DD202701A5 - PROCESS FOR THE PREPARATION OF CHINOLINE DERIVATIVES - Google Patents

Abstract

The invention relates to compounds of the formula wherein A is the radical - (CH 2 deep) 2 - which may carry one or two defined substituents; R can be high 1 C deep 3-C deep 4-alkyl or cyclopropyl or phenyl, which may optionally bear one or two defined substituents, or is a heteroaryl group with five or six ring atoms, optionally a C deep 3-C deep 4-alkyl substituents can carry; R is high 2 and R is highly hydrogen or a C 1-C deep 2-alkyl radical or R 2 is a C 2-C deep deep 4-alkylene radical attached to one of the carbon atoms which binds the two carbon atoms. Form the main chain of A so that together with the adjacent nitrogen atom they form a pyrrolidinyl or piperidyl radical; and one of R 4 or R 4 is hydrogen and the other is hydrogen, halogen or C 1-C deep 3-alkyl or C 1-C deep 3-alkoxy, and their acid addition salts. Methods of making these compounds are also described, as well as pharmaceutical compositions containing one of these compounds and a pharmaceutical dismutating agent or carrier. The compounds are 5-hydroxytryptamine antagonists.

Description

Berlin, September 24, 1982 AP G 07 D / 240 577

Process for the preparation of quinoline derivatives

Field of application of the invention

The invention relates to methods of preparation of novel quinoline derivatives, which are effective as 5-Bydrox7tryptamin antagonists in Y / Armbleüterntern »The new compounds can thus be used as a remedy in medicine.

C. Characteristics of the known technical solutions

The compounds to be prepared according to the invention are quinoline derivatives which are characterized by the presence of a substituted aminoalkylthio substituent or the like in the 2-position and a defined substituent, for example a phenyl radical in the 3-position. Compounds of this type are new, but chemically similar compounds have already been described in the literature. Thus, 3-aryl-4-aminoalkyl-monochlorin derivatives, for example 4- (3-dimethylaminopropylthio) -3-phenyl-quinoline, which are positional isomers of some compounds according to the invention, have been described in DE-PS 1 049 379. These known compounds show nicotinolytic and anti-inflammatory efficacy and inhibitory activity in parasympathetic ganglia. Positional isomers of lower homologues of some of the compounds of the invention, for example 2- (2-Diethylami noethylthio) -4- »methylquinoline are in J. Amer, Chem. Soc. 1949, H, 3667. Finally, 2- (2-diethylamino-ethoxy) -3-phenylquinoline, which has an oxygen / sulfur relationship with one of the compounds of the present invention, has been described in U.S. Patent 1,860,286 and has been referred to therein as having antipyretic activity.

Ό / η K- 7 4t 4 U b /

10 , 11.1982 60 940/12 R ¹ SA-NR ² R ³

wherein

A is the radical - (CHg) ₂ ^- * ^may be 9®9 ^eDenen f ^a u ^s substituted by one or two alkyl of 1 to 2 carbon atoms or substituted by an alkylene radical so that it together with the rest of the - (CH ₂ ! Radical forms a cycloalkylene radical with not more than 6 carbon atoms;

R is an n-, iso- or α-alkyl radical having 3 to 4 carbon atoms or a cyclopropyl radical, or R is a phenyl radical which may optionally be substituted by one or two substituents, where in the latter case these substituents may be identical or different and from the group halogen atoms and hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms, perfluoroalkyl having 1 to 2 carbon atoms, cyano, carboxy, alkoxycarbonyl having 1 to

2 carbon atoms, carbamoyl, N-alkylcarbamoyl with 1 to

May be 3 carbon atoms in the alkyl portion and N, N-Oialkylcarbamoyl having 1 to 3 carbon atoms in the alkyl moiety, or R is a heteroaryl group having five or six ring atoms and a single heteroatom selected from the group oxygen, sulfur and nitrogen or two heteroatoms, either a Nitrogen and a sulfur atom or a nitrogen atom and an oxygen atom, wherein the heteroaryl radical may be optionally substituted with an alkyl group having 1 to 3 carbon atoms;

2 3 R and R, which may be the same or different, are water

or R is ethylene, trimethylene or tetramethylene, which with the

60 940 12

240 5 7 7 8 -1. -

Object of the invention

It is an object of the invention to enrich the state of the art with new 5-hydroxytryptamine antagonists.

Explanation of the essence of the invention

The invention has for its object to develop processes for the preparation of new CMnolinderivate. Quinoline derivatives of the general formula are prepared according to the invention

η ur j λ r- ~

L fi h 7 7

«4 U J / /

10 * 11.1982 7 7 Q '- ⁴ - ⁶⁰ 940/12

1 to 2 carbon atoms, such as methyl, alkoxy having 1 to 4 carbon atoms, for example methoxy or n-propoxy _Ä alkylthio of 1 to 2 carbon atoms, for example methylthio, trifluoromethyl, cyano, carboxy, alkoxycarbonyl having 1 to 2 carbon atoms, for example methoxycarbonyl, carbamoyl, N-alkylcarbamoyl having 1 to 2 carbon atoms in the alkyl part, for example, N-methylcarbamoyl, and Ν, Ν-dialkylcarbamoyl having 1 to 2 carbon atoms in the alkyl part, for example, N, N-Oimethylcarbamoyl be selected. Alternatively, R may be, for example, a furyl, thienyl, pyridyl, thiazolyl or oxazolyl radical, which may optionally be substituted by an alkyl radical having 1 to 2 carbon atoms, for example methyl, "

One of the radicals R or R is hydrogen and the other may be, for example, hydrogen, fluorine, chlorine, bromine, alkyl having 1 to 2 carbon atoms, for example methyl or alkoxy having 1 to 4 carbon atoms, for example methoxy or n-propoxy,

According to one embodiment d r invention quinoline derivatives of formula I are provided wherein A is the radical - (CH ₂₎ -, which can be substituted by one or two methyl radicals, or it 1st through an alkylene group substituted so that it of together with the rest - (CH ₂ ) radical forms a cycloalkylene radical having not more than 6 carbon atoms;

R is an n-propyl, isopropyl, η-butyl or cyclopropyl radical or is phenyl which may optionally be substituted by one or two substituents, which may be identical or different, selected from the group consisting of halogen and

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one or the other of the carbon atoms which form the two-carbon atom main chain of the radical A and together with the adjacent nitrogen atom form a pyrrolidinyl or piperidyl radical; and one of the substituents R or R is hydrogen and the other is hydrogen, a halogen atom or an alkyl group having 1 to 3 "carbon atoms or an alkoxy group having 1 to 3 carbon atoms and their pharmaceutically acceptable acid addition salts.

Some of the compounds according to the invention have at least one asymmetric carbon atom, for example when A is a 1,2-propylene radical. The racemic form of such compounds having at least one asymmetric carbon atom can be converted to the corresponding optical isomers by conventional methods. The compounds according to the invention thus consist of a) compounds of the formula I in racemic form and b) their optical isomers, which are 5-hydroxytryptamine (5-HT) antagonists.

A can be, for example, 1,2-ethylene, 1,2-propylene, 2,3-propylene, 1,1-dimethyl-1,2-ethylene, 2,2-dimethyl-1,2-ethylene, cyclopropylene, 1,2- cis-cyclohexylene or 1,2-trans-cyclohexylene.

i R can be, for example, n-propyl, isopropyl, η-butyl, s-butyl or cyclopropyl. Alternatively, R may be, for example, a phenyl radical which may optionally be substituted by one or two substituents. In the latter case, these may be the same or different and from the group fluorine, chlorine, bromine, hydroxyl, alkyl with

10.11.1982 - 6 - 60 940/12

Suitable salts according to the invention are derived from inorganic or organic acids which give a pharmaceutically acceptable anion, for example salt, phosphoric, citric, succinic or benzoic acid and acids, for example 2-hydroxy-3-naphthoic acid or Ι, Ι'-methylenebis-2-hydroxy-3-naphthoic acid, which lead to salts that are relatively insoluble in water and therefore develop activity over a longer period of time *

The compounds according to the invention and the substances used as starting materials can be obtained by processes known for the preparation of chemically analogous compounds. A compound containing at least one asymmetric carbon atom, which serves as starting material in a process according to the invention, can be present in racemic or optically active form to be used ·

The process according to the invention for the preparation of quinoline

12 3 derivatives of the general formula I, wherein A ₁ R, R, R, R and R have the abovementioned meaning and their pharmaceutically acceptable Säureadditionssalza is characterized in that a compound of general formula

II, shark

wherein Hal is a halogen atom, with a compound of the formula

HS

- A - NR ² R ³ III

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atoms, hydroxy, methyl, methoxy, n-propoxy, methylthio, trifluoromethyl, cyano, carboxy, methoxycarbonyl, carbaraoyl, N-methylcarbamoyl and Ν, Ν-dimethylcarbaraoyl, or R is a heteroaryl radical having five or six ring atoms, containing a single heteroatom, selected from the group consisting of oxygen, sulfur and nitrogen, or it contains two heteroatoms which are either nitrogen and sulfur or nitrogen and oxygen, which heteroaryl radical may optionally be substituted by a methyl radical;

2 3

R and R, which may be the same or different, are water

or R ^ is a dimethylene, trimethylene or tetramethylene group attached to one or other of the carbon atoms forming the two-carbon atom backbone of A to form a piperidyl group together with the adjacent nitrogen atom to build;

one of R and R is hydrogen and the other of R or R is hydrogen, halogen or methyl or methoxy; and pharmaceutically acceptable acid addition salts thereof «

A group of preferred compounds of the invention

2- (2-Diraethylaminoethylthio) -3-isopropylquinoline, 2- {2-Dimethylarainoethylthio) -3-p-fluorphenylchinolin, 2- (2-0imethylaminoethylthio) -3-o-methoxyphenylchinolin, 2- (2-dimethylaminoethylthio) -3- p-tolylquinoline, 2- (2-dimethylamino-2-methylpropylthio) -3-phenylquinoline and 2- (2-dimethylaminopropylthio) -3-phenylquinoline

and their pharmaceutically acceptable acid addition salts. Particularly preferred compounds are 2- (2-dimethylaminoethylthio) -3-phenylchiolein and their pharmaceutically acceptable acid addition salts.

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or their acid addition salt is reacted in the presence of an acid-binding agent;

Hal may be, for example, a chloro or bromo-ion. The salt of the compound of formula III may be, for example, a salt of an inorganic acid, for example a hydrogen halide, for example hydrochloric acid. The acid-binding agent may be, for example, sodium hydride a suitable organic solvent, for example dimethylformamide, and can be accelerated or terminated by applying heat.

Another variant of the method of producing the

12 3 compounds of the general formula I, wherein A, R, R, R, R and R have the abovementioned meaning * and their pharmaceutically acceptable acid addition salts is characterized in that a compound of the general formula

IV

with a compound of the formula

ZA-NR ² R ³ V

or their acid addition salts,

wherein Z is a halogen atom or an arenesulfonyloxy or alkanesulfonyloxy group, in the presence of an acid-binding agent;

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Z can be, for example, a chlorine or bromine atom or a p-toluenesulfonyloxy or methanesulfonyloxy radical. The salt of the compound of the formula V can be, for example, a salt of an inorganic acid, for example a hydrohalic acid, for example hydrochloric acid. The acid-binding agent can be, for example The reaction is usually carried out in an organic solvent, for example dimethylformamide, and at ambient temperature or moderately elevated temperature.

A further process variant for the preparation of compounds of the general formula

wherein R

SX-CHR ³ -NR ³ R ⁶

4 5 R and R have the abovementioned meaning

and wherein X is a methylene radical optionally substituted by one or two alkyl radicals having 1 to 2 carbon atoms, as well as their pharmaceutically acceptable acid addition salts, is a compound of the general formula

VII SX-COR ³

3 6

react with an amine of the formula R R NH under reducing conditions »

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The reducing conditions can be achieved by using a) a borohydride having reducing properties, for example sodium cyanoborohydride or b) hydrogen in the presence of a hydrogenation catalyst, for example palladium on charcoal. Both types of reaction are preferably carried out at ambient temperature in a suitable organic solvent, for example in an alkanol having 1 to 3 carbon atoms, for example ethanol, together with acetic acid if appropriate * The process b) is usually carried out in a suitable organic solvent, for example in an alkanol having 1 to 3 carbon atoms For example, ethanol. In the case where any part of the compound of formula VII is susceptible to reduction or hydrogenolysis if catalytic hydrogenation is employed, process a) should be used (with, for example, sodium borohydride as reducing means) to avoid unwanted side reactions.

A further process variant for the preparation of compounds of the general formula

VIII,

SY-CH ₂ NR ³ R ⁷

wherein R is hydrogen or an alkyl radical having 1 to 2 carbon atoms and Y is a methylene radical, optionally substituted by one or two alkyl radicals having 1 to 2 carbon atoms, or R is a diraethylene, trimethylene

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or tetraraethylene radical linked to Y such that it forms a pyrrolidinyl or piperidyl radical with the adjacent nitrogen atom, and their pharmaceutically acceptable acid addition salts, with the proviso that R is not a phenyl radical to which a cyano, carbamoyl, N- Alkylcarbamoyl- (having 1 to 3 carbon atoms in the alkyl moiety) - or N, N-dialkylcarbaraoyl (having 1 to 3 carbon atoms in the alkyl moiety) radical is that an amide of the general formula

IX

SY-CO-NR ³ R ⁷

is reduced »

A suitable reducing agent is, for example, a borane complex having reducing properties, for example a borane-oxyethyl sulfide complex, or an aluminum hydride derivative having reducing properties, for example lithium aluminum hydride or sodium cis (2-methoxyethoxy) aluminum hydride (trade name "Red"). al "for the 3,4 M solution in toluene). When R is a phenyl radical with a carboxy substituent, the JBorane complex is not a suitable reducing agent and it is better to use the aluminum hydride derivative." Conversely, when R is a phenyl radical with alkoxycarbonyl substituents. With 1 to 2 C atoms in the alkoxy part, the aluminum hydride derivative is not a suitable reducing agent and therefore better to use the borane complex. The reduction is carried out in a suitable organic solvent, for example in tetrahydrofuran, and can be accelerated or completed by supplying heat.

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A further process variant for the preparation of compounds of the general formula

12 4 5

wherein A, R, R, R and R have the abovementioned meaning and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical which contains a cyano, carbamoyl, N-alkylcarbamoyl (having 1 to 3 C) Atoms in the alkyl moiety) - or Ν, Ν-dialkylcarbamoyl (having up to 3 carbon atoms in the alkyl group) substituents, is that a compound of the general formula

COCH-

reduced·

A suitable reducing agent is, for example, a borane complex having reducing properties *, for example a borane-dimethyl sulfide complex, or an aluminum hydride derivative having reducing properties, for example lithium aluminum hydride or sodium bis (2-methoxyethoxy) aluminum hydride. When R represents a phenyl radical with a carboxy substituent, the borane complex is not a suitable reducing agent and it is better to use the aluminum hydride derivative * In contrast, when R is a phenyl radical having alkoxycarbonyl substituents with 1 to 2 carbon atoms.

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Represents atoms in the alkoxy part, the Aluminiumhydridderivat is not a suitable reducing agent and therefore better to use the borane complex. The reduction is carried out in a suitable organic solvent , for example in tetrahydrofuran. The reaction may preferably be carried out in an inert atmosphere, for example under argon, and may be accelerated or completed by the introduction of heat.

A further process variant for the preparation of compounds of the general formula

XII, SA-NH ₂

14 5

in which A, R, R and R have the abovementioned meaning and their pharmaceutically acceptable acid addition

1, provided that R can not be a carboxyphenyl radical, is that a Curtius reaction with a compound of formula

XIII

SA-CO ₂ H

performs "

The Curtius reaction is known in chemistry and consists essentially in adding a carboxylic acid successively into the corresponding azide, the corresponding transitional

_{0 /} nr ₇₇ Q '10.11.1982

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In the present case, the azide can be obtained, for example, by reacting the carboxylic acid (XIII) with diphenylphosphoryl azide in the presence of a suitable solvent, for example toluene and in an inert atmosphere, for example under argon The resulting azide can be obtained, for example, in the corresponding urethane derivative by reacting with 2- (trimethyl-3-ethyl) ethanol in a suitable solvent, for example toluene, and in an inert atmosphere, for example under argon The reaction can be accelerated or completed by supplying heat. The final stage can be carried out, for example, by reacting the urethane derivative with a fluoride ion donating compound, for example tetra-n-butylammonium fluoride in a suitable solvent, for example In a mixture of acetonitrile and tetrahydrofuran, is reacted * The final stage can be carried out in an inert atmosphere, for example under argon, and accelerated or completed by supplying heat.

A further process variant for the preparation of the compounds of general formula XII and their pharmaceutically acceptable acid addition salts is _f , a compound of general formula

XIV SA-NH-CO-O (CH ₂ ) ₂ Si (CH ₃ ) ₃

to react with a fluoride ion donating compound

14 5 Here A, R, R and R have the abovementioned meaning ·

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This process is carried out as described immediately above.

A further process variant for the preparation of a compound of the general formula

S-A-N

^ R ₂

and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical to which a cyano, alkoxycarbonyl (having 1 or 2 C atoms in the alkoxy part), carbamoyl, N-alkylcarbamoyl (having 1 to 3 C) Atoms in the alkyl moiety) -, or Ν, Ν-dialkylcarbamoyl (having 1 to 3 C atoms in the alkyl moiety) is bonded, is that a compound of formula

CO ₂ R ⁸ XVI, SAN '

8 in which R is an alkyl radical having 1 to 5 carbon atoms,

12 4 5 reduced «A, R, R, R and R have the above

Meaning"

A suitable reducing agent is, for example, an aluminum hydride derivative having reducing properties, for example lithium aluminum hydride, or sodium bis (2-methoxyethoxy) aluminum hydride. The reduction can be carried out in a suitable process

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organic solvents «, for example in Qi- (2-methoxy ethyl) ether and under an inert atmosphere, for example under argon, are performed. It can be accelerated or completed by heat supply.

Another process variant for the preparation of compounds containing the group

- S - A - N (CH ₃ J ₂ XVII

or

CH ₃

- s - A - H ^ XVIII

and their pharmaceutically acceptable acid addition salts, is that one has a corresponding compound with the group

- S - A - NH ₂ XIX

or H

-S-A-N ^ V XX

^ «2

2 with formaldehyde and formic acid »A and R have the abovementioned meaning« The process can be accelerated or completed by supplying heat.

A further process variant for the preparation of compounds of the general formula XII and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical, to the cyano * carboxy, alkoxycarbonyl having 1 to 2 C atoms in the alkyl part,

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Ca rbamoyl, N-Al ky lea rbamoyl rait 1 to 3 carbon atoms in the alkyl ,, in part, or N, N-Dialkylca rbamoyl is bound with 1 to 3 carbon atoms in the alkyl moiety, beεte in that a compound of the general formula

XXI, SA-NH-CO ₂ R ⁸

in which R has the abovementioned meaning, with an alkali metal hydroxide under essentially anhydrous conditions

The alkali metal hydroxid oxide may be, for example, sodium hydroxide which has been liberated in situ from a sodium hydroxide-dimethyl sulfoxide complex and the equivalent amount of water. The process may be carried out in a suitable organic solvent, for example dimethyl sulfoxide, either at ambient temperature or at a moderately elevated temperature.

A further process variant for the preparation of a compound of the general formula

CONH ₂

XXIIV

SA-NR ² R ³

g wherein R is hydrogen, a halogen atom or a radical of the group hydroxy, alkyl having 1 to 4 carbon atoms, alkoxy with

240577

10.11.1982 60 940/12

1 to 4 carbon atoms, alkylthio having 1 to 4 carbon atoms or perfluoroalkyl having 1 to 2 carbon atoms, as well as their pharmaceutically acceptable Säuraadditionssalze, is that a compound of formula

N "SA-NR ² R ³

XXIII

hydrolyzed under alkaline conditions

2 3 4 A, R, R and R have the abovementioned meaning ·

A suitable agent for hydrolyzing is, for example, an alkali metal hydroxide, for example potassium hydroxide. The hydrolysis is carried out in a suitable organic solvent, for example in an alkanol having 1 to 4 C atoms, for example t-butanol, it can be accelerated or completed by supplying heat.

Another variant for the preparation of compounds of the general formula

CONR ¹⁰ R ¹¹

SA-NR ² R ³

XXIV,

In which R and R, which can be identical or different, represent hydrogen or an alkyl radical having 1 to 3 C atoms and their pharmaceutically acceptable acid addition salts, is a compound of the general formula

240577

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COHaI

SA-NR ² R ³

XXV,

where Hal, A, R

R ³ .

4 5 R and R the above-mentioned meaning

10 11 tung, with a compound of the formula R R NH um

· enforce

A suitable Hal substituent is, for example, a chlorine atom. The process can be carried out in a suitable solvent, for example in toluene or methylene dichloride, or in an aqueous medium. It can be accelerated or completed by heat supply. If the compound of the formula R R is NH dimethylamine, the process can be carried out in situ using dimethylformamide. In this case, dimethylformamide also serves as a solvent for the reaction. The starting material of the formula XXV, in which Hal represents chlorine, can be carried out, for example, by reacting the corresponding carboxylic acid with oxalyl chloride together with a catalytic amount of dimethylformamide in a suitable organic solvent, for example methylene dichloride, at ambient temperature.

Another variant for the preparation of compounds of the general formula

40577

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SA-NR ² R ³

XXVI,

wherein R has the meaning given above, as well as their pharmaceutically acceptable acid addition salts, is that a compound of formula

CO ₂ H

XXVII

SA-NR ² R ³

2 3 ipit methanol or ethanol esterified. Here A, R, R ₁

4 5 R and R have the abovementioned meaning.

The esterification can be carried out, for example, by reacting the carboxylic acid (XXVII) with a suitable acid halide, for example thionyl chloride, and reacting the resulting halides with methanol or ethanol. The process can be carried out at ambient or elevated temperature.

Another variant for the preparation of compounds of the general formula

S-A-N

XXVIII

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and their pharmaceutically acceptable acid addition salts, with the proviso that A can not be a cyclopropylene radical, is that a compound of the general formula

¹

S-A-N

1 _2 A 5 with an acid. A, R, FT *, R and R have the abovementioned meaning.

A suitable acid is, for example, a hydrogen halide acid "for example hydrochloric acid" or trifluoroacetic acid. Hydrochloric acid may be used in the form of an aqueous solution, for example at a concentration between 1M and a saturated solution, or as a solution in an organic solvent, for example ethyl acetate, for example in the range of 2M to 6M

 If trifluoroacetic acid is used, it may be used alone or in 5 to 10 vol. Dilution with water. The process is usually carried out at ambient temperature.

Another variant for the preparation of a compound of the general formula

XXX,

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wherein R has the meaning given above, and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical to which a hydroxy or carboxy substituent is bonded, is that a compound of general formula XXVIII with a compound of Formula R Hai, in which Hai has the abovementioned meaning, and an acid-binding agent,

12 4 5

A, R, R, R and R have the abovementioned meaning »

For example, shark may represent a god atom. A suitable acid-binding agent is, for example, an alkali metal carbonate, for example potassium carbonate. The process is usually carried out in a suitable organic solvent, for example in an alkanol having 1 to 3 C atoms, for example ethanol, and can be carried out at ambient or elevated temperature. It is clear that this process allows for monoalkylation, for example in US Pat

In the case where R in the starting product is methyl or ethyl, or a transalkylation is made possible, for example when R in the starting material is hydrogen.

The invention further relates to a process for the preparation of optically active compounds of the formula I and their pharmaceutically acceptable acid addition salts. The process comprises splitting a compound of the formula I which has at least one asymmetric carbon atom

1 2 3 Ά 5

and wherein R, R, R, R, R and A have the abovementioned meaning.

A suitable acid for splitting is, for example, an optical isomer of tartaric acid, dibenzoyltartaric acid

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or di- (p-toluoyl) tartaric acid _# The resolution is carried out in a suitable solvent, for example in an alkanol having 1 to 3 carbon atoms, for example methanol or ethanol, if appropriate in a mixture with water, ethyl acetate or diethyl ether.

The efficacy of the edible compounds as 5-HT antagonists was demonstrated in the following experiments,

(1) In Vitro Binding of the 5-HT Receptor

a) Binding of tritiated 5-hydroxytryptamine ³

It is an in vitro test of the affinity of the test compounds for the central 5-HT.RTM. Receptor (Molecular Pharmacology, 1979, 16, 687). The compounds are tested for their ability, L H3 5-HT, from a Replace receptor site of a synaptosomal preparation from rat brain tissue. The compounds were tested at 3 μg / ml and considered to be effective if they elicit more than 30 % inhibition of specific binding. Interesting compounds were tested in a range of concentrations to determine the absolute potency for this receptor. The results are expressed as Pl ₅₀ values, where the Pl _{50 is} the -Iog _{1Q of} the concentration of compound required, 50 % of the specific bound Replace ³ h3 5-HT.

Binding of tritium-treated spiroperidol spiroperidol)

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It is an in vitro test of the affinity of the test compounds for the central 5-HT ₂ receptor (Molecular Pharmacology 1979, Ij5 _# 687). The compounds are tested for their ability to replace C H "} spiroperidol from a receptor of a synaptosomal rat brain cortex preparation." Compounds were tested at 0.3 μg / ml and considered to be effective if they elicit more than 30 % inhibition of specific binding «Interesting

, Compounds were tested in a range of concentrations as outlined above for C HJ 5-HT binding. The results were expressed as pI_ ₀ values, where pI _{50 is} the -log _{10 of} the concentration of compound needed, 50 % of the specific bound

, C Hl replace spiroperidol.

2. Inhibition of Mouse Head Sucking by 5-Hydroxytryptophan (5-HT P)

It is an in vivo test of efficacy in central 5-HT receptors. "The test involves the administration of a precursor of 5-HT, e.g. B. 5-HTP in the mouse. The resulting high levels of 5-HT produced in the brain are believed to be responsible for the spontaneous twitching of the head and ears, which can be observed over a period of time after administration of 5-HTP. All known centrally acting 5-HT antagonists inhibit the twitch response in a dose-dependent manner.

A dose range of compounds to be tested was administered intraperitoneally to male mice (mean weight 18 to 20 g, in groups of 5) 15 minutes before the intraperitoneal injection of 5-HTP at 300 mg / kg. The mouse was

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then observed for head twitching 15 minutes later and the results expressed as ID_ ₀ values. "Non-specific inhibition of the reaction by, for example, sedation was eliminated by determining the presence or absence of the Pinna reflex on palpation stirulation of the ear.

3 · Antagonism of fenfluramine-induced hyperthermia in rats

It is a sensitive in vivo test based on the ability of fenfluramine to release 5-HT from endogenous neuronal stores. Female rats (Alderley Park Staram; 180-220 g) were dissolved in relatively warm environment maintained (5 per cage) (25 to 28 ⁰ C) one hour before the start of the test to allow the animals to acclimate · After the acclimation period, The rectal temperature of each animal was measured. These temperatures served as the control value from which all changes were calculated. For recording the control temperatures (-1 hour), either a test compound or a placebo (distilled water) was administered orally or subcutaneously, and after another hour (0 hour), the rectal temperature of each rat was measured »A dose of 15 mg / kg fenfluramine or distilled water (control) was then injected intraperitoneally. Subsequently, the rectal temperatures were measured at the following times after administration of fenfluramine or distilled water:

30 minutes, 1 hour, 2, 3, 4, 5 and 6 hours.

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U «/ / 0

The potency of a tested compound is expressed as ID ₅₀ -VVert, i. h »the dose of the compound which reduces by 50 % the reaction at a standard dose of fenfluramine.

The potency of a specific compound of the present invention depends on its exact chemical structure, but in general the compounds of the invention exhibit the following activities in the following quantities in the above-mentioned tests:

Test l) a) i I ³ Hl 5-HT binding: Pl ₅₀ 5-9

Test l) b): £ HU spiroperidol bandages: Pl ₅₀ ⁵ ** ⁹

Test 2): ID ₅₀ 0.1-50 mg / kg

Test 3): ^ID ₅ o ⁰ A- ¹ SO mg / kg

No toxic or other undesirable effects of the compounds in the investigated dose ranges were observed in the named tests. «

LD_ ₀ values for some compounds of the invention: 2- (2-dimethylaminoethylthio) -3-phenylquinoline hydrochloride

LD ₅₀ [ mg / KGj

> 1000 128 485 75

2- (2-dimethylaminoethylthio) -3- (o-methoxyphenyl) quinoline hydrochloride

LD - approximately 150 mg / kg intraperitoneally in the mouse

kind gender Verabreichunq rat Female orally rat Female intraperitoneally mouse male orally mouse male int raperitoneal

r in « A d Q 0 α. Π h Ή i \ L · fi

10.11.1982

24 0 5 77 8 ~ ²⁶ ' ^{6G940 / 12}

2- (2-Direthylaminoethylthio) -3-isoprol-quinoline-hydrazloride LD ₅₀ approximately 100 mg / kg int raperitoneal in the mouse.

Because of their efficacy as 5-HT antagonists, the compounds of the present invention can be used clinically in human patients as psychotropic agents for the treatment of central nervous system disorders or functional disorders, such as psychosis, schizophrenia, manic states, anxiety or depression, for the treatment of migraine , Urticaria, asthma, hypertension, pulmonary hypertension, vascular spasms and gastrointestinal disorders, as well as to inhibit platelet aggregation. If one of the compounds according to the invention is used clinically in human patients, the following dosage is recommended:

a) orally at a dose of 0.5 mg / kg to 100 mg / kg at appropriate intervals, for example three times daily, or

b) intramuscularly at a dose of 0.1 mg / kg to 20 mg / kg at appropriate intervals,

c) as depot injection (2.5 to 100 mg / kg), or

d) rectally at a dose of 0.5 mg / kg to 200 mg / kg.

The invention further relates to a pharmaceutical composition which contains a quinoline derivative of the formula I in which A, R, R, R, R and R have the abovementioned meaning, or a pharmaceutically acceptable acid addition salt of this compound and an inert

α urine -in η η ... η λ ϊ "ϊ η /, η

10.11.1982

2405778 - ²⁷ ~ ^6o 940/12

pharmaceutically acceptable carrier or diluent

The pharmaceutical compositions according to the invention may be in a form suitable for oral, parenteral or rectal administration. They may therefore be present, for example, in an orally administrable, uniform dosage form, for example as tablets or capsules, optionally one They may also be in an injectable form, for example as a sterile injectable solution or suspension. Finally, they may also be in the form of suppositories for rectal administration. The pharmaceutical compositions can be prepared by standard methods using conventional diluents and carriers.

The pharmaceutical compositions of the present invention, in addition to compounds of the formula I in which all substituents have the abovementioned meaning, or their pharmaceutically acceptable acid addition salts, may contain one or more of the following medicaments: 1. known psychotropic agents, for example antipsychotics, for example chlorpromazine, Sharkoperidol or fluphenazine, or antidepressants, for example imipramine, mianserin or desmethylamitryptaline; Known anti-migraine agents, for example ergot alkaloids and their derivatives, and also propranolol, chloridine, pitzotifen, acetylsalicylic acid or acetoacetanolj3 known antihypertonica, for example "(methyldopa, ai-adrenergic blocking agent, for example prazosin, beta-adrenergic Blocking agent, for example

10.11 * 1982

" ²⁸ " ^{60 94} ° / ¹²

Propranolol or atenolol, diuretics, for example, hydrochlorothiazide or frusemit, and vasodilator, for example, minoxidil or hydrallazine; and 4. known platelet aggregation inhibitors, for example dipyridamole, anturan, sulfinpyrazone »ticlopidine and o-acetylsalxycylic acid,

The invention is illustrated but not limited by the following examples. The temperatures are given in degrees Celsius, the Eindarapfungen were carried out under reduced pressure (approximately 15 mraHg), unless stated otherwise, and the petroleum ether used had a boiling point of 60 to 80 ⁰ C.

example 1

3.4 g of 2-Dimethylaminoe.thanthiol hydrochloride were added to a stirred suspension of 2.32 g of sodium hydride (50 % w / w dispersion in mineral oil) in 25 ml of dimethylformamide at 0 to 5. When all the hydrogen had escaped, 4.0 g of 2-chloro-S-XSOPrOPyIChXnOUn were added and the mixture was heated at 80 ° for 5 hours. Then, the reaction mixture was poured into 500 ml of ice-water and extracted with 3 × 120 ml of ethyl acetate. The ethyl acetate extract was washed successively with 100 ml of water and 100 ml of saturated brine, and then with MgSO 4. dried. The ethyl acetate solution was then evaporated and the residual oil was chromatographed on 70 g of basic alumina (Brockmann Sorte III) and eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained with 20 % v / v chloroform in petroleum ether was evaporated, the residual oil was dissolved in diethyl ether and ethereal hydrochloric acid added until the precipitation was complete. The solid residue was collected by filtration

, _{} Λί} . _10η 10.11.1982

2 4 υ 5 7 7 8 - ²⁹ - ^{6ο 94} ° / ¹²

and recrystallized from ethanol-diethyl ether »2- {2-Dimathylamino8thylthio) -3-isopropylquinoline hydrochloride melting point 154-167 °»

The starting 2-chloro-3-isopropylquinoline was obtained in the following manner »

15.2 ml of dimethylformamide were added dropwise with stirring to 85 ml of phosphorous oxychloride at 0 to 5 °. The mixture was stirred for 30 minutes at 0 to 5 °. Then heated at 75 ° for 16 hours, cooled, poured into 3 1 of ice-water and treated with 4 liters of water χ 250 ml of ethyl acetate extracted. The ethyl acetate extract was washed successively with 200 ml of water and 200 ml of brine and dried over MgSO 4. dried. The ethyl acetate solution was evaporated, the residual oil chromatographed on 500 g silica gel (Merck, type 7739) and eluted with increasing concentrations of chloroform in petroleum ether. The resulting eluate (containing 30 % VoIAoI-chloroform in petroleum ether) was evaporated to give 2-chloro-3-isopropylquinoline as a viscous oil which was used without further purification.

Examples 2 to 5

Example 2

58.40 g of 2-dimethylaminoethyl hydrochloride (80 % w / w) were added to a suspension of 31.68 g of sodium hydride (50% w / w dispersion in mineral oil) in 500 ml of dimethylformamide at 0-5. After all of the hydrogen had escaped, a solution of 72.70 g of 2-chloro-3-phenylquinoline in 100 ml of dimethylformamide was added and the mixture was heated at 75 ° for 5 hours and stirred. The reaction mixture was then poured into 4000 ml of ice-water

10.11.1982

24 0 5 7 7 8 - ³⁰ - ^{6o 94} ° / ¹²

and extracted with 6 χ 5CO ml of ethyl acetate. The ethyl acetate extract was washed successively with 1000 ml of water and 1000 ml of saturated brine and then dried over MgSO 4. The ethyl acetate solution was evaporated, the residual oil chromatographed on 1200 g of basic alumina (Brockmann grade III) and eluted with increasing concentrations of chloroform in petroleum ether. The resulting eluate (with 10 % v / v chloroform in petroleum ether) was evaporated. The residual solid was dissolved in 800 ml ethanol and treated with 25.2 ml concentrated hydrochloric acid. Ethanol was evaporated and the oily residue was azetropically distilled with toluene. The solid obtained was recrystallised from ethanol-diethyl ether, washed with a little cold acetone and filtered. The solid was 2- (2-dimethylaminoethylthio) -3-phenylquinoline hydrochloride, mp 195-198 °,

The above procedure was repeated using the corresponding 2-chloro-3- (substituted phenyl) quinoline derivative as the starting product to obtain the following compounds:

R p-F SCH ₂ CH ₂ NCGH ₃ ), > * melting point example P-CH ₃ salt 198-201 3 0-OCH ₃ HCl. ^ 4H ₂ O 165-166 4 HCl 214-216 5 HCl

, λ "ι η. C \ Τι 'Ί k *

10.11 * 1982

240577 8 " ³¹ ~ ⁶⁰⁹⁴ ° / ¹²

The 2-chloro-3- (substituted phenyl) quinoline derivatives used as the starting material were obtained in the following manner

Preparation of anilides

A mixture of 10 g of o-methoxyphenylacetic acid, 10 mL of oxalyl chloride and 2 drops of dimethylformamide was stirred at ambient temperature for 16 hours. The excess Qxalyl chloride was evaporated, the residue dissolved in 20 mL of methylene dichloride and added dropwise with stirring to 5.6 g of an iced aniline solution and 6 * 1 g of triethylamine in 50 ml of methylene dichloride. The mixture was stirred at ambient temperature for 16 hours, washed successively with 25 ml of 2 M hydrochloric acid and 2 × 25 ml of water and dried over MgSO 4. dried. The methylene dichloride was evaporated and the residue recrystallized from ethylene acetate / patrol ether. To give o-methoxy-phenylacetanilid, melting point 204-206 ⁰ C,

In a similar way were obtained:

p-fluorophenylacetanilide, mp 128-131 ° (crystallized from toluene); p-Tolylacetanilide, mp 144-147 ° (crystallized from toluene).

Production of chloroquinoline derivatives

The following compounds were obtained using the corresponding ancillary derivatives as starting material in an analogous manner as described in Example 1 for the preparation of 2-chloro-3-isopropylquinoline:

240577

10.11.1982 60 940/12

p-F

P-CH ₃

o-OCH.

melting point

88-90 oil

84-85

Example 6

1.92 g of a 50 % w / w dispersion of sodium hydride in mineral oil was added to a solution of 4.74 g of 3-phenylquinoline · 2-thione in 50 ml of dimethylformamide at ambient temperature. "After all of the hydrogen had escaped, 2 , 6 g of 2-Methylarainoethylchlorid added and the mixture stirred at ambient temperature for 20 minutes. The reaction mixture was poured into 600 ml of water and extracted with 2 × 100 ml of ethyl acetate. The ethyl acetate extract was washed with 2 × 50 ml of water and then over MgSO 4. dried·

The solvent was evaporated, the residue was dissolved in 75 ml of diethyl ether and treated with ethereal hydrochloric acid until the precipitation had ended. The mixture was filtered and the solid residue was recrystallised from ethanol / diethyl ether. 2- (2-Methylaminoethylthio) -3-phenylquinoline was obtained. Hydrochloride hemihydrate, m.p. 168-170 °.

10 '11.1982

0 5 7 7 8 - ^κ - ^{s0 940/12}

A mixture of 3 * 4 g of 2-chloro-3-phenylquinoline and 1.2 g of thiourea in 20 ml of ethanol was refluxed for one hour. Then the solution was allowed to cool to ambient temperature and 10 ml of diethyl ether added. The precipitated solid became * filtered off, dispersed in 70 ml of M sodium hydroxide and heated for 2 hours on a steam bath. The reaction mixture was acidified with 2 M hydrochloric acid. The resulting mixture was filtered off and the solid residue was stirred with 50 ml. of hot ethanol and filtered off. The solid residue obtained was 3-p-nylquinoline-2-thione "Melting point 242 ^ 44?"

A solution of 2.2 g of 2- (2-oxoprapylthio) -3-phenylquinoline in 50 ml of dry ethanol was added to a mixture of dimethylataine in ethanol (1 ml of a 33% w / v% solution) and 0, 7 g of glacial acetic acid were added. 0.3 g of cyanoborohydride were then added. The mixture was stirred for 13 hours at ambient temperature in the presence of Q 5 g of a molecular sieve (type 3A). Then more dimethylamine solution in ethanol was added. ml of 33 _^%: ö added weight ^ / v ^^ LSeung) ^> 9 g of glacial acetic acid and 0.3 g cyanoborohydride and the mixture stirred for 24 hours at ambient temperature, the molecular sieve was filtered off and the solution evaporated "was then added 20 mL of 2. The aqueous phase was basified with 25 ml of 2 M sodium hydroxide solution and extracted with 3 × 5 ml of diethyl ether was evaporated and d he residue on 75 g of basic alumina (Brockmann grade IZI) ₁ achomatographed eluted with increasing concentra-

0 5 7 7 8 " ³ ^" ^{6G 940/12}

Eluate obtained with 20 % v / v chloroform in petroleum ether was evaporated. The remaining residue was dissolved in 20 ml diethyl ether and ethereal hydrochloric acid added until the precipitation was completed. The solid was collected by filtration and precipitated Recrystallized from ethanol / diethyl ether to give 2- (2-dimethylaminopropylthio) -3-phenylquinoline hydrochloride _# Melting point 158-160 °.

^The as start connection; used quinoline derivative was obtained in the following manner:

5 # 5 g of 3-phenylehinelin Z-thione was added portionwise to a stirred suspension of sodium hydride (0.72 g of a 50% w / w dispersion in mineral oil) in 50 ml of dimethylformamide at ambient temperature. "After all the hydrogen was released The reaction mixture was poured into 400 ml of water and extracted with 2 × 100 ml of ethyl acetate. The ethyl acetate extract was washed with 2 × 50 ml of water and dried over MgSO 4. dried "The solvent was evaporated and the residue chromatographed on basic alumina (100 g Brockmann variety III) chroraatografiert eluted with st eigenden concentrate ion Chlorofοrn" in petroleum ether _# The eluate obtained with 10%; Chloroform in petroleum ether was evaporated. 2- (2-Oxopropyl-thio) -3-phenylquinoline was obtained, and sulfuric acid was 88-90 °.

Example 8

1.5 ml of 10 to 10.2 H borane-oimethylsulfide complex were added dropwise to a solution of 2 g of 2 - / (1- (methylcarbamoyl) ethylthoyl-3-phenylquinoline in 50 ml of dry

r iinu Mn η η .. η r, 'η

O 5 7 7 8 - ³⁵ · ^6o 940/12

Tetrahydrofuran was added at ambient temperature. The mixture was then heated evenly under reflux for 6 hours. 20 ml of methanol were added, the mixture stirred for 18 hours at ambient temperature and then refluxed for 2 hours. The solvent was evaporated and an excess of a saturated hydrochloric acid solution in diethyl ether was added to the oily residue. The solvent was evaporated and the residual oil dissolved in 20 ml of water * basified with 10 ml of 2N sodium hydroxide solution and extracted with 3 × 20 ml of ethyl acetate »The ethyl acetate extract was washed with 20 ml of water and dried over MgSO ₄ «. The solution was evaporated »the residual oil was eluted on 20 g of basic alumina (Brockmann SorteIII) chroma tog rafiertri with increasing concentrations of chloroform in petroleum ether, with 50 % Vol / vol · chloroform in; The resulting oil was evaporated and the residual oil was dissolved in 20 ml of diethyl ether and ethereal hydrochloric acid was added until the precipitation was complete. The solid residue was collected by filtration and recrystallized from ethanol / disthyl ether to give 2- (Tl) (dimethylaminoethyl) ethylthiophene. 3-phenylquinoline hydrochloride, mp 197-200 °.

Dbs received ghinoline derivative as-outgrowth product

one as followst _1_ -

4 * 74 g. 3-phenylquinolin-2-thione (see Example 6) were added portionwise to a well stirred suspension of 1 * 06 g of sodium hydride (50% w _# / 6EW * -Dlsperslon in mineral oil) in 25 ml of dimethylformamide at 0 to 5 ° · After When all of the gaseous hydrogen had escaped, 2-chloro-N, N-dimethylacetamide was added and the

η r 7 7 Ö 10.11.1982

UJ / / Ο "36-60 940/12

Mixture heated for 2 hours at 80 °. The reaction mixture was then poured into 300 ml of water and extracted with 4 × 50 ml of ethyl acetate. The ethyl acetate extract was washed with 50 ml of water and dried over MgSO 4. The solvent was evaporated, the remaining residue was chromatographed on 70 g of basic aluminum hydroxide (Brockmann grade III) and eluted with increasing concentrations of chloroform in petroleum ether. The resulting eluate with 20 % Vol # / vol. Chloroform in petroleum ether was evaporated and the residual solid recrystallized from ethyl acetate / petroleum ether. »2- (Dimethylcarbamoylmethylthio) -3-phenylquinoline, mp 86-89 °.

To a solution of lithiura di-isopropylamide prepared from 6.2 ml of diisopropylamine and 24.7 ml of n-butyllithium

(1.7 M solution in hexane) in 100 ml of dry tetrahydrofuran at -78 under argon 3, a solution consisting of 6.6 g of 2- (dimethylcarbamoylmethylthio) -3-phenylquinoline

in 50 ml of dry tetrahydrofuran at -60. The mixture was then stirred for 15 minutes at -60 °, 2.7 ml of iodomethane added and the mixture allowed to reach ambient temperature. Then, 2.6 ml of glacial acetic acid was added followed by 200 ml of water. The tetrahydrofuran phase was separated and stored and the aqueous layer was extracted with 2 x 30 ml of ethyl acetate. The ethyl acetate and tetrahydrofuran phases were combined and dried over MgSO 4. After evaporation of the solvent, the residual oil was chromatographed on 100 g of basic alumina (Brockmann grade III) eluted with increasing concentrations of chloroform in petroleum ether. · From the eluate obtained with 20 % v / v. Chloroform in petroleum ether was obtained after evaporation of 2-l- (dimethyl-

λ c Mn »λ η ο η ^. π λ! * "? P.

10.11.1982

2A0577 8 ~ ³⁷ ~ ^50940/12

carbatnoyl-ethylthio ^ -S-phenylquinoline as a viscous oil which was used without further purification,

Example 9

A solution of 1.7 g of 2-dimethylaminoethylthiol hydrochloride in 25 ml of dimethylformamide was added dropwise to a suspension of 0.5 g of sodium hydride in a solution of 2.0 g of 2-chloro-3-cyclopropylquinoline in 25% dimethylformamide at 0 to 5 The mixture was heated to 80 for 4 hours, poured into 200 ml of ice-water and then extracted with 3 × 100 ml of ethyl acetate. The ethyl acetate extract was washed successively with 100 ml of saturated brine and 3 × 100 ml of water over Na ₂ SO ₄ . and the solvent was evaporated. The residue was chromatographed on 200 g of silica gel (Merck 9385) using 10 % v / v. Methanol in ethyl acetate as eluent. The appropriate fraction (determined by thin layer chromatography) was evaporated, dissolved in methanol, and one equivalent of anhydrous oxalic acid was added. The solvent was then evaporated and the residue recrystallized from methanol / diethyl ether. There was obtained 3-cyclopropyl-2- (2-dimethylaminoethylthio) quinoline hydrogen oxalate, mp 158 °.

The above procedure was repeated using the corresponding 2-chloroquinoline derivatives as the starting material to obtain the compounds listed in the following table. Where listed »the hydrochloride salt was prepared using hydrochloric acid instead of oxalic acid»

Λ C MOV HQQO Π * Z /

240577

10 * 11 .. 1982 60 940/12

R *

SCH ₂ CH ₂ N (CH ₃ ) ₂

In game R ¹ R ⁴ R ⁵ H H salt 10 n-propyl H H H H Hydrogen oxalate 11 o-methoxyphenyl Methyl H H H Hydrogen oxalate 12 n-butyl H Cl H Hydrogen chloride 13 s-butyl H br H Hydrogen oxalate 14 2-pyridyl H H Hydrogen oxalate 15 2-thienyl H methoxy Hydrogen oxalate 16 3-thienyl H t. H Hydrogen oxalate 17 2-methyl-4-thiazolyl - H n-propoxy Hydrogen oxalate 18 phenyl H methyl Dihydrochloride 19 Phenyl methoxy br Hydrogen oxalate 20 phenyl H Hydrogen oxalate 21 phenyl H Hydrogen oxalate 22 phenyl Hydrogen oxalate 23 phenyl Hydrogen oxalate 24 phenyl Hydrogen oxalate

Melting point

164-6

164

164-6

153-5

134-6

184-94

167-9

167

84-5 176-8 174-5 210-2 216-8 200-2 208-10

240577

10.11.1982 940/12

Some 2-chloroquinoline derivatives used as starting compounds are new compounds. They can be prepared from the corresponding anilides by the process described in Example 1 to give the following compounds:

R *

Melting point

n-propyl H Cyclop ropyl H s-butyl H 2-pyridyl H 2-thienyl H 3-thienyl H 2 ~ Methyl-4- thiazolyl H phenyl H phenyl methoxy phenyl H phenyl H

H H H H H H

H methoxy

n-propoxy methyl

oil

oil

79-82

oil

oil

117-9

126-8

oil

65-7

68-70

The following new anilides are prepared as described in Example 1:

NHCOCH ₂ R

240577

10.11.1982 60 940/12

Melting / boiling point

£ -methoxyphenyl 3-thienyl phenyl

methyl

H H

H Pr ⁿ 0

123-5 sp. 95-8 / 0.5 mm

Preparation of a £ - (2-methyl-4-thiazolyl) acetanilide

A solution of 6.4 g of cC - (2-methyl-4-thiazolyl) acetic acid and 3.6 mL of aniline in 50 mL of dry methylene dichloride was stirred at ambient temperature and 9 g of oicyclohexylcarbodicinide added in 1 g portions over 30 minutes. * The mixture stirred at ambient temperature for 2 hours, filtered off and the solvent evaporated. The solid residue was recrystallised from aqueous ethanol to give the anilide; Melting point 124 ° »

Preparation of 6- and 7-halo-2-chloro-3-phenylquinolines

The process for preparing the 2-chloroquinoline derivatives described in this example is unsuitable if the aniline component is substituted by a halogen substituent. In such a case, the following procedure is to be used:

7.6 g of 6-chloro-3-phenylquinolin-2-one and 100 ml of phosphorus oxychloride were heated together under reflux for 2 hours. Then, the reaction mixture was poured into 1000 ml of ice water and extracted with 3 × 100 ml of ethyl acetate. The ethyl acetate extract was washed with 3 × 50 ml of water, dried over Na ₂ SO ₄ and the solvent was evaporated. The resulting solid was recrystallized from ethanol to give 2,6-dichloro-3-phenylquinoline, m.p. 147-149 °.

10.11.1982 - 41 - 60 940/12

Similarly prepared were e-bromo - ^ - chloro-S-phenylquinoline, m.p. 136-137, and 7-bromo-2-chloro-3-phenylquinoline (as a mixture with the S-bromo-sorboran). "The substituted quinolines used as starting material were recovered prepared by the method of Manimaran and Ramakrishnan (described in Indian Oournal of Chemistry, 1979, 188 , 324-330) and used without purification »

Examples 25 to 38

The procedure described in Example 2 was repeated. The equivalent amounts of the corresponding 2-chloro-3- (substituted phenyl) quinoline as the starting material were used. The following compounds were obtained:

example R melting point rn-methoxy 191-3 25 £ methoxy 194-5 26 £ chloro 209-11 27 £ bromo 216-8 28 £ -n-propoxy 156-62 29 £-cyano 251-2 30 £ -trifluoromethyl 220-2 31 2,5-dimethoxy 205 32 £ methylthio 208-11 33 £ methyl 207-9 34 £ fluoro 187-9 35

- -.- .. ί ίΛίΜΙ. fl / l w i «Li.>

405

Example no.

77

-42-

10.11.1982 60 940/12

melting point

36 37 38

£ -chloro ^ fluoro-methyl 210-2

169-71

157-9

The 2-chloroquinoline derivatives used as starting materials in Examples 25 to 38 were obtained from the corresponding anilides in an analogous manner as described in Example 1.

melting point

ITi ₁ -Me th oxy £ -Methoxy £ -Chlor £ -Brom £ -nP ropoxy £ -Cyan p_ -trifluoromethyl 2,5-Dimethoxy £ -Methylthio £ -Methyl £ -Fluor-Chloro-in-fluoro n ^ -Met hy I oil

87-8 90-2 96-8 oil

112-4 89-92 102-4 105-8 93-5

111-3 116-8 50-2 77-8

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10.11.1982 60 940/12

The following novel anilides, which served as starting compounds for the preparation of the corresponding 2-chloroquinolines, were prepared from aniline and the corresponding substituted phenylacetic acid by the method described in Example 2.

NHCOCH,

melting point

jn-methoxy-methoxy g-n-propoxy-trifluoromethyl-2,5-dimethoxy-methylthio-fluoro

tn-fluoro

rn-methyl

107-0 115-6 115 154-6 118 115-7 127-9 104-7 77-8

Examples 39 and 40

The procedure described in Example 2 was repeated using an equivalent amount of 2-aminoethanethiol hydrochloride instead of 2-dimethylaminoethanethiol hydrochloride. There was thus obtained 2- (2-aminoethylthio) -3-phenylquinoline hydrochloride, m.p. 232-237 ° (Example 39) and 2- (2-aminoraethylthio) -3- (o-methoxyphenyl) quinoline hydrochloride, mp 180 ° (Ex 40).

10.11.1982 - 44 - 60 940/12

Examples 41 and 42

The procedure described in Example 6 was repeated using an equivalent amount of 3-n-butylquinoline-2-thione or 3- (o-methoxyphenyl) quinoline-2-thione as a starting compound in place of S-phenylquinoline-thione. 3-n-butyl-2- (2-methylaminoethylthio) quinoline hydrogen oxalate was obtained,

Melting point 167-169 (Example 41) and 3- (o-methoxyphenyl) -2- (2-methylaminoethylthio) quinoline hydrochloride _f melting point 210 ° (Example 42) in a corresponding manner.

Beisptel 43

The procedure described in Example 2 was repeated using an equivalent amount of 2-diethylaminoethanethiol hydrochloride instead of 2-dimethylaminoethanethiol hydrochloride. There was obtained 2- (2-diethylaminoethylthio) -S-phenylquinoline hydrochloride, mp 144-146 °.

Example 44

0.37 ml of borane-dimethyl sulfide complex was added dropwise to a solution of 0.5 g of 2- (2-N-acetyl-N-methylaminoethylthio) -3-phenyichinoline in 10 ml of anhydrous tetrahydrofuran under an argon atmosphere. The mixture was heated at reflux for 4 hours and then cooled.

2 ml of methanol was added and the mixture allowed to stand for 16 hours at ambient temperature. The solvent was then evaporated off. The remaining residue was admixed with 10 ml of 2 M hydrochloric acid and 5 ml of methanol, and the mixture was heated on a steam bath for 1.5 hours. The solution was cooled to ambient temperature, basified with solid sodium bicarbonate and extracted with 3 × 15 ml of ethyl acetate. The organic extract was with

Washed 3 × 10 ml of water, over Na ₂ SO. dried and under

ι η 11 J rs Π Π. Γ \

10.11.1982

24 0 5 7 7 8 " ⁴⁵ " ^{δ0 940/12}

reduced pressure evaporated to dryness. The residue was applied to 80 g of silica gel (Merck 9385) using 10 % v / v. Methanol in ethyl acetate as the eluent chromatographed. The desired fraction was collected and evaporated. The residue was dissolved in methanol and treated with 0.064 g of anhydrous oxalic acid. The resulting mixture was filtered off and the solid residue was recrystallized from methanol / ether. There was obtained 2- (2-N-ethyl-N-methylaminoethylthio) -3-phenylquinoline hydrogen oxalate hemihydrate, m.p. 179-181 °.

The starting 2- (2-N-acetyl-N-methylaminoethylthio) -3-phenylchlorine was obtained in the following manner:

0.2 ml of acetyl chloride was added to a solution of 0.8 g of 2- (2-methylaminoethylthio) -3-phenylquinoline in 25 ml of methylene dichloride and 0.56 ml of triethylamine. The mixture was kept at ambient temperature for 1 hour, washed successively with 3 × 10 ml of 2 M hydrochloric acid and 3 × 10 ml of water, dried over Na ₃ SO ₄ and concentrated to dryness. The N-acetyl derivative was obtained which was widely used without purification.

Example 45

12 ml of a 1 M solution of tetra-n-butylammonium fluoride in tetrahydrofuran was added to a solution of 3.5 g of 2-l-trans-2 ~ 2 ~ (trimethylsilyl) ethoxycarbonylaminoJ-cyclopropylthioJ-3-phenylquinoline in 35 ml of dry acetonitrile and the mixture was stirred at 50 ° under argon for 5 hours. The mixture was cooled, the solvent evaporated and the residual oil between 70 ml of ethyl acetate.

a uni! -4Q Q 9 * ft h Ίϋ ^ ΰ

10.11.1982 0 5 7 7 3 " ⁴⁶ " ^{60 940/12}

acetate and 35 ml of water. The mixture was separated and the organic phase was washed with 2 × 30 ml of water and dried over Na ₃ SO _4. The solvent was evaporated, the residual brown oil (2.7 g) chromatographed on basic alumina (180 g, Brockmann grade III) , eluted with 30 % v / v. Chloroform in petroleum ether. There was obtained 2- (trans-2-aminocyclopropylthio) -3-phenylquinoline as a pale yellow oil, which gave a hydrochloride with a melting point of 140 °.

The quinoline derivative used as starting material was obtained as follows:

6.40 g of 3-phenylquinoline-2-thione was added portionwise to a stirred suspension of sodium hydride (1.34 g of a 50 % w / w dispersion in mineral oil) in 43 ml of dry dimethylformamide at 0 to 5 under argon. The mixture was stirred for 1 hour at ambient temperature and then a solution of a cis / trans mixture of 5.17 g of ethyl 1-bromoacyclopropanecarboxylate in 10 ml of dimethylformamide was added. The mixture was stirred for 2/2 hours at 90 °, cooled to 10 ° and poured into a mixture of 700 ml of water and 250 ml of saturated brine. The mixture was extracted with 5 χ 120 ml of ethyl acetate. The organic extract was washed with 200 ml of saturated brine, dried over Na ₅ SO ₄ and the solvent was evaporated. The remaining yellow oil was randomly chromatographed on 210 g of basic aluminum oxide (Brockmann variety III), eluted with petroleum ether. 2- (trans-2-ethoxycarbonylcyclopropylthio) -3-phenylquinoline, mp 94-94.5 ° (crystallized from isopropanol), was obtained.

α r nnu Mn η η. r » r. ^ i

10.11,1982

240577 8 " ⁴⁷ ~ ^{60940 / i2}

A solution of 0.37 g of sodium hydroxide in 3.6 ml of water was added to a solution of 2.43 g of the above-mentioned ethoxycarbonyl derivative in 90 ml of t-butanol. The mixture was allowed to stand for 16 hours at 20 ° and then for 5 hours Stirred 40 ° * Then allowed to cool to ambient temperature, poured into a mixture of 400 ml of water and 200 ml of saturated brine and washed with 100 ml of diethyl ether. The aqueous phase was then cooled to 5 °, acidified to pH 3 with dilute hydrochloric acid and extracted with 5 × 150 ml of ethyl acetate. The organic extract was dried over Na ₂ SO. dried and the solvent evaporated. The residual solid was recrystallized from ethyl acetate (petroleum ether). 2- (trans-2-carboxycyclopropylthio) -3-phenylquinoline, mp 168.5-169.5 °, was obtained.

A solution of 3.26 g of 2- (trans-2-carboxycyclopropylthio) -3-phenylquinoline, 2.21 ml of diphenylphosphoryl azide and 1.43 ml of triethylamine in 65 ml of dry toluene were stirred at 90 ° under argon for 2 hours. 1.53 ral of 2- (trimethylsilyl) ethanol were added and the reaction stirred for a further 16 hours at 90 °. The mixture was then cooled to ambient temperature, washed with 2 x 20 ml of water over Na ₂ SO ₄ . dried and the toluene removed under reduced pressure. The remaining brown oil (5.5 g) was purified on a column of 200 g of basic alumina (Brockmann Sorte III) by elution with 20 % VoI./Vol. Chloroform in petroleum ether. There was obtained 2- £ trans -2-Z2- (trimethylsilyl) ethoxycarbonylamino7-cyclopropylthioJ-3-phenylquinoline as a light yellow oil, as determined by mass spectrometry, molecular ion equal to 436, and by NMR {CDClj solution, 90 MHz) multiplet 2 , 5cT (2H, cyelopropanemethine).

10.11.1982

0 5 7 7 8 " ⁴⁸ " ^{50 940/12}

Example 46

3.2 ml of a 3.4 M solution of sodium bis (2-methoxyethoxy) -aluminum hydride in toluene was added to a solution of 1.0 g of 2- (2 N -ethoxycarbonyl-N-ethylaminoethylthio) -3-phenylquinoline Add 3.2 ml of di- (2-methoxyethyl) ether at 20 ° under argon atmosphere. The mixture was heated at 85 ° for 2 hours, then cooled to ambient temperature and the solvent evaporated under high vacuum (approximately 0.5 mm Hg) at 20 °. To the remainder was added 10 ml of water and 10 ml of 2M sodium hydroxide. The mixture was extracted with 3 χ 20 ml of methylene dichloride. The organic extract was dried over Na ₂ SO ₄ , the solvent was evaporated and the residue was concentrated to 80 g silica gel (Merck 9385) using 5 % VoI./Vol. Methanol chromatographed in ethyl acetate. 2- (2-Dimethylatninoethylthio) -3-phenylquinoline was obtained which was identical to the product of Example 2.

The starting ethoxycarbonyl derivative was prepared as follows:

0.5 ml of ethyl chloroformate was added to a solution of 2- (2-methylarainoethylthio) -3-phenylquinoline in 20 ml of methylene dichloride and 1.15 ml of triethylamine, and the mixture was kept at ambient temperature for 1 hour. It was then washed successively with 3 × 100 ml of 2 M hydrochloric acid and 3 × 10 ml of water, dried over Na ₃ SO ₄ and the solvent was evaporated off. The remaining residue was recrystallized from ethanol. 2- (2-N-ethoxycarbonyl-N-methylaminoethylthio) -3-phenylquinoline, mp 99-101 °, was obtained.

'10.11.1982

24O5 / 7 3 ~ ⁴⁹ "

Example 47

0.88 g of 2-dimethylanethanethanethiol hydrochloride was added to a suspension of sodium hydride (1.1 g of a 50 % w / w dispersion in mineral oil) in 50 ml of dimethylformamide at 0 to 5. After all of the hydrogen had been liberated A solution of 1.6 g of 2-chloro-3-p-hydroxyphenylquinoline in 10 ml of dimethylformamide was added and the mixture was stirred at ambient temperature for 16 hours. In addition, 0.32 g of 2- (dimethylarainoethanethiol hydrochloride followed by a suspension of sodium hydride ( 0.4 g of a 50 % wt / wt. Dispersion in mineral oil) and the mixture was heated at 65 ° for 2 hours. Then the solution was cooled to ambient temperature, poured into 500 ml of water and adjusted to pH 2 with 2M hydrochloric acid The solution was then adjusted to pH 8 with saturated bicarbonate solution and extracted with 2 × 100 ml of ethyl ether. The ethyl acetate extract was washed with 2 × 50 ml of water and dried over MgSO ₄ The residue was dissolved in 200 ml of diethyl ether and ethereal hydrochloric acid added. The solvent was evaporated and the remaining residue was recrystallized from ethanol / diethyl ether. 2- (2-Dimethylaminoethylthio) -3- (p-hydroxyphenyl) quinoline hydrochloride, mp 220-222 °,

The starting quinoline derivative was obtained as follows:

A mixture of 6.2 g of p-acetoxyphenylacetic acid, 10 g of oxalyl chloride and 2 drops of dimethylformamide were stirred at ambient temperature for 16 hours. The excess oxalyl chloride was evaporated, the remainder remaining in

10.11.1982

24 0 5 7 7 B - ⁵⁰ - ^{60 94} ° / ¹²

Dissolved 50 ml of methylene chloride and the solution was added dropwise to a stirred, ice-cold solution of 3 g of aniline and 3.2 g of triethylamine in 50 ml of methylene chloride. The mixture was stirred at ambient temperature for 3 hours and then successively with 25 ml of 2 M hydrochloric acid, 25 ml Water, 10 ml of saturated sodium carbonate solution and 2 χ 25 ml of water and washed over MgSO. The solvent was evaporated and the remainder, consisting of p-acetoxyphenylacetanilide, was used further without further purification.

1.7 g of dimethylformamide was added dropwise with stirring to 10 ml of phosphorus oxychloride at 0 to 5 °. Then 4 g of p-acetoxyphenylacetanilide were added and the mixture heated to 75 ° for 16 hours, cooled to ambient temperature, poured into 600 ml of water and washed with Extracted 3 × 100 ml of ethyl acetate. The ethyl acetate extract was washed successively with 25 ml of saturated sodium carbonate solution and 2 × 25 ml of water and dried over MgSO ₄ . The solvent was evaporated and the residual oil chromatographed on 200 g of basic alumina (Brockmann grade XII) eluting with increasing concentrations of chloroform in petroleum ether, followed by methanol in chloroform. The eluate obtained was obtained. 1 % w / v, methanol in chloroform was evaporated and the residue was recrystallized from ethyl acetate / petroleum ether. 2-Chloro-3- (p-hydroxyphenyl) -quinoline, mp 164-166 °,

Example 48

0.68 g of a 50 % w / w dispersion of sodium hydride in mineral oil was added to a solution of 1.6 g of 3-phenylquinoline-2-thione in 10 ml of dimethylformamide at ambient temperature

10 * 11.1982 - 51 - 60 940/12

given. After all of the hydrogen had been released, 1.2 g of trans-2-chlorocyclohexylamine hydrachloride were added and the reaction mixture was stirred at 50 ° for 20 hours. The reaction mixture was cooled to ambient temperature and diluted with 100 ml of water and extracted with 2 × 30 ml of ethyl acetate »The ethyl acetate extract was washed with 2 × 10 ml of water and then over MgSO 4. The solvent was evaporated and the residual residue chromatographed on 100 g of basic alumina (Brockmann Sorte III) eluting with increasing concentrations of chloroform in petroleum ether, followed by chloroform. The chloroform eluate was evaporated. The residue was dissolved in 100 ml of diethyl ether and ethereal hydrochloric acid was added until completion of the precipitation. The solvent was evaporated and the residue was recrystallized from ethyl acetate. 2- (trans-2-aminocyclohexylthio) -3 was obtained phenylquinoline hydrochloride, m.p. 223-225 °.

Example 49

3.2 ml of a 37 % w / v solution of formaldehyde in water was added to a solution of 1.7 g of 2- (trans-2-aminocyclohexylthio) -3-phenylquinoline in 4 ml of formic acid at ambient temperature. The mixture was heated at reflux for 16 hours, then cooled to ambient temperature and poured into 50 ml of water. With the aid of 2 N sodium hydroxide solution, the mixture was adjusted to pH 10 and extracted with 3 × 15 ml of ethyl acetate. The ethyl acetate extract was washed with 3 × 10 ml of water and dried over MgSO _4. The solvent was evaporated and the residue was concentrated to 100 g of basic alumina (Brockmann

10.11.1982

0 5 7 7 8 " ⁵² " ^{50 940/12}

Grade III), eluted with increasing concentrations of chloroform in petroleum ether, the resulting eluate with 20 % v / v. Chloroform in patrol ether was evaporated. The remaining residue was dissolved in 25 ml of diethyl ether and ethereal hydrochloric acid was added until completion of the precipitation. After evaporation of the solvent, the residue was recrystallised from ethyl acetate. 2- (trans-2-dimethylaminocyclohexylthio) -S was obtained phenylquinoline hydrochloride, m.p. 199-202 °.

The 2- (trans-2-amino-cyclohexylthio) -3-phenylquinoline used as starting material was obtained by the process described in Example 48 up to the stage where the chloroformeluate was evaporated.

Example 50

0.48 g of sodium hydride (50 % w / w dispersion in mineral oil) was washed with 25 ml of petroleum ether under argon atmosphere. The solvent was decanted off. 5 ml of dimethyl sulfoxide was added and the mixture was heated to 50 for 1 hour. The mixture was then cooled to ambient temperature and 0.18 ml of water was added, followed by a solution of 1.3 g of methyl 1-N-TTc is-2- (3-phenyl-2-quinolylthio) cyclohexyl-carbamate in 5 ml Dimethyl sulfoxide, The mixture was stirred at ambient temperature for 1 hour and at 50 ° for 1.5 hours. It was then cooled to ambient temperature, diluted with 100 ml of water and extracted with 2 × 25 ml of ethyl acetate. The ethyl acetate extract was washed with 2 × 10 ml of water and dried over NgSO 4. The solvent was evaporated and the residue chromatographed on 100 g of basic alumina (Brockmann Sorte III), eluted with increasing

- .. Λ fei J

λ η η

, η / ι fj; i L

_o 10,11,1982

O - 53 - 60 940/12

concentrations of chloroform in petroleum ether. The eluate obtained is 60% vol. Chloroform in petroleum ether was evaporated, the residue dissolved in 50 ml of diethyl ether and ethereal hydrochloric acid added to the solution until the precipitation was completed. The solvent was evaporated and the residue was recrystallized from ethyl acetate. There was obtained 2- (cis -2-aracinocyclohexylthio) -3-phenylquinoline hydrochloride, m.p. 170-175 ° (Zers) *

The carbamate used as starting material was obtained as follows:

0.24 g of a 50% w / w dispersion of sodium hydride in mineral oil was added to a solution of 1.19 g of 3-phenylquinoline-2-thione in 10 ml of dimethylformamide at ambient temperature. After the hydrogen was completely released, 1 was added 4 g of methyl N- (trans-2-iodocyclohexyl) carbamate were added and the mixture stirred at 60 for 4 hours. The mixture was cooled to ambient temperature, washed with 100 ml of water and extracted with 2 × 25 ml of ethyl acetate. The organic extract was washed with 2 x 10 ml of water and dried over MgSO 4. After evaporation of the solvent, a gummy residue was obtained which contained methyl N-rcis-2- (3-phenyl-2-quinolylthio) cyclohexyl carbamate and was used without further purification.

Example 51

A mixture of 0.65 g of 3- (p-cyanophenyl) -2- (2-dimethylaminoethylthio) quinoline hydrochloride (see Example 30), 25 ml of t-butanol and 0.6 g of potassium hydroxide were warmed up for 1 hour 20 ml of water are added to the mixture

^ nnn. η /,; - ~ "τ.

240 5 77 Γ ^10αι · ¹⁹⁸²

- 54 - 60 940/12

and t-butanol evaporated. A further 20 ml of water were added and the mixture was extracted with 3 × 30 ml of chloroform. The chloroform extract was washed with 2 × 10 ml of water and dried over MgSO 4. dried. After evaporation of the solvent, the residue was recrystallized from ethanol, the crystalline material was dissolved in 50 ml of ethanol and the solution was treated with ethereal hydrochloric acid. The solvents were evaporated and the residue recrystallized from ethanol / diethyl ether. 3- (p-Carbamoylphenyl) -2- (2-dimethylaminoethylthio) quinoline hydrochloride, mp 253-255 °,

Example 52

6.87 g of S-Cp-carboxyphenylquinoline-thione were added to a suspension of 3.9 g of sodium hydride (50% w / w dispersion)

in mineral oil) in 50 ml of dimethylformamide at 0 to 5. After all of the hydrogen had been released, 3.5 g of 2-dimethylaioethyl chloride hydrochloride were added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into 300 ml of ice-water, filtered off and the filtrate was adjusted to pH 7 with 2 M hydrochloric acid. The resulting mixture was filtered off and the solid residue was dissolved in 2 M hydrochloric acid in methanol at 0. The solvent was evaporated and the solid residue was recrystallized from methanol / ethyl acetate. There was thus obtained 3- (p-carboxyphenyl) -2- (2-dimethylethyl amino thio) quinoline hydrochloride, mp 246-247 °.

The quinoline derivative used as starting material was obtained in the following manner:

0.26 g of 3- (p-cyanophenyl) quinoline-2-thione was added to 2 ml

10.11.1982

240 5 77 8 ^'55 ~ 60940/12

Hydrogen bromide (48 % w / v, aqueous solution) was added and the mixture heated to 140 ° for 3 hours. The mixture was cooled to ambient temperature and poured into 20 ml of ice-water. The resulting mixture was filtered, the solid residue was stirred with 20 ml of hot ethanol for 5 minutes and then filtered off. A solid residue was 3- (p-carboxyphenylquinoline-2-thione, melting point> 300 °.

The starting cyano derivative was obtained as follows:

A mixture of 6.25 g of 2-chloro-3- (p-cyanophenyl) quinoline (see Example 30) and 1.8 g of thiourea in 30 ml of ethanol was refluxed for 2 hours. The solution was allowed to cool to ambient temperature, the precipitated solid filtered off, and dispersed in 100 ml

1M sodium hydroxide solution and heat the dispersion for 20 minutes on the steam bath. The Geraisch was then with

2 M hydrochloric acid solution acidified. The resulting mixture was filtered, the solid residue was stirred with 75 ml of hot ethanol for 5 minutes, and the mixture was filtered off. In this way, the solid residue obtained was 3- (p-cyanophenyl) -quinoline-2-thione; Melting point 284-289 °.

Example 53

2.35 ml of oxalyl chloride and 1 drop of dimethylformamide were added to a solution of 0.7 g of 3- (p-carboxyphenyl) -2- (2-dimethylaminoethylthio) quinoline in 30 ml of methylene chloride The mixture was stirred at ambient temperature for 16 hours the solvent was evaporated, the residue was dissolved in 5 ml of dimethylformamide and the solution

_n - _n 10.11.1982

UJ / / Q- ⁵⁶ - ⁶⁰ 940/12

The mixture was then poured into 50 ml of ice-water for 4 hours, the solution was adjusted to pH 10 by means of saturated potassium carbonate solution and extracted with 3 × 20 ml of ethyl acetate. The cetyl acetate extract was washed with 20 ml of saturated brine, over MgSO 4. The residue was dissolved in 10 ml of diethyl ether and ethereal hydrochloric acid was added until the precipitation had ended. The mixture was filtered off and the solid residue was recrystallised from methanol / ethyl acetate. 2- (2-Dimethyl-1-aminoethylthio) Cp -dimethylcarbaraoylphenyl) quinoline hydrochloride, mp 199-201 °.

Example 541 -

0.7 g of 3- (p -carboxyphenyl) -2- (2-dimethylaminoethylthio) -quinoline was added to a solution of 1.5 ml of thionyl chloride in 20 ml of methanol at 0 °. The mixture was stirred at ambient temperature for 16 hours and then the solvent was evaporated. The solid residue was recrystallized from methanol / ethyl acetate. 2- (2-DimethylaminoethylthioJ-S-Cp-methoxycarbonylphenyl) quinoline hydrochloride, m.p. 224-225 ° *, was obtained.

Example 55

0.96 g of sodium hydride (50% w / w dispersion in mineral oil) was added to a solution of 2.37 g of 3-phenylquinoline-2-thione in 100 ml of dimethylformamide at ambient temperature. After all of the hydrogen had liberated, 1.84 g of 2-chloromethyl-1-methylpiperidine hydrochloride was added and the mixture was stirred at ambient temperature for 16 hours. The mixture was poured into 750 ml of water and extracted with 2 × 150 ml of ethyl acetate.

jr »nil -ιη.'Ί η. Γ \ r,: *: '' /

10.11.1982

24 0 5 7 7 8 - ⁵⁷ - ^{60 940 / l2}

Acetate extract was washed with 2 × 50 ml of water and then over MgSO 4. dried. The solvent was evaporated and the remaining residue chromatographed on 150 g of basic alumina (Brockmann grade III), eluted with increasing concentrations of chloroform in petroleum ether. The eluate obtained was admixed with 20 % v / v. Chloroform in petroleum ether was evaporated t. The residue was dissolved in 50 ml of diethyl ether and added with concentrated hydrochloric acid until completion of the precipitation. The solid was collected by filtration and recrystallised from ethanol / diethyl ether. There was obtained 2-f (1-methyl-2-piperidylmethylthio3-3-phenylquinoline hydrochloride, m.p. 198-200 °.

Example 56

A solution of 2.94 g of 3- (p-fluorophenyl) -2- (2-oxopropylthio) -quinoline in 120 g of dry ethanol was added to a mixture of dimethylamine in ethanol (8.5 ml of a 33 % w / v. Solution) and 1.1 ml of glacial acetic acid. Then, 0.42 g of sodium cyanoborohydride was added. The mixture was stirred at ambient temperature for 96 hours in the presence of a molecular sieve (2.0 g, Type 3A). The molecular sieve was filtered off and the solvent was evaporated. Then, 25 ml of 2 M hydrochloric acid solution was added to the residue, and the mixture was washed with 20 ml of ethyl acetate. The aqueous phase was basified with 30 ml of 2M sodium hydroxide solution and the mixture extracted with 3 × 50 ml diethyl ether. The ethereal extract was washed with 50 ml brine and dried over MgSO 4. dried. The solvent was evaporated and the residue chromatographed with 100 g of basic alumina (Brockmann grade III), eluting with increasing concentrations of ethyl acetate in petroleum ether. The resulting eluate with 10 % vol.

Γ η 'Λ 10.11.1982

240577 8 " ⁵⁸ ~ ⁶ °

Ethyl acetate in petroleum ether was evaporated, the residue dissolved in 25 ml of diethyl ether and ethereal hydrochloric acid added until the precipitation was complete. The solid was collected by filtration and recrystallized from ethyl acetate to give 2- (2-dimethylaminopropyl-thioJ-S-Cp-fluprphenyl-quinoline hydrochloride, mp 176-173 °.

The starting quinoline derivative was obtained as follows:

5.05 g of 3- (p-fluorophenyl) quinoline-2-thione were added portionwise to a stirred suspension of 1.0 g of sodium hydride (50 % w / w dispersion in mineral oil) in 30 ml of dimethylformamide at 0-5 , After all of the hydrogen had liberated, 1.83 g of chloroacetone was added and the mixture stirred at ambient temperature for 13 hours. The mixture was poured into 300 ml of ice-water and extracted with 3 × 100 ml of ethyl acetate. The ethyl acetate extract was washed with 75 ml brine and dried over MgSO 4. dried. After evaporation of the solvent, the residue was chromatographed on 200 g of basic alumina (Brockmann grade III) eluting with increasing concentrations of ethyl acetate in petroleum ether. The resulting eluate with 10 % v / v. Ethyl acetate in petroleum ether was evaporated to give 3- (p-fluorophenyl) -2- (2-oxopropylthio) quinoline, mp 95-96 °.

The 3- (p-fluorophenyl) quinoline-2-thione itself was obtained in the following manner:

10,11.1982

240577 3 " ⁵⁹ " ^{50940 / i2}

A mixture of 6.03 g of 2-chloro-3- (p-fluorophenyl) quinoline (see Example 3) and 1.8 g of thiourea in 30 ml of ethanol were heated at reflux for 2 hours. The solution was allowed to cool to ambient temperature. The precipitated solid was filtered off, dispersed in 100 ml of 1 M sodium hydroxide solution and the dispersion was heated on the steam bath for 20 minutes. The mixture was acidified with 2 M hydrochloric acid solution and the solid residue was stirred with 75 ml of hot ethanol for 5 minutes and then filtered. As a solid residue, 3- (p-fluorophenyl) -quinoline-2-thione, mp 259-262 °.

Example 57

3.9 g of (S) -2- (2-t-butoxycarbonylaminopropylthio) -3-phenylquinoline was added to 6 M hydrochloric acid in 50 ml of ethyl acetate, and the mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated, the remaining Q1 dissolved in 100 ml of diethyl ether and extracted with 6 χ 25 ml of 1 M hydrochloric acid. The hydrochloric acid extract was adjusted to pH with saturated sodium carbonate solution and extracted with 2 × 50 ml diethyl ether. The diethyl ether extract was dried over MgSO 4, and ethereal hydrochloric acid was added until completion of the precipitation. The solid residue was collected by filtration and recrystallized from methanol / ethyl acetate. There was obtained (+) - (S) -2- (2-aminopropylthio) -3-phenylquinoline hydrochloride, m.p.

223-224 °, · C ^ Jp ⁵ + 39.7 ° (C, 0.78 in methanol) «

The quinoline derivative used as starting material was obtained in the following manner:

15.7 g of di-t-butylcarbohate was added to a solution of 5.0 g of (+) - (S) -2-amino-1-propanol in 13.2 ml of water and 6.6 ml

unil HlO Q 0 * Π U -WO 4t

10.11,1982

240577 8 ~ ⁶ ° - ⁶⁰

T-butanol was added at ambient temperature and the mixture was stirred at this temperature for 16 hours * Then 2 ml of 1,1-dimethylethylenediamine were added and the mixture was stirred at ambient temperature for 1 hour. The solution was poured into 200 ml of water and 3 × 100 ml of diethyl ether The ethereal extract was washed successively with 50 ml of 1 M hydrochloric acid, 50 ml of saturated sodium carbonate solution and 100 ml of brine and dried over MgSO 4. The solvent was evaporated to give (S) -2-t-butoxycarbonylamino-1-propanol, Melting point 42-43 °.

4.2 g of p-toluenesulfonyl chloride were added to a solution of 3.5 g of (S) -2-t-butoxycarbonylamino-1-propanol in 10 ml of pyridine at 0 °. The mixture was kept at 0 to 5 ° for 20 hours, poured into 200 ml of ice-water and then extracted with 3 χ 50 ml of diethyl ether. The diethyl ether extract was washed successively with 50 ml of 1 M hydrochloric acid, 50 ml of saturated sodium carbonate solution and 50 ml of brine, and dried over MgSq. The solvent was evaporated and the residue recrystallised from ethyl acetate / petroleum ether. There was obtained (S) -2-t-butoxycabonyl-amino-1-p-tolucylsulfonyloxypropane »m.p. 73-74 °.

2.5 g of 3-phenylquinoline-2-thione was added to a suspension of 0.55 g of sodium hydride (50 % w / w dispersion in mineral oil) in 15 ml of dimethylformamide at 0 to 5 °.

After all the hydrogen had liberated, 3.5 g of (S, 1- tert -butoxycarbonylamino-lp-toluenesulfonyloxypropane were added and the mixture was stirred at ambient temperature for 16 hours, then the mixture was poured into 160 ml of ice water and extracted with 3 × 50 ml of ethyl acetate »

unn η ... f \ h

10.11.1982

" ⁶¹ ~ ^{50 940/12}

The ethyl acetate extract was washed with 50 ml brine and then dried over MgSO 4. The solvent was evaporated and the residue recrystallized from Pstrolether. There was obtained (S) -2- (2-t-butoxycarbonylaminopropylthio) -3-phenylquinoline, mp 86-87 °.

Example 58

3.2 ml of a 37 % w / v formaldehyde solution in Waeser was added to a solution of 1.55 g of (+) - (S) -2- (2-aminopropylthio) -3-phenylethynoline in 4 ml of formic acid Ambient temperature and the mixture heated for 16 hours at reflux. The mixture was evaporated and the residual oil dissolved in 10 ml of water. The solution was adjusted to pH 10 with saturated sodium carbonate solution and extracted with 2 × 10 ml of diethyl ether. The diethyl ether extract was washed with 10 ml brine and dried over MgSO 4. dried. The solvent was evaporated and the solid residue chromatographed on 80 g of basic alumina (Brockmann grade III) eluting with increasing concentrations of methylene dichloride in petroleum ether. The resulting eluate with 10 % Vol.AoI. Methylene dichloride in petroleum ether was evaporated. The remaining solid was dissolved in 10 ml of diethyl ether and ethereal hydrochloric acid was added until complete precipitation. The mixture was filtered off and recrystallized from ethyl acetate. To give (-) - (S) -2- (2-Dimethylaminopropylthio) -3-phenylquinoline hydrochloride, m.p. 167-168 ° / XJP ^5-36.3 ° (C, 2.0 in methanol).

The starting (+) - (S) - (2-aminopropylthio) -3-phenylquinoline was obtained from the corresponding

run » AO 0 0 -i. Π h \ / t \

10.11.1982

24 0 5 7 7 8 " ⁶² " ^{50 940/12}

hydrochloric acid (see Example 57) by dissolving the latter in water, making the solution osmic with a dilute aqueous sodium hydroxide solution, extracting with ethyl acetate, washing the extract with water, drying over H 2 SO 4, and evaporating the solvent. The desired compound was obtained, which was used without further purification.

Example 59

5.3 ml of formaldehyde (37% w / v solution in water) was added to a solution of 2.85 g of 3-phenyl-2- (3-piperidylthio) -quinoline in 6.7 ml of formic acid at ambient temperature * The mixture was heated at reflux for 16 hours, then evaporated and the residual oil dissolved in 15 ml of water. The solution was adjusted to pH 10 with 2 M sodium hydroxide solution and extracted with 2 × 15 ml of diethyl ether. The diethyl ether extract was washed with 15 mL brine and dried over MgSO 4. The solvent was evaporated and the residual oil chromatographed on 120 g of basic alumina (Brockmann Sorte III) eluting with increasing concentrations of ethyl acetate in petroleum ether. The resulting eluate with 10 % VoI. / V / ethyl acetate in petroleum ether was evaporated, the remaining solid in Dissolved 15 ml of diethyl ether and added ethereal hydrochloric acid until the precipitation was complete. The mixture was filtered and the solid residue was recrystallized from ethyl acetate. There was obtained 2- (1-methyl-3-piperidylthio) -3-phenylquinoline hydrochloride, m.p. 221-223 °.

The quinoline derivative used as the starting material was obtained in the following manner:

10.11 * 1982 - 63 - 60 940/12

11.9 g of di-t-butyl carbonate were added to a solution of 5.0 g of 3-hydroxypiperidine in 10 ml of water and 5 ml of t-butanol at ambient temperature and the mixture stirred at ambient temperature for 1 hour. The solution was poured into 150 ml of water The diethyl ether extract was washed successively with 50 ml of 1 M hydrochloric acid, 50 ml of saturated sodium carbonate solution and 50 ml of brine and dried over MgSO 4. The solvent was evaporated to give 1-t-butoxycarbony1-3 -hydroxypiperidine which was used without further purification *

5.8 g of p-toluenesulfonyl chloride were added to a solution of 6.0 g of the abovementioned t-butoxycarbonyl derivative in 20 ml of pyridine at 0. The mixture was kept at 0 to 5 ° for 20 hours, then poured into 400 ml of ice water and washed with Extracted 3 × 100 ml of diethyl ether. The diethyl ether extract was washed successively with 100 ml of 1 M hydrochloric acid, 100 ml of saturated sodium carbonate solution and 100 ml of brine, and then dried over MgSO 4. After evaporation of the solvent, 1-t-Butoxycarbony1-3-p-toluenesulfonyloxypiperidine, which was used without further purification.

5.2 g of 3-phenylquinoline-2-thione was added to a suspension of 1.15 g of sodium hydride (50 % w / w dispersion in mineral oil) in 35 ml of dimethylformamide at 0 to 5 °. After all of the hydrogen had been released, 7.8 g of it-butoxycarbonyl-3-p-toluenesulfonyloxypiperidine was added and the mixture heated at 80 ° for 2 hours. The mixture was then cooled to ambient temperature, poured into 350 ml of ice water and washed with 3 × 150 ml of ethyl acetate

15ROVl 1982 * 047343

10,11,1982

240577 S " ⁶⁴ " ^60940/12

extracted. The ethyl acetate extract was washed with 150 ml of brine and dried over MgSO 4. dried. Evaporation of the solvent gave 2- (i-t-butoxy-carbonyl-3-piperidylthio) -3-phenylquinoline, which was used without purification.

4.2 g of 2- (tert-butoxycarbonyl-3-piperidylthio) -3-phenylquinoline were added to 6 M hydrochloric acid in 50 ml of ethyl acetate and the mixture stirred at ambient temperature for 1 hour. The solvent was evaporated and the residual oil in 100 ml of diethyl ether dissolved and extracted with 2 χ 30 ml of 1 M hydrochloric acid solution. The hydrochloric acid extract was adjusted to pH 10 with saturated fitriumkarbonatlösung and extracted with 2 χ 100 ml of diethyl ether. The diethyl ether was washed with 75 ml of brine and then over MgSO 4. The solvent was evaporated off to give 3-phenyl-2- (3-piperidylthio) -quinoline, which was used without further purification.

Seismic Example 60

1 g of S-phenylquinoline-thiol was added to a suspension of 0.68 g of sodium hydride (50% w / w dispersion in mineral oil) in 10 ml of dimethylformamide at 0 ° to 5 °. After all of the hydrogen had been released, a slurry of 1.1 g of 1-chloro-2-dimethylamino-2-i-ethylpropane hydrochloride in 10 mL of dimethylformamide was added and the mixture was stirred at ambient temperature for 20 hours. Then, the mixture was poured into 100 ml of ice water and extracted with 3 × 30 ml of ethyl acetate. The ethyl acetate extract was washed with 30 ml of brine and then dried with MgSO ₄ . The solvent was evaporated and the residual oil to 125 g basic

10.11.1982 - 65 - 60 940/12

Alumina (Brockmann variety III), eluted with increasing concentrations of methylene dichloride in petroleum ether. The resulting eluate with 10 % VoI »/ Vol

 Methylene chloride in petroleum ether was evaporated, the residual oil dissolved in 20 ml of diethyl ether and ethereal hydrochloric acid added until the precipitation was complete. The mixture was filtered and the solid residue recrystallized from ethyl acetate. There was obtained 2 ~ (2-dimethylamino-2-methylpropylthio) -3-phenylquinoline hydrochloride, mp 199-201 °.

Example 61

1.2 ml of a 1 M solution of borane-dimethylsulfide was added to a solution of 2.1 g of 2- (1-diraethylcarbamoyl-1-methylethylthio) -3-phenylohinoline in 60 ml of tetrahydrofuran at ambient temperature and under argon atmosphere. The mixture was heated at reflux for 4 hours. Then, 20 ml of methanol was added and the mixture was heated under reflux for 2 hours. The solvents were evaporated and the residual oil chromatographed on 150 g of basic alumina (Brockmann Sorte III) eluted with increasing concentrations of ethyl acetate in petroleum ether. The eluate obtained was admixed with 2 % v / v. Ethyl acetate in petroleum ether was evaporated. The residual oil was dissolved in 20 ml of diethyl ether, and ethereal hydrochloric acid was added until the precipitation was completed. The mixture was filtered and the solid residue was recrystallized from methanol / ethyl acetate. There was obtained 2- (1,1-dimethyl-2-dimethylaminoethylthio) -3-phenylquinoline hydrochloride, m.p. 223-224 °.

The quinoline derivative used as the starting material was obtained in the following manner;

10,11.1982

240577 8- ⁵⁶ - ^50940/12

1.18 g of S-phenylquinoline-thione were added to a suspension of 0.46 g of sodium hydride (50 % w / viv dispersion in mineral oil) in 10 ml of dimethylformamide at 0-5. After all of the hydrogen had liberated, 0.88 g of 2-bromoisobutyrate were added and the mixture heated at 80 ° for 16 hours. The mixture was cooled to ambient temperature, poured into 50 ml of ice-water, brought to pH 2 with concentrated hydrochloric acid and washed with 3 χ Extracted 25 ml of ethyl acetate. The ethyl acetate extract was washed with 25 ml brine and dried over MgSO4. The solvent was evaporated and the residual oil chromatographed on 100 g of silica gel (Merck Type 7734) eluting with increasing concentrations of ethyl acetate in petroleum ether. The resulting eluate with 10 % v / v. Ethyl acetate in petroleum ether was evaporated and the solid residue was recrystallized from cyclohexane to give 2- (1-carboxy-1-methylethylthio) -3-phenylquinoline, mp 144-146 °.

3 ml of oxalyl chloride and 2 drops of dimethylformamide were added to a solution of 5.64 g of 2- (1-carboxy-1-methylethylthio) -3-phenylquinoline in 35 ml of methylene dichloride and the mixture was stirred at ambient temperature for 16 hours. The solvent was evaporated, the solid residue dissolved in 250 ml of toluene and a solution of dimethylamine in toluene (30 ml of a 6 M solution) added at 0 °. The mixture was stirred at ambient temperature for 20 hours, poured into 200 ml of water and the mixture separated, both phases being annealed. The aqueous phase was extracted with 2 × 50 ml of ethyl acetate, and the combined ethyl acetate and toluene phases were washed with 100 ml of brine and then dried. The

10.11.1982 - 67 - 60 940/12

was evaporated and the solid residue chromatographed on 150 g of basic alumina (Brockmann variety III), eluting with increasing concentrations of ethyl acetate in Petrolethsr. The resulting eluate with 5 % v / v. Ethyl acetate in petroleum ether was evaporated to give 2- (1-dimethylcarbamoyl-1-methylethylthio) -3-phenylquinoline, mp 149-156 °.

Example 62

0.85 g of methyl iodide was added to a mixture of 1.65 g of 2- (2-methylaminoethylthio) -3-phenylquinoline hydrochloride and 1.65 g of potassium carbonate in 50 ml of dry ethanol at ambient temperature. The mixture was stirred at ambient temperature for 3 hours and the solvent evaporated afterwards. The residue was dissolved in 50 ml of water and extracted with 3 × 25 ml of diethyl ether. The diethyl ether extract was washed with 25 ml brine, over MgSO4. dried and the solvent evaporated. The residual oil was chromatographed on 75 g of basic alumina (Brockmann grade III) eluted with increasing concentrations of methylene dichloride in petroleum ether. The eluate with 50 % v / v. Methylene dichloride in petroleum ether was evaporated. The residue was dissolved in 25 ml of diethyl ether and ethereal hydrochloric acid was added until completion of the precipitation. The mixture was filtered and the solid residue was recrystallized from methanol / ethyl acetate. There was obtained 2- (2-dimethylaminoethylthio) -3-phenylquinoline hydrochloride, mp 196-198 °.

Claims (6)

60 940 12 240577 8 - ⁶³ - invention claim 1. A process for the preparation of quinoline derivatives of the general formula SA-UR ² R ³ wherein A is the radical - (CH ₂ ) n - which may optionally be substituted by one or two alkyl radicals of 1 to 2 carbon atoms or substituted by an alkylene radical so that it together with the radical of the - (CHp) radical is a cycloalkylene radical does not form more than 6 carbon atoms; R is an n, iso or s-alkyl radical having 3 to 4 carbon atoms, or a cyclopropyl radical, or R is a phenyl radical which may optionally be substituted by one or two substituents, which substituents may be the same or different and from the group Halogen, hydroxy, alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, alkylthio of 1 to 4 carbon atoms, perfluoroalkyl of 1 to 2 carbon atoms, cyano, carboxy, alkoxycarbonyl of 1 to 2 carbon atoms, carbamoyl, N-alkylcarbamoyl of 1 up to 3 carbon atoms in the alkyl moiety and H, IT dialkylcarbamoyl having 1 to 3 carbon atoms in the alkyl moiety, or R is a heteroaryl moiety having five or six ring atoms and a single heteroatom selected from the group consisting of oxygen, η i / T λ η -i η. η ·. » 60 940 12 24 0 5 77 8 .β, Sulfur and nitrogen or two heteroatoms which are either a nitrogen atom and a sulfur atom or a nitrogen atom and an oxygen atom "wherein the heteroaryl radical may optionally be substituted with an alkyl radical having 1 to 3 carbon atoms; R and R, which may be the same or different, Are hydrogen or an ethyl or methyl radical, ρ or R is dimethylene, trimethylene or tetramethylene linked to one or the other carbon atom forming the two carbon atom backbone of A and forming together with the adjacent nitrogen atom a pyrrolidinyl or piperidyl radical; and 4 5 one of the substituents R or R is hydrogen and the other is hydrogen, a halogen atom or an alkyl radical having 1 to 3 carbon atoms or an alkoxy radical having 1 to 3 carbon atoms; and their pharmaceutically acceptable acid addition salts, characterized in that a) a compound of the general formula II shark wherein Hal is a halogen atom, with a compound the formula _o -, HS-A-HirR · * III or their acid addition salt is reacted in the presence of an acid-binding agent; 60 940 12 240577 - TS-- b) a compound of the general formula IV with a connection of the iOrmel ZAm ² R ³ V, 40577 10j.ll. 1982
60 940/12 wherein Z is a halogen atom or an arenesulfonyloxy or alkanesulfonyloxy radical, in the presence of an acid-binding agent; c) compounds of the general formula VI, SX ~ CHR ³ -NR ³ R ⁶ wherein X is a methylene radical optionally substituted by one or two alkyl radicals having from 1 to 2 carbon atoms and R is an alkyl radical having from 1 to 2 carbon atoms, and pharmaceutically acceptable acid addition salts thereof, a compound of the general formula VII S-X-COR ^ is reacted with an amine of the formula R R NH under reducing conditions; d) compounds of the general formula SY-CH ₂ NR ³ R ⁷ VIII, wherein R is hydrogen or an alkyl radical having 1 to 2 carbon atoms and Y is a methylene radical optionally substituted with one or two alkyl radicals having 1 to 2 carbon atoms, or R is a dimethylene t 240577 - 74 - - 10,11,1982 60 940/12 Trimethylene or tetramethylene radical which is connected to Y such that it forms a pyrrolidinyl or piperidyl radical with the adjacent nitrogen atom "and their pharmaceutically acceptable Säuraadditionssalze, raLt the proviso that R is not a phenyl radical to which a cyano, carbamoyl, N Alkylcarbamoyl- (having 1 to 3 carbon atoms in the alkyl moiety) - or Ν, Ν-dialkylcarbamoyl (having 1 to 3 carbon atoms in the alkyl moiety) is rest, an amide of the general formula IX SY-CO-NR ³ R ⁷ is reduced; β) for compounds of the general formula N ^ S-A-N ^C 2 ^H 5 and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical containing a cyano, carbaraoyl, N-alkylcarbamoyl (having 1 to 3 carbon atoms in the alkyl moiety) or N, N-dialkylcarbamoyl (having 1 to 3 C-atoms in Alk (dteil) 3πtituenten bears, a compound of the general formula COCH. N ^N SAN XI reduced; 240 5 77 8 - «- f) in the case of compounds of the general formula 10.11.1982 60 940/12 Xil N "S-A-NH, and their pharmaceutically acceptable acid addition 1
salts, provided that R can not be a carboxyphenyl radical, a Curtius reaction with a compound of the formula SA-CO ₂ H XIII is carried out,· g) in Vorbindungen of the general formula XII and their pharmaceutically acceptable acid addition salts, a compound of the general formula XIV SA-NH-CO-O (CH ₂ ) ₂ Si {CH ₃ ) is reacted with a fluoride ion donating compound; h) in a compound of the general formula S-A-N CH XV R ² ^ _{/ N} r "" _n 10.11.1982 Z 4. U D / / O - ^ - 60 940/12 and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical to which a cyano, alkoxycarbonyl (having 1 to 2 C atoms in the alkoxy moiety), carbamoyl, N-alkylcarbamoyl (having 1 to 3-C -Atomen in the alkyl moiety) - or N, N-dialkylcarbamoyl (having 1 to 3 carbon atoms in the alkyl moiety) rest is bound, a compound of the formula S
wherein R is an alkyl radical having 1 to 5 carbon atoms is reduced; i) for compounds containing the group XVII or and their pharmaceutically acceptable acid addition salts, a corresponding compound with the group - S - A - NH ₂ XIX or - S - A - N XX is reacted with formaldehyde and formic acid; 10.11.1982 5 77 β "'*" 60940/12 j) for compounds of general formula XII and their pharmaceutically acceptable acid addition salts, with the proviso that R can not be a phenyl radical to the cyano, carboxy, alkoxycarbonyl having 1 to 2 C atoms in the alkyl moiety, carbamoyl, N-alkylcarbamoyl rait I to 3 C atoms in the alkyl moiety or Ν, Ν-Oialkylcarbamoyl is bonded with 1 to 3 carbon atoms in the alkyl moiety, a compound of the general formula XXI, SA-NH-CO ₀ R ⁸ 8th * wherein R is as defined above, is reacted with an alkali metal hydroxide under substantially anhydrous conditions; k) at © iner compound of the general formula CONH ₂ XXII, "SA-NR ² R ³ 9
in which R represents hydrogen, a halogen atom or a radical from the group hydroxy, alkyl having 1 to 4 C atoms, alkoxy having 1 to 4 C atoms, alkylthio having 1 to 4 C atoms or perfluoroalkyX having 1 to 2 C atoms, as their pharmaceutically acceptable acid addition salts, a compound of formula 240 5 77 8 - 10.11.1982
60 940/12 SA-NR ² R ³ is hydrolyzed under alkaline conditions; 1) for compounds of the general formula CONR ¹⁰ R ¹¹ XXIV, SA-NR ² R ⁴ 10 11
wherein R and R, which may be the same or different, is hydrogen or an alkyl group containing 1 to 3 carbon atoms, and their pharmaceutically acceptable acid addition salts, a compound of the general formula COHaI XXV, SA-NR ² R * where Hai has the meaning above, with a 10 11 compound of the formula R R NH is reacted; m) for compounds of the general formula j ν hau Jrt r \ r » 240577 10.11.1982 60 940/12 XXVI, SANR ² R ³ wherein R has the meaning given above, as well as their pharmaceutically acceptable acid addition salts, a compound of formula SA-NR ² R ³ is esterified; n) in the case of compounds of the general formula XXVII S-A-N XXVIII and their pharmaceutically acceptable acid addition salts, with the proviso that A can not be a cyclopropylene radical, a compound of the general formula MH K MHV -IQ P ₁ 9 * Π Li 'Ί ί \ A-, 240577 8 10.11.1982 60 940/12 S-A-N CO.OC XXIX is reacted with an acid; or ο) for a compound of the general formula XXX, S-A-N wherein R has the meaning mentioned above, and their pharmaceutically acceptable acid addition salts «with the 1
In that R can not be a phenyl radical to which a hydroxy or carboxy substituent is attached, a
Compound of the general formula XXVIII is reacted with a compound of the formula R Hal, in which Hal has the abovementioned meaning, and an acid-binding agent; and A, R ¹ , R ² , R ³ , R ⁴ and R ^{5 have} the meaning given in point 1, unless stated otherwise at this point · γ ti η Ii jnrifi. · .. f \ /. *;