DD297810A5 - METHOD FOR PRODUCING A THIOFORMAMIDE DERIVATIVE - Google Patents

Abstract

The invention relates to processes for the preparation of thioformamide derivatives of general formula (I) (see formula sheet), wherein R is alkyl; A is an optionally substituted phenyl or heteroaromatic group; R1 is hydrogen, alkyl, cyano, carboxy, formyl, carbamoyl, alkoxycarbonyl, or a group (CH2) nOR2, (CH2) nSR2, (CH2) nN (R2) 2, CHCHR3, CHNOR4, CONHR5 or COR6; R 2 is hydrogen, alkyl, alkanoyl, aryl, aryl (CH 2) n or arylCO or, when attached to nitro, two R 2 groups together may be alkylene; R3 is hydrogen, R3 is hydrogen, alkyl, alkanoyl, carboxy, carbamoyl, cyano, aryl, arylCO, aryl (CH2) n or aryl (CH2) nCO; R4 is hydrogen, alkyl, aryl, aryl (CH2) n, optionally substituted alkyl, alkenyl, amino, or carbamoyl NN-disubstituted by alkyl, alkenyl, amino, or carbamoyl N, N-disubstituted by alkylene; R5 is alkyl, aryl, aryl (CH2) n; * is a single or double bond, with the metric that when R1 is formyl it is a double bond; Y is ethylene, methylene or a direct bond; n is 1 to 6 and their salts, which have pharmacologically useful properties. {Thioformamide derivatives preparation; pharmaceuticals}

Description

Field of application of the invention

The invention relates to a process for the preparation of a thioformamide derivative which finds use as a medicament.

Characteristic of the known state of the art

The compounds described in European Applications Nos. 321272 and 321273, which have activity-modifying properties due to their potassium channel, have a carbon-oxygen bond in the 2-position. The compounds of the present invention have a carbon-carbon bond in this position, and it is surprising that it nevertheless has a measurable level of activity in the modification of the potassium channel.

Object of the invention

By the method according to the invention pharmaceutically valuable compounds are provided.

Explanation of the essence of the invention

The present invention has for its object to provide methods for the preparation of therapeutically active compounds to avail mg.

According to the invention, there are provided processes for the preparation of novel thioformamide derivatives of general formula (I) (see formula sheet), wherein R represents an alkyl group;

A is (1) a phenyl group which is optionally substituted, preferably at the 3- and / or the 5-position, by a halogen atom or cyano, nitro, trifluoromethyl, carbamoyl, carboxy, alkoxycarbonyl or alkylsulfonyl and which may be further substituted halo-atom (s), alkyl group (s), aryl-containing moiety, group (s) having six to twelve carbon atoms or substituents forming a condensed ring thereon; or

(2) a heteroaromatic group containing 7 or a nitrogen atom selected from pyrid-3-yl, quinolin-3-yl, isoquinolin-4-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrazine-3 yl, indol-3-yl and thiazol-5-yl optionally substituted by an alkyl or alkoxy group or a halogen atom;

R ¹ is hydrogen; Alkyl, cyano, carboxy, formyl, carbamoyl or alkoxycarbonyl; or a group of the formula - (CHz) _n OR ² , - (CHj) _n SR ² , - (CH ₂ J _n N (R ² I ₂ , -CH = CHR ³ , -CH = NOR ⁴ , -CONHR ⁶ or -COR ⁶ ;

R ² , which may each be the same or different when attached to nitrogen, represents hydrogen; Alkyl, alkanoyl, aryl, aryl (CH ₂ ) _n - or arylCO-; or when it is attached to nitrogen, the two R ² groups together may form an alkylene group having three to six carbon atoms;

R ³ is hydrogen; Alkyl, alkanyol, carboxy, carbamoyl, cyano, aryl, arylCO-, aryl (CH ₂ ) _n - or aryl (CH ₂ ) _n CO-; or an alkyl group substituted by hydroxy, alkoxy or carboxy;

R ⁴ is hydrogen; Alkyl, aryl or aryl (CH ₂ ) _n ; or an alkyl group substituted by one or more groups selected from carboxy, alkoxycarbonyl, hydroxy, alkoxy, carbamoyl, N-alkylcarbamoyl, Ν, Ν-dialkylcarbamoyl, amino, alkylamino, dialkylamino, and alkenylylene having two to four carbon atoms and amino and Carbamoyl groups N, N-disubstituted by an alkylene group having from three to six carbon atoms;

R ⁵ is alkyl, aryl or aryl (CH ₂ ) "-; or an amino acid residue wherein the nitrogen atom of the -CONHR ⁶ group is derived from an amine nitrogen atom of the amino acid;

R^8th is alkyl, aryl or aryl (CH₂), wherein aryl may be a carbocyclic or heterocyclic, monocyclic or polycyclic aromatic ring system, preferably phenyl, which may be substituted by one or more substituents selected from halogen, hydroxy, alkyl, alkoxy, cyano, nitro, trifluoromethyl , Carboxy, alkoxycarbonyi, amino, alkylamino, dialkylamino, carbamoyl, N-alkylcarbamoyl, Ν, Ν-dialkylcarbamoyl and carboxyalkyl and amino and carbamoyl groups which may be Ν, Ν-disubstituted by an alkylene group having three to six carbon atoms; Y is an ethylene or methylene group or a direct bond (methylene is preferred) the bond is a single or double bond, wherein represents a double bond when R¹ is a formyl group; and

η is an integer from 1 to 6;

wherein all alkyl groups or their parts, including those in alkoxy, alkoxycarbonyl and alkanoyl groups, may be, branched or straight-chain and, unless otherwise indicated, contain one to four carbon atoms; and stereoisomers and salts thereof.

It should be made clear that in this specification, including the appended claims, alkylene chains produced by

- (CHj) _n - or - (CH ₂ ) _m - may be straight-chain or branched-chain.

Particularly important classes of compounds of the formula I are those which have one or more of the following features:

(a) R ¹ is hydrogen or cyano, carboxy, formyl or alkoxycarbonyl; or a group of the formula - (CHj) _n OR ² , - (CHj) _n SR ² , - (CHj) _n N (R ² I ₂ , -CH = CHR ³ or -CH = N JR ⁴ , preferably hydrogen or cyano Carboxy, formyl, methoxycarbonyl, ethoxycarbonyl or hydroxymethyl or an optionally substituted phenoxymethyl group, eg phenoxymethyl, hydroxyphenoxymethyl or nitrophenoxymethyl, and also phenylthiomethyl, optionally substituted phenylvinyl, eg fluorostyryl, and optionally substituted phenoxyiminomethyl, eg fluorophenoxyiminomethyl, and benzyloxyiminomethyl, optionally substituted alkoxylminomethyl, for example, dihydroxyalkoxyiminomethyl such as dihydroxypropoxyiminomethyl, or aminomethyl, benzoyloxymethyl or acetoxymethyl;

(b) R ² is hydrogen or alkanoyl, aryl or arylCO-, preferably hydrogen or optionally substituted phenyl, ζ. Hydroxyphenyl or nitrophenyl, or a benzoyl or acetyl group;

(c) R ³ is aryl, preferably optionally substituted phenyl, ζ. For example, fluorophenyl;

(d) R ⁴ is aryl or aralkyl or alkyl, optionally substituted by one or more hydroxy groups, preferably optionally substituted phenyl, ζ. For example, fluorophenyl or an optionally substituted phenylmethyl group, for. Phenylmethyl;

(e) "aryl" represents a phenyl group which may be substituted by one or more substituents selected from halogen atoms, hydroxy and nitro;

(f) Y is a methylene group;

(g) η is equal to one; (h) R is methyl; and

(i) A is pyrid-3-yl or quinolin-3-yl; the other symbols having the meaning given here; As well as their

Stereoisomers and pharmaceutically acceptable salts. The presence of an exocyclic olefinic group = CHR 'or a group -CHjR ¹ on the ring leads to an isomeric Center in the molecule, which in conjunction with the adjacent asymmetric ring carbon atom to 4 stereoisomers

which may optionally be separated into two racemic pairs. When a group -CH ₂ R 'is present, the racemic pair and enantiomers in which the -CH ₂ R ¹ "and -CSNHR groups are trans-related are preferred. In certain cases, the substituents A, R and R ^{1 may be} also contribute to stereoisomerism All of these forms are included in the present invention.

Particularly important inventions of the present invention are the following: A (±) -2-cyanomethylene-N-methyl-1- (pyrid-3-yl) -cyclohexane carbothioamide B (1J) -formylmethylene-N-methyl-pyridine-S-yl-cyclohexane-carbothioamide C (±) -2-cyanomethylene-N-methyl-1- (quinolin-3-yl) -cyclohexane carbothioamide D (±) -2-formylmethylene-N-methyl-1- (quinolin-3-yl) -cyclohexane carbothioamide E (±) -2- (2-hydroxyethylidene) -N-methyl-1- (quinolin-3-yl) -cyclohexane-carbothioamide F (±) -trans / cis-2-ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexane carbothioamide G (±) -trans-2-ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexane carbothioamide H (±) -2- (2-hydroxyethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexane-carbothioamide I (±) -2-carboxymethylene-N-methyl-1- (quinolin-3-yl) cyclohexane carbothioamic J (±) -2-phenoxyethylidene) -N-m9thyl-1- (pyrid-3-yl) cyclchexane carbothioamide K (±) -2- (2- (4-hydroxyphenoxy) ethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexane carbothioamide L (±) -2- (2- (4-nitrophenoxy) ethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexane carbothioamide M (±) -2- (2-phenylthioethylidene) -N-methyl-1- (pyrid-3-yl) -cyclohexane-carbothioamide N (±) -2- (4-fluorostyn / 1) methylene-N-methyl-1- (pyrid-3-yl) -cyclohexane-carbothioamide O (D) -formylmethylene-N-methyl-i-pyridine-S-yD-cyclohexane-carbothioamidine / antl-fluorobenzyloxime P (II) -formylmethylene-N-methyl-1-pyridine-S-yl-cyclohexane-carbothioamide sys / anti ^. S -dihydroxypropyl oxime Q (±) -2-methylene-N-methyl-1- (pyrid-3-yl) -cyclohexane carbothioamide R (±) -trans-2-cyanomethyl-N-methyl-1- (quinolin-3-yl) cyclohexane carbothioamide S (±) -trans-2-cyanomethyl-N-methyl-1- (pyrid-3-yl) cyclohexane carbothioamide T (±) -trans-2- (2-hydroxyethyl) -N-methyl-1- (pyrid-3-yl) cyclohexane carbothioamide U (±) -trans-2- (2-aminoethyl) -N-methyl-1- (pyrid-3-yl) cyclohexane-carbothioamide V (±) -trans-2-methoxycarbonylmethyl-N-methyl-1- (pyrid-3-yl) -cyclohexane-carbothioamide

W (±) -trans-2-formylmethyl-N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide ss / antl-benzyloxime X (tl-trans ^ -Benzoyloxyethyl-N-methyl-1-pyrid-S-yD- cyclohexane-carbothioamide

Y (±) -trans-2-acetoxy-ethenyl-N-methyl-1- (pyrid-3-yl) -cyclohexane-carbothioamide

and their stereoisomeric forms and pharmaceutically acceptable salts

The preceding letters A to Y are for ease of reference in other parts of the Description. The compounds have valuable pharmacological properties, in particular properties that make their usefulness

indicated in the treatment and / or prophylaxis of the following diseases:

(1) vascular smooth muscle contraction including hypertension and other cardiovascular diseases such as congestive heart failure and conditions associated with tissue ischemia such as angina, peripheral vascular disease and csrebrovascular disease;

(2) respiratory smooth muscle contraction including reversible airway obstruction and asthma;

(3) contraction of the smooth muscles of the gastrointestinal tract, urinary bladder and uterus, including peptic ulcer, irritable bowel syndrome and diverticular disease; Irritable bladder; and premature birth.

The compounds are also useful by topical application in preventing baldness associated with baldness in men.

For example, the compounds of general formula (I) were subjected to vascular occlusion assays. The applied test methodology was that of Winslow et al. (Eur. J. Pharmacol., 131, 219-228 [1986]) and Karaki (J. Pharmacol., Methods, 18, 1-221 [1987]) for variable vaso-relaxant activity.

Test A: Activity Against Contractions Caused by Low K * Concentrations in the Isolated Rat Aorta The thoracic aorta was removed from rats and transverse strips freed of endothelium were suspended in a bath containing Krebs solution. The voltage was recorded as well as a concentration generated by adding 2OmM K ⁺ (potassium ion) to the bath solution. The test compound was added to the bath as a solution in increasing cumulative concentration. The concentration of the test compound in the bath solution, which reduced the K ⁺ -induced concentration by 90%, was determined and expressed in μΜ as the effective concentration (EC ₉₀ ) as shown in Table Ί.

Table 1

connection Activity Test A connection Activity Test A EC ₉₀ μΜ EC ₉₀ μΜ A 10 M 0,003 B 10 N 0.03 C 0.2 O 0.1 D 3 P 3 e 3 O 3 F 0.3 R 0.1 G 0.3 S 0.3 H 10 T 1.7 J 0.07 V 0.03 K 0.3 W 0.03 L 0.1

Test B: Activity Against Contractions Caused by High K ⁺ Concentration on the Isolated Rat Aorta The test method was similar to Test A with d-3r except that the concentrations were adjusted by adding 6OmMK ⁺ to the bath solution. The cumulative addition of the test compounds to the solutions was made and the concentration in the bath was found to decrease the K ⁺ -induced concentration expressed as the EC ₉₀ . For each compound tested, it was greater than 30μΜ.

The compounds of the general formula (I) can be prepared by applying and adapting known methods such as described below. By "known method" as used in this specification are meant methods already used or described in the literature.

According to one embodiment of the present invention, the compounds of formula (I) wherein R ^{1 is} cyano or

Alkoxycarbonyl represents, is a double bond and the other symbols have the meaning already mentioned,

are prepared by the reaction of a compound of the general formula (II) (see formula sheet) in which A, Y and R have the abovementioned meaning, with a phosphonate of the general formula (III)

(R ⁷ O) ₂ P (O) CH ₂ R ¹

(III)

wherein R ^{7 represents} an alkyl group having 1 to 4 carbon atoms, preferably a methyl or ethyl group, and R ¹ 'is cyano or alkoxycarbonyl. The reaction is generally carried out in the presence of a base, preferably sodium hydride, in an ethical solvent (B. B.tetrahydrofuran) and preferably at a temperature of 20 to 100 ^° C. Compounds of formula (I) wherein R ^{1 is} formyl and The other symbols that have the meaning defined above can be turned off

Compounds of formula (I) wherein R 'is cyano, is a double bond and the other symbols have the above

defined meaning, by reaction with a complex metal reducing agent, preferably a dialkylaluminum hydride (eg diisobutylaluminum hydride) in a dry, inert, organic solvent, for example a mixture of an ether (ζ.tetrahydrofuran) and an aromatic hydrocarbon (e.g. B. toluene) at a temperature of -80 ° C to + 3O ⁰ C.

Compounds of the formula (I) in which R 'is hydroxymehyl and the other symbols have the abovementioned meaning can be obtained from compounds of the formula (I) in which R ^{1 is} formyl and the other symbols have the meaning described above, or from compounds of the formula (XXXIV) (see formula sheet) in which R "is a p-methoxybenzyl group and the other symbols have the meaning described above, by reaction with a complexing agent, preferably with a borohydride (eg sodium borohydride ) in an alcoholic solvent (eg methanol)

Room temperature; if represents a single bond, the reaction may also be carried out with an aluminum alkoxide (e.g.

Aluminum isopropoxide) in an alcoholic solvent (eg isopropanol) at reflux. Compounds of the general formula (II) in which A, Y and R have the abovementioned meaning can be prepared by reacting a compound of the general formula (IV) (see formula sheet) in which A and Y have the abovementioned meaning an isothiocyanate of the general formula (V)

R-N = C = S

'/' urine R has the meaning given above.

The reaction is generally performed in an anhydrous inert organic solvent such as tetrahydrofuran, dimethylformamide or hexamethylphosphoramide, or a mixture of these solvents, at einerTempr temperature of -8O ⁰ C to + 5O ⁰ C in the presence of an inorganic base such as potassium tert-butoxide or an Organo-lithium derivative such as n-butyllithium or carried out by sodium hydride.

Compounds of the formula (IV) in which A has the abovementioned meaning and Y is a methylene or ethylene group can be prepared via a dehydrobromination / rearrangement reaction of compounds of the formula (VI) (see formula sheet) where A and Y are as defined above to have. This can be done by a bromide extracting agent, such as. A silver salt (for example, silver perchlorate) and in an inert anhydrous solvent (for example, an ether such as tetrahydrofuran).

Compounds of the formula (VI) in which A and Y have the above meanings can be prepared by addition of hypobromous acid to the double bond of the compounds of the formula (VII) (see formula sheet) in which A and Y have the above meaning. This can be done with a bromorizing agent (e.g., 1,3-dibromo-5,5-dimethylhydantoin) in an aqueous acid medium, optionally in the presence of a cosolvent. Compounds of formula (VII) wherein A and Y are as defined above can be prepared via a coupling reaction between a phosphorane of formula (VIII) [usually prepared in situ by reaction of a compound of formula (IX) wherein Y is as defined above and R ⁸ and Z are conventional groups present in a Wittig reagent and its phosphonium salt precursor (e.g., corresponding to phenyl and bromine) with a strong base such as potassium t-butoxide in an anhydrous solvent such as tetrahydrofuran, preferably under an inert gas atmosphere] and a compound of the formula (X)

A-CHO (X),

where A has the above meaning.

Alternatively, compounds of the formula (IV) wherein Y may be ethylene, methylene or a direct bond and A has the above significance may be prepared by removing methanol from compounds of the formula (XI) wherein A and Y are as defined above. This is usually carried out in the presence of a strongly acidic agent (for example phosphorus pentoxide or sulfuric acid), if appropriate in a solvent such as toluene and at elevated temperature.

Compounds of the formula (XI) can be prepared by reaction of a compound of the formula (XII)

A-HaI (XII),

wherein A has the abovementioned meaning and Hal is halogen, preferably a bromo or chloro atom, in the presence of a strong base such as alkyllithium (eg butyllithium) with a compound of formula (XIII) in which Y has the above meaning, in an inert solvent such as an ether (ζB. diethyl ether) or a hydrocarbon (eg toluene). According to a further feature of the invention, compounds of general formula (I) wherein R 'is a cyano "of the alkoxycarbonyl group or a group of the formula - (CH ₂ )" OR ² , - (CH ₂ I _n SR ² or -CH = NOR ⁴ , as previously defined, or -CH = CHK ³ ', wherein R ³ ' is hydrogen, an alkyl, alkanoyl, cyano, aryl, arylCO, aryl (CH ₂ ) _n or AryKCH ^ CO group or

an alkyl group substituted by an alkoxy group, is a double bond, R is preferably methyl and the

other symbols corresponding to those described above are prepared from compounds of the general formula (XIV) in which A and Y have the above meaning, R ¹ 'is a cyano or alkoxycarbonyl group or a group of the formula - (CH ₂ J _n OR ² , - (CH ₂ J _n SR ² or -CH = NOR, as defined above OdOr-CH = CHR ³ , wherein R ³ 'is hydrogen, alkyl, alkanoyl, cyano, aryl, aryl CO-, aryl (CH ₂ ) "- or Aryl (CH ₂ ) _n CO-; or an alkyl group substituted by an alkoxy group, and R ⁹ is an alkyl group of 1 to 4 carbon atoms, by reaction with an alkylamine of the general formula (XV)

R-NH ₂ (XV),

wherein R has the abovementioned meaning and preferably represents methyl. The reaction is generally carried out in an inert organic solvent such as tetrahydrofuran at room temperature, and the amine is usually added in alcoholic solution, preferably in ethanol.

The dithioester of the formula (XIV) in which Y, A and R ^{9 have} the abovementioned meaning and R ¹ "aryloxymethyl or arylthiomethyl are prepared via the Mitsunobu reaction of an alcohol of the general formula (XVI) in which Y, A and R ⁹ having the abovementioned meaning, using phenols or thiophenols of the general formula (XVII)

R'-XH (XVII),

wherein R ^{10 is} aryl and X is oxygen or sulfur. The reaction is carried out at room temperature in an inert organic solvent, preferably tetrahydrofuran, in the presence of triphenylphosphine and a dialkyl (ζ, Di, di-isopropyl) azodicarboxylate.

Compounds of the formula (XVI) in which the various symbols have the abovementioned meaning can be prepared from aldehydes of the formula (XVIII) by reaction with a complex metal reducing agent, preferably a borohydride (for example sodium borohydride) in an alcoholic solvent ( eg methanol) at room temperature. Compounds of formula (XVIII) may be prepared from cyanides of formula (XIX) by reaction with a complex metal reducing agent, preferably a dialkylaluminum hydride (e.g., diisobutylaluminum hydride) in a dry, inert organic solvent, for example a mixture of an ether ( ζ. Β. tetrahydrofuran) and an aromatic hydrocarbon (eg toluene) at a temperature of -80 ° C to +30 ⁰ C.

The compounds of the formula (XIX) in which the various symbols have the meaning given here can be prepared by reacting a compound of the formula (XX) in which Y, A and R ^{9 have} the above meaning, with a phosphonate of the general formula ( III), wherein R ^{7 has} the above meaning and R 'is a cyano group, under the conditions previously described.

Compounds of formula (XX) wherein Y, A and R ⁹ are as hereinbefore defined can be prepared by the reaction of compounds of formula (IV) wherein Y and A are as defined above, with carbon disulfide followed by reaction with a compound Alkyl halide of the formula (XXI)

R ⁹ -X (XXI),

wherein R ^{9 has} the above meaning and X is halogen, preferably IOD. The reaction is generally carried out in an anhydrous inert solvent such as tetrahydrofuran at a temperature of -8O ⁰ C to + 5O ⁰ C in the presence of an organic base such as potassium tert-butoxide or an organo-lithium derivative such as butyllithium or sodium hydride. The dithioesters of the formula (XIV) in which the various symbols have the abovementioned meaning and R ¹ 'is a group of the formula -CH = NOR ⁴ can be prepared by reacting a compound of the formula (XVIII) with an acid addition salt of an optionally O -substituted hydroxylamine (preferably hydrochloride) of general formula (XXII)

NH ₂ -OR ⁴ (XXII),

wherein R ^{4 has} the abovementioned meaning. The reaction is generally carried out in the presence of an organic base e.g. B. pyridine, which may serve as a solvent, in an otherwise inert organic solvent at a temperature of ^{0 0} C to 40 ⁰ C.

According to a further feature of the present invention compounds of formula (I) wherein R ^{1 represents} a carboxy group and the other symbols have the meaning described above, by the reaction of a compound of formula (I) wherein R ^{1 is} an alkoxycarbonyl, preferably ethoxycarbonyl is, and the other symbols have the meaning already mentioned, with an inorganic aqueous base, preferably sodium hydroxide, at room temperature. According to a further feature of the present invention compounds of formula (I) wherein R ^{1 is} a group of the formula -CH = CHR ³ "wherein R ³ 'is hydrogen, alkyl, aryl, aryl (CH ₂ ) _n alkanoyl, aryl CO - or aryl (CH ₂ ) _n CO- or hydroxy or alkoxy-substituted alkyl, and the other symbols have the meaning described above, be prepared from compounds of general formula (I), wherein R ^{1 is} formyl, or from compounds of Formula (XXXIV), wherein the other symbols have the abovementioned meaning, via a coupling reaction with a phosphorus of the formula (XXIII)

R ³ -CH = _PPh3 (XXIII),

wherein Ph is phenyl and R ³ "is as defined above, provided that when R ³ 'is hydroxy substituted alkyl, the hydroxy group is protected, for example as a tetrahydropyranyloxy group, and subsequently deprotected again by the reaction of a compound of formula (XXIV)

(R3'_cHj-PPh ₃₎ ⁺ Z "(XXIV),

wherein R ³ ', Ph and Z have the meaning already mentioned, prepared with a strong base such as butyl lithium in an anhydrous solvent such as tetrahydrofuran, preferably under an inert atmosphere at room temperature.

According to a further feature of the invention, compounds of formula (I) wherein R ^{1 represents} a group of the formula -CH = CHR ³ wherein R ³ is alkoxy substituted by carboxy! is, and the other symbols have the meaning given, are prepared by oxidation by means of known methods of the corresponding Vorbindungen the forms! (I) wherein R ³ is hydroxy substituted alkyl.

Compounds of formula (I) wherein R ^{1 is} a group of the formula -CH = CHR ³ wherein R ^{3 is} carboxy and the other symbols are as defined above may be prepared by oxidation in known manner of the corresponding formyl compound.

The formyl compound can be prepared by the procedure described above for the preparation of compounds in which R ^{3 is} alkanoyl.

Compounds of formula (I) wherein R ^{1 represents} a group of formula -CH = CHR ³ wherein R ^{3 is} carbamoyl may be prepared by the reaction of the corresponding compound wherein H ^{3 is} carboxy or its acid chloride with ammonia. The reaction may be carried out in the manner described below for the reaction of ammonia with a compound of formula (I) in which R 'is carboxy.

Compounds of formula (I) wherein R ¹ represents a group of formula -CH = CHR ³ wherein R ³ is cyano can be prepared in a known manner by dehydration of the corresponding compound in which R ³ is carbamoyl.

Compounds of the formula (I), wherein R ^{1 is} a group of the formula -CH = CHR ³ , where R ^{3 is} cyano, and the other symbols are as defined above, can be prepared by reactions of compounds of the formula (II) I) or (XXXIV) in which R ^{1 is} formyl and the other symbols have the abovementioned meaning, with a compound of the formula (INA)

(R ⁷ O) ₂ P (O) CH ₂ CN (III A),

wherein R ^{7 has} the meaning given here, under conditions similar to those described for the reaction of a compound of formula (II) with a phosphonate of formula (III).

The compounds of formula (I) wherein R ¹ represents a group of formula -CH = CHR ³ wherein R ³ is cyano obtained can be converted into the corresponding compounds in which R ³ is carbamoyl or carboxy by hydrolysis in ascending known way.

According to a further feature of the invention, compounds of formula (I) wherein R ^{1 is} carbamoyl or a group of formula CONHR ⁶ as defined above can be prepared by reacting the corresponding acid chloride of formula (XXV) with ammonia or an amine Formula (XXVI)

R ⁶ -NH ₂ (XXVI),

wherein R ^{5 has} the above meaning, in the presence of an acid acceptor, for example a tertiary amine such as triethylamine or an inorganic bevels such as sodium bicarbonate, preferably in an anhydrous inert solvent, for. Example, chloroform or acetone and preferably at a temperature of -3O ⁰ C to 30 ° C.

The acid chloride of formula (XXV) may be prepared from the corresponding acid [the compound of formula (I) wherein R ^{1 is} carboxy] with a conventional reagent such as thionyl chloride in the absence or preferably in the presence of an inert solvent such as toluene or tetrahydrofuran in the range from room temperature to reflux temperature. According to a further feature of the invention, compounds of the formula (I) in which R 'represents a group of the formula COR ⁸ and the other symbols have the abovementioned meaning can be prepared by the reaction of an acid chloride of the formula (XXV) with an organocadmium compound of the formula ( XXVII)

Cd (R ⁶ J ₂ (XXVII),

wherein R ^{6 has} the meaning given, are prepared under the usual Reaktionsbedingungon in an inert solvent such as tetrahydrofuran.

The organocadmium compounds of the formula (XXVII) can be prepared by reaction of a cadmium halide, for example of the chloride, with the corresponding Grignard reagent of the formula (XXVIII)

R ⁶ MgBr (XXVIII)

in an inert solvent, for example diethyl ether or tetrahydrofuran.

According to a further feature of the invention, compounds of the formula (I) wherein R ^{1 is} alkyl and the other symbols have the abovementioned meaning can be prepared from the corresponding compounds of the formula (I) wherein R ^{1 is} formyl or COR ⁶ , or from compounds of formula (XXXIV) by reaction with hydrazine and an inorganic base, preferably sodium or potassium hydroxide in a high boiling organic solvent, e.g. B. diethylene glycol at elevated temperature, preferably at reflux temperature.

According to a further feature of the invention, compounds of formula (I) wherein R ^{1 is} a group of formula - (CH ₂ LL wherein L is -OR ² , -SR ² or -N (R ² J ₂ m is an integer from 2 to 6, and the other symbols already mentioned above are prepared by reduction of a ketone of formula (XXIX) using hydrazine and a strong base under conditions similar to those described above.

Verbirentungen of formula (XXIX) can be prepared from the acid chloride of the formula (XXV) and the corresponding organocadmium compound of the formula (XXX)

Cd [(CH ₂ ) _m -, L) ₂ (XXX)

under similar conditions as described above.

The organocadmium compound is similarly prepared from the corresponding Grignard compound of formula (XXXI)

BrMg [(CH ₂ ) _m ., L) (XXXI)

again under similar conditions as described.

When the group L contains active hydrogen (eg, when R ^{2 is} hydrogen), it should be suitably protected if required during the above reaction sequences involving organometallic components, and then later deprotected respectively. For example, if the active hydrogen is present in a hydroxyl group, it may be protected by the formation of the tetrahydropyranyl ether, if present as a thiol group, by use of a p-methoxybenzyl group, and if present in an amino or imino group, by formation of a t- butoxycarbonyl. In any event, protection and later deprotection may be accomplished by conventional means (and procedures).

According to a further feature of the invention, compounds in which R ^{1 has} the meaning -CH ₂ NHR ² 'or -CH ₂ N (R ² J ₂ , where R ² ' represents an alkyl or aryl (CH ₂ ) _n group, and the other symbols have the abovementioned meaning, are prepared by reaction of compounds of formula (I) wherein R 'is aminomethyl with a corresponding alkyl or alkylaryl halide in the presence or absence of an inert organic solvent such as an aromatic hydrocarbon (eg benzene or toluene), a halogenated solvent (for example chloroform or dichloromethane), an ether (ζ B. tetrahydrofuran) or dimethylformamide, generally at a temperature of from ⁰ ° C. to the reflux temperature of the reaction mixture.

According to a further feature of the invention, compounds of formula (I) wherein R 'represents aminomethyl and the other symbols have the abovementioned meaning can be prepared from the corresponding compounds wherein R ^{1 is} cyano by reduction according to known methods, for example by reaction with a complex metal Ireduzierenden agent such as an aluminum hydride (eg lithium aluminum hydride) in a dry organic solvent such as an ether (e.g., tetrahydrofuran) at elevated temperature, preferably at 40 to 8O ⁰ C.

According to a further feature of the invention, compounds of formula (I) in which R 'represents the group -CH ₂ SH and the other symbols already mentioned above can be prepared by hydrolysis of the corresponding thiol acetate esters of formula (XXXII), in general by reaction with an aqueous base in an organic solvent, for example ethanolic ammonia, at room temperature.

The esters of formula (XXXII) can be prepared by reaction of the corresponding alcohol [i.e. H. the compound of formula (I) wherein R 'is hydroxymethyl] by reaction under Mltsunobu conditions in the presence of thioacetic acid. The reaction is usually carried out in an inert solvent, preferably tetrahydrofuran and in the presence of triphenylphosphine and a dialkyl (e.g., diisopropyl-lazodicarboxylate) at room temperature.

According to another feature of the invention, compounds of formula (I) wherein R 'is a group of the formula -CHjS-alkyl, -CHj-S-tCHjln-aryl, -CfyO-alkyl or -CH ₂ O- (CH ₂ ) _n -aryl and the other symbols already having the abovementioned meaning, are prepared from the corresponding alcohol or thioi of the formula (I) by reaction with the corresponding alkyl or aralkyl halide, preferably the bromide, generally in the presence of a strong base such as sodium hydride, in one inert organic solvent! tetrahydrofuran or dimethylformamide at a temperature until reflux of the reaction mixture.

According to a further feature of the invention, compounds of formula (I) wherein R ^{1 represents} a group of the formula - (CH ₂ I _n OR ² or - (CHj) _n SR ² , wherein R ^{2 is} alkanoyl or arylCO-, and the other symbols have the abovementioned meaning, are prepared from the corresponding compounds wherein R ^{2 is} hydrogen, optionally with the thioamide group suitably gestimtrt, -vie described below, by reaction with the appropriate acyl or Aroylhalogenid, preferably the chloride, in an inert organic solvent such as toluene or dichloromethane at a temperature of 0 to 25 ° C, optionally in the presence of a suitable activating agent, eg.

4-dimethylaminopyridine.

According to a further feature of the invention, compounds of formula (I) wherein A, R and Y are as defined above

respectively, is a double bond and R¹ is hydrogen, by dehydration of an alcohol of formula (XXXIII)

getting produced. This reaction is carried out under Mitsunobu conditions in an inert solvent in the presence of triphenylphosphine and a dialkyl (ζB. diisopropyl-lazodicarboxylate and at room temperature. The compounds of formula (XXXIII) can be prepared by reaction of a ketone of formula (I). with methyl magnesium bromide in an inert solvent such as diethyl ether or tetrahydrofuran at temperatures below 1O ⁰ C.

According to a further feature of the invention, compounds of formula (I) wherein R¹ Cyan represents, is a

Single bond and A, Y and R have the above meaning, are prepared by reduction of the corresponding

Compound of the general formula (I) in which a double bond! st, with a complex metal reducing agent such as

an aluminum hydride (e.g., lithium aluminum hydride) in a dry inert organic solvent such as an ether (e.g., tetrahydrofuran) at room temperature.

This reaction preferably results in the reduced product (I) wherein the -CSNHR group is trans-to the -CH ₂ CN group.

According to a further feature of the invention, compounds of the formula (I) in which R ^{1 represents} the group -CH = NOR ⁴ , as defined above, and the other symbols which have already mentioned above, may be prepared from the corresponding compounds of the formula (I) in which R ^{1 is} formyl, or from the compounds of formula (XXXIV) by reaction with an acid addition salt of an optionally O-substituted hydroxylamine (preferably the hydrochlorides) of formula (XXII), wherein R ^{4 has} the meaning already mentioned, wherein the thioamide group CSNHR is in protected form before the reaction and then the protective group is split off. The reaction is generally conducted in the presence of an organic base (eg. B. pyridine), which may also serve as solvent, in an otherwise inert solvent at a temperature of from ⁰ C to 40 C. ^c

According to another feature of the invention, compounds of the formula (I) in which R 'represents a group of the formula -CH ₂ XR ² ', where '. .I ^s "aryl and X has the meaning given above, _1J _ _l ^ ₁ is a single bond, and the other symbols have the

already described above, from the corresponding compounds of the formula (I) in which R 'has the meaning -CH ₂ OH, by conversion of the hydroxyl group in R' to a suitable leaving group, for example by conversion of the hydroxymethyl group into a bromomethyl group. or p-toluenesulfonyloxymethyl group, e.g. By reaction with phosphorus tribromide or p-toluenesulfonylchloride, followed <η of a reaction with a compound of formula MXR ² ', wherein R ² ' and X have the abovementioned meaning, and M is an alkali metal atom, eg sodium, under usual reaction conditions. The thioamide group is protected from the reaction and then deprotected again, as described below.

According to a further feature of the invention, compounds of formula (I) wherein R ^{1 is} alkoxycarbonyl and the other symbols have the abovementioned meaning can be prepared from the corresponding compounds of formula (I) wherein R ^{1 is} cyano with an alcohol in the presence of hydrogen chloride, optionally in a cosolvent such as an ether (eg diethyl ether) at room temperature.

According to a further feature of the invention, compounds of formula (I) in which R 'represents carboxy and the other symbols have the abovementioned meaning can be prepared from the corresponding compounds of formula (I) wherein R' represents cyano or alkoxycarbonyl Hydrolysis with an inorganic base, preferably sodium hydroxide, at room temperature or with gentle heating.

Alternatively, the compounds of formula (I) wherein R ^{1 is} carboxy and the other symbols are as defined above can be prepared from the corresponding compounds of formula (I) wherein R ^{1 is} formyl or from the compounds of formula (XXXIV ) using, for example, silver oxide, sodium chloride or potassium dichromate and pyridine under conventional reaction conditions.

According to a further feature of the invention, compounds of the formula (I) in which A, R and Y have the abovementioned meaning

respectively, represents a single bond, and R¹ isi hydrogen, made of the corresponding compounds

in which a double bond is, by catalytic hydrogenation using, for example, one

supported platinum or palladium catalyst, by Raney nickel or a homogeneous catalyst, e.g. Wilkinson's catalyst.

According to a further feature of the invention, compounds of the formula (I) in which R ^{1 has} the meaning CONHR ⁵ or CONH ₂ and the other symbols have the abovementioned meaning, by reaction of a compound of the formula! (I) wherein R ^{1 is} carboxy and the other symbols have the abovementioned meaning, with a compound of formula (XXV) or with ammonia in a solvent such as dichloromethane and in the presence of a

Coupling agents such as dicyclohexylcarbodlimide usually at room temperature. The reaction with ammonia can also be carried out in aqueous solution either at room temperature or under heating in a closed pressure vessel.

According to a further feature of the invention, compounds of formula (I) wherein A, K and Y have the abovementioned meaning and R 'represents carbamoyl can be prepared by mild hydrolysis of a compound of formula (I) wherein A, R and Y have the meaning mentioned and R ^{1 is} cyano.

During a number of the above reaction sequences it is desirable or essential to use as starting material a compound in which the thioamide group is protected, for example in the form of a group of the formula -Cf = NR) -SR ¹¹ , where R and R ¹¹ are as already defined to have. These may be prepared, for example, by reaction with p-methoxybenzyl chloride in an anhydrous organic solvent such as tetrahydrofuran or dimethylformamide at a temperature of -2O ⁰ C to 20 ° C in the presence of a base such as potassium t-butoxide, an organolithium compound (such as n butyllithium), or sodium hydride, to form the said group of formula -Cf = NR) -SR. ¹¹ Compounds of formula (XXXIV) are examples of such protected compounds. The thioamide group can later be regenerated by addition of acid or by Entsnnützen in acidic media, preferably with formic acid at 5 to 2O ⁰ C or with trifluoroacetic acid and anisole at 0 to 5 ⁰ C.

Compounds of the formulas (III), (MIA), (V), (IX), (X), (XII), (XV), (XVII), (XXI), (XXII), (XXIV), (XXVI) , (XXVIII) and (XXXI) can be easily prepared by applying or adapting known methods.

The conversion, for example, by known methods such as those described above, of a compound of the general formula (I) to another compound of the formula (I) is understood as a feature of the present invention.

The invention is further to be understood that it may be desirable to change one or more substituents at a corresponding stage during the synthesis of the compounds of the invention. For example, the compounds of the general formula (I) wherein A represents a phenyl group substituted by a carbamoyl group may alternatively be prepared from the corresponding vinyl bonds of the general formula (i) wherein A represents a phenyl group substituted by a cyano group by known methods for such a conversion are applied or adapted.

The term "pharmaceutically acceptable salts" as used in this specification means salts whose anions and cations are relatively innocuous to animal organisms when applied at therapeutic doses, such that the advantageous pharmaceutical properties of the active compounds of the general formula (I) that can form salts can not be affected by side effects from these anions or cations.

Acid addition salts suitable for use in pharmaceutical compositions can be selected from salts of inorganic acids, for example from hydrochlorides, hydrobromides, phosphates, sulfates and nitrates, and from salts of organic acids, for example from oxalates, lactates, tartrates, acetates, salicylates, citrates, propionates, Succinates, fumarates, maleates, methylene bis-β-hydroxynaphthoates, gentisates and di-p-toluoyl tartrates.

As are themselves useful as active compounds, the salts of compounds of the general formula (I) which are capable of salt formation with bases are useful for the purification of the active compounds (which are to be understood as the pure compounds) of the general formula ( I), for example, by exploiting the differences in solubility between the salts and the active compounds by methods known to those skilled in the art.

Suitable salts with bases include salts of alkali metals (eg, sodium and potassium), alkaline earth metals (eg, calcium and magnesium), ammonium, and amines (e.g., diethanolamine, triethanolamine, octylamine, morpholine, and dioctylmethylamine).

The description of the present invention is to be understood as referring to compounds of formula (I) also where the context permits, the pharmaceutically acceptable salts thereof being included.

The thioformamide derivatives of general formula (I) obtained by the previously described methods can be purified by conventional physical methods, in particular by chromatography and crystallization, especially to separate enantiomeric mixtures using a chiral column. The following are structural formulas of the compounds mentioned in the text above.

(D

it

(Π)

(IV)

OH

(VI)

(VII)

PR

PR ⁸ , 2

OH

(Χι)

OCH;

(XIII)

OCH

(XIV)

(XVI)

A CH ₁ OH

^x (XVIII)

CVlO

(XIX)

(XXV)

(XXIX)

C5NIHR

(XXXII) ho

^(Mni)

(XXXIV)

CHO

embodiments

The following examples illustrate the preparation of compounds of the present invention.

All NMR spectra were taken at 200Mz. The chemical shifts are expressed in ppm relative to tetramethylsilane. Abbreviations in the text are the following:

s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, ddd = doublet of doublets of doublets, dt = doublet of triplets, m = multiple », c = unresolved complex peak, br = broad signal ,

The term ("m / z") indicates the peak assigned to the molecular ion in the mass spectrum.

example 1

Connection A

A solution of diethyl cyano methyl phosphonate (215 mg, 1.2 mmol) in dry tetrahydrofuran (20 ml) at

Room temperature was treated with a 60% oil dispersion of sodium hydride (40 mg, ImMoI). After 15 minutes at room temperature, (+ (- N -methyl) -oxo-1-pyrid-S-y-cyclohexanecarbothioamide (245 mg, 1 mmol / ml) was added and the resulting solution stirred at room temperature for 3 hours to yield ethyl acetate (50 ml). and then water (50 ml) was added to the reaction mixture The layers were separated and the organic portion was washed with 50 ml of water The organic extract was dried over magnesium sulfate and concentrated in vacuo to give a crude gum After purification by flash chromatography eluting with 1: 1 (v / v, v / v) of ethyl acetate / hexane gave (±) -2-cyanomethylene-N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide as a colorless gum (190 mg, 0.7 mmol .) trituration with ether resulting in a white solid (190 mg; 0.7 mmol), melting point 182-183 ⁰ C.

NMR (CDCl ₃ ): 1.47-1.78 (c, 2H), 1.78-2.00 (c, 2H), 2.20-2.38 (m, 1H), 2.46- 2.64 (m, 1H), 2.82-2.96 (m, 1H), 3.06-3.24 (m, 1H), 3.22-3.26 (d, 3H) , 3.94 (s, 1H), 7.26-7.36 (m, 1H), 7.48-7.64 (m, 2H), 8.48-8.52 (m, 1H) H), 8.52-8.58 (m, 1H).

Found: C66.6; H6,3; N 15.7 /.

Calcd for C ₁₆ H ₁₇ N ₃ S: C66.4; H6,3; N 15.5%.

Example 2

Compound B

A solution of (±) -2-cyanomethylene-N-methyl-1- (pyrid-3-yl) cyclohexincarbothioamid (1.3 g, 4,8mMol) in dichloromethane (30ml) was cooled to -20 ⁰ C and with a 1 M solution of diisobutylaluminum hydride in toluene (10.6 ml; 10.6 mmol). The mixture was allowed to warm to room temperature over 2 hours. Dichloromethane (50 ml) was added to the reaction mixture, followed by an aqueous solution of Rochelle salt (sodium potassium tartrate) (50 ml). The layers were separated and the organic layer washed with an aqueous solution of Rochelles salt (50 ml). The organic extract was dried over magnesium sulfate and concentrated in vacuo. A crude gum was obtained which was purified by flash chromatography on silica gel eluting with a 4: 1 (v / v) mixture of ethyl acetate / hexane to give (±) -2-formylmethylene-N-methyl- 1 - (pyrid-5-ylcyclohexanecarbothioamide as a white foam (230 mg, 0.84 mmol).

NMR (CDCl ₃ ): 1.64-1.82 (c, 2H), 1.82-2.04 (c, 2H), 2.30-2.46 (m, 1H), 2.46- 2.70 (m, 1H), 3.10-3.20 (c, 2H), 3.20-3.28 (d, 3H), 5.66-5.72 (d, 1H), 7.28-7.36 (m, 1H), 7.36-7.48 (br s, 1H), 7.52-7.60 (m, 1H), 8.48-8.52 (m, 1H), 8.62-8.58 (m, 1H), 10.06-10.12 (d,

Found: C65.4; H6,8; N 10.0%

berechnetfürC, ₆ H, _e N ₂ OS: C65.7; H6,6; N10,2%.

Example 3

Compound C

A solution of diethyl cyano methyl phosphonate (2.97 g, 16.76 mmol) at room temperature in dry tetrahydrofuran (100 mL) was treated with a 60% oil dispersion of sodium hydride (670 mg, 16.76 mmol). After 30 minutes at room temperature, 5 g (16.76 mmol) of (±) -N-methyl-2-oxo-1- (quinolin-3-yl) -cyclohoxane carbothioamide were added in one portion and the resulting solution stirred at room temperature for three hours. Subsequently, 200 ml of ethyl acetate and then water (200 ml) were added to the reaction mixture. The layers were separated and the organic extract dried over magnesium sulfate.

Concentration in vacuo afforded a brown gum which was purified by flash chromatography on silica gel eluting with a 3: 7 (v / v) mixture of ethyl acetate / hexane to give (±) -2-cyanomethyl. -N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide (2.8g, 8.72mmol) as a white solid, mp 108-111 ° C.

NMR (CDCl ₃ ): 1.60-2.00 (c, 4H), 2.38-2.52 (c, 2H), 2.80-2.96 (m, 1H), 3.10- 3.22 (m, 1H), 3.22-3.26 (d, 3H), 5.08 (s, 1H), 7.26-7.42 (br s, 1H), 7.58- 7.64 (dd, 1H), 7.70-7.84 (m, 2H), 7.82-7.86 (d, 1H), 8.06-8.12 (dd, 1H) , 8,7v> -8,80 (d, 1 H).

found: C71.1; H6.15; N 12.7; S 9.5%

calculated for C ₁₉ H ₁₉ N ₃ S: C71.0; H5,9; N13.1; S10,0%.

Example 4 Compound D

A solution of (±) -2-cyanomethylene-N-methyl-1-quinolin-3-yl) cyclohexane carbothioamide (1g;! 3.1 mmol) in dichloromethane (25ml) was cooled to -20 ⁰ C and with a 1 M solution of diisobutylaluminum hydride in toluene (3.1 mL, 3.1 mmol). The mixture was allowed 90 minutes to warm to 1O ⁰ C. Dichloromethane (50 ml) was added to the reaction mixture, followed by an aqueous solution of Rochelle salt (SOmI). The layers were separated and the organic layer washed with an aqueous solution of Rochelle salt (50 ml). The organic extract was dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. Purification by flash chromatography over

Silica gel eluting with a 1: 1 (v / v) mixture of ethyl acetate / hexane gave (±) -2-formylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide (300 mg, 0; 93 mmol) as a pale yellow solid. Melting point 145-151 ° C. NMR (CDCl ₃ ): 1.60-2.04 (c, 4H), 2.46-2.74 (c, 2H), 3.10-3.24 (c, 2H), 3.24-3 , 28 (d, 3H), 5.68-5.74 (d, 1H), 7.44-7.60 (br s, 1H), 7.52-7.64 (m, 1H) , 7.70-7.82 (m, 2H), 7.90-7.96 (d, 1H), 8.04-8.12 (dd, 1H), 8.98-9.02 ( d, 1H) ₁ 10.10-10.16 (d, 1H). found: C 70.1; H 6.3; N 8.1%

berechnetfürC _ie HjoN ₂ OS: C70.4; H6,2; N8,6%.

Examples

Connection E

A solution of (±) -2-formylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide (150 mg, 0.46 mmol) at room temperature in methanol (5 mL) was treated with sodium borohydride (20 mg, 0.5 mmol). treated. The mixture was stirred at room temperature for 45 minutes. Subsequently, ethyl acetate (20 ml) and then water (20 ml) were added to the reaction mixture. The layers were separated and the organic extract dried over magnesium sulfate.

Concentration in vacuo gave a crude solid which was purified by flash chromatography on silica gel, eluting with a 1: 1 (v / v) mixture of ethyl acetate / hexane to give (±) -2- Hydroxyethylidene-N-methyl- (quinolin-3-yl) -cyclohexanecarbothioamide (100 mg, 0.31 mmol) as a white solid; Melting point 104-110 ° C.

NMR (CDCl ₃ ): 1.40-2.00 (c, 6H), 2.10-2.38 (m, 1H), 2.58-2.72 (dt, 1H), 3.12 -3.26 (m, 1H), 3.28-3.32 (d, 3H), 4.22-4.30 (dd, 2H), 5.12-5.22 (dt, 1H) , 7.46-7.58 (m, 1H), 7.64-7.78 (m, 2H), 7.88-7.92 (d, 1H), 8.00-8.06 (dd, 1H), 8.06-8.20 (brs, 1H), 8.78-8.82 (d,

found: C 68.2; H 6,7; N 8.2%

calculated for C ₁₉ H ₂₂ N ₂ OS -Vi H ₂ O: C 68.1; H 6.9; N 8.4%.

Example 6 Compound F

A solution of triethyl phosphonoacetate (1.23 g, 5.5 mmol) at room temperature in dry tetrahydrofuran (50 mL) was treated with a 60% oil dispersion of sodium hydride (250 mg, 7.2 mmol). After 15 hours at room temperature, (±) -N-methyl-2-oxo-1- (quinolin-3-yl) -cyclohexanecarbothioamide (1.5 g, 5.1 mmol) was added in one portion and the resulting solution was allowed to stand for 16 hours Room temperature stirred. Subsequently, ethyl acetate (150 ml) and then water (100 ml) were added to the reaction mixture. The layers were separated and the organic extract dried over magnesium sulfate. Concentration in vacuo gave a crude gum which was purified by flash chromatography on silica gel eluting with a 1: 4 (v / v) mixture of ethyl acetate / hexane to give a 5: 2 trans / cis. A mixture of (±) -2-ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide as a white solid (220 mg, 0.6 mmol); Melting point 177-179 ⁰ C.

NMR (CDCl ₃ ): 1.06-1.26 (2t, 3H), 1.40-1.96 (c, 4H), 2.14-2.36 / 2.38-2.56 (2m, 2H) , 2.64-2.82 / 2.96-3.10 (2m, 1H), 3.38-3.52 / 3.60-3.74 (2m, 1h), 3.94-4 , 18 (2q, 2H), 5.08-5.14 / 5.90-5.96 (2s, 1H), 7.56-7.68 (m, 1H), 7.72-7, 82 (m, 1H); 7.96-8.10 (m, 2H), 8,14-8,20 / 8,30-8,36 ¹ Zd, 1H ), 8,78-8,82 / 8,86-8,90 (2d, 1H), 9.48-9.62 (br d, 1H). found: C68.8; H6,7; N7,1%

Calcd for C ₂ , H ₂₄ N ₂ O ₂ S: C68.5; H6,5; N7,6%.

Example 7 Compound G

The cis / trans mixture prepared in Example 6 was chromatographed over silica gel, eluting with a 1: 4 (v / v) mixture of ethyl acetate / hexane. This gave (iMrans ^ -ethoxycarbonylmethyl-N-methyl-1-quinoline-S-cyclohexanecarbothioamide in pure form as a white solid, mp 204-206 ° C.

NMR (CD ₃ SOCD ₃ ): 1.06-1.18 (t, 3H), 1.40-1.84 (c, 4H), 2.38-2.60 (c, 2H), 2.96 3,12 (m, 1H), 3,12-3,16 (d, 3H), 3,60-3,74 (dt, 1H), 3,94-4,08 (q, 2H) , 5.08-5.14 (s, 1H), 7.56-7.68 (m, 1H), 7.72-7.82 (m, 1H), 7.96-8.04 (dd, 2H), 8.14-8.20 (d, 1H), 8.78-8.82 (d, 1H), 9.48-9.62 (br d, 1H).

found: C67.6; H6,6; N7,2; S8,4%

calculated for C ₂₁ H ₂₄ N ₂ O ₂ S: C 68.5; H 6.6; N 7.6; S 8.7%.

Example 8

Connection H

A solution of (±) -2- (pyrid-3-yl) -2-methyldithiocarbonyl-1-hydroxyethylidenecyclohexane (120 mg, 0.41 mmol) in tetrahydrofuran (5 ml) was treated with a solution of 33% methylamine in ethanol (5 ml ). After 15 hours at 25 ° C., the mixture was diluted with ethyl acetate (40 ml) and washed with water (50 ml) The organic phase was removed and dried over magnesium sulfate.

Concentration in vacuo gave a crude oil which was purified by flash chromatography on silica gel eluting with ethyl acetate / methanol (98: 2). As a result, (±) -2- (2-hydroxyethylidene) -N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide (90 mg, 0.33 mmol) was obtained as a colorless gum. Solidification with diethyl ether / n-hexane gave a white solid, mp 172-173 ° C.

NMR (CDCl ₃ ZCD ₃ SOCd ₃ ): 1.28-1.54 (m, 1H), 1.56-1.88 (c, 4H), 1.98-2.26 (m, 1H) , 2.58-2.72 (m, 1H), 3.00-3.18 (m, 1H), 3.18-3.24 (d, 3H), 3.94-4.08 ( dd, 1H), 4.18-4.32 (dd, 1H), 5.00-5.10 (t, 1H), 6.30-6.90 (br s, 1H), 7 , 16-7.24 (m, 1H), 7.50-7.58 (m, 1H), 8.34-8.24 (m, 2H), 8.50-8.62 (brs. 1 H).

found: C65.1; H7,3; N 9.9%

calculated for C ₁₆ H ₂₀ N ₂ OS: C 65.2; H 7.3; N 10.1%.

Example 9 Compound I

A suspension of (±) -trans-2-ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide (1.2 g, 3.53 mmol) in ethanol (30 mL) at 25 ° C was treated with 2-M -Sodium hydroxide (30ml) treated. After 2 hours at 25 ° C, the mixture was diluted with water (50ml) and extracted with ethyl acetate (2x50ml). The organic phases were separated and dried over MgSO ₄ . Concentration in vacuo gave a colorless gum. Trituration with diethyl ether / hexane gave (±) -2-carboxymethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide (1 g, 2.94 mmol) as a white foam.

NMR (CD ₃ SOCD ₃ ): 1.40-1.82 (c, 5H), 2.28-2.42 (m, 1H), 2.92-3.12 (m, 1H), 3 , 08-3.14 (d, 3H), 3.52-3.66 (m, 1H), 5.10 (s, 1H), 7.56-7.64 (dt, 2H), 7.70-7.80 (dt, 2H), 7.98-8.02 (d, 2H), 8.16-8.18 (d, 1H), 8.78-8.00 ( d, 1H), 11.98-12.14 (br s, 1H).

found: C 63.5; H 5.6; N 7.1%

calculated for C ₁₉ H ₂₀ NjO ₂ S: C 67.0; H 5.9; N 8.2%.

m / z = 340 (M + H peak).

Example 10 Compound J

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1- (2-phenoxyethylidene) cyclohexane (750 mg, 2 mmol) in tetrahydrofuran (10 ml) at 25 ° C was treated with a solution of 33% methylamine in ethanol ( 10ml). After 2 hours at 25 ° C, the solution was concentrated in vacuo. Purification on silica gel eluting with ethyl acetate / n-hexane gave (±) -2- (2-phenoxyethylidene-N-methyl-1-pyrid-S-y-cyclohexanecarbothioamide (300 mg, 0.85 mmol) as a white solid, mp 121 -122 ⁰ C.

NMR (CDCl ₃ ): 1.38-1.58 (m, 1H), 1.60-2.00 (c, 5H), 2.06-2.24 (m, 1H), 2.66 -2.80 (m, 1H), 3.10-3.18 (d, 3H), 4.50-4.58 (dd, 1H), 4.64-4.76 (dd, 1H 6,18-6,26 (t, 1H), 6,78-6,86 (dd, 1H), 6,90-7,02 (t, 1H), 7,18-7, 34 (m, 3H), 7.46-7.52 (m, 1H), 7.66-7.86 (br s, 1H), 8.44-8.48 (m, 2H).

found: C71.2; H6,9; N 7.9%

calculated for C ₂ , H ₂₄ N ₂ OS: C71.6; H6,9; N7,9%.

Example 11 Connection K

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1- (2- (4-hydroxyphenoxy) ethylidene) cyclohexane (1.6 g, 4,1, μmol) in tetrahydrofuran (50 ml) was added with a solution of 33% methylamine in ethanol (30ml). After 60 hours at 25 ⁰ C the mixture with Ethyiacetat (200ml) was diluted and extracted with water. The organic phase was extracted and dried over magnesium sulfate. Concentration in vacuo gave a crude oil which was purified by flash chromatography on silica gel eluting with ethyl acetate / n-hexane / dichloromethane (3: 2: 5). (±) -2- (2- (4-Hydroxyphenoxy) ethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide (1.28 g, 3.48 mmol) was obtained as a white solid; Melting point 82-88 ⁰ C.

NMR (CDCl ₃ ): 1.18-2.02 (c, 5H), 2.04-2.22 (m, 1H), 2.66-2.82 (m, 1H), 3.14 -3.24 (m, 1H), 3.18-3.24 (d, 3H), 4.26-4.54 (dd, ', M), 4.58-4.72 (dd, 1 H), 5.16-5.24 (t, 1H), 6.68-6.84 (m, 4H), 7.28-7.36 (m, 1H), 7.56-7.62 ( m, 1H), 7.78-7.88 (brs, 1H), 8.46-8.54 (m,

Found: C 68.0; H 6.9; N 6.8%

berechnetfürC ₂₁ H ₂₄ N ₂ O ₂ S: C68,4; H6,6; N7,6%.

Example 12 Connection L

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1- (2- (4-nitrophenoxy) ethylidene) cyclohexane (180 mg, 0.44 mmol) in tetrahydrofuran (5 mL) was added a solution of 33 % Methylamine in ethanol (5ml). After G hours at 25 ⁰ C, the mixture was diluted with ethyl acetate (50 ml). The organic phase was removed and dried over MgSO ₄ . Concentration in vacuo gave a crude oil which was purified by flash chromatography on silica gel, eluting with ethyl acetate / n-hexane (4: 6) to give a colorless gum. Solidification using diethyl ether / n-hexane gave (±) -2- (2- (4-nitrophenoxy) ethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide (110 mg, 0.28 mmol). as a white solid; Melting point 201-202 ⁰ C.

NMR (CDCl ₃ ): 1.24-2.0 (c, 4H), 2.00-2.30 (m, 2H), 2.56-2.70 (dt, 1H), 3.08 3.24 (m, 1H), 3.22-3.26 (d, 3H), 4.62-4.80 (m, 2H), 5.26-5.34 (t, 1H), 6.86-6.98 (m, 2H), 7.22-7.32 (m, 2H), 7.52-7.60 (m, 1H), 7.62-7.78 (brs. 1H), 8.14-8.24 (m, 2H), 8.46-8.56 (m,

found: C63.5; H5,9; N 10.4%

berechnetfürC _2, H _2J N ₃ O ₃ S: C63,5; H5,8; N 10.6%.

Example 13 Compound M

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1- (2-phenylthioethylidene) cyclohexane (300 mg, 0.78 mmol) in tetrahydrofuran (10 ml) was treated with a solution of 33% methylamine in ethanol (10 ml). treated. After 18 hours at 25 ⁰ C the mixture with Ethyiacetat (50ml) was diluted with water (50ml) extracted. The organic phase was removed and dried over magnesium sulfate. The appearance of a crude oil after concentration in vacuo was recorded. Thereafter, purification was by flash chromatography over silica gel eluting with ethyl acetate / n-hexane (1: 1) to give (±) -2- (2-phenylthioethylidene) -N-methyl-1- (pyrid-S-ylcyclohexanecarbothioamide (100 mg, 0.27 mmol) as a creamy paste.

NMR (CDCl ₃ ): 1.20-1.44 (m, 1H), 1.50-1.90 (m, 4H), 1.98-2.12 (dt, 1H), 2.58 -2.70 (m, 1H), 3.02-3.14 (m, 1H), 3.06-3.14 (d, 3H), 3.44-3.56 (dd, 1H ), 3.66-3.78 (dd, 1H), 5.00-5.18 (t, 1H), 7.12-7.40 (m, 7H), 7.48-7.66 (brs, 1H), 8.36-8.38 (d, 1H), 8.42-8.48 (dd,

found: C 67.6; H 6.6; N 7.3%

calculated for C ₂₁ H ₂₄ N ₂ S _2: C, 68.4; H 6.6; N 7.6%.

Example 14 Compound N

A solution of butyllithium in hexane (1.6M; 0,96ml) and diisopropylamine (0.22 ml; 1.54 mmol) at -78 ⁰ C was added a solution of 4-Fluorbenzyltriphenylphosphoniumchlorid (630 mg; 1.54 mmol) in tetrahydrofuran (15ml ). After the solution over 40 minutes, heated to -4o hf'te ⁰ C was added (±) -2-formylmethylene-N-methyl-1 - (quinolin-3-yOcyclohexancarbothioamid (0.5 g; 1.54 mmol was added). After 3 hours at 25 ^° C., dilution with ethyl acetate (50 ml) and washing with water (50 ml), two layers were obtained, the organic phase was separated and dried over magnesium sulfate, concentration in vacuo gave the crude solid, purification by flash chromatography Silica gel eluting with ethyl acetate / n-hexane gave a 9: 1 cis / trans mixture of (±) -2 - ((4-fluorostyryl) methylene) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide (190 mg, 0.46 mmol) as a white solid, mp 100-102 ° C. The pure trans product was isolated by reverse phase HPLC.

NMR (CD ₃ SOCD ₃ ): 1.55-1.70 (c, 2H), 1.80-1.95 (m, 1H), 2.05-2.10, (m, 1H), 2.36-2.45 (m, 1H), 2.88-2.95 (dt, 1H), 3.25-3.28 (d, 3H), 3.24-3.35 (m , 1H), 5.98-6.02 (d, 1H), 5.90-6.65 (m, 2H), 6.58-6.65 (m, 2H), 6.90 -6.95 (m, 2H), 7.52-7.58 (dt, 1H), 7.70-7.75 (m, 2H), 7.75-7.82 (br s, 1H), 7.87-7.89 (d, 1H), 8.04-8.14 (d, 1H), (8.87-8.89)

 found: C75.3; H6,2; N 6.5%

calculated for C ₂₆ H ₂₆ FN ₂ S: C 75.0; H 6.1; N 6.7%.

Examples

Compound O

A solution of (±) -2-methyldithiocarbonyl-2- (pyrid-3-yl) -1-formylmethylene-cyclohexane-syn / anti-fluorobenzyloxime (200mg) in dry tetrahydrofuran (5ml) was stirred at room temperature and a 33% ethanolic Solution of methylamine (1 ml) was added. The solution was stirred for 48 hours, concentrated in vacuo and the residue purified by silica gel chromatography. It was eluted with ethyl acetate / n-hexane (1: 4) to give (±) -2-formylmethylene-N-methyl-1-pyridine-S-yD-cyclohexanecarbothioamide-syn / antM-fluorobenzyloxime (130 mg) as a white solid; Melting point 69-70 ⁰ C.

NMR (CDCl ₃ ): 1.4-2.4 (m, 6H), 2.65-2.9 (m, 1H), 3.15-3.2 (m, 1H), 3.3 (dd, 3H), 5.0 (d, 2H), 5.65 and 6.2 (d, 1H), 7.0-7.2 (m, 2H), 7.2-7.4 ( m, 3H), 7.6 (m, 1H), 7.65 (br s, 1H), 8.2 (d, 1H), 8.5 (br s, 2H).

found: C65.0; H6,2; N 10.0%

calculated for C ₂ JH ₂₄ FN ₃ OS: C66.5; H6,1; N 10.57%.

Example 16

Connection P

Following the procedure of Example 15 but using (±) -2-methyldithiocarbonyl-2- (pyrid-3-yl) -1-formylmethylene-cyclohexane-syn / anti ^. S -dihydroxypropyloxime instead of (±) -2-methyldithiocarbonyl -2- (pyrid-3-yl) -1-formylmethylene-cyclohexane-syn / anti-4-fluorobenzyloxime gave (±) -2-formylmethylene-N-methyl-1 - (pyrid-3-y-cyclohexanecarbothioamide-syn / anti ^. S-dihydroxypropyloxim (180mg); mp 55-57 ⁰ C.

NMR (CDCl ₃ ): 1.4-1.95 (m, 4H), 2.1-2.3 (dt, 2H), 2.7 (d, 1H), 3.2 (d, 1H ), 3.3 (d, 3H), 3.6 (dd, 1H), 3.7 (dd, 1H), 4.0 (m, 1H), 4.1 (m, 2H) , 5.7 (d, 1H), 7.3 (q, 1H), 7.6 (brs, 1H), 8.2 (d, 1H), 8.5 (q, 1H ).

found: C58.4; H6,9; N 10.9; S8,4%

berechnetfürC, ₈ H ₂₆ N ₃ O ₃ SV2H ₂ O: C58.0; H7,0; N11.3; S8,6%.

Example 17 Compound Q

A solution of triphenylphosphine (2.35 g, 9 mmol) in anhydrous tetrahydrofuran (30 mL) was treated dropwise with diethyl azodicarboxylate (1.4 mL, 9 mmol) over 5 minutes at ⁰ ° C. The solution was stirred at this temperature for 30 minutes and then treated with a solution of 2-hydroxy-2, N-dimethyl-1- (pyrid-3-yl) cyclohexanecarbothioamide (1.59 g, 6 mmol) in anhydrous tetrahydrofuran (15 ml). The mixture was allowed to warm to room temperature and stirred for 16 hours. The solution was then poured into aqueous hydrochloric acid (0.5 M, 60 ml hydrochloric acid) and extracted with ethyl acetate (3 × 45 ml). The aqueous phase was basified with 2M aqueous sodium carbonate solution and extracted with dichloromethane (3x 45ml). The organic extract was dried over MgSO ₄ and concentrated to give a pale brown oil. This was subjected to flash chromatography on silica gel eluting with ethyl acetate / methanol (93: 2). Melting point 106.5 to 108.5 ⁰ C, taking one -2-methylene-N-methyl-1- (pyrid-3-yOcyclohexancarbothioamid (0.25 g) give (±) as a colorless solid

NMR (CDCl ₃ ): 1.5-1.58 (m, 1H), 1.64-1.82 (m, 3H), 2.07-2.13 (m, 2H), 2.4- 2.47 (m, 1H), 3.1-3.16 (m, 1H), 3.26-3.29 (d, 3H), 4.47-4.49 (m, 1H ), 5.26 (s, 1H), 7.22-7.26 (m, 1H), 7.55-7.59 (m, 1H), 7.9-8.03 (br , 1H), 8.46-8.49 (m, 1H), 8.51-8.53 (m, 1H). found: C67.7; H7,3; N 11.3%

berechnetfürC, ₄ H _ie N ₂ S: C68.3; H7,4; N 11.3%.

Example 18 Compound R

A suspension of lithium aluminum hydride (36 mg, 0.93 mmol) at room temperature in dry tetrahydrofuran (8 ml) was added dropwise in dry tetrahydrofuran solution (5 ml) of 2-cyanomethylene-N-methyl-1- (quinolin-3-y-cyclohexanecarbothioamide (300 mg, 0.03 mmol The mixture was stirred at room temperature for 10 minutes and cooled in an ice-bath Water (2 ml) was added dropwise followed by ethyl acetate (20 ml) The mixture was washed with an aqueous solution of Rochelle salt (sodium potassium tartrate) (20 ml) and the separated organic extract was dried over magnesium sulfate, concentrated in vacuo to give a crude solid which was purified by flash chromatography on silica gel, eluting with a 1: 1 (v / v) mixture of ethyl acetate / hexane Crystallization from ether / hexane gave (±) -trans-2-cyanomethyl-N-methyl-1- (quinolin-3-yl) -cyclohexanecarbothioamide (120mg, 0.37mL) to give a white solid Mole) as a white solid; Melting point 205-207 ⁰ C. NMR (CDCI _3): 1.38 to 1.70 (c, 3H); 1.70-2.10 (c, 4H), 2.22-2.30 (d, 1H), 2.30-2.38 (d, 1H), 2.88-3.04 (m , 1H), 3.02-3.06 (d, 3H), 3.78-3.92 (m, 1H), 7.52-7.62 (m, 1H), 7.64- 7.74 (m, 1H), 7.78-7.84 (dd, 1H), 8.00-8.04 (dd, 1H), 8.20-8.22 (d, 1H) ), 8.96-9.10 (brs, 1H), 9.02-9.04 (d, 1H).

found: C70.2; H6,6; N 13.0%

berechnetfürC, ₉ H ₂₁ N ₃ S: C70.6; H6,5; N 13.0% m / z = 323.

Example 19

Connection S

A suspension of lithium aluminum hydride (135 mg, 3.54 mmol) at room temperature in dry tetrahydrofuran (20 ml) was added dropwise with a dry tetrahydrofuran solution (10 ml) of 2-cyanomethylene-N-methyl-1- (pyrid-3-y-cyclohexanecarbothioamide (960 mg, 3; 54 mmol) The mixture was stirred at room temperature for 10 minutes.

Then, water (5 ml) was added dropwise, followed by ethyl acetate (50 ml). The mixture was washed in an aqueous solution of Rochelle salt (50 ml) and the separated organic extract was dried over magnesium sulfate. Concentration in vacuo gave a yellow gum which was purified by flash chromatography on silica gel eluting with ethyl acetate. This gave a pale yellow gum (610 mg, 2.23 mmol). Trituration with ether / hexane gave (±) -lrans-2-cyanomethyl-N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide (610 mg, 2.23 mmol) as a white solid; Melting point 177-178 ° C.

NMR (CDCl ₃ ): 1.38-2.6 (c, 10H), 3.08-3.14 (d, 3H), 3.64-3.80 (m, 1H), 7.28 7.36 (m, 1H), 7.48-7.68 (brs, ΪH), 7.72-8.00 (m, 1H), 8.52-8.60 (m, 1 H).

found: C65.5; H6,9; N 15.1%

calculated for C, ₆ H _ie N ₃ S: C65.9; H7,0; N 15.4%

Example 20

Connection T

2- (2-Hydroxymethyl) -1 - ((N -methylimino) (4-methoxybenzylthio) methyl) -1- (pyrid-3-yl) cyclohexane (500 mg) (1.25 mmol) was added to 98% formic acid ( 10 ml) and stirred at 0 to 5 ⁰ C for half an hour. Then the mixture was allowed to warm to room temperature. The solution was concentrated in vacuo. A yellow oil was obtained, which was purified by flash chromatography on silica gel eluting with a 5:95 mixture of methanol / ethyl acetate. There was obtained (+ 1-trans -hydroxyethyl-N-methyl-1-pyridine-S-yD-cyclohexanecarbothioamide (60 mg);

NMR (CDCl ₃ ): 1.4 (m, 1H), 1.5-1.7 (m, 6H), 2.0 (m, 1H), 2.2 (m, 1H), 2 , 6 (q, 1H), 3.05 (m, 1H), 3.1 (d, 1H), 3.5-3.7 (m, 2H), 7.3 (q, 1H ), 7.4 (brs, 1H), 8.4 (d, 1H), 8.5 (dd, 1H), 8.7 (d, 1H).

found: C64.5; H8,1; N 9.7; S 11.3%

calculated for C ₁₆ H ₂₂ N ₂ OS: C64 / 7; H8,0; N10.0; S11,5%.

Example 21 Compound U

A solution of (±) -trans-2-cyanomethyl-N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide (3g, 10.8 mmol) in dry tetrahydrofuran (30 ml) was added dropwise at room temperature under argon stirred suspension of lithium aluminum hydride (1.25 g, 33 mmol) in dry tetrahydrofuran (75 mL). After the addition, the mixture was stirred at reflux for one hour, cooled and treated with Rochelle salt solution (20 ml) and ethyl acetate (50 ml). The layers were separated and the aqueous extracted with ethyl acetate (30 ml). The combined extracts were washed with water, dried (MgSO ₄ ) and concentrated in vacuo to give a yellow oil which was triturated with ether. This gave (±) -trans-2- (2-aminoethyl) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide (2g) as a yellow solid. NMR (CDCl ₃ ): 1.0-1.1 (m, 1H), 1.4-1.8 (m, 4H), 2.0 (m, 1H), 2.1 (m, 1H) , 2.5 (m, 2H), 2.7 (m, 4H), 3.1 (d, 3H), 3.15-3.3 (m, 2H), 7.25 (q, 1H) , 7.9 (dt, 1H), 8.4 (dd, 1H), 8.7 (d, 1H).

Example 22

Connection V

A solution of (±) -trans-2-cyanomethyl-N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide (1 g, 3.66 mmol in diethyl ether 620 ml) and methanol (20 ml) was treated with gaseous hydrogen chloride until saturation of the solution. The mixture was then stirred for 3 hours and allowed to stand overnight. Subsequently, the mixture was treated with water (10 ml) and adjusted to pH 12 by addition of 5% (w / v) sodium hydroxide solution. The basic mixture was extracted with ethyl acetate (100 ml). The organic layer was separated and dried over magnesium sulfate.

Filtration and concentration in vacuo gave a colorless gum which was purified by flash chromatography on silica gel. Elution with ethyl acetate gave (±) -trans-2-methoxycarbonylmethyl-N-methyl-1- (pyrid-3-yDcyclohexancarbothloamld (150mg; 0 5 mmol) as a white solid, melting point 158-159 ⁰ C.

NMR (CDCl ₃ ): 1.40-1.60 (c, 3H), 1.68-1.76 (m, 2H), 1.88-2.0 (c, 2H), 2.08-2.16 (m, 1H), 2.28-2.35 (dd, 1H), 2.68-2.7 (m, 1H), 3.12-3.16 (d, 3H), 3, 60 (s, 3H), 3.68-3.75 (m, 1H), 7.25-7.30 (dd, 1H), 7.78-7.86 (br, 1H), 7 , 94-7.98 (dt, 1H), 8.48-8.52 (dd, 1H), 8.58-8.62 (d, 1H).

Found: C 62.5; H 7.2; N 9.2%

calculated for C, _e H22Nj0 ₂ S: C62.7; H7,2; N9,1%

Example 23

Connection W

A solution of 2-formylmethyl-1 - ((N -methylimino) - (4-methoxybenzylthio) methyl) -1- (pyrid-3-yl) cyclohexane (70μg, 1.77mmol) in anhydrous toluene (40ml) with O-benzylhydroxylamine hydrochloride (282 mg, 1.77 mmol) and the mixture heated at reflux for 30 minutes and washed with water (100 ml) followed by saturated brine (100 ml) The layers were separated and the organic extract was transferred Dried magnesium sulfate, filtered and the solvents removed in vacuo to give a colorless gum, triturated with hexane / diethyl ether to give (+ J-trans -formylmethyl-N-methyl-ipyrid-S-ylcyclohexanecarbothioamide-id / antibenzyloxime (240 mg; 0.63 mmol) as a white solid, mp 158-160 ° C.

NMR (CDCl ₃ ): 1.35-1.88 (c, 4H), 2.05-2.20 (m, 2H), 2.48-2.50 (m, 2H), 3, 05-3.12 (d, 3H), 3.28-3.38 (m, 1H), 4.96-5.04 (d, 2H), 6.55-6.59 / 7, 14-7.18 (2dd, 1H), 7.20-7.40 (c, 7H), 7.85-7.92 (m, 1H), 8.46-8.54 (m, 1H) H), 8.62-8.66 (m, 1H).

found: C69.23; H7,18; N 10.95%

berechnetfürC ₂₂ H27N ₃ OS: C69.25; H7.13; N 11.01.

m / e = 382 (m + H peak).

Example 24

Connection X

"An ice cold solution of anisole (0.2 ml) in trifluoroacetic acid (2 ml) at ⁰ ° C was treated with (±) -2- (2-benzoyloxyethyl) -1- (N-methylimino) (4-methoxybenzylthio) methyl) -" After 10 minutes at ⁰ ° C., the solution was adjusted to pH 12 by treatment with cold aqueous sodium hydroxide solution (25% mass / volume). The crude extract was subjected to flash silica gel chromatography, eluting with a mixture of ethyl acetate and hexane (3: 2 v / v) and eluting with ethyl acetate (50ml). Trituration with hexane yielded a white solid which recrystallised from a mixture of ethyl acetate and hexane to give (+) - trans-2-benzoyloxyethyl-N -methyl-1- (pyrid-3-yDcyclohexanecarbothioamide (120mg); eld point 179-18O ⁰ C.

NMR (CDCl ₃ ): 1.35-1.84 (c, 7H), 2.04-2.26 (m, 2H), 2.54-2.7 (m, 1H), 3.08 3.14 (d, 3H), 3.2-3.36 (m, 1H), 4.1-4.38 (m, 2H), 7.16-7.24 (dd, 1H), 7.38-7.62 (c, 4H), 7.9-8.06 (c, 3H), 7.46-7.54 (dd, 2H), 7.62-7.66 (d, 1 H).

Found: C 68.9; H 6.8; N 7.3%

calculated for C ₂₂ H ₂₆ N ₂ O ₂ S: Cf 1.07; H, 6.85; N 7.33%

Example 25

Connection Y

In a procedure similar to that described in Example 24 above, but using the appropriate amount of 2- (2-acetoxyethyl) -1 [(N -methylimino) (4-methoxybenzylthio) methyl 1- (pyridyl-3-yl) cyclohexane as starting material and treatment (trituration) with a mixture of diethyl ether and hexane, (±) -trans-2-acetoxyethyl-N-me'-ethyl-1- (pyrid-3-yl) cyclohexanecarbothioamide was prepared as a white solid; melting point

NMR (CDCl ₃ ): 1.2-1.34 (m, 2H), 1.35-1.7 (c, 5H), 2.02 (s, 3H), 1.94-2.16 (m , 1H), 3.08-3.14 (d, 3H), 3.10-3.20 (m, 1H), 3.86-3.95 (m, 1H), 4.04-4, 1 (m, 1H), 7.25-7.32 (dd, 1H), 7.68-7.78 (brs, 1H), 7.92-7.98 (dd, 1H), 8.48-8.52 (dd, 1H), 8.58-8.62 (d, 1H), 2.6-2.74 (m,

Found: C63.5; H 7.5; N 8.8%

Calcd for C ₁₇ H ₂ N ₂ O ₂ S: C63.71; H7.54; N8,74%.

Reference Example 1

A strongly stirred solution of (±) -2- (pyrid-3-yl) cyclohexanone (5.5 g, 30 mmol) in anhydrous tetrahydrofuran (50 ml) under argon at -15 ° C was treated with potassium t-butoxide (3.36 g 3OmMoI).

After 60 minutes at 0 ° C, a solution of methyl isothiocyanate (2.4 g, 33 mmol) in anhydrous tetrahydrofuran (10 mL) was added over a period of 5 minutes. After 2.5 hours at 0 ° C, the solution was warmed to 20 ° C and then poured into a saturated aqueous brine solution (250 ml). The mixture was extracted with ethyl acetate (50 ml) followed by chloroform (3 × 50 ml). The combined organic extracts were dried over sodium sulfate and concentrated in vacuo (3O ⁰ C; 14mm Hg).

The crude product was recrystallized from methanol to give (±) -N-methyl-2-oxo-1-pyrid-S-y-cyclohexanecarbothioamide (4.8 g; 19 mmol); Melting point 188-190 ° C.

NMR (CDCl ₃ ): 1.62-2.06 (m, 4H), 2.42-2.60 (rrs, 2H), 2.60-2.82 (m, 1H), 2.84- 3.06 (m, 1H), 3.16-3.2 (d, 3H), 7.24-7.34 (ddd, 1H), 7.6-7.68 (ddd, 1H) , 8.43-8.47 (d, 1H), 8.48-8.54 (dd, 1H), 8.9-9.2 (br s, 1H).

 found: C62.9; H6,6; N11.3; S13,1%

calculated for C ₁₃ H ₁₆ N ₂ OS: C62,9; H6,5; N 11.3; S 12.9%.

Reference Example 2

A solution of (tl-trans-i-MPyrid-S-y-bromomethylcyclopentanol (10.24g, 40mMoI) in anhydrous tetrahydrofuran (500ml) at 0 ° C was added dropwise over 30 minutes with a solution of silver perchlorate (9.9g, 48mmol) After 60 minutes at ⁰ ° C., the mixture was poured into a mixture of saturated aqueous brine (500 ml) and 10% (mass / volume) aqueous sodium bicarbonate solution (500 ml) The combined organic extracts were washed with brine and then dried over sodium sulfate, concentrated in vacuo (30 ° C, 14mm

Hg) gave a crude oil which was recrystallized from cyclohexane (120 ml). This gave (±) -2- (pyrid-3-yl) -cyclohexane (6.7 g, 3 μmol); Melting point 78-8O ⁰ C.

NMR (CDCl ₃ ): 1.72-2.12 (m, 4H); 2.12-2.40 (m, 2H), 2.40-2.64 (m, 2H), 3.56-3.72 (dd, 1H), 7.22-7.32 ( m, 1H), 7.44-7.54 (ddd, 1H), 8.34-8.42 (dd, 1H), 8.46-8.54 (dd, 1H).

References 3

A solution of 3-cyclopentylidenemethylpyridine (62.2g, 0.39mol) in acetone (600ml) and water (100ml) was added a solution of concentrated sulfuric acid (18.9g, 0.19mol) in water (100ml) at 5 ° C treated. The ice-cold solution wu ^r de with 1,3-dibromo-5,5-dimethylhydantoin (55g; 0,19MoI) treated for 20 minutes. After 3.5 hours at ⁰ ° C, the mixture was treated with sodium bicarbonate solution (33.6g, 0.4 mole), followed by water (2I) and then extracted with ethyl acetate (2x500ml). The organic phase was removed and treated with 10% (mass / volume) aqueous sodium bicarbonate solution (500 ml), followed by water (200 ml) and brine (200 ml). The crude extract was dried over magnesium sulfate and then filtered through a column of flash silica gel (10 cm χ 2.4 cm diameter). After concentration in vacuo (20 ° C, 14 mm Hg), the dark oil crystallized on standing. (+ Mrans-HPyrid-S-yDbrommethyDcyclopentariol (56 g, 0.22 mol), mp 92-94 ° C.

NMR (CDCl ₃ ): 1.36-2.06 (c, 8H), 2.32-2.46 (br s, 1H), 5.02 (s, 1H), 7.24-7, 34 (ddd, IH), 8.01-8.1 (ddd, 1H), 8.52-8.56 (dd, 1H), 8.62-8.66 (d, 1H).

found: C51.9; H5,6; Br30,6; N 5.5%

C51.6; H5.5; Br31,2; N5,5%.

Reference Example 4

A suspension of cyclopentyltriphenylphosphonium bromide (226 g, 0.55 mol) in anhydrous tetrahydrofuran (1000 mL) at 2 ° C was treated with potassium t-butoxide (61.7 g, 0.55 mol) with vigorous stirring under argon atmosphere mixture was stirred at 5 ⁰ C for 80 minutes and then treated with pyridine-3-carbaldehyde (58,9g; 0,55 mol) over a period of 20 minutes The reaction mixture was stirred at 0 ° C for 2 hours and then at. . 20 ° C for 18 hours the tetrahydrofuran was removed in vacuo (3O ⁰ C; 14mm Hg) and the residue extracted with pentane (2x 500ml) After treatment with decolourising charcoal (5g), the mixture was charged through a column packed with. Flash silica gel (Merck 70-230 mesh; 13cm χ 2 cm diameter). filtered, The filtrate was concentrated in vacuo (3O ⁰ C; 14mmHg), then 20 ° C;. 0.01 mm Hg) there was obtained 3- Cyclopentylidenemethylpyridine (54g, 0.34 mol) as an orange oil which was purified without further purification is used.

NMR (CDCl ₃ ): 1.6-1.95 (m, 4H), 2.4-2.65 (m, 4H), 6.26-6.34 (m, 1H), 7.16 7.25 (ddd, 1H), 7.56-7.65 (ddd, 1H), 8.52-8.52 (d, 1H).

Reference Example 5

A 4: 1 mixture of (1-cis / trans 1 -methoxy-1-pyrid-S-yU-cyclohexanol (2 g, 10 mmol, toluene and phosphorus pentoxide (3.4 g, 24 mmol) was added over a period of The mixture was then refluxed for 5 hours, then the mixture was filtered and the precipitate partitioned between 2M sodium hydroxide solution (80ml) and diethyl ether (25ml) The aqueous layer was extracted with ether (3x 25ml) and the combined organic extracts dried over sodium sulfate in vacuo gave a crude oil which was purified by flash chromatography to give 2- (pyrid-3-y-cyclohexanone (0.7g, 4 mmol).

Referenzbelsplel β

To a solution vcm 2.5M n-butyllithium in hexane (13,2ml; 33mMol) at -78 ⁰ C was added diethyl ether (15ml) followed by a solution of 3-bromopyridine (4.7 g; 3OmMoI) in ether (90ml ) over a period of 90 minutes. (3,84g; 30 mmol) after one hour at -78 ⁰ C a solution of (±) -2-Mathoxycyclohexanon was added in ether (20ml) dropwise over 10 minutes. After 2 hours at -78 ⁰ C and 30 minutes at ⁰ C the reaction mixture was heated to 20 ° C and then in ice (150 g) was poured. The mixture was extracted with ether (2 x 50 ml), and then the combined organic extracts were washed (extracted) with 1N hydrochloric acid (50 ml). This aqueous extract was washed with ether (20ml) and then treated with 2M sodium hydroxide solution (25ml) and extracted with ether (3x 100ml). The organic extracts were combined, washed with brine and then dried over anhydrous sodium sulfate. Concentration in vacuo gave (±) -2-methoxy-1- (pyrid-3-yl) cyclohexanol (5, Or); 24 mmol) as a mixture of cis and trans isomers.

NMR (CDCl ₃ ): 1.2-2.14 (c), 2.24-2.44 (m), 2.90-3.28 (c), 3.48-3.60 (m), 7.18-7.30 (m), 7.78-7.96 (m), 8.40-8.48 (m), 8.62-8.72 (m), 8.78-8, 82 (m).

Reference Example 7

A solution of (±) -2- (quinolin-3-yl) cyclohexanone (0.78 g; 3.5 mmol) in tetrahydrofuran (10ml) at -5 ⁰ C was treated with potassium t-butoxide (0,43g; 3,9mMol) treated. After 25 minutes at -b "C, the tielroto mixture was treated dropwise over one minute with a solution of methyl isothiocyanate (0.28 g, 3.9 mmol) in tetrahydrofuran (2 mL) After 4 h at 0 ° C, the reaction mixture was interposed . aqueous saturated ammonium chloride solution (50ml) and chloroform (50ml) distributed The aqueous layer was again extracted with chloroform (50 ml) The combined organic extracts were then dried over sodium sulfate and concentrated in vacuo. (20 ⁰ C; 14mm Hg) and concentrated to give a crude The oil was purified by flash chromatography on silica gel eluting with ethyl acetate to give (±) -N-methyl-2-oxo (quinolin-3-yl) cyclohexanecarbothioamide (0.1 g, 0.33 mmol) Melting point 235-236 ° C.

NMR (.CDCI ₃ ): 1.7-2.18 (c, 4H), 2.46-2.64 (m, 2H), 2.72-2.90 (m, 1H), 2.96 -3.16 (m, 1H), 3.16-3.22 (d, 3H), 7.50-7.62 (ddd, 1H), 7.66-7.76 (ddd, 1H 7.76-8.02 (dd, 1H), 8.04-8.12 (dd, 1H), 8.78-8.80 (d, 1H), 8.92-9, 18 (br s, 1 h).

Found: C 68.0; H 5.8; N 9.0; S 10.4%

berechnetfürC, ₇ H, _e N ₂ GS: C68,4; H6,1; N9,4; S10,7%.

Reflection play 8

A solution of (fl-trans-Kf-quinoline-S-ylbromethyl) cyclopentanol (1.1 g, 3.6 mmol) in tetrahydrofuran (20 ml) at ⁰ ° C. was added dropwise over 2 minutes with a solution of silver perchlorate (0.893 g, 4.3 mmol). After one hour at 0 ° C., a mixture consisting of saturated brine (20 ml) and saturated aqueous sodium bicarbonate solution (20 ml) was added to the reaction mixture followed by the addition of ethyl acetate (40 ml) and the resulting mixture The aqueous layer was removed and extracted with ethyl acetate (50 ml) The combined organic extracts were washed with brine (30 ml), dried over sodium sulfate and concentrated in vacuo to give (±) -2- (quinoline -3-yl) cyclohexanone (0.8 g; 3.5 mmol) as an oil which solidified on standing, melting point 114-115 ⁰ C.

NMR (CDCl ₃ ): 1.72-2.68 (c, 8H), 3.74-3.88 (dd, 1H), 7.46-7.56 (ddd, 1H), 7.62 -7.70 (ddd, 1H), 7.72-7.82 (d, 1H), 7.88-7 96 (d, 1H), 8.04-8.12 (d, 1H ), 8.68 (d, 1H).

Reference Example 9

A mixture of S-cyclopentylidenemethylquinoline (3g, 14 mmol), water (100ml), dimethyl sulphoxide (50ml), acetone (100ml) and concentrated sulfuric acid (3,4ml; 35 mmol) at 5 ⁰ C was treated with 1,3-dibromo-5 , 5-dimethylhydantoin (4.0 g; 14 mmol). After 5 minutes at 5 ° C, the mixture was stirred at 20 ° C for 2 hours. The mixture was filtered and washed with ethyl acetate (2x50ml). Subsequently, the aqueous phase was treated with saturated aqueous sodium bicarbonate solution (GOm!) And extracted with ethyl acetate (100 ml). The organic phase was then washed with water (50 ml) and brine (50 ml) and then dried over sodium sulfate. Concentration in vacuo gave a crude oil which was purified by flash chromatography eluting with a 1: 1 (v / v) mixture of diethyl ether and hexane and then ether. The product thus obtained was then recrystallized from cyclohexane to give (+ 1-trans-i-quinoline-S-y-bromomethylcyclopentanol (1.1 g, 3.6 mmol).

NMR (CDCl ₃ ): 1.4-1.85 (c, 4H), 1.8-2.06 (c, 4H), 5.03 (s, 1H), 7.44-7, 56 (ddd, 1H), 7.60-7.72 (ddd, 1H), 7.74-8.02 (dd, 1H), 8.04-8.12 (dd, 1H), 8.38-8.40 (dd, 1H), 9.0 id, 1H).

Reference booklet 10

A solution of 2-chloro-3-cyclopentylidenemethylquinoline (7.6g; 31,3mMol) in glacial acetic acid (80ml) at 6O ⁰ C was treated with zinc powder (4.0 g; 62,6mMol) treated. After stirring at 6O ⁰ C for 3 hours, the reaction mixture was cooled and then treated dropwise with 2M sodium hydroxide solution (330ml) treated. The temperature was kept throughout the time below 20 ⁰ C. Subsequently, the resulting mixture was extracted with ethyl acetate (2 x 250 ml).

The combined organic extracts were dried over sodium sulfate and then concentrated in vacuo to give a crude oil (8 g) of red color, which was extracted with hot pentane (2 x 200 ml). Concentration of the combined extracts in vacuo (20 ° C, 14mm Hg) yielded 3-cyclopentylidenemethylquinoline (4g, 31mmol), which was used without further purification.

NMR (CDCl ₃ ): 1.6-1.96 (m, 4H), 2.5-2.72 (m, 4H), 6.50 (m, 1H), 7.46-7.58 ( ddd, 1H), 7.60-7.68 (ddd, 1H), 7.76-7.80 (dd, 1H), 8.0-8.08 (c, 2H).

Reference Example 11

A suspension of cyclopentyltriphenylphosphonium bromide (4.1g, 10mMoI) in tetrahydrofuran (50ml) at 0 ° C was treated portionwise with potassium t-butoxide (1.1g, 10mMoI) for 5 minutes. After one hour at O'C, the deep red mixture was treated with 2-chloroquinoline-3-carbaldehyde (1.9 g; 10 mM MoI). After 4 hours at ⁰ ° C, hexane (250 ml) and then brine (50 ml) were added to the reaction mixture. The organic layer was removed and dried over sodium sulfate. After concentration in vacuo (3O ⁰ C, 14mm Hg) the crude oil was recrystallized from hexane to give 2-chloro-3-cyclopentylidenemethylquinoline (1.7g, 7 mmol) received; Melting point 84-86 ⁰ C.

NMR (CDCl ₃ ): 1.64-1.90 (m, 4H), 2.44-2.66 (m, 4H), 6.52 (m, 1H), 7.44-7.56 ( ddd, 1H), 7.58-7.68 (ddd, 1H), 7.70-7.78 (dd, 1H), 7.92-8.00 (dd, 1H), 8, 04 (s, 1H).

found: C74.3; H5,8; Cl 14.6; N5,7%

uCIN: C73.9; H5,7; CI14.6; N5,7%.

Reference Example 12

A mixture of sil cisitrans-l + ^ -methoxy-1-quinoline-S-yl-cydohexanol (1.35 g, 5.3 mmol) and 40% (mass / volume) sulfuric acid (25 ml) was refluxed for one hour , The cooled mixture was basified with 1M sodium carbonate solution (200ml) and the mixture extracted with ethyl acetate (3x125ml). The United

organic extracts were washed with brine (30 ml) and then dried over sodium sulfate. Concentration in vacuo gave crude oil (1.4 g) which was recrystallised from a 4: 1 (v / v) mixture of hexane and ethyl acetate (20 ml) to give (±) -2- (quinoline -3-yl) cyclohexanone (0.53 g; 2.3 mmol), melting point 114-115 ⁰ C.

Reference Example 13

A 2.5M solution of n-butyllithium in hexane (18ml) in ether (30ml) at -78 ° C was added dropwise with a solution of 3-bromoquinoline (4.7g, 22.5mmol) in ether (30ml). treated. (5.8 g; 45 mmol) after one hour at -78 ⁰ C a solution of (±) -2-methoxycyclohexanone was added dropwise in ether (30 mL for 35 minutes to the reaction mixture kept for 2 hours at -78 ⁰ C! was was then Oine hour at 0 ° C and finally heated for one hour at 20 ⁰ C. the reaction mixture was poured onto ice eaten (50g) and water (50ml) and the resulting aqueous layer extracted with ether (3x 50 mL) the combined. organic extracts were treated with 2M hydrochloric acid (75 ml) and the organic phase was discarded The aqueous layer was washed with ether (2 x 30 ml) and then basified with 2M sodium hydroxide solution (75 ml) The aqueous layer was then washed with ether (4x The combined organic extracts were washed with brine (30 ml), dried over sodium sulfate and then concentrated in vacuo to give a crude oil which was extracted from a 4: 1 (v / v) mixture. H exan and ethyl acetate (60ml). This gave a mixture of (±) -cis- and trans -methoxy-quinoline-syllcyclohexanol (3.2 g, 12 mmol); Melting point 114-115 ° C

NMR (CDCl ₃ ): significant features 3.06 (s, trans OMe), 3.12 (s, ice OMe).

Reference Example 14

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1-formylmethylenecyclohexane (890mg; 3 mmol) in methanol (20ml) at 25 ⁰ C was treated with sodium borohydride (127 mg); 3.36 mmol). After 30 minutes at 25 ^° C., the solution was treated with ethyl acetate (50 ml) and water was added dropwise (20 ml). The organic phase was removed and dried over magnesium sulfate. Concentration in vacuo gave a crude oil. Purification on silica gel eluting with ethyl acetate / n-hexane (7: 3) gave 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1- (2-hydroxyethylidene) cyclohexane (590 mg) (2 mmol) as a orange solid; Melting point 139-140 ⁰ C.

NMR (CDCl ₃ ): 1.46-1.80 (c, 5H), 1.84-1.98 (brs, 1H), 2.3O-2.50 (c, 4H), 2.60 ( s, 3H), 3.02-3.20 (m, 1H), 4.28-4.34 (d, 3H), 5,? ^ - 5.36 (t, 1H), 7.22 -7.30 (m, 1H), 7.62-7.70 (m, 1H), 7.62-7.70 (m, 1H), 8.46-8.52 (dd, 1 H), 8.58-8.62 (m, 1H).

found: C61.0; H6,5; N4,7%

berechnetfürC, ₆ H, _s NOS _2: C61.4; H6,5; N4,8%

Reference Example 15

A solution of 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1-cyanmethylencyclohexan (7.2 g; 0.025 mol) in dichloromethane (200ml) at 2O ⁰ C was treated with a solution of 1M diisobutylaluminum hydride in toluene (50ml; 0 , 05 mol) treated. The mixture was allowed to warm to 25 ° C over 3 hours. It was then diluted with dichloromethane (200 ml) and then washed with brine (200 ml). The organic phase was removed, filtered through Celite, dried over magnesium sulfate and filtered. Concentration in vacuo (50 ° C, 20mm Hg) yielded a crude gum which was purified by flash chromatography on silica gel eluting with ethyl acetate / n-hexane (30:70). There was thus obtained 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1-formylmethylene-cyclohexane as an orange gum (3.17g;

NMR (CDCl ₃ ): 0.78-1.02 (c, 1H); 1.56-1.94 (c, 4H), 2.44-2.62 (m, 1H), 2.64 (s, 3H), 5L, 36-3, C6 (m, 1H) , 3.12-3.34 (m, 1H), 5.70-5.78 (d, 1H), 7.24-7.36 (m, 1H), 7.62-7.70 (m, 1H), 8.50-8.64 (m, 2H), 10.08-10.14 (d, i H).

Found: C 61.60; H 6.09; N 5.00%

Calcd for C, ₆ H, ₇ NOS ₂ : C61.82; Η5, ε8; N4,81%

Reference Example 16

A solution of dihydrocyanomethylphosphonate (18.2 g, 0.1 mol) in dry tetrahydrofuran (200 mL) at 2 ° C was treated with sodium thiourea (4.5 g of a 60% oil dispersion). After 30 minutes at 25 ⁰ C the mixture was treated with 2- (pyrid-3-yl) -methyldithiocarbonylcyclohexanon (24.7 g; 0.93 mol) in dry tetrahydrofuran (100ml). After 3 hours at reflux the mixture for 30 minutes was cooled to ⁰ C 2E, with ethyl acetate (500ml) and washed with water (500ml). The organic phase was removed and dried over magnesium sulfate and then filtered. The Aufkonzeniriorung in vacuo (5O ⁰ C; 20 mm Hg) resulted in a crude oil which was purified by flash chromatography over silica gel, elution with ethyl acetate / n-hexane (25:75) was carried out. There was thus obtained 2- (pyrid-3-yl) -2-methyldithiocarbonyl-1-cyanomethylenecyclohexane (7.4 g, 0.026 mol) as an orange gum.

Reference lobe 17

A solution of 2- (pyrid-3-yl) cyclohexanone (20 g, 0.11 mol) in dry tetrahydrofuran (200 mL) at -40 ° C was added potassium tert-butoxide (16.7 g, 0.14 mol) Moi). (10 ml; 0.165 mmol) according IB -4o minutes at ⁰ C the mixture was treated with carbon disulfide. The mixture was heated at 25 ^° C. for 30 minutes. After 30 minutes at 25 ⁰ C, the mixture was treated with Methylicdid (10,3ml; 0.165 mol). After 12 hours at 25 ⁰ C v / urde the mixture was diluted with Ethyiacetat (500ml) followed by water (500 ml). The organic phase was removed, dried over magnesium sulfate and filtered. Concentration in vacuo (5O ⁰ C; 20 mm Hg) afforded a crude oil which was purified by flash chromatography over silica gel, elution with ethyl acetate / n-hexane (30:70) was performed. As a result, 2- (pyrid-3-yl) -2-methyldithiocarbonylcyclohexanone (24.7 g, 0.09 mol) was obtained as an orange solid.

Reference Example 18

A solution of 2-methyldithiocarbonyl -2- (pyrid-3-yl) -1-formylmethylenecyclohexane (300mg) was dissolved in toluene (10ml) and refluxed with 0-4-fluobenzyl) hydroxylamine hydrochloride (180mg) for 3 hours heated for a long time. After that time, that became

Cooled mixture and concentrated in vacuo to a brown oil. The oil was purified by silica gel chromatography using n-hexane / ethyl acetate (3: 1) as eluent. This gave (±) -2-methyldithiocarbonyl-2- (pyrid-S-y-O-i-formylmethylene-cyclohexane-syn / ant-M-fluorobenzyloxime (200 mg).

NMR (CDCl ₃ ): 1.4-2.0 (m, 4H), 2.2-2.6 (m, 3H), 2.6 (d, 3H), 3.1 (m, 1H), 5.0 (d, 2H), 5.8 and 6.4 (d, 1H), 7.0-7.2 (m, 2H), 7.2-7.4 ( m, 3H), 7.6 (m, 1H), 7.65 (br s, 1H), 8.2 (d, 1H), 8.5 (br s, 2H).

Reference Example 19

A solution of 2-methyldithiocarbonyl-2- (pyrid-3-yl) -1-formylmethylenecyclohexane (220mg) was added at reflux in dry toluene (5ml) and dry pyridine (5ml) with 2,3-dihydroxypropyloxyamine hydrochloride (112mg) Heated for 3 hours. At the end of this time, the mixture was cooled and concentrated in vacuo. The residue was treated with water and extracted with dichloromethane. Evaporation gave a brown oil which was purified by silica gel chromatography using ethyl acetate / methanol (95: 5) as eluent. In this way we came to (IJ ^ ^ -Methyldithiocarbonyl -lpyrid S y D-i formylmethylenecyclohexane-syn / anti ^ .S-dihydroxypropyloximlBOmg).

NMR (CDCl ₃ ): 1.4-2.6 (m, 7H), 2.6 (d, 3H), 3.2 'J ₁ 1H), 3.6 (dd, 1H), 3.7 (dd, 1H), 4.0 (m, 1H), 4.1 (m, 2H), 5.7 (d, 1H), 7.3 (q, 1H), 7.6 (brs, 1H), 8.2 (d, 1H), 8.5 (q, 1H).

Referenzbelsple! 2 *>

A solution of (±) -N-methyl-2-oxo-i-pyrid-S-ylcyclohexanecarbothioamide (10 g, 0.04 mol) in dry tetrahydrofuran (100 mL) was stirred under an argonate atmosphere and partitioned with sodium hydride (1.8 g 60% dispersion in oil).

Was uaran Following the solution added dropwise to a 3 M solution of methylmagnesium bromide in diethyl ether (4 ml;? 0.14 mol) was added, under stirring and under argon while maintaining a temperature below 1O ⁰ C. The resulting mixture was stirred at room temperature Stirred for two hours, cooled in an ice bath and treated with 15% (mass / volume) of aqueous ammonium chloride solution (100ml). The mixture was then extracted with ethyl acetate (3 × 100 ml) and the extract was dried over magnesium sulfate and concentrated in vacuo. A crude gum was obtained and flash chromatography on silica gel eluting with cyclohexane / ethyl acetate / isopropanol (5: 4: 1) gave (1H-hydroxy-N, N-dimethyl-1-pyrid-S-y-cyclohexanecarbothioamide (2.5g). as a colorless gum.

NMR (CDCl ₃ ): 1.38-1.8 (m, 5H), 2.14-2.66 (m, 3H), 3.05-3.11 (d, 3H), 3.45- 3.62 (br s, 1H), 7.17-7.28 (m, 1H), 8.08-8.18 (m, 1H), 8.37-8.43 (m, 1H) H), 8.94-9.12 (brs, 1H), 9.22-9.3 (m, 1H).

Reference Example 21

A mixture of 2-formylmethyl-1- ((N-methylimino) - (4-methoxybenzylthio) methyl) -1- (pyrid-3-y-cyclohexane (1g, 2.52 mmol) and aluminum isopropoxide (1.03 g, 5.04 in dry isopropanol (50 ml) were refluxed under a McIntention hood under argon for 5 hours, cooled, the solution was concentrated in vacuo, and the residue was treated with dichloromethane (50 ml) and Rochelle salt solution (20 ml) filtered and separated and the organic layer washed with water, dried over magnesium sulfate and concentrated in vacuo to give a creamy solid, recrystallization from ethyl acetate gave 2 (2-hydroxyethyl) -1 - ((N-methylimino) - (4-methoxybenzylthio ) -methyl) -1- (pyrid-3-yl) cyclohexane (0.5g) as a white solid, mp 145-146 ° C.

NMR (CDCl ₃ ): 1.0 (m, 1H), 1.2-1.4 (m, 2H), 1.4-1.55 (m, 3H), 1.7-1.8 ( br, 1H), 1.9 (dt, 1H), 2.0 (m, 1H), 2.7 (d, 1H), 2.85 (br d, 1H), 3.1 (d, 1H), 3.4 (m, 1H), 3.55 (m, 1H), 3.6 (s, 1H), 3.7 (d, 1H), 3.75 (s, 3H), 6.7 (m, 3H), 7.25 (m, 1H), 7.65 (dd, 1H), 8.5 (dd, 1H), 8.65

found: C69.0; H7,6; N6,9; S8.1%.

calculated for C ₂₃ H ₃₀ N ₂ O ₂ S: C, 69.3; H 7.6; N 7.0; S 8.0%.

Reference Bullet 22

A solution of diisohutylaluminum hydride (10.2 ml of a 1 M solution in oichloromethane, 10.2 mmol) was added dropwise under argon to a stirred solution of 2-cyanomethyl-1- ((N-methylimino) (4-methoxybenzylthio) methyl). Add -1 - (pyrid-3-yl) cyclohexane (2g, 5.1mmol) in dry dichloromethane (60ml) at -20 ° C. After adding, the mixture was stirred at -2O ⁰ C for one hour, and then allowed to warm slowly to room temperature over a period of 3 hours. The mixture was then treated with Rochelle salt solution, filtered, and the layers were separated. The aqueous layer was extracted with dichloromethane (50 ml) and the combined extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give a golden oil. The oil was purified by flash chromatography on silica gel eluting with ethyl acetate. There was thus obtained 2-formylmethyl-1 - ((N-methyl) (4-methoxybenzylthio) methyl) -1- (pyrid-3-yl) cyclohexane (1g).

NMR (CDCl ₃ ): 1.2 (dt, 1H), 1.4 (m, 2H), 1.5 (m, 1H), 1.7 (m, 2H), 1.75 ( dt, 1H), 2.1 (m, 1H), 2.3 (m, 1H), 2.8 (br d, 1H), 3.15 (d, 1H), 3.6 (br S, 1H), 3.65 (s, 3H), 3.7 (d, 1H), 3.75 (s, 3H), 6.7 (q, 4H), 7.25 (q , 1H), 7.6 (dt, 1H), 8.5 (dd, 1H), 8.65 (d, 1H), 9.2 (s, 1H).

Reference Example 23

To a stirred suspension of (±) -trans-2-cyanomethyl-N-mothyl-1 - (pyrid-3-yl) cyclohexanecarbothioamide (1g, 3.7mmol) in dry tetrahydrofuran (20ml) at room temperature was added portions of potassium bicarbonate. t-butoxide (405 mg, 3.7 mmol). After stirring for 20 minutes, the resulting clear solution was cooled to -20 ° C and treated with 4-methoxybenzyl chloride (0.5 ml) (3.7 mmol). The resulting solution was stirred for a further 10 minutes at -2O ⁰ C, and then allowed to warm slowly to room temperature. The mixture was then stirred for two hours and then treated with water and concentrated in vacuo. The residue was treated with water (20ml) and extracted with ethyl acetate (2x3cmol). The combined organic extracts were washed with water, dried over magnesium sulfate and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography on silica gel eluting with ethyl acetate. This gave (±) -trans-2-cyanomethyl-1 - ((N-methylimino) (S-methoxybenzylthiolmethyl) -1-pyrid-S-ylcyclohexane (1 g).

NMR (CDCl ₃ ): 1.2 (tt, 1H), 1.4 (m, 1H), 1.6 (br d, 1H), 1.8 (m, 4H), 2.1- 2,3 (m, 2H), 2,8 (d, 1H), 3,15 (d, 1H), 3,25 (d, 1H), 3,6 (s, 3H), 3, 7 (d, 1H), 3.75 (s, 3H), 6.7 (m, 4H), 7.3 (q, 1H), 7.6 (dt, 1H), 8.55 (dd, 1H), 8.6 (d, 1H).

Reference Example 24

A solution of 2- (2-hydroxyethyl) -1 - ((N -methylimino) (4-methoxybenzylthio) methyl) -1- (pyrid-3-yl) cyclohexane (400 mg) in dichloromethane (10 ml) at ⁰ ° C treated with 4-dimethylaminopyridine (147 mg). The stirred mixture was treated dropwise with acetyl chloride (0.085 ml) and then allowed to warm to 25 ° C. over one hour with stirring, and the mixture was stirred for an additional 1 h at 25 ° C. and then with dichloromethane. The reaction mixture was washed with saturated aqueous sodium bicarbonate solution (50 ml), the organic layer was separated, dried over magnesium sulfate and evaporated in vacuo to give an oil.

The oil was subjected to flash silica gel chromatography eluting with a mixture of ethyl acetate and hexane (3: 2 v / v). This gave 2- (2-acetoxyethyl) -1 - ((N-methylimino) (4-methoxybenzylthio) methyl) -1- (pyrid-3-yl) cyclohexane (60 mg) as a colorless gum.

NMR (CDCl ₃ ): Diagnostic signals 1.98 (s, 3H), 3.64 (s, 3H), 3.75 (s, 3H).

Reference Example 25

It was worked in a conventional manner as described in Reference Example 24, but using benzoyl chloride, starting from acetyl chloride to give 2- (2-benzoyloxyethyl) -1- ((N-methylimino) (4-methoxybenzylthio) methyl). -1- (pyrid-3-yl) cyciohexan.

NMR (CDCl ₃ ): Diagnostic Signals 3.64 (s, 3H), 3.75 (s, 3H), 7.4-7.46 (m, 2H) ₁ 7.52-7.58 (m, 1 H), 7.95-7.99 (m, 1H).

The scope of the present invention also includes compositions having pharmaceutical activity consisting of a compound of general formula (I) or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier or coating. In clinical practice, the compounds of the present invention may be administered rectally, but they are preferably administered parenterally, if necessary by inhalation or, in particular, orally.

Solid compositions for oral administration include compressed tablets, pills, powders, and granules. In such solid compositions, one or more active compounds are present in admixture with at least one inert diluent such as starch, sucrose or lactose.

The compositions may also, as is conventional, contain additional substances which are not inert diluents, e.g. Lubricants such as magnesium stearate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, with inert materials such as water and liquid paraffin commonly used in the art as inert diluents. In addition to inert diluents, such compositions may contain such concomitants as wetting and suspending agents, as well as sweetening, flavoring, flavoring and preservative agents. Compositions for oral administration according to the invention also include capsules of absorbable material, such as gelatin, containing one or more of the active substance (s), with or without the addition of diluents or exclulpts.

Compositions for parenteral administration according to the invention include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. The compositions may also contain adjuncts such as stabilizers, preservatives, wetting agents, emulsifying agents and dispersing agents. They may be sterilized, for example, by filtration through a filter that retains bacteria, by incorporating sterilants into the composition, by irradiation or by heating. They may also be prepared in the form of sterile solid compositions which may be dissolved in sterile water or in another sterile injectable medium immediately prior to actual use.

Inhalation compositions may be sterile aqueous solutions which are then sprayed, or they may be dry powders formulated in accordance with known techniques.

Solid compositions for rectal administration include suppositories which also contain in accordance with known methods of formula (I) or a pharmaceutically acceptable salt thereof.

The percentage of active ingredient in the composition of the invention may vary. It should be sized in its proportion so that a suitable dosage can be achieved. It is apparent that various unit dosage forms can be administered at about the same time. The dose employed will be determined by the attending physician and will depend on the desired therapeutic effect, the route of administration, the duration of the treatment and the particular conditions of the patient.

In adults, the dose is generally from 0.001 to 50 mg / kg of body mass per day when administered orally. When inhaled, either by a nebulised solution or as a formulated dry powder, the preferred daily dose is 0.001 to 5 mg / kg of body mass.

The compounds can also be used topically for the inhibition of head loss and male baldness. The preferred daily dose is between 0.1 and 10 mg / kg of body mass, the application being carried out, for example, in 5 ml portions, two to three times a day.

The following example illustrates a pharmaceutical composition of the present invention.

composition example Size 2 gelatin capsules each contained:

(±) -2-cyanomethylene-N-methyl-1- (quinolin-3-YD

cyclohexanecarbothioamide (active ingredient) 20 mg

Lactose 100 mg

Starch 60 mg

Dextrin 40 mg

Magnesium steate 1 mg The production took place according to the common process catfish. Similar capsules were prepared, but with the active ingredient replaced by (±) -trans-2-cyanomethyl-N-methyl-1

(Quinolin-3-yl) cyclohexane.

Claims (9)

1. Process for the preparation of a thioformamide derivative of the general formula (I) (see formula sheet),
wherein R represents an alkyl group;
A has the meaning (1) a phenyl group which is optionally substituted by a halogen atom or cyano, nitro, trifluoromethyl, carbamoyl, carboxy, alkoxycarbonyl or alkylsulfonyl and which may be further substituted by halogen atom (s), alkyl group (s), aryl containing group (s) six to twelve carbon atoms, or substituents that form a condensed ring thereon; or (2) a heteroaromatic group containing 1 or 2 nitrogen atoms selected from pyrid-3-yl, quinolin-3-yl, isoquinolin-3-yl, pyridazin-4-yl, pyrimidin-5-yl, pyrazine-3 yl, indol-3-yl, and thiazol-5-yl optionally substituted by an alkyl or alkoxy group or a halogen atom; R ¹ is hydrogen, alkyl, cyano, carboxy, formyl, carbamoyl or alkoxycarbonyl; or a group of the formula - (CH ₂ J _n OR ² , - (CH ₂ ) _n SR ² , - (CH ₂ ) _n N (R ² ) ₂ , -CH = CHR ³ , -CH = NOR ⁴ , CONHR ⁵ or -COR ⁶ ; R ² is where each may be the same or different when substituted with nitrogen; Hydrogen, alkyl, alkanoyl, aryl, aryl (CH ₂ ) _n - or arylCO-; or the two R ² groups, when attached to nitrogen, form an alkylene group of three to six carbon atoms; R ³ is hydrogen, alkyl, alkanoyl, carboxy, carbamoyl, cyano, aryl, arylCO-, aryl (CH ₂ ) _n - or aryl (CH ₂ ) _n CO-; or an alkyl group substituted by a hydroxy, alkoxy or carboxy group; R ⁴ is hydrogen, alkyl, aryl or aryl (CH 2) _n -; or an alkyl group which is substituted by one or more groups selected from carboxy, alkoxycarbonyl, hydroxy, alkoxy, carbamoyl, N-alkylcarbamoyl, Ν, Ν-dialkylcarbamoyl, amino, alkylamino, dialkylamino, alkenyl groups having two to four carbon atoms, amino and carbamoyl groups which are Ν, Ν-disubstituted by an alkylene group having three to six carbon atoms; R ⁶ is alkyl, aryl, or aryl (CH ₂ ) _n -; or an amino acid residue wherein the nitrogen atom of the -CONHR ⁶ group is derived from an amino nitrogen atom of the amino acid; R ⁸ is alkyl, aryl or aryl (CH ₂ ) _n -, wherein aryl may be: a carbocyclic or heterocyclic, monocyclic or polycyclic, aromatic ring system which may be substituted by one or more substituents selected from halogen, hydroxy, alkyl, Alkoxy, cyano, nitro, trifluoromethyl, carboxy, alkoxycarbonyl, amino, alkylamino, dialkylamino, carbamoyl, N-alkylcarbamoyl, Ν, Ν-dialkylcarbamoyl and carboxyalkyl, and amino and carbamoyl groups which are Ν, Ν-disubstituted by an alkylene group having three to six carbon atoms; Y is an ethylene or methylene group or the like; a direct bond; by illustrated Binding is a single or double bond or when R ^{1 is} a formyl group it is a double bond; and η is an integer from 1 to 6; wherein alkyl groups and parts, including those in alkoxy, alkoxycarbonyl and alkanoyl groups, straight-chain or branched, unless otherwise stated, contain one to four carbon atoms; and stereoisomers and salts thereof, characterized in that (A) if R¹CyanoderAlkoxycarbonylistund represents a double bond, a compound of the formula (II) (see formula sheet) in which A, Y and R have the abovementioned meaning, with a phosphonate of the formula (III) (R ⁷ O) ₂ P (O) CH ₂ R ¹ '(III) wherein R ^{7 is} an alkyl group having 1 to 4 carbon atoms and R ^{1 is} cyano or alkoxycarbonyl; (B) when R ^{1 is} a cyano or alkoxycarbonyl group or a group of the formula - (CH ₂ J _n OR ² , - (CH ₂ J _n SR ² or -CH = NOR ⁴ as defined above, or -CH = CHR ³ ', wherein R ³ ' is hydrogen, alkyl, alkanoyl, cyano, aryl, arylCO or aryl (CH ₂ ) _n CO-; or an alkyl group substituted by an alkoxy group, and represents a double formation, a compound of formula (XIV) (see formula sheet) in which A and Y have the abovementioned meaning, R ¹ "is cyano or alkoxycarbonyl or a group of the formula - (CH ² ) _n OR ² , - (CH ₂ ) _n SR ² or -CH = NOR ⁴ with the abovementioned meaning, or -CH = CHR ³ ', in which R ^{3 is} hydrogen, alkyl, alkanoyl, cyano, aryl, arylCO or aryl (CH ₂ ) _n CO, or an alkyl group substituted by an alkoxy group, and R ⁹ is a C 1-6 alkyl group, with an alkylamine of the formula (XV) R-NH ₂ (XV) in which R has the abovementioned meaning; (C) when R ¹ 'is a group of the formula -CH = CHR ³ "i.t, where R ³ " is hydrogen, alkyl, aryl, aryl (CH ₂ ) _n -, alkanoyl, arylCO or aryl (CH ₂ ) "CO is, or alkyl substituted by hydroxy or alkoxy, a compound of formula (I) wherein A, R and Y have the abovementioned meaning and R ^{1 is} formyl or a compound of formula (XXXIV) (see formula sheet), wherein R ¹¹ is a p-methoxybenzyl group and the other symbols have the abovementioned meaning, with a phosphorane of the formula (XXIII) R ³ "-CH = PPh ₃ (XXXII) where Ph is phenyl and R ³ "is as defined above, provided that when R ³ is hydroxy substituted alkyl, the hydroxy group is protected and finally deprotected again; (D) when R ^{1 is} a group of the formula COR ⁶ , wherein R ^{6 has} the abovementioned meaning, an acid chloride of the formula (XXV) (see formula sheet), wherein A, R and Y have the abovementioned meaning Snben, with an organocadmium compound of formula (XXVII) Cd (R ⁶ J ₂ (XXVII) is reacted, wherein R ^{6 has} the abovementioned meaning; (E) when R ^{1 is} alkyl Lsi, a compound of formula (I) wherein R ^{1 is} formyl or a group COR ⁶ or (XXXIV), with hydrazine and an inorganic base; (F) when R ^{1 represents} a group of the formula - (CH ₂ ) _m -L, wherein L is -OR ² , SR ² or -N (R ² ) ₂ , m is an integer from 2 to 6 and R ² has the abovementioned meaning, using hydrazine and a strong base, a ketone of the formula (XXIX) (see formula sheet), reduced, wherein the various symbols have the meaning already mentioned; (G) when R ^{1 is} a group of the formula -CH ₂ SH, a thiol acetate ester of the formula (XXXII) (see formula sheet) wherein the various symbols have the meanings already mentioned hydrolyzes; (H) when R ^{1 represents} a group of formula -CH ₂ S-alkyl, -CH ₂ S (CH ₂ ) _n -aryl, -CH ₂ O -alkyl, or -CH ₂ O- (CH ₂ ) _n -aryl reacting the corresponding alcohol or thiol with an alkyl or aralkyl halide; (I) when R ¹ is a group of the formula - (CH ₂ J _n OR ² or- (CH _{2) n} SR _2, wherein R ² is alkanoyl or ArylCO-, a corresponding compound of formula (I) wherein R ² Hydrogen, optionally protected with the thioamide group, reacted with an acyl or Aroylhalogenid; (J) if R¹ Hydrogen is and is a double bond, an alcohol of the formula (XXXIII) (see formula sheet) in which the various symbols have the abovementioned meaning, dehydrated; (K) when R ^{1 is} a group of the formula -CH = NOR ⁴ , a compound of formula (I) wherein R ^{1 is} formyl or the formula (XXXIV) (see formula sheet) with an acid addition salt of an optionally O-substituted hydroxylamine of formula (XXII) NH ₂ OR ⁴ (XXII) where R ^{4 has} the abovementioned meaning, the thioamide group -CSNHR is present in the protected form before the reaction and is subsequently split off again; (L) when R ^{3 is} cyano, a compound of general formula (I) wherein R ^{1 is} formyl, or of formula (XXXIV) with a compound of formula (IHA) (R ⁷ O) -POCH ₂ CN (IIIA) in which R ^{7 has} the abovementioned meaning. 2. The method according to claim 1, characterized in that the Thioformamidderivat the general formula (I) or (XXXIV) is converted into another thioformamide of the formula (I) or in another salt thereof by known methods. 3. The method according to claim 1 or 2, characterized in that Y is a methylene group. 4. The method according to claim 1,2 or 3, characterized in that η is equal to one. 5. The method according to any one of claims 1 to 4, characterized in that R is methyl. 6. The method according to any one of claims 1 to 5, characterized in that A is pyrid-3-yl or quinolin-3-yl. 7. The method according to any one of claims 1 to 6, characterized in that it comprises one or more of the following features: (a) R ¹ is hydrogen or a cyano, carboxy, formyl or alkoxycarbonyl group; or a group of formula - (CH ₂ J _n OR ² , - (CHa) _n SR ² , - (CH ₂ ) _n N (R ² ) ₂ , -CH = CH ³ or -CH = NOR ⁴ ; (b) R ² is hydrogen or an alkanoyl, aryl or arylCO group; (c) R ³ represents an aryl group; (d) R ⁴ is an aryl or arylalkyl group; or an alkyl group substituted by one or more hydroxy groups; (e) "aryl" is a phenyl group which may be substituted by one or more substituents selected from hydrogen, hydroxy and nitro. 8. The method according to any one of claims 1 to 7, characterized in that it comprises one or more of the following features: (a) R ¹ is hydrogen, cyano, carboxy, formyl, methoxycarbonyl, ethoxycarbonyl or hydroxymethyl, or an optionally substituted phenoxylmethyl group, a phenylthiomethyl group, an optionally substituted phenylvinyl group, an optionally substituted phenoxyiminomethyl group, a benzyloxyiminomethyl group, an optionally substituted alkoxyiminomethyl group or an aminomethyl Benzyloxymethyl or acetoxymethyl group; (b) R ² is hydrogen or an optionally substituted * / phenyl group or a benzoyl or acetyl group; (c) R ³ represents an optionally substituted phenyl group; (d) R ⁴ is an optionally substituted phenyl group or an optionally substituted phenylmethyl group. 9. The method according to claim 1, characterized in that one produces the following compound of general formula (I): (1) -formylmethylene-N-methyl-1-ipyrid-S-y-cyclohexanecarbothioamide, (±) -2-cyanomethylene-N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, (±) -2-cyanomethylene-N -methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide, (±) -2-formylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide, (±) -2- (2-hydroxyethylidene) -N-methyl-1- (quinolin-3-yl) -cyclohexanecarbothioamide, (±) -trans / cis-2-ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) cyclohexanecarbothioamide, (±) -trans- 2-Ethoxycarbonylmethylene-N-methyl-1- (quinolin-3-yl) -cyclohexanecarbothioamide, (±) -2- (2-hydroxyethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, (±) -2-carboxymethylene-N-methyl) -1- (quinolin-3-yl) cyclohexanecarbothioamide, (±) -2- (2-phenoxyethylidene) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, (± ) -2- (2- (4-hydroxyphenoxy) ethylidene) -N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide, (±) -2- (2- (4-nitrophenoxy) ethylidene) -N- Methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide, (±) -2- (2-phenylthioetyl) -N-methyl-1- (pyrid-3-yl) cyclo hexanecarbothioamide, (±) -2 - ((4-fluorostyryl) methyl) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, (±) -2-formylmethylene-N-methyl-1- (pyrid-3 yl) cyclohexane-syn / anti-2-fluorbenzyloxim, (T ^ -Formylmethylen-N-methyl-Hpyrid-S-yOcyclohexancarbothioamid-syn / anti ^ .S-dihydroxypropyloxim, (IJ-methyl-N-methyl-pyrid-S-y-cyclohexanecarbothioamide, (iMrans 1 -cyanomethyl-N-methyl-quinoline-S-y-cyclohexanecarbothioamide, (1-yl-trans-cyano-methyl-N-methyl-1-ipyrid-S) yDcyclohexanecarbothioamide, (±) -trans-2- (2-hydroxyethyl) -N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, (±) -tronic-2- (2-aminoethyl) -N-methyl-1 - (pyrid-3-yl) cyclohexanecarbothioamide, (±) -trans-2-methoxycarbonylmethyl-N-methyl-1- (pyrid-3-yl) -cyclohexanecarbothioamide, (D-trans -formylmethyl-N-methyl-i- ipyrid-a-yDcyclohexanecarbothioamide-syn / anti-benzyloxime, (±) -trans-2-benzoyloxyethyl-N-methyl-1- (pyrid-3-yl) cyc! hexane carbothioamide or (±) -trans 2-acetoxyethyl-N-methyl-1- (pyrid-3-yl) cyclohexanecarbothioamide, or a pharmaceutically acceptable salt thereof.