisplatin solution is prepared by adding physiological saline solution at 70 ° C, stirring and sonication until dissolution. The resulting 4 mg / ml solution was stored at 40 ° C and administered intravenously using a 12 mg / kg catheter. Following cisplatin administration, ferrets are continuously observed for 4 hours, recording the number of emissions. Two or more Emissions within one minute are considered as one Emissions.

At the end of the test, ferrets are sacrificed by intravenous administration of T-61 and the correct placement of the catheter is verified. The results of this test are shown in Table 1 in percentage of protection against emesis compared to that in animals treated with saline only. The dose and number of test animals are also shown for each test.

D) Gastrokinetic efficacy

A number of compounds of the invention have been found to increase contractions of guinea pig ileum irritated by electric current. This activity is believed to correlate with gastrokinetic (prokinetic) activity in vivo, i.e., increase in gastric motility and gastric emptying.

Normal male guinea pigs (Hartley; Charles River) weighing 300-400 g are sacrificed by breaking the ligament and removing the terminal portion of their ileum after discarding a 10 cm segment close to the ileocecal junction. The 3 to 4 cm long ileum strips are suspended in a 20 ml organ bath containing Krebs physiological buffer solution, which is heated to 37 ° C and mixed with 95% oxygen and 5% carbon dioxide. A constant tension of 1.0 g is set and the tissues are equilibrated for 15 minutes without irritation. Platinum wire (cathode) is used for electrical irritation, which is passed through the lumen of the intestine and another platinum wire anode which is mounted on a glass rod on which suspended muscle. Tissues are coaxially 1.5 times the voltage required to induce maximum contraction, using single pulses of 0.5 ms duration, applied every 10 seconds. After equilibration for 15 minutes (without irritation), the stimulator (Grass S88 Stimulator) is turned on and the tissues are allowed to stabilize for about 1 hour or until the contraction level has stabilized, washing every 20 minutes. The ileum contractions were recorded with isometrics using a force transducer (Crass FT03C) and a Dynograph recording device. Some of the compounds of formula I which cause an increase in contractions of guinea pig ileum irritated preparations are shown in Table 2 together with their average percentage maximum increase, the ininimal effective concentration (^ mol), the effective concentration ₃ θ (EC ₃₀ ) and in some cases effective concentration ((EC ₅₀ ) in pmol.

Dopaminargic antagonism and antiemetic activity

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Tables 1 and 2 show that the compounds of formula I exhibit anti-emetic and gastrokinetic activity, with the data in Table 1 suggesting that the disclosed compounds are not substantially dopaminergic antagonists and therefore do not tend to cause side effects characteristic of currently available anti-emetic and substituted benzamide gastrokinetic agents.

The compounds of formula I may be administered either orally or parenterally or in the form of suppositories. When used as an antiemetic in patients treated with chemotherepeutic anti-cancer agents, the compound of the invention is preferably administered by intravenous infusion diluted with a large volume of parenteral solution (such as 5% aqueous dextrose solution, 5% dextrose solution in 0.45% sodium chloride, Ringer's solution for injection and the like) When used as gastrokinetic agents, the compounds are preferably administered orally when the symptoms of the disease are not severe. In severe symptoms, treatment is preferably initiated by intramuscular or intravenous administration, which is continued until the severe symptoms have resolved, and then oral administration may be initiated.

The dosage of the compounds of the invention depends on the purpose for which they are used (antiemetics or gastrokinetics), the particular compound administered, the age, weight and general health of the patient, as well as the severity of the disease, and is in any case a physician's concern.

For gastrokinetic purposes, the compounds of the formula I are generally administered in doses of from 1 to 100 mg, preferably from 5 to 50 mg, two to five times a day, preferably four times a day, for example before each meal and at bedtime.

In order to prevent nausea and vomiting induced by emetogenic chemotherepeutic agents for the treatment of cancer, the compounds of formula I are generally administered (diluted with a large volume of solution for parenteral administration) at a dose of from 0.1 to 50 mg / kg, preferably from 0.5 to 10 mg. / kg, several times a day. The particular dosage employed depends on the above factors as well as on the emetogenicity of the chemotherepeutic agent for the treatment of cancer. Generally, a first dose of a compound of Formula I should be administered prior to the administration of a chemotherapeutic agent for the treatment of cancer, for example 30 minutes, and thereafter every 2 to 8 hours after administration of the chemotherepeutic agent until relief or alleviation of nausea and vomiting. 24 hours.

Tablets and capsules for oral administration are preferably in unit dosage form and may contain conventional ingredients such as binding agents, fillers, glidants, tablet disintegrating agents, wetting agents, and the like. The tablets may optionally be coated using conventional techniques. Liquid preparations for oral administration may take the form of aqueous or oily suspensions, solutions, emulsions, syrups, or elixirs, or may be presented as a dry product for reconstitution with water or other suitable vehicle before use. Liquid preparations may contain conventional additives such as suspending agents, emulsifiers, non-aqueous vehicles (including edible oils), preservatives, as well as flavoring and / or coloring agents.

For parenteral administration, the compounds of formula I are combined with a sterile vehicle. Depending on the vehicle and concentration of the active ingredient, the resulting dosage form may be a solution or suspension. This vehicle is normally constituted of sterile water, at least in large part, although saline solutions, glucose solutions and the like may also be used. Suspensions for injection may also be used, in which case conventional suspending agents may be used. Conventional preservatives, buffering substances and the like may also be added to parenteral dosage forms.

For the preparation of solid dosage forms either a compound of the formula sůl in free base form or a salt of a compound of formula I may be used. In the case of aqueous solutions, whether for oral or parenteral administration, salts of the compounds of formula I are often preferred. for the usually higher solubility of these salts in aqueous solutions.

For ease of administration and uniformity of dosage, the aforementioned pharmaceutical compositions are used

CS 271462 82 are particularly preferably formulated in unit dosage forms. By unit dosage forms is meant physically discrete units suitable as single doses, each containing a predetermined amount of active ingredient to produce the desired effect, in combination with the desired pharmaceutical carrier.

The invention also provides pharmaceutical compositions for the relief of nausea and vomiting comprising an anti-emetically effective amount of at least one compound of formula I or a salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

The invention further provides pharmaceutical compositions for treating disorders associated with impaired gastric motility comprising at least one compound of formula I, a salt, a hydrate or a solvate thereof in an amount effective to enhance gastric motility, and a pharmaceutically acceptable carrier.

The invention also provides a method of alleviating nausea and vomiting in a warm-blooded animal in need thereof, comprising administering to said animal an anti-emetically effective amount of at least one compound of formula I or a salt, hydrate or solvate thereof in a pharmaceutically acceptable carrier.

The invention further provides a method of treating disorders associated with impaired gastric and warm-blooded motility disorders, which comprises administering to such an animal at least one compound of formula I or a salt, hydrate or solvate thereof in a pharmaceutically acceptable carrier in an amount effective to increase motility. stomach.

The invention is illustrated by the following non-limiting examples. .

Prepared

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide

A) 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride

To a suspension of 57.44 g 60% sodium hydride (1.436 mol) in 1275 ml dimethylformamide, cooled below 10 ° C, a cold solution of 89.22 g (1.436 mol) ethanethiol in 250 ml dimethylformamide was added dropwise. After hydrogen evolution ceased, 287.0 g (0.957 mol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide prepared according to U.S. Pat. No. 3,357,978 (1965) was added. The mixture was heated to 100-105 ° C in an oil bath for 90 minutes. The solvent was evaporated in vacuo and the residue was partitioned between 800 ml methylene chloride and 400 ml water. The aqueous layer was washed with an additional portion of methylene chloride and the combined organic extracts were washed with 150 mL of water. The combined aqueous phases are cooled in ice and 200 ml of concentrated hydrochloric acid are added. After 20 minutes, the precipitate is filtered off, sucked briefly on the filter, then stirred in 500 ml of methanol and filtered again. After drying under vacuum, the product yields 302.3 g (98%) of the title compound as a slightly beige solid, mp 235-237 ° C.

Analysis calculated for: ^{C 13 H} 20 ^ClN 3 O 2 • C, 48.46; H, 6.57; N, 13.04; Cl, 22.00; Found: C, 47.67; H, 6.73; N, 12.84; Cl, 21.43.

8) 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide

To 6 ml of concentrated ammonium hydroxide, 3.00 g (0.0093 mol) of 4-amino-5-chloro-N- (2- (diethylamino) ethyl) -2-hydroxybenzamide hydrochloride was added with stirring, and the mixture was stirred for 5 minutes 3 to 4 moles of water are added thereto and stirring is continued for a further 5 minutes.The precipitated solid is filtered off, washed twice with 3 ml of water each time and dried to give 2.37 g of the title compound. mp 134-136 ° C.

NMR (90 MHz, CDCl3):

7.26 (singlet, 1 H), 6.90 (singlet, 1 H),

6.14 (singlet, 1 H), 4.39 (singlet, 2 H),

3.40 (singlet, 2 H). 2.60 (multiplet, 6H), 1 _{out of} 06 (triplet, 6H).

Preparation 2

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (alternative procedure)

A mixture of 29.5 g (0.1 mol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide. 4.0 g (0.1 mol) of sodium hydroxide in the pellets and 70 ml of 1,2-propanediol were heated to reflux for 20 hours with stirring and then concentrated in vacuo. The residue is stirred with 100 ml of 1N hydrochloric acid and concentrated again in vacuo. The residue is chromatographed on silica gel using methylene chloride. 90: 10: 0.5 methanol / ammonia. The appropriate fractions were combined, concentrated in vacuo and the residue crystallized from ether. 9.3 g of product are obtained, which is dissolved in hot water. The solution is filtered through charcoal, the filtrate is cooled, and 6.7 g of the reddish-brown title compound melting at 126 DEG -127 DEG C. (melting point 160 DEG C.) is isolated by filtration. ).

Analysis: for ^C 13 ^H 20 ^CIN 3 ° 2 requires 54.64% C, 7.05% H, 14.70% N; found: 54.44% C, 7.15% H. 14.65% N.

Preparation 3

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide, tetra-n-butylammonium salt

To a solution of 10 g (0.031 mol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride and 5 g of sodium hydroxide in 100 ml of water was added 10.6 g (0.031 mol) with stirring ) tetra-n-butylammonium hydrogen sulfate. The precipitated crystals are collected and dried after washing with water. 14.7 g (87%) of material are obtained which, after recrystallization from ethyl acetate, yields the title compound containing 0.5 moles of crystalline water, m.p. 136.5-138.5 ° C.

Analysis: for ^C, 2 g ^H 55 ^CIN 4 ⁰ * 2 ° ^{/ 5H} 2 ° Calculated 64.95% C 10.63% H 10.55% N 1.71% H ₂ 0;

found 65.06% C, 10.42% H, 10.40% N, 1.41% H ₂ 0th

Example 1

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-methoxyethoxy) benzamide

A mixture of 2.50 g (7.76 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride, 1.47 g (15.5 mmol) of 2-chloroethyl methyl ether. 2.14 g (15.5 mmol) of potassium carbonate and 0.80 g (7.76 mmol) of sodium bromide in 40 ml of dimethylformamide were stirred and refluxed for 4 hours. The dimethylformamide was evaporated in vacuo, the residue redissolved in methylene chloride and the solution was washed with water and dilute sodium hydroxide. The solvent was evaporated and the product was chromatographed using a gradient elution of methanol / methylene chloride containing 0.25% ammonium hydroxide. The appropriate fractions were combined and evaporated. to give 2.34 g (87.6%) of a cream colored solid which, after recrystallization from ethyl acetate, affords the title compound as a white solid, mp 108-110.5 ° C.

NMR (90 MHz, CDCl3, eT):

8.19 (singlet. Lil). 6.35 (singlet, 1 H).

4.5 (broad singlet, 2H). 4.2 (multiplet.

2H), 3.8 (multiplet. 2H), 3.5 (multiplet,

2H), 3.49 (singlet, 3H). 2.59 (multiplet,

6H), 1.02 (triplet, 6N).

Analysis: for ^C i6 ^H 26 ^CIN 3 ° 3 Calculated 55.89% C 7.62% II, 12.22% N, 10.31% Cl; Found: C, 55.66; H, 7.66; N, 12.15; Cl, 10.35.

Example 2

-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-hydroxyethoxy) benzamide

The general procedure described in Example 1 was repeated except that 1.50 g (18.62 mmol) of 2-chloroethanol was used in place of 2-chloroethyl methyl ether. The crude product was purified by flash chromatography on 50 g of silica gel (230-400 mesh) eluting with a gradient of methanol / methylene chloride containing 0.25% ammonia. The appropriate fractions were combined, evaporated and the solid residue recrystallized from acetonitrile to give 1.30 g (42.5%) of the title compound, mp 144-146.5 ° C.

NMR (90 MHz, mixture of dimethylsulfoxide and deuterochloroform, cT values): 8/1 (singlet, 1H),

6.4 (s inglet / 1H), 4.75 (broad singlet, 2H), 4.05 (multiplet, 4H), 3.6 (multiplet, 2H), 2.7 (multiplet, 6H), 1.1 (triplet, 6 H).

Analysis for ^C ₂ 4 ^H i5 ^CIN 3 ⁰ 3

calculated 54,62% H, 7.33; N, 12.74. 10.31% Cl; found 54,67% C, 7.88% H, 12.92% N, 10.69% Cl. Example 1 ad 3 4-amino-5- chloro-N- [2- (diethylamino) ethyl} -2- (2,2-dimethoxyethoxy) benzamide

A mixture of 8/06 g (0/025 mol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride / 6/23 g (0.05 mol) of chloroacetaldehyde dimethylacetal / 6, - 91 g (0.05 mol) of potassium carbonate and 2.57 g (0.025 mol) of sodium bromide in 100 ml of dry dimethylformamide are heated under reflux for 8 hours. After refluxing for four hours, an additional 6.23 g (0.05 mol) of the alkylating agent is added. The resulting mixture was filtered and dimethylformamide was evaporated in vacuo. The oily residue was redissolved in methylene chloride and washed successively with water, 1.0 N aqueous sodium hydroxide solution, water and saturated sodium chloride solution, the solvent was evaporated and the product was further purified by chromatography using a gradient of 0.25 methanol-methylene chloride. % ammonia. The appropriate fractions were combined and evaporated. The yellow residue was recrystallized from ethyl acetate / petroleum ether to give 5 _of 5 g (59.8%) of the title compound as a white solid, mp 64-67 ° C.

NMR (90 MHz, CDCl3):

8.19 (singlet, 1 H), 6.32 (singlet, 1 H),

4.83 (triplet, 2H), 4.42 (broad singlet, 2H), 4.08 (doublet, 2H), 3.55 (multiplet, 2H), 3.50 (multiplet, 2H), 2, 41 multiplet, 6H), 1.1 (triplet, 6H)

Analysis: for ^C 17 ^H ₂ ^N-Q 3 ^C ° 4 Calculated 54.61% C, 7.55% H, 11.24% N, 9.48% Cl; Found: 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) methyl] oxyamide

To a vigorously stirred suspension of 0.34 g of sodium hydride (60%, 0.014 mol) in 5 ml of dry dimethylformamide was added a solution of 3.57 g (0.12 mol) of 4-amino-5-chloro-N- at room temperature over 18 minutes. [2- (diethylamino) ethyl] -2-hydroxybenzamide in 15 mol of dry dimethylformamide. The mixture is stirred for an additional hour to a practically clear solution, to which is added dropwise a solution of 1.74 g (0.014 mol) of 2-methoxyethoxymethyl chloride in 5 mol. ml of dry dimethylformamide. After an additional reaction for 4 hours at room temperature, the mixture was concentrated in vacuo and the residue was partitioned between 200 ml of water and 75 ml of methylene chloride. The aqueous phase is extracted twice with 75 ml of methylene chloride each time. The organic phases were combined, washed first with 3 times 50 ml of 10% aqueous sodium hydroxide solution and then three times with brine, dried over sodium sulfate and, after filtration, concentrated in vacuo. The residue was recrystallized from ether to give 2.53 g of the title compound, m.p. 79-81 ° C.

NMR (90 MHz, CDCl3):

8.18 (singlet, 2H), 6.61 (singlet, 1H),

5.40 (singlet, 2H); 4.40 (singlet, 2H),

3.84 (multiplet, 2H), 3.50 (multiplet, 4H), 3.44 (singlet, 3H), 2.56 (multiplet, 6H) / 1.04 (triplet, 6H).

Analysis: for ^C 17 ^H 28 ^CIN 3 ° 4 Calculated 54.60% C, 7.56% H, 11.24% N; Found: C, 54.16; H, 7.75; N, 11.16.

Example 5

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-propanone-1-yl) oxybenzamide

To a stirred suspension of 5.0 g (16 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride and 10.62 g (77 mmol) of potassium carbonate in 25 ml of dimethylformamide 2.32 g of 90% chloroacetone (22 mmol) are added, the mixture is stirred vigorously for 5 hours and then poured into 130 ml of water. After filtration and drying, 4.57 g of crude product is obtained. This product was dissolved in methylene chloride and filtered through a short column of alumina. The filtrate was concentrated and the residue was recrystallized from toluene to give 4.16 g (78%) of the title compound as a white solid, mp 105-106.5 ° C.

NMR (90 MHz, CDCl3):

8.44 (singlet, 1 H), 8.24 (singlet, 1 H),

6.16 (singlet, 1 H), 4.72 (singlet, 2 H),

4.4 (singlet, 2H), 3.6 (multiplet, 2H),

2.68 (multiplet, 6H), 2.28 (singlet, 3H), 1.08 (triplet, 6H).

Analysis: calculated for ^C ₁₆ ^H 24 ^ClN 3 ° 3: C 56.21, H 7.08, N 12.29, Cl 10.37; Found: 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

To a stirred suspension of 320 mg of sodium hydride (60%, washed with n-pentane, 8 mmol) in 15 ml of dimethylformamide was added 1.289 g (4 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide. 619 mg (4 mmol) of chloroacetophenone was added. The resulting mixture was stirred for a further 4 hours and then poured into 50 ml of ice-cold water to precipitate a solid. This solid was filtered, dried and recrystallized from methanol to give 810 mg (50%) of the title compound as a white solid, mp 153-154 ° C.

NMR (90 MHz, CDCl3):

8.64 (broad singlet, 1H), 8.2 (singlet,

1H), 8 (multiplet, 2H), 7.6 (multiplet, 3H), 6.22 (singlet, 1H), 5.36 (singlet, 2H), 4.4 (singlet, 2H), 3.52 (singlet, 2H) multiplet, 2H), 2.64 (multiplet, 6H), 1.01 (multiplet, 6H).

Analysis: for ^C 21 ^H 26 ^CIN 3 ° 3 calculated 62.45% C, 6.49% H, 10.40% N, 8.78% Cl; Found: C, 62.54; H, 6.39; N, 10.83; Cl, 8.68.

Example 7

A) 4-Amino-2- (butan-2-one-3-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide

To a stirred suspension of 40 mg of 60% sodium hydride (1 mmol, washed with n-pentane) in 2 mL of dimethylformamide was added 0.349 g (1 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] - The 2- (2-propanone-1-yl) oxybenzamide prepared in Example 5 was stirred until hydrogen evolution ceased, then iodomethane (0.07 mL, 160 mg, 1.1 mmol) was added and stirring continued. one more hour. The reaction mixture is partitioned between water and methylene chloride, the organic phase is washed with water, dried, concentrated and the residue is chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (4.5) and ammonia (0.5) as eluent. reagents. 160 mg of the title compound is obtained as the heavy oil from the appropriate combined fractions.

NMR (90 MHz, CDCl3):

8.24 (singlet, overlapping broad singlet, 2H), 6.08 (singlet, 1H), 4.70 (quartet, J = 5.4 Hz, 1H) 4.44 (singlet, 2H), 3, 56 (multiplet, 2H), 2.62 (multiplet, 6H), 2.2 (singlet, 3H), 1.6 (doublet, 3 = 5.4 Hz, 3H), 1.04 (triplet, 6H).

B) 4-Amino-2- (butan-2-one-3-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide hydrochloride

To a stirred suspension of 1.94 g (6 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride and 4.16 g (30 mmol) of potassium carbonate in 10 ml of dimethylformamide was added. 0.95 g (8.9 mmol) of 3-chloro-2-butanone are added, the mixture is stirred for 3 hours, then poured into water and extracted with methylene chloride. The extract was washed well with water, dried and concentrated in vacuo. The residue was dissolved in 1-propanol, 2N hydrochloric acid was added and the mixture was concentrated. The oily residue was crystallized from acetone and the product was then recrystallized from 2-propanol. 1.4 g of the title compound is obtained as a hemihydrate, m.p. 98 ° C.

Analysis: for C? ₇ H ₂₆ C1N ₃ O ₃ .HC1 O 5 H ₂ 0 calculated 51.00% C, 6.80% H, 10.50% N, 17.71% Cl; found: C 51.26, H 6.86, N 10.51, Cl 17.38.

C) 4-Amino-2- (butan-2-on-3-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide-hydro35

CS 271462 02 chloride

To a stirred suspension of 19.4 g (60 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride, 41.6 g (0.3 mol) of potassium carbonate and 10 g Sodium iodide in 100 ml of dimethylformamide was added 9.5 g (89 mmol) of 3-chloro-2-butanone, the mixture was heated to 70-80 ° C with vigorous stirring for 2 hours, then cooled and partitioned between water and methylene chloride. The organic phase is washed with water and, after drying, concentrated. The residue was treated with 2N hydrochloric acid. After azeotropic distillation with n-propanol and crystallization of ₂ acetone, 19.0 g (81%) of the title compound is obtained, m.p. 177-179 ° C.

Example 1 a d 8

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2 - ((3-ethyl) -5-hexen-2-one-3-yl) oxybenzanedione

To a stirred suspension of 0.2 g of 60% sodium hydride (5 mmol, washed with n-pentane) in 10 mL of dimethylformamide was added dropwise a solution of 1.78 g (5 mmol) of 4-amino-2- (butan-2-on-3-yl). of oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide in 10 ml of dimethylformamide. After the hydrogen evolution had ceased, allyl bromide (690 mg, 5.7 mmol) was added, the mixture was stirred for 72 hours, and then partitioned between water and methylene chloride. The organic phase is washed with water and, after drying, concentrated. The residue was chromatographed on silica gel using methylene chloride (100), methanol (4) and ammonia (0.5) as eluent. The appropriate fractions were combined and evaporated to give 0.58 g of crude product as a heavy oil, which upon crystallization from ether gave the title compound as a white solid, m.p. 138-140 ° C.

NMR (90 MHz, CDCl3, δ):

8.24 (singlet, 1H), 8.0 (broad singlet,

1H), 5.92 (singlet, 1H), 5.9-5.0 (multiplet, 4H), 4.38 (broad singlet, 2H), 3.58 (multiplet, 2H), 3.0-2, 3 (multiplet, 8H), 2.82 (singlet, 3H), 1.62 (singlet, 3H), 1.04 (triplet, 6H).

Analysis for ^C 2o ^{H C1N} 3 O 3 Calculated ° 3 60.67% C, 7.68% H, 10.61% N; Found: C, 60.34; H, 7.67; N, 10.54.

Example 9

4-Amino-5-chloro-2- (cyclohexanone-2-yl) oxy-N- [2- (diethylamino) ethyl] benzamide

A suspension of 6.4 g (20 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride and 13.8 g (0.1 mol) of potassium carbonate in 34 ml of dimethylformamide θ 3.8 g (28.6 mmol) of 2-chlorocyclohexanone are stirred for 4 days and then partitioned between water and methylene chloride. The organic phase is washed thoroughly with water and, after drying, concentrated. The residue is chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (4) and ammonia (0.5) as the solvent system. The appropriate fractions were combined and further purified by low pressure liquid chromatography to give 1.0 g of the title compound as a colorless foam, NMR (90 MHz, CDCl 3):

8.4 (broad singlet, 1H), 8.16 (singlet,

1H), 6.14 (singlet, 1H), 4.7 (multiplet,

1H), 4.3 (singlet, 211), 3.56 (quartet, J = 7.2 Hz, 2H), 2.62 (multiCS 271462 B2 plet, 6H), 2.3 - 1.4 (multiplet, 8H),

1.04 (triplet, J = 7.2 Hz, 6H).

Analysis for ^C ₂ ^H 8 .mu.g ^C1N 3 ° 3 calculated 59.75% C, 7.39% Ц, 11.00% N, 9.29% Cl; found: 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] oxybenzamide A mixture of 1.0 g (2.9 mmol) of 4-amino-5- chloro-N- [2- (diethylamino) ethyl] -2- (2-propanone-1-yl) oxybenzamide and 0.3 g (4.3 mmol) of hydroxylamine hydrochloride were heated to boiling under reflux in 20 ml of methanol for 10 min. and then concentrated in vacuo. The residue is partitioned between aqueous sodium carbonate solution and methylene chloride, the organic phase is dried and concentrated. The residue was dissolved in methanol, the solution was clarified with charcoal and filtered. The filtrate was concentrated in vacuo and the residue was crystallized from a mixture of ethyl acetate and n-pentane. 0.58 g (56%) of the title compound was obtained, containing 0.25 mol of crystalline water. The product melts at 112-113 ° C.

NMR (90 MHz, CDCl3):

9.16 (singlet, 1 H), 8.32 (singlet, 1 H),

6.36 (singlet, 1 H), 4.72 (singlet, 2 H),

4.36 (singlet, 2H); 3.68 (multiplet, 2H),

2.68 (multiplet, 6H), 1.92 (singlet, Broad Signal Overlap, 4H), 1.12 (triplet, 6H).

Analysis: for ^C 25 ^H ig ^N ° 3 4 * ^4H 2 ^// ^ ° Calculated 53.18% C, 7.11% H, 15.50% N, 9.80% Cl; Found: 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 was repeated except that instead of the hydroxy lamin The hydrochloride used is methoxyamine hydrochloride and that the reaction is carried out at room temperature for 16 hours. The title compound is obtained in a yield of 70% as a white solid melting after recrystallization from a mixture of methylene chloride and n-pentane at 121-123 ° C.

The NMR spectrum of this product, measured at 90 MHz in deuterochloroform, corresponds to that of Example 10 except that it contains an additional singlet at S * 3.92 (3H).

H, 7.34; N, 15.11; Cl, 9.56. Found: 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

A mixture of 1.28 g (3.7 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-propanone-1-yl) oxybenzamide and 80 mg (2.1 mmol) of sodium borohydride in 15 ml of absolute ethanol was refluxed for 30 minutes, then an additional 50 mg (1.3 mmol) of sodium borohydride was added and refluxing was continued for 10 minutes. The reaction mixture was acidified with 2N hydrochloric acid and concentrated in vacuo. The residue was partitioned between water and ether, the ether layer was discarded, the aqueous layer was basified with sodium carbonate and the solid product was filtered off. There was obtained 0.80 g (77%) of the title compound, m.p. 149-150 ° C.

NMR (90 MHz, CDCl3) .delta.

8.48 (broad singlet, 1H), 8.16 (singlet,

1H), 6.28 (singlet, 1H), 4.4-3.4 (multiplet, 7H), 2.64 (multiplet, 6H), 1.26 (doublet, 0 = 7.5 Hz, 3H), 1.08 (triplet, 3H).

For C 16 ^H 26 ^Cl 2 ^N 3 ^O 3 calculated C 55.88%, H 7.62%, N 12.22%, Cl 10.31; Found: 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

To a stirred suspension of 420 mg of 60% sodium hydride (10.5 mmol, washed with n-pentane) in 10 mL of dimethylformamide was added 1.612 g (5 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] - 2-hydroxybenzamide hydrochloride was stirred for 20 minutes, then cooled in ice, and 418 mg (5.5 mmol) of chloroacetonitrile and 100 mg of sodium bromide were added. The reaction mixture was stirred first for 1 hour cold and then for 16 hours at room temperature, then poured into a mixture of water and ice, and the precipitated solid material was filtered off. This product was dissolved in methylene chloride, the solution was filtered through alumina and the filtrate was concentrated in vacuo. The crude product was recrystallized from methanol to give 930 mg (57%) of the title compound as a white crystalline solid, m.p. 188-189 ° C. NMR (90 MHz, CDCl3, S *):

8.1 (singlet, 1H), 7.78 (broad singlet, 1H), 6.44 (singlet, 1H), 4.84 (singlet, 2H), 4.60 (singlet, 2H), 3.43 (multiplet, 2H), 2.59 (multiplet, 6H), 1.02 (triplet, 6H).

Analysis: for ^C x ₅ ^H 21 ^C1N 4 ° 2 requires 55.47% C, 6.52% H, 17.25% N, 10.92% Cl; Found: 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

A mixture of 4.036 g (12.5 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride, 8.56 g (62 mmol) of potassium carbonate, 1.57 g (17 mmol) of the title compound. (54 mmol) of 2-chloropropionitrile and 300 ml of sodium iodide in 18 ml of dimethylformamide are heated to 50 DEG C. with stirring for 20 hours and then poured into ice-water. The crude solid was filtered off, dissolved in methylene chloride, and filtered through a short column of alumina. The filtrate was concentrated and the residue was recrystallized from methylene chloride / ether to give 3.57 g (84.4%) of the title compound, mp 139-140 ° C.

NMR (90 MHz, CDCl3):

8.2 (singlet, 1H), 7.75 (broad singlet, 1H), 6.28 (singlet, 1H), 4.97 (quartet, = 7.0 Hz, 1H), 4.5 (wide singlet, 2H) ,

⁶²

3.54 (multiplet, 2H); 2.6 (multiplet, 6H);

1.88 (doublet, 3 = 7.0 Hz, 3H), 1.02 (triplet, 6H).

Analysis: for ^C i6 ^H 23 ^C1N 4 ° 2 requires 56.71% C, 6.84% H, 16.53% N, 10.46% Cl; Found: 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

To a stirred suspension of 420 mg of 60% sodium hydride (10.5 mmol) in 10 mL of dimethylformamide was added 1.612 g (5 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride After stirring for 20 minutes, the mixture was cooled in ice-water and methyl 1-bromoacetate (832 mg, 5.44 mmol) was added. The resulting mixture was stirred first for 20 minutes cold and then for an additional 10 minutes at room temperature, then poured into 70 ml of ice-cold water. The precipitated solid was filtered and dried to give 1.58 g of crude product, m.p. 92-94 ° C. The crude product was recrystallized from methylene chloride / ether to give the title compound (1.21 g) as a white crystalline solid, m.p. 94-95 ° C. Yield: 67.6%.

NMR (90 MHz, CDCl3):

8.2 (singlet, 1 H), 6.16 (singlet, 1 H),

4.7 (singlet, 2H), 4.40 (broad singlet, 2H), 3.86 (singlet, 3H), 3.54 (multiplet, 2H), 2.6 (multiplet, 6H), 1.04 (triplet, 6H).

Analysis: for ^C 10 ^H 24 ^Cl 2 ^N 3 ^O 4 calculated C 53.70, H 6.76, N 11.47, Cl 9.82; found: 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

A mixture of 2.0 g (6.2 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride, 2.57 g (18.6 mmol) of potassium carbonate, 0 Sodium iodide (93 g, 6.8 mmol) and 2-chloroacetamide (0.64 g, 6.8 mmol) were heated to 75 ° C with vigorous stirring for 3 hours. The reaction mixture was evaporated in vacuo and the residue was partitioned between water and methylene chloride. The aqueous phase was extracted twice with methylene chloride, the combined extracts were treated with excess acetic acid, and the mixture was concentrated in vacuo. The semi-solid residue is stirred with 150 ml of methylene chloride and the precipitated colorless solid is filtered off. This material recrystallized from acetonitrile to give 1.04 g (41%) of the title compound as an off-white solid, mp 116-125 ° C.

NMR (90 MHz, deuterium oxide, values):

7.8 (singlet, 1 H), 6.26 (singlet, 1 H),

4.8 (s, 2H), 3.8 (m, 2H) _Z

3.3 (multiplet, 6H), 1.95 (singlet, 3H),

1.3 (triplet, 6H).

Analysis: for C ₁₆ H ₂₃ ClN ^ .CHgCOgH .HgO Calculated 48.51% С 6.94% Η, 13.31% Ν, 8.43% Cl; found 48.37% С, 6.88% Η, 13.26% Ν, 8.32% Cl.

Example 17

4-emino-5-chloro-N- [2- (dimethylamino) ethyl] -2-hydroxybenzamide

The general procedure described in Preparation 1A is repeated except that 4-amino-5-chloro-2-methoxybenzamide is substituted for 4-amino-5-chloro-N- 2- (dimethylaminomethyl) -2-methoxybenzamide. N-

2-dimethylamino) ethyl -2-methoxybenzainide (prepared according to British Patent Specification No. 1,793,771). The solvent (dimethylformamide) is evaporated in vacuo, the residue is stirred with water and saturated carbon dioxide, the mixture is concentrated and the crude product is isolated by extraction with ethanol. A sample of this product was chromatographed on a silica gel column using a mixture of methylene chloride (97), methanol (3) and ammonia (0.3) as the solvent system. Appropriate fractions were combined, evaporated and concentrated in vacuo. Crystallization of the residue from methanol gave the title compound as a colorless solid, m.p. 163-165 ° C.

For C pro СN 1 ^O 0: C, 51.26; H, 6.62; N, 16.31; Cl, 13.76. Found 51.46% C _6.35% II 16.12% N, 13.60% Cl.

Example 18

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2,2-dimethyl-1,3-dioxalan-4-yl) methoxybenzamide

A mixture of 3.22 g (10 mmol) of 4 amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride, 1.65 g (10 mmol) of 4-chloromethyl-2,2-dimethyl 1,3-dioxalane, 2.76 g (20 mmol) of potassium carbonate, 1.03 g (10 mmol) of sodium bromide and 40 ml of dimethylformamide were heated under reflux for 20 hours. Dimethylformamide was evaporated under reduced pressure, the residue was stirred with water and extracted with methylene chloride. The resin material was purified by high performance liquid chromatography (Waters prep 500 silica gel) using a mixture of methylene chloride, 2-propanol and concentrated ammonia (100: 1; 0.5) as eluent. Appropriate fractions were combined and evaporated to give 1.8 g of the title compound as a crystalline solid, m.p. 76-78 ° C.

Analysis: ^{C H} ig 3Q ^C1N 3 ° 4 calculated 57.06% C, 7.56% H, 10.51% N, 8.87% Cl; Found: 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

To a solution of 4.82 g (9.14 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide tetrabutylammonium salt in 50 mL of acetonitrile was added 5-bromomethyl-3-methylisoxazole and the mixture was stirred for 1.5 hours. The crystalline product was collected and dried (2.53 g). A second crop was obtained by concentrating the filtrate and crystallizing the residue from ethyl acetate (0.51 g). Yield: 87%. After recrystallization from ethyl acetate, an analytical sample melted at 109-111 ° C.

Analysis: for ^C 25 ^H I8 ^C1N 4 ° 3 Calculated 56.76% C, 6.62% H, 14.71% N, 9.31% Cl; found: 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

A mixture of 10.0 g (31.06 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride (from Preparation 1A), 12.84 g (93.16 mmol) of anhydrous potassium carbonate, 4.66 g (31.06 mmol) of sodium iodide and 3.70 ml (4.10 g, 37.26 mmol) of 2-chloroethylmethylsulfide in 60 ml of dry dimethylformamide are heated under stirring for 10 hours. reflux. The solvent was evaporated under reduced pressure and the dark colored semi-solid residue was partitioned between water and methylene chloride. The aqueous layer was adjusted to pH 14 with sodium hydroxide solution, shaken vigorously, and the layers were separated. The aqueous layer was extracted three times with methylene chloride, the combined organic solutions were dried over magnesium sulfate and evaporated. The solid residue is dissolved in 100 ml of warm acetonitrile, the solution is clarified with charcoal, evaporated to 30 ml after filtration and stored at -15 ° C. Filtration of the solid product gave 3.56 g (32%) of the title compound as off-white crystals, m.p. 118-120 ° C.

Analysis: for ^C 16 ^H 26 ^C1N 3 ° 2 ^S Calculated 53.39% C, 7.28% H, 11.67% N, 9.85% Cl, 8.91% S; found: 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

To a stirred solution of 1.0 g (2.28 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2- (methylthio) ethoxy] benzamide (prepared in Example 20) and 1, A 4N solution of hydrogen chloride (3.97 mL, 5.56 mmol) in 15 mL of water at 0-5 ° C was added with 0.625 g (2.92 mmol) of sodium meta periodate. The mixture, which soon became dark, was stirred at 0-5 ° C for 2 hours, diluted to 50 ml and basified to pH 12 with sodium hydroxide solution. After addition of 50 ml of methylene chloride, the mixture was shaken vigorously and the layers were shaken. separates. The aqueous layer was extracted three times with methylene chloride, the combined organic solutions were dried over anhydrous magnesium sulfate and evaporated. 0.96 g of a dark colored oil is obtained, which solidifies on standing. The crude product was subjected to flash chromatography on silica gel, eluting with dichloromethane: methanol: ammonium hydroxide (80: 20: 0.5). The appropriate fractions were combined and evaporated to give 0.80 g (77%) of the title compound as a yellow gum which solidified on standing and melted at 110-114 ° C.

Analysis: for ^C 26 ^H i5 ^ 3 ° ^C 3 ^S calculated 51.12% C, 6.97% H, 11.18% N, 9.43% Cl, 8.53% S; Found: C, 50.42; H, 6.94; N, 10.91; Cl, 9.94.

Example 22 4-Amino-2- (2-butanone-3-yl) oxy-5-chloro-N- [2 (diethylamino) ethyl] benzamide hydrochloride

To a solution of 0.53 g (1.0 mmol) of tetra-n-butylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide in 6 ml of acetonitrile is added 0, 11 mL (0.12 g, 1.1 mmol)

Of 3-chloro-2-butanone and the mixture was stirred at 20 ° C for 16 hours. After evaporation of the acetonitrile under reduced pressure, the residue is stirred with 10 ml of water and extracted with ethyl acetate. The extracts were washed with dilute sodium carbonate solution, dried and concentrated to an oily product which was converted to the monohydrochloride by treatment with 1.0 ml of 1N hydrochloric acid. Crystallization of this salt from a mixture of 2-propanol and ethyl acetate gave the title compound, m.p. 176-179 ° C. This material is identical to the material prepared in Example 7C.

Example 23

A) 4-Amino-5-chloro-2- (cyclohexanone-2-yl) oxy-N- [2- (diethylamino) ethyl] benzamide

A mixture of 15 g (47 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxyberisamide hydrochloride (from Preparation 1A), 15 g (47 mmol) of tetrabutylammonium bromide, 34.32 g ( Anhydrous potassium carbonate (0.234 mol) and 2-chlorocyclohexanone (8.9 g, 67 mmol) in dimethylformamide (60 ml) were stirred for 4 days, then partitioned between water and ethyl acetate. The ethyl acetate solution was washed with 0.4N sodium hydroxide and water ml of 1N hydrochloric acid. The acidic extract was basified with saturated sodium carbonate solution and extracted with methylene chloride. The extract is dried, filtered through a silica gel column, the filtrate is concentrated and the concentrate is diluted with pentane. The material precipitated as an oily solidified on standing and crystallized from 30 ml of toluene to give the title compound, m.p. 96-99 ° C.

Analysis calculated for: ^C 19 ^H 28 ^ClN 3 ° 3: ^{C 59.75} , H 7.39, N 11.00, Cl 9.29; found: 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 sulfate

190 mg (0.5 mmol) of 4-amino-5-chloro-2- (cyclohexanone-2-yl) oxy-N- [2- (diethylamino) ethyl] benzamide was dissolved in 25 ml of 2-propanol and a solution. 1 ml of 1N sulfuric acid is added. After concentration, the title compound crystallizes from the reaction solution, m.p. 175 ° C.

Analysis: for ^C 19 ^H 30 ^C1N 3 ° 3 ^S calculated 47.54% C, 6.30% H, 8.75% N, 7.39% Cl, 6.68% S; Found: C 47.52, H 6.39, N 8.46, Cl 7.26, S 6.80.

C) 4-Amino-5-chloro-2- (cyclohexanone-2-yl) oxy-N- [2- (diethylamino) ethyl] benzamide hydrochloride

The title compound was prepared in the same manner as sulfate using 1N hydrochloric acid. The product melts at 150-153 ° C with decomposition.

Analysis: CigH _{2 g} Cl ₂ N ₃ 0 ₃ calculated 54.54% C, 6.99% Н - 10.04% N; Found: 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

To a stirred suspension of 400 mg of 60% sodium hydride (10 mmol, washed with n-pentane) in 10 mL of dimethylformamide was added 3.4 g (10 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] under nitrogen. 1] -2- (2-propanone-1'-axybenzamide (prepared in Example 5)) The mixture was stirred until the evolution of hydrogen ceased, then 0.9 ml (1.26 g, 10.5 mmol) of allyl bromide was added and stirring was continued for 18 hours The reaction mixture was partitioned between water and methylene chloride, the organic phase was washed with water, dried, concentrated and the residue was chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (4) and methanol. The appropriate fractions were combined and evaporated to give 1.14 g of the free base, dissolved in 1-propanol, 7 ml of 2N hydrochloric acid was added and the mixture was concentrated. The residue was crystallized from a mixture of acetone and ether product from

42 ·

2-Propanol gave 0.53 g of the title compound, m.p. 171-173 ° C. NMR (90 MHz, deuterium oxide, S 'values) ·

7.88 (singlet, 1 H), 6.42 (singlet, 1 H),

6.12 - 4.88 (multiplet, 3H), 3.76 (broad doublet, 2H), 3.28 (multiplet, 6H),

2.88 (broad triplet, 2H), 2.4 (singlet, 3H), 1.35 (triplet, 6H).

. Analysis for C19 ^H 29 ^C1 2 ^N ° 3 3 calculated 54.55% C, 6.99% H, 10.04% N, 16.95% Cl; Found: C, 54.22; H, 7.11; N, 9.90; Cl, 16.51.

Example 25

4-Amino-5-chloro-N- (2- (diethylamino) ethyl) -2- (peritan-2-on-3-yl) oxybenzamide

To a solution of 10.5 g (20 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (from Preparation No. 3) in 150 ml of acetonitrile was added 3. 3 g of 80% 3-bromo-2-pentanone (20 mmol, contaminated with 15% 1-bromo-2-pentanone) was obtained as described by ETBorrows, 0.0. Holland and J. Kenon, J. Chem. Soc. 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. The semi-solid residue was triturated with ether to give a solid, which recrystallized from ether / petroleum ether to give 1.5 g of the title compound, mp 75-78 ° C.

NMR (90 MHz, CDCl3):

8.26 (singlet, 1H), 8.14 (wide singlet,

1H), 6.1 (singlet, 1H), 4.5 (triplet, 1H),

4.4 (singlet, 2H), 3.69 (quartet, 2H),

2.64 (multiplet, 6H), 2.1 (singlet, 3H),

2.1 - 1.7 (multiplet, 2H), 1.05 (multiplet, 9H)

Analysis: for ^C 18 ^H 28 ^C1N 3 ° 3 calculated 58.45% C, 7.63% H, 11.36% N, 9.59% Cl; Found: C, 58.30; H, 7.61; N, 11.20.

Example 1 a d 26

4-Amino-2- (2-butanone-1-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide

To a solution of 5.3 g (10 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide in 100 ml of acetonitrile was added 1.5 g (10 mmol) of 1- bromo-2-butanone, stirred at 20 ° C for 2 hours, then concentrated. The residue was stirred with water and extracted with ethyl acetate and a mixture of methylene chloride and 2-propanol (5: 1). The insoluble solid material was collected and combined with the organic extracts. Concentration of the mixture yielded a sticky crystalline material which, after recrystallization from acetonitrile: water (4: 1), gave 3.1 g (86%) of the title compound, mp 103.0-104.5 ° C.

Analysis: for ^C 17 ^H 26 ^C1N 3 ° 3 calculated 57.37% C, 7.37% H, 11.81% N, 9.96% Cl; Found: C, 57.21; H, 7.34; N, 11.76; Cl, 9.67.

CS 271462 ^ΰ2

Example 27

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (pentan-2-one-1-yl) oxybenzamide

To a solution of 10.54 g (20 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide in 150 ml of acetonitrile was added 1-bromo-2-pentanone [3]. 3 g of a substance having a purity of 45%, obtained as a by-product of bromination of 2-pentanone according to the procedure described in ET Borrows, D.O. Holland and O. Kenyon, 0. Chem. Soc. 1083 (1946), and identified by NMR spectroscopy, and the mixture was stirred for 16 hours. The solvent evaporation residue was partitioned between water and ethyl acetate. The organic phase was washed with water, dried and the solvent was evaporated. The residue is chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (2) and ammonia (0.5) as the solvent system. Appropriate fractions were combined and evaporated to give a solid which was recrystallized from ethyl acetate to give 0.8 g of the title compound, mp 112-115 ° C.

NMR (90 MHz, CDCl3):

8.48 (broad triplet, 1H), 8.24 (singlet,

1H), 6.14 (singlet, 1H), 4.7 (singlet, 2H), 4.4 (singlet, 2H), 3.56 (quartet, 2H), 2.66 (multiplet, 8H), 1, Δ (multiplet, 2H), 1.06 (triplet, 9H).

Analysis: for ^C 28 ^H I8 ^C1N 3 ° 3 calculated 58.45% C, 7.63% H, 11.36% N; Found: C, 58.16; H, 7.66; N, 11.28.

Example 1 a d 28

4-Amino-5-chloro-2- (pentan-3-one-2-yl) oxy-N- (2-diethylaminoethyl) benzamide hydrochloride

A mixture of 4.83 g (0.015 mol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide hydrochloride (from Preparation 1A), 2.72 g (0.0165 mol) of 2 -bromo-3-pentanone [prepared according to the procedure described by М.М. McIntosh and G.M. Masse, □. Org. Chem. 40, 1294 (1975) and 4.14 g (0.030 mol) of potassium carbonate in 80 ml of dry dimethylformamide were heated at 90-95 ° C for 2 hours with stirring. The reaction mixture was filtered and dimethylforinamide was evaporated in vacuo. The oily residue was dissolved in methylene chloride, washed successively with water, 1.0 N aqueous sodium hydroxide solution and again with water, dried over sodium sulfate and the solvent was evaporated. The crude oily residue was purified by flash chromatography on 86 g of silica gel (230-400 mesh) eluting with a gradient of methanol / methylene chloride containing 0.25% ammonium hydroxide. Appropriate fractions were combined and evaporated to give 4.31 g (77.7%) of product as a yellowish resin.

4.30 g (0.0116 mol) of the obtained free base are dissolved in 75 ml of isopropanol, 2.90 ml of 4.0 N aqueous hydrogen chloride are added and the resulting solution is concentrated to a volume of about 30 ml. After cooling, filtration and drying in vacuo, 3.85 g (63.2%) of the crude product is obtained, which after recrystallization! from acetonitrile gives the title compound as a white solid, mp 100-112 ° C.

Analysis; for ^C i8 ^H 28 ^C1N 3 ° 3 calculated 53.20% C, 7.19% H, 10.34% N, 17.45% Cl; Found: 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) butan-2-one-1-yl] oxybenzamide

A mixture of 5.82 g (18 mmol) of 4-amino-5-chloro-N- [2- (diethylomino) ethyl] -2-hydroxybenzamide hydrochloride, 12.48 g (90 mmol) of anhydrous potassium carbonate in 30 ml of diinethylCS 271462 B2 formamide and 4.5 g (27 mmol) of 1-bromo-3-methyl-2-butanone [prepared by the procedure of M. Gaudry and A. Marquet, Org. Syn, 55, 24 (1976)] was stirred under nitrogen for 20 hours. The reaction mixture was poured into 150 ml of water, the solid product collected, dried and crystallized from toluene. There was obtained 4.86 g (73%) of the title compound, m.p. 109-110 ° C.

NMR (90 MHz, data (7)): 8.56 (broad triplet,

1H), 8.24 (singlet, 1H), 6.18 singlet,

1H), 4.8 (singlet, 2H), 4.44 (singlet,

2H), 3.56 (multiplet, 2H), 2.62 (multiplet, 7H), 1.2 (doublet, 6H), 1.06 (triplet, 6H).

Analysis:

for C ₈ ^H 28 ^C1N 3 ° 3 calculated 58.45% C, 7.63% H, 11.36% N;

Found: C, 58.38; H, 7.63; N, 11.25.

Example 30

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (3-phenyl-2-propanen-1-yl) oxybenzamide

A solution of 3.45 g (6.5 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide and 1.1 g (6.5 mmol) of 1- of chloro-3-phenyl-2-propanone in acetonitrile was stirred at 20 ° C for 18 hours. The evaporation residue of acetonitrile under reduced pressure is stirred with water and extracted with methylene chloride. The extracts were concentrated and the residue was chromatographed on alumina (activity III) using ethyl acetate as eluent. The appropriate fractions were combined and evaporated to give 1.1 g of product which, after recrystallization from ethyl acetate, gave the title compound, m.p. 138-139 ° C.

Analysis:

for ^C 22 ^H 28 ^C1N 3 ° 3 calculated 63.22% C, 6.71% H, 10.05% N, 8.48% Cl;

Found: C, 63.23; H, 6.71; N, 9.92; Cl, 8.28.

At 1 and d 31.

4-Amino-5-chloro-N- [2- (dlethylamino) ethyl] -2 - [(3-methyl) butan-2-one-3-yl] oxybenzamide monohydrate

To a solution of 15.81 g (30 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide in dimethylformamide was added 4.95 g (30 mmol) of 3 bromo-3. methyl-2-butanone purity 80%; prepared by the method of M. Gaudry and A. Marquet, Tetrahedron 26, 5611 (1970)]. After stirring for 20 hours, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with 0.4 N sodium hydroxide and water, dried and the solvent was evaporated. The residue is chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (2) and ammonia (0.5) as the solvent system. The appropriate fractions were combined and evaporated to give 4.86 g of an oily material. A portion of this material (3.86 g) gave, after crystallization from acetonitrile / water and recrystallization from methanol / water, 1.23 g of the title compound, m.p. 84-88 ° C.

NMR (90 MHz, CDCl3):

8.24 (sine go, 1H), 8.08 (Wide Sing singlet, 1H), 5.92 (with inglet, 1H), 4.34 (with ing years, 2H), 3.58 (quartet, 2H), 2.6 (quartet, 6H), 2.32 (with inglet, 3H), 1.66 (with ing years, 2H), 1.64 (with ing le t, 6H), 1.04 (trip years, 6H).

Analysis: for ^C 28 ^H i3 ^C ^ ^N ° 3 * 3 ^H 2 ^Q Calculated Found

C 55.73, H 7.80,

C 55.75, H 7.83,

10.83% N, 9.14% C, 4.67% H ₂ 0;

10.72% N, 8.74% C, 4.62% H ₂ 0th

Example 32

4-Amino-2- (2-butanone-3-yl) oxy-5-chloro-N- [2- (dimethylamino) ethyl] benzatnide

A solution of 1.90 g (7.37 mmol) of 4-amino-5-chloro-N- [2- (dimethylamino) ethyl] -2-hydroxybenzamide (prepared in Example 17), 3.06 g (2 , 21 mmol) of potassium carbonate, 1.11 g (7.37 mmol) of sodium iodide and 1.81 g (12 mmol) of 91% 3-bromo-2-butanone in 30 ml of dimethylformamide were stirred for 1.5 hours, then stirred the solvent was evaporated in vacuo and the residue was partitioned between water and methylene chloride. The aqueous phase is extracted twice more with methylene chloride. The combined extracts were dried, concentrated in vacuo and the residue was subjected to silica gel column chromatography using a mixture of methylene chloride (99.5), methanol (0.5) and ammonia (0.2) as the solvent system. The appropriate fractions were combined and concentrated in vacuo to a solid which was recrystallized from acetonitrile to give 1.85 g of the title compound as a colorless solid, mp 124-125 ° C.

Analysis: for ^C 15 ^H 22 ^C1N 3 ° 3 calculated 54.96% C, 6.76% H, 12.82% N, 10.82% Cl; Found: 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

A solution of 2.64 g (5 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide and 0.85 g (5 mmol) of 1-chloro-2-hydroxy Of 3-phenylpropane in 10: 1 dimethylformamide was refluxed for 2 hours. The reaction mixture is concentrated under reduced pressure, the residue is taken up in methylene chloride, the solution is washed with dilute sodium hydroxide and, after drying with sodium sulfate, concentrated. The product provides after recrystallization! from ethyl acetate 1.05 g of the title compound, m.p. 155-157 ° C.

Analysis: for ^C 22 ^H 30 ^C1N 3 ° 3 calculated 62.92% C, 7.20% H, 10.01% N, 8.44% Cl; Found: 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) oxyberisamide

A solution of 1.14 g (2.9 mmol) of 4-amino-2- (2-butanone-3-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide hydrochloride (prepared in of Example 7C) and 0.3 g (4.3 mmol) of hydroxylamine hydrochloride in 20 ml of methanol are heated under reflux for 15 minutes. The solvent was evaporated and the residue was partitioned between methylene chloride and saturated sodium carbonate solution. 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 0.37 g of the title compound, m.p. 113-115 ° C.

NMR (90 MHz, CDCl3, У *):

9.8 (broad snglet, 1H), 8.16 (singlet,

1H), 6.4 (singlet, 1H), 4.96 (quartet,

1H), 4.4 (singlet, 2H), 4.02 - 3.08 (broad multiplet, 3H), 2.66 (multiplet, 6H),

1.84 (singlet, ЗН), 1.6 (doublet, ЗН),

1.08 (triplet, 6H).

Analysis: for C ₁₇ H ₂₇ C1N ₃ O ₄ calculated 55.05% C, 7.34% H, 15.11% N, 9.56% Cl; Found: C, 54.91; H, 7.34; N, 14.97; Cl, 9.45.

Example 35

N - [3-Amino-4-chloro-6- [N- (2- [diethylamino] ethyl)] carbamoylphenoxy / acetic acid ethyl ester

To a vigorously stirred suspension of 0.36 g of 60% sodium hydride (9 mmol, washed with n-pentane) in 5 mL of dry dimethylformamide was added a solution of 2.28 g (8 mmol) of 4-amino-5-chloro-2- (diethylamino). ethyl] -2-hydroxybenzamide (from Preparation 1B) in 10 mL of dry dimethylformamide. After the hydrogen evolution had subsided, a solution of 2.12 g (8.7 mmol) of ethyl ethyl acetate was added dropwise.

bromophenylacetate in 5 ml of dry dimethylformamide, the mixture is allowed to react for an additional 18 hours at room temperature, then concentrated in vacuo and the residue is partitioned between 200 ml of water and 75 ml of methylene chloride. The aqueous phase is extracted twice with 75 ml of methylene chloride each time, the organic phases are combined, washed three times with 50 ml each of 10% aqueous sodium hydroxide solution and three times with brine, dried over sodium sulfate and concentrated by evaporation in vacuo. 3.5 g of oily material are obtained, which crystallizes slowly and, after trituration with pentane, gives 3.34 g of the title compound, m.p. 64-87 ° C.

NMR (90 MHz, CDCl3, δ):

8.55 (broad triplet, 1H), 8.20 (singlet,

1H), 7.50 (multiplet, 5H), 6.09 (singlet, 1H), 5.65 (singlet, 1H), 4.25 (multiplet, 4H), 3.55 (multiplet, 2H), 2, 60 (multiplet, 6H), 1.05 (multiplet, 9H).

Analysis: for ^C 23 ^H 30 ^CIN 3 ° 4 calculated 61.66% C, 6.76% H, 9.38% N; Found: C, 61.75; H, 6.76; N, 9.27.

Example 1 a d 36

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-hydrazino-2-oxoethoxy) benzamide trihydrate

A suspension of 3.58 g (10 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-methoxy-2-oxoethoxy) benzamide (prepared in Example 15) in 0.6 g (12 mmol) of 64% aqueous hydrazine in 3 mL of methanol was stirred for 1 h, resulting in a clear solution. The mixture was concentrated in vacuo and the residue was recrystallized from water. After drying, 3.65 g (88.6%) of the title compound is obtained as a trihydrate, m.p. 130-131 ° C.

Analysis: for ^C 24 ^H i5 ^ 5 ^ ^C ° 3 ° 2 * ^3H calculated 43.73% C, 7.34% H, 17.00% N, 8.60% Cl, 13.12% Found 44,07 % C, 7.46% H, 17.19% N, 8.77% Cl, 11.60% H ₂ O.

Example 37

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2- (2-acetylhydrazino) -2-oxoethoxy] benzamide acetate

1.0 g (2.43 mmol) of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-hydrazino-2-oxoethoxy) benzamide trihydrate (prepared in the example) 36) was heat-dried for 3 hours47

CS 267464 B2 at 110 ° C under a vacuum of 2.7 Pa to give 865 mg of the corresponding anhydrous material. This material was treated with 248 mg (2.428 mmol) of acetic anhydride dissolved in 5 mL of methylene chloride until a clear solution was formed. From this solution, after concentration in vacuo, 1.115 g (100%) of the title compound was obtained as a white hygroscopic solid.

For C 6 gHH NNgClO ^ requires C, 49.62; H, 6.58; N, 15.23; Cl, 7.71. Found: C, 48.86; H, 6.67; N, 14.87; Cl, 8.20.

Example 38

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [beta] - (phthalimido) propoxy] benzamide

To a suspension of 15.8 g (30 mmol) of the tetra-n-butylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) in 50 ml of acetonitrile is added N- ( The mixture was stirred at room temperature for 16 hours and then at 65-70 [deg.] C. The reaction mixture was concentrated in vacuo and the residue was partitioned between water and a mixture of equal portions of ether and methylene chloride. The precipitated solid product was filtered and washed with ether to give 12.3 g (86.7%) of the title compound as a white solid, m.p. mp 141-143 ° C.

Analysis: for ^C 24 ^H 29 ^N 4 ^C '4 ^t0 calculated 60.94% C 6.18% II N 11.85%, Cl 7.5%; found: C 61.05, H 6.43, N 11.80, Cl 7.63.

Example 39

4-Amino-2- (3-ammonium) -5-chloro-N- [2- (diethylamino) ethyl] benzamide

A mixture of 4.73 g (10 mmol) of 4-amino-5-chloro * -N- [2- (diethylamino) ethyl] -2- [3- (phthalimido) propoxy] benzamide (prepared in Example 38), 800 mg (16 mmol) 64% hydrazine hydrate and 15 ml of absolute ethanol are briefly heated to reflux until a clear solution is obtained, which is then heated at 55-57 ° C for 16 hours and then at reflux for 16 hours. The precipitated solid is filtered off and washed with ethanol. The filtrate is combined with the washings, concentrated in vacuo, the residue is dissolved in methylene chloride and the insoluble solid is filtered off. recrystallization with methylene chloride and n-pentane gave 2.96 g (86.3%) of the title compound as a white solid, mp 119-121 ° C.

Analysis: for ^C 27 ^H J5 ^N @ 4 ° ^C 2 Calculated: 56.05% C, 7.94% H, 16.34% N, 10.34% Cl; Found: 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

To a suspension of 1.074 g (3 inmol) of 4-amino-5-chloro-N- [2- (diethylaninomethyl) -2- (2-methoxy-2-oxoethoxy) benzamide (prepared in Example 15) in 10 ml of a 1N solution of inethylamine in toluene The reaction mixture was concentrated in vacuo and the residue was crystallized from a mixture of methanol and ether to give 815 mg (76%) of the title compound as a white solid, m.p. to 151 ° C.

Analysis for ^C ₆ ^H 25 ^N 4 ¹⁰ 3 calculated 53.85% C, 7.06% H, 15.70% N, 9.94% Cl;

found 53.85% С, 7.16% Η, 15.63% Ν, 10.00% Cl.

К ř 1 and d 41

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2 - [(2-hydroxy) but-3-yl] oxybenzamide (mixture of threo- and erythro-isomers)

A mixture of 4-amino-2- (2-butanone-3-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide was obtained by reaction of 1.2 g (3.1 mmol) of the corresponding hydrochloride, prepared in Example 7C, with a saturated solution of sodium carbonate] and 100 mg of sodium borohydride in 20 ml of ethanol were heated at reflux for 1 hour. The reaction solution was concentrated, the residue was diluted with water, acidified with 2N hydrochloric acid and basified with saturated sodium carbonate solution. Extraction of the mixture with methylene chloride yielded 1.16 g of foamed material which was chromatographed on deactivated silica gel using methylene chloride (100), methanol (2) and ammonia (0.5) as solvent system. Appropriate fractions were combined and evaporated to give 470 mg of the title compound as a foamed mixture of diastereomers.

NMR (90 MHz, CDCl3):

8.54 (broad doublet, 1H), 8.2, 8.15 (two singlets, 1H), 6.32, 6.35 (two singlets, 1H), 4.36 (singlet, 2H), 4.24 - 4 (multiplet, 1H), 4 - 2.12 (multiplet, 3H), 2.8 - 2.52 (multiplet, 6H)), 1.41 - 0.96 (multiplet, 12H)

Analysis for ^C ₇ H ₂ 0 _{3 3} qC1N calculated 57.05% C, 7.89% H, 11.74% N, 9.91% Cl; Found: 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 described in Example 35 was repeated except that an equimolar amount of ethyl 3-methoxy-4-chlorocarbonate (prepared according to U.S. Pat. No. 4,348,333) was used instead of ethyl .alpha.-bromophenylacetate. The solvent (dimethylformamide) was evaporated in vacuo and the residue was stirred with water and methylene chloride. The methylene chloride layer was washed with 10% sodium hydroxide solution, water and brine, dried over sodium sulfate and concentrated by filtration. The crude solid was recrystallized from ether / methylene chloride to give the title compound, m.p. 109-111 ° C.

Analysis: for ^C ₂₀ H ₃₀ C1N ₃ 0 ₅ calculated 55.99% C, 7.06% H, 9.80% N; Found:% 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 except that an equimolar amount of 2-bromoethyl-1,3-dioxolane was used in place of ethyl X-bromophenylacetate and the reaction mixture was heated at 80 ° C for 30.5 hours. The solvent (dimethylformamide) was evaporated in vacuo and the residue was stirred with brine and methylene chloride.

The methylene chloride solution was washed with 10% sodium hydroxide solution and brine, dried over sodium sulfate and concentrated by filtration. The residue is recrystallized from methylene chloride / hexane to give the title compound, m.p.

Analysis: for ^C 17 ^H 26 ^C1N 3 ° 4 Calculated 54.90% C, 7.06% H, 11.30% N; Found: C, 54.98; H, 7.07; N, 11.40.

Example 44

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (oxazolidin-2-one-5-ylinethyl) oxybenzamide fumarate

An equimolar amount (6 mmol) of the tetra-n-butylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) and 5-chloromethyl-2-oxazolidinone was added in 15 minutes. ml of dimethylformamide were stirred at reflux for 3 hours. After evaporation of the solvent, the residue is dissolved in methylene chloride, the solution is washed with water, dried over magnesium sulphate and concentrated. 2.7 g of crude product are obtained, which is purified by chromatography on alumina (activity III) using ethyl acetate containing 5 to 10% ethanol as eluent. The partially purified 1.1 g product was treated with 0.33 g of fumaric acid in 1-propanol to give 0.81 g (30.5%) of crystalline fumarate, m.p. 165-167 ° C.

Analysis: for ^[C 17 ^H 25 ^C1N 4 ° 4J 2 ^C 4 ^H 4 ° 4 Calculated 51.52% C, 6.15% H, 12.65% N, 8.01% Cl; Found: 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

To a solution of 2.64 g (0.005 mol) of the tetra-n-butylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) in 30 ml of acetonitrile was added. 2-chloromethylpyridine (prepared by neutralizing 0.01 mol of the corresponding hydrochloride with potassium carbonate) is added. The reaction mixture was stirred for 18 hours then concentrated and the residue was chromatographed on alumina (activity III) using ethyl acetate and ethyl acetate / ethanol (100: 2) as eluents. 1.8 g of purified product are obtained, which after recrystallization from a mixture of ethyl acetate and n-hexane (2; 1) gives 1.45 g (77%) of the title compound, m.p. 84-85 ° C.

Analysis: for ^C 25 ^H i9 ^C ^ ^N ° 2 4 Calculated 60.55% C, 6.69% H, 14.87% N, 9.41% Cl; Found: 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 except that an ethyimolar amount of 1-bromo-2- (2-methoxyethoxy) ethane was used instead of ethyl bromophenylacetate. The solvent (dimethylformamide) was evaporated in vacuo and the residue was partitioned between brine and methylene chloride. The methylene chloride layer was washed with 10% sodium hydroxide and brine, dried over sodium sulfate and concentrated by filtration. The residue was recrystallized from ether to give the title compound, m.p. 49-51 ° C.

Analysis: for C ₃₀ H _le CLN ₃ 0 ₄ calculated 55.72% C, 7.81% H, 10.83% N; Found: C 55.50, H 7.69, N 10.78.

Example 47

4-Amino-2- (2-aminoethoxy) -5-chloro-N- [2- (diethylamino) ethyl] benzamide

To a suspension of 1 teaspoon of Raney-nickel (thoroughly washed with methanol) in 130 mL of methanol was added 12.05 g (37.1 mmol) of 4 amino-5-chloro-2-cyanomethyl-N- [2- (diethylamino) ethyl] benzamide (prepared in Example 13), and the mixture was hydrogenated at 50 mbar for 5 hours. The catalyst was filtered off under nitrogen and the filtrate was concentrated in vacuo. The residue was dissolved in methylene chloride and the solution was washed four times with 1 ml of 1N sodium hydroxide. The washings are back-extracted with methylene chloride, the organic phases are combined and, after drying, concentrated in vacuo. 5.56 g of the title product is obtained as a semi-solid which, after recrystallization from a mixture of methanol and ether, melts cold at 97-99 ° C.

Analysis: ^C 15 ^H 25 ^Cl 2 ^N 4 ^O 2 requires C 54.78, H 7.60, Cl 10.78, N 17.04; Found: 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

To a solution of 780 mg (2.4 mmol) of 4-amino-2- (2-aminoethoxy) -5-chloro-N- [2- (diethylamino) ethyl] -benzamide (prepared in Example 47) in methylene chloride was added 245 mg. (2.4 mmol) of scetanhydride, the mixture is stirred for 30 minutes, then concentrated in vacuo and the residue is partitioned between methylene chloride and sodium bicarbonate solution. The organic phase is concentrated and the residue is subjected to flash chromatography on silica gel using methylene chloride / methanol / ammonia (100: 4: 0.5) as the solvent system. Appropriate fractions were combined and concentrated in vacuo. The residue was recrystallized from methylene chloride / ether to give 445 mg of the title compound as a white solid, mp 143-145 ° C.

For C ^ HH ^^Cl ClNNO ^ requires C, 55.05; H, 7.37; Cl, 9.56; N, 15.11. found: 54.82% C, 7.28% H, 9.71% Cl, 14.54% N.

Example 49

4-Amino-5-chloro-N- [* 2- (diethylamino) ethyl] -2- [3- (methylthio) propoxy] benzamide

To a solution of 10.54 g (20 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) in 100 ml of dimethylformamide was added 3.268 g. (2.2 mL, 20.76 mmol) of 1-bromo-3-chloropropane, the mixture was stirred at room temperature for 2 hours and then at 40 ° C for 30 minutes. The reaction mixture was cooled to 0 ° C and poured under nitrogen into sodium hydride (1.0 g of a 60% dispersion in a mineral oil washed with n-pentanes; 25 mmol). The mixture was stirred cold while introducing methyl mercaptan until hydrogen evolution ceased. The resulting mixture was then heated at 35-40 ° C for 2 hours, poured into 700 ml of water and after standing for one hour the precipitated solid product was filtered off with suction. Drying in air gave 7.06 g (94%) of the crude product, m.p. 58-59 ° C. This product was dissolved in methylene chloride and filtered through a short column of silica gel and alumina. The filtrate was concentrated and the residue was crystallized from ether. 4.95 g (66%) of the title compound are obtained as a white solid, m.p. 79-80 ° C.

Analysis: for ^C 28 ^H xy ^C calculated 54.61% C, 7.55% H, 9.48% Cl, 11.24% N, 8.56% S;

Found: 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- [α- (methylsulfinyl) piperazine] benzamide

To a stirred solution of 1.496 g (4 mmol) of the product from Example 49 to 5.0 mL of 2N hydrochloric acid (10 mmol) and 20 mL of water was added 856 mg (4.0 mmol) of sodium periodate. The mixture was stirred for 2.5 hours, then basified with 3 ml of 4N sodium hydroxide and extracted three times with 30 ml of methylene chloride each time. The extract was concentrated in vacuo and the residue was flash chromatographed on a deactivated silica gel column using methylene chloride / methanol / ammonia (100; 3.5: 0.5) as the solvent system. The appropriate fractions were combined and concentrated to a yellow oily residue which was crystallized from methylene chloride / ether to give 770 mg of the title compound as a yellowish solid, mp 116-117 ° C.

Analysis: for ^C 17 ^H 28 ^C1N 3 ° 3 ^S calculated 52.37% C, 7.24% H, 9.09% Cl, 10.78% N, 8.21% S; Found: C, 52.31; H, 7.25; Cl, 8.70; N, 10.68;

Example 51

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (1H-4,5-dihydroimidazol-2-yl) methoxybenzamide

A mixture of 3.25 g (10 mmol) of 4-amino-5-chloro-2-cyanomethoxy-N- [2- (diethylamino) ethyl] benzamide (prepared in Example 13) and 0.6 g (10 mmol) of 1,2- of diaminoethane in 25 ml of methanol was heated under reflux for 3 hours. The reaction mixture was concentrated to a crystalline residue which, after recrystallization from ethyl acetate, gave 2.78 g (76%) of the title compound, m.p. 144-145 ° C.

Analysis: for ^C | 7 ^H 26 ^{N C-5} ° 2 requires 55.50% C, 7.12% H, 9.64% Cl, 19.04% N; Found: 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

A mixture of 2.6 g (20 mmol) of 2-thiophenecarboxylic acid, 2.4 g (20 mmol) of thionyl chloride and 15 ml of toluene was heated at reflux for 1 hour. The reaction mixture is concentrated to an oily residue (2.8 g). A solution of this oil in 10 ml of diethyl ether is added to a solution of diazomethane prepared from 8.1 g (80 mmol) of N-methyl-N-nitrosourea] in 200 ml of ether. The reaction mixture was stirred at 20 ° C for 2 hours and then treated with excess hydrogen chloride gas for 20 minutes. After stirring for another half an hour, the reaction mixture was concentrated to give 3.2 g of chloroacetyl-2-thiophene as a dark colored oil. A portion of this dark colored oil (1.6 g) was taken up in 25 ml of acetonitrile and 2.6 g (5 mmol) of tetra-n-butylammonium salt of 4-amino-5-chloro-N- [2- (diethyl)] was added. lamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) and stirred for 18 hours. After concentration, the residue is purified by chromatography on alumina (activity III), eluting with ethyl acetate containing 2% ethanol. Recrystallization from acetonitrile melts at 135-139 ° C.

For C ^ HH ^N INO ^S: C, 55.67; C, 5.90; N, 10.25; S, 7.82. Found: 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

To a stirred solution of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide sodium salt [obtained from the corresponding hydrochloride; 5.0 g (16 mmol)] (prepared in Preparation 1) and 1.3 g of 60% sodium hydride (32.6 mmol) in 15 ml of DMF were added 3.64 g (16 mmol) of 2-chloroethyl p-toluenesulfonate. and the mixture was stirred at room temperature for 16 hours and then at 80-90 ° C for 3 hours. The reaction mixture was concentrated in vacuo and the residue was partitioned between brine and methylene chloride. The organic phase was washed with aqueous sodium hydroxide solution, brine and water, dried and concentrated in vacuo. The residue was recrystallized from ether to give 2.02 g of the title compound, m.p. 153-154 ° C.

Analysis calculated for: ^C 15 ^H 23 ^Cl 2 ^N 3 ^O 2: C, 51.72; H, 6.67; N, 12.06. Found: C 51.76, H 6.64, N 11.42.

Example 54 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2-methyl-1- (1,3-dioxolan) -4-yl] oxybenzamide

To a vigorously stirred suspension of 1.26 g of 60% sodium hydride (32 mmol), washed with pentane, in 3 mL of dry dimethylformamide, was added 8.57 g (3 mmol) of 4-amino-5-chloro-N- [2] over 35 minutes. - (diethylamino) ethyl] -2-hydroxybenzamide in 12 ml dimethylformamide. After stirring for 1.5 hours, 6.54 g (27 mmol) of 2-methyl-2- (2-iodoethyl) -1,3-dioxolane [prepared according to □] was added over 8 minutes. Org. Chem., 48, 5381-5382 (1983)] and the mixture is stirred for an additional 24 hours. The reaction mixture was poured into 300 ml of sodium chloride solution and extracted four times with 100 ml of methylene chloride each time. The organic phases were combined, washed twice with 100 ml of 10% aqueous sodium hydroxide solution and brine each time, dried over sodium sulfate and concentrated in vacuo. 9.44 g of an oily residue are obtained, of which a 5 g portion is purified by chromatography on a silica gel column (flash chromatography), eluting with a mixture of methylene chloride (93), methanol (7) and ammonia (0.2). . The appropriate fractions were combined and concentrated in vacuo to give 2.68 g of the title compound, mp 84-85 ° C.

Analysis calculated for: ^C 19 ^H 30 ^ClN 3 ^O 4: C, 57.05; H, 7.58; N, 10.51. Found: 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 except that instead of methylamine use dimethylamine. After six days of reaction, the mixture was concentrated in vacuo and the residue was partitioned between water and methylene chloride. The organic phase is dried, concentrated in vacuo and the residue is crystallized from a mixture of methanol, methylene chloride and ether. The title compound was obtained as a white solid containing 1/2 mol of water of crystallization. The product melts at 130-131 ° C.

Analysis: for C ₁₇ H ₂₇ C1N ₃ O ₄ .l / 2H ₂ 0 Calculated 53.74% C 7.42% H 9.33% Cl 14.36% N; Found: 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

To a vigorously stirred suspension of 0.52 g of 60% sodium hydride (3 mmol) washed with pentane, 3.43 g (12 mmol) of 4 amino-5-chloro-N-2- (diethylamino) ethyl] is added in 3 ml of dry dimethylformamide. 2-hydroxybenzamide (prepared in Example 53). After addition of 1 ml of dimethylformamide, the mixture was stirred at room temperature for 45 minutes, then heated to 50 ° C for 15 minutes, and 1.92 g (11 mmol) of 4-chloro-N, N-diethylbutyramide were added. The reaction mixture was stirred at 60-70 ° C for 6 hours, at room temperature for 2 days and then at 60-70 ° C for 4 hours. After cooling, the mixture was poured into 400 ml of sodium chloride solution and extracted four times with 100 ml of methylene chloride each time. The combined organic phases are washed twice with 100 ml of 10% aqueous sodium hydroxide solution each time and brine, dried over sodium sulphate and, after filtration, concentrated in vacuo to an oily residue (3.75 g). Chromatography on silica gel 1.64 g of the title compound as an oil.

Analysis: ^С 21 ^Н 35 ^ 4 ° ^С 3 Calculated 59.06% C, 8.28% H, 13.12% N; Found: C 57.71, H 8.15, N 12.71.

Example 1 a d 57.

2- (2-acetoxyethoxy) -4-amino-5-chloro-N- [2- (diethylamino) ethyl] benzamide

A solution of 5.27 g (10 mmol) of the tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) in 100 ml of acetonitrile together with 2 g ( mmol) of 2-bromoethyl acetate was stirred for 48 hours. The solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was washed with ice-cold 0.4N sodium hydroxide solution and water, dried and the solvent was evaporated. The residue is chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (2) and ammonia (0.5) as the solvent system. Appropriate fractions were combined and the solvent was evaporated. 3.18 g (85%) of the title compound is obtained as a residue, which melts at 101-102 ° C after crystallization from toluene.

Analysis; for ^C 26 ^H i7 ^C1N 3 ° 4 calculated 54.91% C, 7.05% H, 11.30% N; Found: C, 54.86; H, 7.01; N, 11.28.

Example 58

4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2,4-methylsulfinylbenzamide

A) 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [4- (methylthio) butoxy] benzamide

A mixture of 15.82 g (30 mmol) of tetrabutylammonium salt of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-hydroxybenzamide (prepared in Preparation 3) in 150 ml of dimethylformamide and 6.48 g ( mmol) of 1,4-dibromobutane was stirred for 24 hours. The resulting solution was cooled and poured into a 500 mL flask containing 1.5 g of a 60% pentane-washed sodium hydride emulsion (37.5 mmol). The resulting suspension was cooled in ice and methylmercaptan was added with stirring until hydrogen evolution ceased. The resulting clear solution was heated at 35-50 ° C for 5 hours, then poured into 1400 mL of water and extracted with ethyl acetate. The organic layer was washed with water and after drying the solvent was evaporated. Subject the residue to silica gel chromatography using a mixture of methylene chloride (100), methanol (2) and ammonia (0.5) as the solvent system. Two compounds are obtained:

(1) 1,4-bis- [4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-oxybenzamido / butane, m.p. 172-176 ° C; and

2) 2.5 g of the title compound, melting at 101-103 ° C after crystallization from 2-propanol.

Analysis: ^{C H} 3q IQ ^{C1N 2 0} 3 calculated 55.72% C, 7.79% H, 10.83% N, 9.14% Cl, 8.27% S; found: C 55.59, H 7.87, N 10.81, Cl 9.26, 8.19%.

B) 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [4- (methylsulfinyl) butoxy] benzamide

The general procedure described in Example 21 was repeated except that the product prepared above was used instead of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2- (methylthio) ethoxy] benzamide. Chromatography on silica gel and crystallization from methylene chloride / ether yielded the title compound (78%) as a solid, m.p. 80-83 ° C.

Analysis for C ^ q ^ ClN? O ^ S calculated 53.51% C, 7.49% H, 10.40% _of N, 8.78% Cl, 7.94% S; found: C 53.70, H 7.72, N 10.36, Cl 8.40, S 7.78.

Example 59

4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2- (1-pyrrolidinyl) 2-oxoethoxy] benzamide Solution 1.07 g (3 mmol) 4-amino-5-chloro N- [2- (diethylamino) ethyl] -2- (2-methoxy-2-oxoethoxy) -benzamide (prepared in Example 15) in 10 ml of methanol and 0.952 g (23 mmol) of pyrrolidine was refluxed overnight. The solvent was evaporated and the residue was chromatographed on deactivated silica gel using a mixture of methylene chloride (100), methanol (2.5) and ammonia (0.5) as the solvent system. The appropriate fractions were combined, the solvent was evaporated and the residue was first crystallized from 2-propanol and then recrystallized from a mixture of methanol and ether. The solid was dried in vacuo giving 0.86 g (72%) of the title compound, mp 160-162 ° C.

Analysis for C ^ gH _{2 g} ClN ₄ 0 ^ .l / 4H ₂ 0 calculated 56.84% C, 7.40% H, 13.96% N; Found:% C, 56.89;% H, 7.24;% J, 57%.

Example 60

4-Amino-5-chloro-N- [2- (diethylaminoethyl) -2- [2- (ethylsulfinyl) ethoxy] benzamide

A) 4-Amino-5-chloro-N- [2- (diethylamino) ethyl] -2- [2- (ethylthio) ethoxy] benzamide

The general procedure described in Example 20 was repeated except that 2-chloroethyl methylsulfide was used instead of 2-chloroethyl methylsulfide. To afford the title compound as an off-white solid after crystallisation from acetonitrile, p ^{| X} and 92 to 94 ° C. Yield 61%.

Analysis: for ^C 17 ^H 28 ^C1N 3 ° 2 ^{with the} calculated 54.60% C, 7.55% H, 11.24% N, 9.48% Cl, 8.58% S; Found: 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- (ethylsulfinyl) ethoxy] benzamide

The procedure of Example 21 was repeated using the product of Step A as the starting material. The title compound is obtained in 53% yield as yellowish shiny crystals melting after crystallization from acetonitrile at 140-142 ° C.

Analysis: for C IN3O3S

CS 271462 02 calculated C 52.36, H 7.24, N 10.78, Cl 9.09, S 8.22; found 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-inonohydrate

A) Cia-4-amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-

-hydroxy-benzamide id

The general procedure described in Preparation 1 was repeated except that 2 g (4.3 mmol) of cis-4 was used in place of 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2-methoxybenzamide. amino-5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] -2-methoxybenzamide prepared as described in published European application No. 76,530 (1983)]. The product obtained after crystallization from 2-propanol yielded the title compound in 54% yield, mp 146-148 ° C.

Analysis: for ^C 22 ^H 27 ^FN 3 ^C ^ 4 ° -в calculated 58.34% C, 6.01% H, 9.28% N, 7.83% Cl; Found: 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

To a stirred suspension of 40 mg of sodium hydride (60% dispersion washed with petroleum ether, 1 mmol) in 10 ml of acetonitrile was added first 0.45 g (1 mmol) of the product obtained in Step A and then 0.32 g (1 mmol) of tetrabutylammonium bromide. The reaction mixture was heated at 40 ° C for 15 minutes, then 0.44 g (4 mmol) of 2-chloroethyl methylsulfide and 50 mg of potassium iodide were added. The reaction mixture was refluxed for 2 hours, then the solvent was evaporated. evaporate and the residue is partitioned between ethyl acetate containing 10% methylene chloride and water. The organic layer was dried and the solvent was evaporated. The residue was crystallized from 2-propanol to give 0.26 g (50%) of the title compound, mp 58-60 ° C.

Analysis: ^ 25 ^H 33 ^C1FN 4 ^S 3 ° 2 ° ^H Calculated 55.18% C, 6.48% H, 7.72% N; found: C 55.46, H 6.42, N 7.47,

Example 1 a d 62

Cis-4-amino-2- (2-amino-2-oxoethoxy) -5-chloro-N- [1- [3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl] benzamide- sesquihydrate

To a stirred suspension of sodium hydride (0.12 g, 60% emulsion washed with petroleum ether, 3 mmol) in 20 mL of acetonitrile was added first 1.35 g (3 mmol) of cis-4-amino-5-chloro-N- / 1- [ 3- (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl / -2-hydroxybenzamide (prepared in Step A of Example 61) followed by 0.96 g (3 mmol) of tetrabutylammonium bromide. The reaction mixture was heated at 40 ° C for 15 min. 0.92 g (6 mmol) of methyl bromoacetate was added and after stirring for 2 days the reaction mixture was partitioned between water and ethyl acetate. The organic phase is dried, concentrated in vacuo and the residue chromatographed on deactivated silica gel using a mixture of ethyl chloride (100), methanol (2) and ammonia (0.5) as the solvent system. Appropriate fractions were combined and the solvent was evaporated. The residue was dissolved in methylene chloride by addition of methanol and the solution was cold saturated with ammonia gas. After 30 minutes the solvent was evaporated and the residue was crystallized from a mixture of ethanol and water. 0.3 g (19%) of the title compound is obtained as a sesquihydrate, m.p. 173-175 ° C.

Analysis calculated for: ^C 24 ^{H 30 ClFN} 4 ^O 5 ** In ^2H 2 ° C; Found: C 53.59, H 6.21, N 10.36.

The above product is also prepared by the following alternative process,

To a stirred suspension of sodium hydride (60 mg, 1.5 mmol, 60% emulsion washed with petroleum ether) in 10 mL of acetone / tril was first added 0.68 g (1.5 mmol) of cis-4-amino-5-chloro-N- / 1. -? - (4-fluorophenoxy) propyl] -3-methoxy-4-piperidinyl / -2-hydroxybenzamide and then 0.48 g (1.5 mmol) of tetrabutylammonium bromide. The reaction mixture was heated at 40 ° C for 15 min. To a clear solution, to which was added 0.56 g (6 mmol) of chloroacetamide and 0.25 g of potassium iodide. The reaction mixture was heated to reflux, the solvent was evaporated and the residue was partitioned between ethyl acetate and water. The organic layer was evaporated and the residue was chromatographed on deactivated silica gel, using a mixture of methylene chloride (100), methanol (2) and ammonia (0.5) as the solvent system. The appropriate fractions were combined, evaporated and the residue (0.2 g) was crystallized from ethanol / water. This gives 60 mg of the title compound, m.p. 173-175 ° C.

Example 63

4-Amino-5-chloro-N- (2-diethylamino) ethyl] -2- (2-methoxypropan-1-yl) oxybenzamide

The general procedure described in Example 31 was repeated except that an equimolar amount of 1-chloro-2-methoxypropane was used instead of bromo-3-methyl-2-butanone. The title compound is obtained which has a purity of more than 95% after high performance liquid chromatography.

Analysis: ^ 17 ^ 28 ^^ ^N ° 3 3 calculated 57.05% C, 7.89% H, 11.74% N, 9.91% Cl; Found: 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

The general procedure described in Example 31 was repeated except that an equimolar amount of 1-chloro-2,3-epoxy-2-methylpropane was used instead of 3-bromo-3-methyl-2-butanone. The resulting intermediate was reduced with sodium borohydride using the procedure described in Example 41 to give the title compound, m.p. 87-89 ° C.

Example 65

The general procedure described in Example 64 was repeated except that an equimolar amount of 2-chloro-3,4-epoxy-3-methylbutane was used instead of 1-chloro-2,3-epoxy-2-methylpropane. There was obtained 4-amino-5-chloro-N- (2-diethylamino) ethyl] -2 - [(2-hydroxy-2-methyl) but-3-yl] oxybenzamide.

Example 66

The general procedure described in Example 63 was repeated except that equimolar amounts were used instead of 1-chloro-2-methoxypropane.

2-chloro-3-methoxybutane and 2-chloro-3-methoxy-3-methylbutane to give a mixture of threo- and erythro-4-amino-5-chloro-N - [(2-diethylamino) ethyl] - 2 - [(2-methoxy) but-3-yl] oxybenzamide and 4-amino-5-chloro-N- (2-diethylamino) ethyl] -2 - [(2-methoxy-2-methyl) but -3-yl] oxybenzamide.

Claims (2)

SUBJECT OF THE INVENTION 1 c i n iq R, R and R are the same or different and are each a hydrogen atom or a C 1 -C 4 alkyl group, either 3 are hydrogen atoms or together form a group or 1214 R and R together with the carbon atoms to which they are attached may form a saturated ring of 5 to 7 atoms, optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, or 1415 R and R together with the carbon and oxygen atom to which they are attached may form a three to seven membered saturated oxygen ring and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates or quaternary alkylammonium salts containing from 1 to 4 carbon atoms in each alkyl moiety; characterized in that the compound of formula (II) ^NH 2 in which Hal a r! are as defined above, reacted with a compound of formula III (III) wherein: R has the meaning given to the body and L represents a conventional leaving group, in the presence of an acid acceptor base, optionally within the above definition, R or / and / or the compound of formula I obtained is optionally converted to its non-toxic, pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt as defined above. 2. A process according to claim 1, wherein the corresponding starting materials are used to produce the compounds of formula (I) in which Hal is chlorine, bromine or fluorine; represents the remainder of the formula wherein R ⁷ and R ⁸ are identical or different alkyl groups containing 1-4 carbon atoms; R! ° represents alkoxy having 1 to 4 carbon atoms, n is an integer from 1 to 4 ares · ^ ⁷ is hydrogen or halogen, and ar represents the remainder of the formula R ¹² l -CHOC 2 Cl 2 OR, R ¹² I. -CHCH ₂ OR, -CH (CH ₂ ) _q B, R ¹² AND -C - CN Or where X represents oxygen or a group = NOR, ₀ W- V is -NHCR ^, -S-R ^, G m i ^e ce lé number 0 value 2 or 3, £ Yippee ce lé number 0 value 0. , 1 or 2, q ’ Yippee ce lé number 0 value 0 to 4, r Yippee ce lé number 0 value 2 or 3, R ⁹ represents a hydrogen atom or a C 1 -C 4 alkyl group, 11 12 13 R, R and R are the same or different and are each a hydrogen atom, a C 1 -C 4 alkyl group, a C 4 -C 4 alkenyl group or a C 5 -C 7 cycloalkyl group, with the proviso that R 1 is an alkenyl group as defined above, the unsaturated carbon atom is not directly attached to the oxygen atom, R is hydrogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy, C 1 -C 4 phenylalkyl or amino, R 15, _q are the same or different and are each hydrogen or alkyl (C 1 -C 4) group; R ²⁰ and R ²¹ are either hydrogen or together form a group R ¹² R ¹⁴ 3. or R together with the carbon atoms to which they are attached may form a saturated ring of 5-7 atoms, optionally containing one or two heteroatoms selected from oxygen, sulfur and nitrogen, or together with the carbon and oxygen atom to which they are attached, they may form a three to seven membered saturated oxygen ring and their non-toxic, pharmaceutically acceptable salts, hydrates, solvates or quaternary alkyl ammonium salts containing from 1 to 4 carbon atoms in each alkyl moiety. The method of claims 1 and 2, wherein the corresponding starting materials are used to give 4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5- chloro-N4-amino-5-chloro-N4-amino-2-benzoylmethyloxy-5-chloro-N- (2- (diethylamino) ethyl) benzamide, 4-amino-2- (butan-2-one-3-yl) ) oxy-5-chloro-N4-amino-5-chloro-2- (cyclohexanone-2-yl) oxy-N4-amino-5-chloro-N4-amino-5-chloro-Ndu, 4-amino-5- chloro-Ndu, 4-amino-5-chloro-N4-amino-5-chloro-2-cyanomethyloxy-N- [2- (diethylamino) ethyl] benzamide, 4-amino-2- (carboxamidomethyloxy) 5-chloro-N- [2- (diethylamino) ethyl] benzamide acetate, 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-butanone-1-yl) oxy-5-chloro-N- [2- (diethylamino) ethyl] benzamide, 4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (pentane) 2-on-1-yl) oxybenzamide, 4-amino-5-chloro-2- (pentan-3-on-2-yl) oxy-N- (2-diethylaminoethyl) benzamide, 4-amino-5-chloro -N- [2- (diethylamino) ethyl] -2- (2-hydrazino-2-oxoethoxy) benzamide, threo-4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- ( 2-hydroxybuta-3-yl) oxybenzamide, erythro-4-amino-5-chloro-N- [2- (diethylamino) ethyl] -2- (2-hydroxybut-3-yl) oxybenzamide, 4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4-amino-5-chloro-N4 -amino-5-chloro-N [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] | [2- (diethylamino) ethyl | [2- (diethylamino) ethyl] [2- (diethylamino) ethyl]] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [2- (diethylamino) ethyl] [ 2- (diethylamino) ethyl] [2- (diethylamino) ethyl] -2- (2-methoxyethoxy) benzamide, -2- (2-hydroxyethoxy) benzamide, -2- (2,2-dimethoxyethoxy) benzamide, -2- (2-methoxyethoxy) methyloxy benzamide, -2- (2-propanone-1-yl) oxybenzamide, [2- (diethylamino) ethyl] benzamide, [2- (diethylamino) ethyl] benzamide -2- (5-hexen-2-one-3-yl) oxybenzamide, 2 - [(2-hydroxyimino) propan-1-yl] oxybenzam-2 - [(2-methoxyimino) propan-1] oxybenzami-2- (2-hydroxypropan-1-yl) oxybenzamide, A process for the manufacture of substituted benzamides of the general formula I in which Hal represents a halogen atom, r! represents the remainder of the formula where R ⁷ and R ⁸ means the same or different alkyl groups always 1 to 4 carbon atoms, RÍO represents an alkoxy group having 1 to 5 carbon atoms 4 atoms carbon, £ is an integer from 1 to 4 a R ¹⁷ represents a hydrogen or halogen atom, and 2 represents the remainder of the formula R ¹² I 11 -CH0CH ₂ CH ₂ 0R ^iJ ·, R ¹² R ² R ¹⁴ I /, - C - ca I \ 13 _R 13 0R ^X5 T / -A - C-CH ^(СН 2 ^ Ш ') R ¹² I R ¹² 1 - сжснр в, 1 - C - CN, R ¹³ or where X means oxygen or a group = NOR ^ ⁶ , 0 (0) - в means -NHCR ⁹ , f P 9 -S-R 0 R ⁹ - C - N ^ R ⁹ a pyridyl or oxazolidinyl residue, CS 271462 82 Yippee whole number o value 2 or 3, Yippee ce lé number O value , 1, or 2 Yippee whole number 0 value 0 to 4, Yippee whole number 0 value 2 or 3, represents a hydrogen atom or a (C1-C4) alkyl group, 12 14 R and R are the same or different and are each hydrogen, C1-C4alkyl, C1-C4alkenyl, C1-C4alkoxyalkyl or C1-C4alkoxyalkyl; 7 carbon atoms, with the proviso that when R6 is an alkenyl group as defined above, the unsaturated carbon atom is not directly attached to an oxygen atom, is a hydrogen atom, a halogen atom, a C1-C4 alkyl group, a C1-C4 alkoxy group carbon atoms, hydrazino, arylhydrazino, thienyl, phenyl, phenylalkyl of 1 to 4 carbon atoms in the alkyl moiety, or amino group, - 2 - [(2-methylamino) -2-oxoethyl] benzamide, -2- (ethyl-3-methoxycroton-4-yl) oxybenzamide, -2- (1,3-dioxolan-2-yl) oxybenzamide, - 2- (oxazolidin-2-one-5-ylmethyl) oxybenzamide, -2- (2-pyridinomethyl) oxybenzamide, -2-tetrahydrofurfuryloxybenzamide or -2- (2-methoxyethoxyethyl) oxybenzamide.